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Background: In addition to stent retrievers, direct aspiration has become a reasonable thrombectomy strategy., Objectives: We carried out the thrombectomy by guiding the aspiration catheter fully over the clot and performing immediate manual aspiration; we call this procedure "embed aspiration"., Methods: In this prospective, non-randomised, single-centre study, we included all patients treated at a high volume-of-care stroke centre between 2017 and 2018 for the TRIANA (Thrombectomy in Andalusia using Aspiration) registry. Thrombectomy was carried out by embed aspiration. Patients were classified according to the success (eTICI 2b67-2c-3) or failure (eTICI 0-1-2a-2b50) of the procedure. Baseline clinical data and outcomes were compared, and multivariate analysis was performed., Results: The embed aspiration technique was used in 370 patients. Treatment was successful in 90.3% of patients. Mean puncture-to-recanalisation time was 25 minutes. The overall rate of good outcomes (mRS 0-2) at 3 months was 64%., Conclusions: This study supports real-life evidence that standardised embed aspiration may be an alternative to stent retrievers for thrombectomy., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

As for many other organisms, CRISPR-Cas9 mediated genetic modification has gained increasing importance for the identification of vaccine candidates and drug targets in Neospora caninum , an apicomplexan parasite causing abortion in cattle and neuromuscular disease in dogs. A widely used approach for generating knock-out (KO) strains devoid of virulence factors is the integration of a drug selectable marker such as mutated dihydrofolate reductase-thymidylate synthase ( mdhfr-ts ) into the target gene, thus preventing the synthesis of respective protein and mediating resistance to pyrimethamine. However, CRISPR-Cas9 mutagenesis is not free of off-target effects, which can lead to integration of multiple mdhfr-ts copies into other sites of the genome. To determine the number of integrated mdhfr-ts in N. caninum , a duplex quantitative TaqMan PCR was developed. For this purpose, primers were designed that amplifies a 106 bp fragment from wild-type (WT) parasites corresponding to the single copy wtdhfrs-ts gene, as well as the mutated mdhfrs-ts present in KO parasites that confers resistance and were used simultaneously with primers amplifying the diagnostic NC5 gene. Thus, the dhfr-ts to NC5 ratio should be approximately 1 in WT parasites, while in KO parasites with a single integrated mdhrf-ts gene this ratio is doubled, and in case of multiple integration events even higher. This approach was applied to the Neospora KO strains Nc ΔGRA7 and Nc ΔROP40 . For Nc ΔGRA7 , the number of tachyzoites determined by dhfr-ts quantification was twice the number of tachyzoites determined by NC5 quantification, thus indicating that only one mdhfr-ts copy was integrated. The results obtained with the Nc ΔROP40 strain, however, showed that the number of dhfr-ts copies per genome was substantially higher, indicating that at least three copies of the selectable mdhfr-ts marker were integrated into the genomic DNA during gene editing by CRISPR-Cas9. This duplex TaqMan-qPCR provides a reliable and easy-to-use tool for assessing CRISPR-Cas9 mediated mutagenesis in WT N. caninum strains., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rico-San Román, Hänggeli, Hemphill, Horcajo, Collantes-Fernández, Ortega-Mora and Boubaker.)

Bovine neosporosis is one of the major causes of reproductive failure in cattle worldwide, and differences in virulence between isolates have been widely shown. However, the molecular basis and mechanisms underlying virulence in Neospora caninum are mostly unknown. Recently, we demonstrated the involvement of NcGRA7 and NcROP40 in the virulence of N. caninum in a pregnant murine model using single knockout mutants in these genes generated by CRISR/Cas9 technology. In this study, the role of these proteins was investigated in two in vitro models using bovine target cells: trophoblast (F3 cell line) and monocyte-derived macrophages (BoMØ). The proliferation capacity of the single knockout mutant parasites was compared to the wild-type strain, the Nc-Spain7 isolate, using both cell populations. For the bovine trophoblast, no differences were observed in the growth of the defective parasites compared to the wild-type strain, neither in the proliferation kinetics nor in the competition assay. However, in naïve BoMØ, a significant decrease in the proliferation capacity of the mutant parasites was observed from 48 h pi onwards. Stimulation of BoMØ with IFN-γ showed a similar inhibition of tachyzoite growth in defective and wild-type strains in a dose-dependent manner. Finally, BoMØ infected with knockout parasites showed higher expression levels of TLR3, which is involved in pathogen recognition. These results suggest that NcGRA7 and NcROP40 may be involved in the manipulation of innate immune defense mechanisms against neosporosis and confirm the usefulness of the BoMØ model for the evaluation of N. caninum virulence mechanisms. However, the specific functions of these proteins remain unknown, opening the way for future research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Research on bovine neosporosis has achieved relevant milestones, but the mechanisms underlying the occurrence of foetal death or protection against foetal death remain unclear. In a recent study, placentas from heifers challenged with the high-virulence isolate Nc-Spain7 exhibited focal necrosis and inflammatory infiltrates as soon as 10 days post-infection (dpi), although parasite detection was minimal. These lesions were more frequent at 20 dpi, coinciding with higher rates of parasite detection and the occurrence of foetal death in some animals. In contrast, such lesions were not observed in placentas from animals infected with the low-virulence isolate Nc-Spain1H, where the parasite was detected only in placenta from one animal at 20 dpi. This work aimed to study which mechanisms are triggered in the placentas (caruncles and cotyledons) of these pregnant heifers at early stages of infection (10 and 20 dpi) through whole-transcriptome analysis. In caruncles, infection with the high-virulence isolate provoked a strong proinflammatory response at 10 dpi. This effect was not observed in heifers infected with the low-virulence isolate, where IL-6/JAK/STAT3 signalling and TNF-alpha signalling via NF-κB pathways were down-regulated. Interestingly, the expression of E2F target genes, related to restraining the inflammatory response, was higher in these animals. At 20 dpi, more pronounced proinflammatory gene signatures were detectable in heifers infected with the high-virulence isolate, being more intense in heifers carrying dead fetuses. However, the low-virulence isolate continued without activating the proinflammatory response. In cotyledons, the response to infection with the high-virulence isolate was similar to that observed in caruncles; however, the low-virulence isolate induced mild proinflammatory signals at 20 dpi. Finally, a deconvolutional analysis of gene signatures from both placentome tissues revealed a markedly higher fraction of activated natural killers, M1 macrophages and CD8+ T cells for the high-virulence isolate. Therefore, our transcriptomic analysis supports the hypothesis that an intense immune response probably triggered by parasite multiplication could be a key contributor to abortion. Further studies are required to determine the parasite effectors that govern the distinct interactions of high- and low-virulence isolates with the host, which could help elucidate the molecular processes underlying the pathogenesis of neosporosis in cattle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Horcajo, Coronado, Pastor-Fernández, Collantes-Fernández, Rico-San Román, Reyes-Palomares and Ortega-Mora.)

Background: Leptomeningeal collateral status on baseline computed tomographic angiography (CTA) is associated with clinical outcome after acute ischemic stroke treatment. However, assessment of collateral status is not uniform. To compare 3 different CTA collateral scores (CS) and imaging techniques about their association with clinical outcome., Methods: Pooled analysis of patient-level data from the Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration. Patients with large vessel occlusion from 7 randomized controlled trials that compared endovascular thrombectomy with standard medical care were included. Three different CS (Tan CS, regional CS [rCS], and regional Alberta Stroke Program Early CT Score CS) and 2 imaging techniques (single-phase [sCTA] and multiphase/dynamic CTA) were evaluated. Functional independence (modified Rankin Scale score 0-2) at 3 months poststroke was the primary outcome. Furthermore, we assessed the effect of sCTA image acquisition time on collateral status assessment using an adjusted ordinal logistic regression model to obtain predicted values for the trichotomized rCS., Results: Among 1147 pooled patients, 948 (82.7%) had sCTA and 199 (17.3%) multiphase/dynamic CTA as baseline angiography. With all 3 collateral scales, better CSs were associated with better 3-month functional outcome. With sCTA images, the rCS (area under the curve [AUC] 0.63) and regional Alberta Stroke Program Early CT Score CS (AUC 0.62) better predicted functional outcome than the Tan CS (AUC 0.60, respectively; P <0.001 and P =0.02). With multiphase/dynamic CTA images, all collateral scales performed similarly in predicting functional outcome (rCS [AUC 0.61]; regional Alberta Stroke Program Early CT Score CS [AUC 0.61] versus Tan CS [AUC 0.61], respectively; P =0.93 and P =0.91). Overall, no endovascular thrombectomy treatment effect modification by collateral status (rCS) was demonstrated ( P =0.41). sCTA timing independently influenced CS assessment. On earlier timed sCTA, the predicted proportions of scans with poor collaterals was higher and vice versa., Conclusions: In this data set of highly selected patients with stroke, using a regional CS on sCTA likely allows for the most accurate prediction of functional outcome while on time-resolved CTA, the type of CS did not matter. Patients across all collateral grades benefit from endovascular thrombectomy. sCTA timing independently influenced CS assessment.

The intraspecific variability among Neospora caninum isolates in their in vitro behaviour and in vivo virulence has been widely studied. In particular, transcriptomic and proteomic analyses have shown a higher expression/abundance of specific genes/proteins in high-virulence isolates. Consequently, the dense granule protein NcGRA7 and the rhoptry protein NcROP40 were proposed as potential virulence factors. The objective of this study was to characterize the role of these proteins using CRISPR/Cas9 knockout (KO) parasites in a well-established pregnant BALB/c mouse model of N. caninum infection at midgestation. The deletion of Nc GRA7 and Nc ROP40 was associated with a reduction of virulence, as infected dams displayed milder clinical signs, lower parasite burdens in the brain, and reduced mortality rates compared to those infected with the wild-type parasite (Nc-Spain7). Specifically, those infected with the Nc GRA7 KO parasites displayed significantly milder clinical signs and a lower brain parasite burden. The median survival time of the pups from dams infected with the two KO parasites was significantly increased, but differences in neonatal mortality rates were not detected. Overall, the present study indicates that the disruption of Nc GRA7 considerably impairs virulence in mice, while the impact of Nc ROP40 deletion was more modest. Further research is needed to understand the role of these virulence factors during N. caninum infection.

Background: Large-bore aspiration catheters enabling greater flow rates and suction force for mechanical thrombectomy might improve outcomes in patients with stroke secondary to large-vessel occlusion. Complete or near-complete reperfusion after a single thrombectomy pass (first-pass effect) is associated with improved clinical outcomes. We assessed the efficacy and safety of novel MIVI Q™ aspiration catheters in combination with stent-retriever devices., Methods: We retrospectively analyzed demographics, procedure characteristics, and clinical data from consecutive patients with acute anterior large-vessel occlusion treated with a combined approach using MIVI Q™ aspiration catheters and stent retrievers. Reperfusion was defined according to the modified thrombolysis in cerebral infarction (mTICI) score. Clinical outcomes were measured by the National Institute of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) scores., Results: We included 52 patients (median age, 75 y IQR: 64-83); 31 (59.6%) women; 14 (26.9%) with terminal internal carotid artery occlusions, 26 (50%) middle cerebral artery (MCA) segment M1 occlusions, and 12 (23.1%) MCA segment M2 occlusions; median NIHSS score at admission was 19 (IQR: 13-22). After the first pass, 25 (48%) patients had mTICI ≥ 2c. At the end of the procedure, 47 (90.4%) had mTICI ≥ 2b and 35 (67.3%) had mTICI ≥ 2c. No serious device-related adverse events were observed. Symptomatic intracranial hemorrhage developed in 1 patient. Mean NIHSS score was 13 at 24 h and 5 at discharge. At 90 days, 24 (46.2%) patients were functionally independent (mRS 0-2)., Conclusion: This preliminary study found good efficacy and safety for MIVI Q™ aspiration catheters used in combination with stent-retriever devices., (© 2021. The Author(s).)

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits., Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion., Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3., Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52)., Main Outcomes and Measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death., Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%)., Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication., Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.

Objective: To compare the usefulness of CT angiography against the gold standard, digital subtraction angiography (DSA), in the characterization of cerebral arteriovenous malformations (AVM) that present with bleeding., Material and Methods: We retrospectively analyzed patients with intracranial bleeding due to an AVM who were included in a prospective database in the period comprising January 2007 through December 2012. We reviewed radiologic variables such as the characteristics of the AVM (size, location, presence of deep venous drainage), involvement of eloquent areas, and the presence of associated aneurysms. Two neuroradiologists blinded to clinical and radiological information analyzed the CT and DSA in consensus., Results: A total of 22 patients were included in the study. CT angiography correctly classified 15 of the 16 cases of AVM measuring less than 3cm (93.75% sensitivity). All cases of deep venous drainage and all those located in eloquent areas were correctly detected (100% sensitivity). The presence of any type of aneurysm related with the AVM was detected in 13 of 15 cases (86.6% sensitivity); 7 of 9 of the intranidal aneurysms were detected (77.78% sensitivity), as were 6 of the 9 flow aneurysms (66.67% sensitivity)., Conclusion: CT angiography is highly sensitive in the characterization of cerebral AVMs measuring less than 3cm, of those located in eloquent areas, and of those with deep venous drainage; it is also highly sensitive in detecting aneurysms related with AVMs. However, CT angiography is less sensitive in detecting intranidal and flow aneurysms related with AVMs., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

The biological variability among Neospora caninum isolates has been widely shown, however, the molecular basis that determines this diversity has not been thoroughly elucidated to date. The latest studies have focused on a limited number of isolates. Therefore, the goal of the present study was to compare the proteome of a larger number of N. caninum isolates with different origins and virulence. Label-free LC-MS/MS was used to investigate the tachyzoite proteomic differences among Nc-Bahia, Nc-Spain4H and Nc-Spain7, representing high virulence isolates and Nc-Ger6, Nc-Spain2H and Nc-Spain1H, representing low virulence isolates. Pairwise comparisons between all isolates and between high virulence and low virulence groups identified a subset of proteins with higher abundance in high virulence isolates. These proteins were involved in energy and redox metabolism, and DNA/RNA processing, which might determine the faster growth rates and parasite survival of the high virulence isolates. Highlighted proteins included a predicted member of the rhoptry kinase family ROP20 specific for N. caninum, Bradyzoite pseudokinase 1 and several dense granule proteins. DNA polymerase, which was more abundant in all high virulence isolates in all comparisons, might also be implicated in virulence. These results reveal insights into possible mechanisms involved in specific phenotypic traits and virulence in N. caninum, and the relevance of these candidate proteins for N. caninum virulence deserves further investigation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The Spanish Group for Children's Pain Study was created in 2017 in an aim to prevent, remove or reduce pain in neonates, infants, children, and adolescents. Along with a diagnosis of pain, a paediatric patient may suffer from acute or chronic pain, neuropathic, nociceptive, or mixed pain, as well as pain from procedures, and post-surgical pain. Pain suffering is too often ignored and not diagnosed. As a result of this, pain prevention and pain treatment fails. Acute pain prevalence in scientific literature is estimated to be between 22% (procedures pain) and 77% (pain on patients in emergency departments and in hospital wards). Furthermore, up to 30% of children could suffer from chronic pain during their childhood. Among the barriers detected in pain management are: difficult assesment caused by a lack of unity in pain registry, difficuties due to the choice of an assessment pain scale (according to age and type of pain), and the absence of training in the management and interpretation of these pain scales. Additionally, in some health areas there is a high workload pressure and generally there are communication difficulties between professionals, and between them and families. From this AEP working group our clear positioning is expressed in the recommendation of the systematic assessment and recording of pain in all children treated in the health system, thus considering pain as the fifth constant to be determined after the other vital signs., (Copyright © 2019 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Revascularization after endovascular therapy for acute ischemic stroke is measured by the Thrombolysis In Cerebral Infarction (TICI) scale, yet variability exists in scale definitions. We examined the degree of reperfusion with the expanded TICI (eTICI) scale and association with outcomes in the HERMES collaboration of recent endovascular trials., Methods: The HERMES Imaging Core, blind to all other data, evaluated angiography after endovascular therapy in HERMES. A battery of TICI scores (mTICI, TICI, TICI2C) was used to define reperfusion of the initial target occlusion defined by non-invasive imaging and conventional angiography., Results: Angiography of 801 subjects was available, including 797 defined by non-invasive imaging (154 internal carotid artery (ICA), 583 M1, 60 M2) and 748 by conventional angiography (195 ICA, 459 M1, 94 M2). Among 729 subjects in whom the reperfusion grade could be established, using eTICI (3=100%, 2C=90-99%, 2b67=67-89%, 2b50=50-66%) of the conventional angiography target occlusion, there were 63 eTICI 3 (9%), 166 eTICI 2c (23%), 218 eTICI 2b67 (30%), 103 eTICI 2b50 (14%), 100 eTICI 2a (14%), 19 eTICI 1 (3%), and 60 eTICI 0 (8%). Modified Rankin Scale shift analyses from baseline to 90 days showed that increasing TICI grades were linked with better outcomes, with significant distinctions between TICI 0/1 versus 2a (p=0.028), 2a versus 2b50 (p=0.017), and 2b50 versus 2b67 (p=0.014)., Conclusions: The benefit of endovascular therapy in HERMES was strongly associated with increasing degrees of reperfusion defined by eTICI. The eTICI metric identified meaningful distinctions in clinical outcomes and may be used in future studies and routine practice., Competing Interests: Competing interests: DSL reports having received grant funding from NINDS and consulting fees as an imaging core laboratory from Stryker and Medtronic. RJ reports consulting with Medtronic. CBLMM reports having received grant funding from the Dutch Heart Foundation and European Commission and an unrestricted grant from Stryker. AvdL reports consulting fees from Stryker and grant funding from the Dutch Heart Foundation, AngioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO, Penumbra, Top Medical/Concentric, and Stryker, received by the Erasmus University Medical Center. LSR proctors for Stryker and Medtronic. PW discloses institutional research grant support within the last 2 years from Microvention Terumo. He declares the following relevant professional relationships: Chair of the European Society of Minimally Invasive Neurotherapeutics Guidelines Committee, sits on the Policy Working Group for Thrombectomy of NHS England and represents the Royal College of Radiologists on the UK Intercollegiate Stroke Working party (none of these are associated with financial reimbursement). He reports the following modest consultancy work: member of Stryker’s Global Hemorrhagic Stroke Advisory Board and educational consultancy work for Microvention Terumo. He has no other interests to declare. MG reports being the principal investigator of an unrestricted research grant to the University of Calgary for the HERMES collaboration by Medtronic. He also reports consulting services with Medtronic, Stryker, Microvention, Cerenovus and a licensing agreement with GE Healthcare re systems of acute stroke diagnosis., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Endovascular treatment with mechanical thrombectomy devices demonstrated high recanalization rates but functional outcome did not correlate with high rates of recanalization obtained. Patient selection prior to the endovascular treatment is very important in the final outcome of the patient. The primary aim of our study was to evaluate the prognostic value of posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS) and Pons-Midbrain Index (PMI) scores in patients with Basilar Artery Occlusion (BAO) treated with successful angiographic recanalization after mechanical thrombectomy., Methods: Retrospective single-center study including 18 patients between 2008 and 2013 who had acute basilar artery occlusion managed with endovascular treatment within 24hours from symptoms onset and with successful angiographic recanalization. The patients were initially classified into two groups according to clinical outcome and mortality at 90 days. For analysis we also divided patients into groups based on pc-ASPECTS (≥8vs.<8) and PMI (≥3vs.<3) on non-contrast CT (NCCT) and CT Angiography Source Images (CTASI). Imaging data were correlated to clinical outcome and mortality rate., Results: CTASI pc-ASPECTS, dichotomized at <8 versus≥8, was associated with a favorable outcome (RR: 2.6; 95% CI: 1.3-5.2) and a reduced risk of death (RR: 6.5: 95% CI: 7.8-23.3). All patients that survived and were functionally independent had pc-ASPECTS score≥8. None of the 5 patients with CTASI pc-ASPECTS score less than 8 survived., Conclusion: PC-ASPECTS on CTASI is helpful for predicting functional outcome after BAO recanalization with endovascular treatment. These results should be validated in a randomized controlled trial in order to decide whether or not to treat a patient with BAO., (Copyright © 2018. Publicado por Elsevier España, S.L.U.)

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome., Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm 2 /s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered., Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, p interaction =0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, p interaction =0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low., Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions., Funding: Medtronic., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Repurposing of currently marketed compounds with proven efficacy against apicomplexan parasites was used as an approach to define novel candidate therapeutics for bovine besnoitiosis. Besnoitia besnoiti tachyzoites grown in MARC-145 cells were exposed to different concentrations of toltrazuril, diclazuril, imidocarb, decoquinate, sulfadiazine and trimethoprim alone or in combination with sulfadiazine. Drugs were added either just prior to infection of MARC-145 cells (0 h post infection, hpi) or at 6 hpi. A primary evaluation of drug effects was done by direct immunofluorescence staining and counting. Potential effects on the host cells were assessed using a XTT kit for cell proliferation. Compounds displaying promising efficacy were selected for IC 50 and IC 99 determination by qPCR. In addition, the impact of drugs on the tachyzoite ultrastructure was assessed by TEM and long-term treatment assays were performed. Cytotoxicity assays confirmed that none of the compounds affected the host cells. Decoquinate and diclazuril displayed invasion inhibition rates of 90 and 83% at 0 h pi and 73 and 72% at 6 h pi, respectively. The remaining drugs showed lower efficacy and were not further studied. Decoquinate and diclazuril exhibited IC 99 values of 100 nM and 29.9 μM, respectively. TEM showed that decoquinate primarily affected the parasite mitochondrium, whilst diclazuril interfered in cytokinesis of daughter zoites. The present study demonstrates the efficacy of diclazuril and decoquinate against B. besnoiti in vitro and further assessments of safety and efficacy of both drugs should be performed in the target species., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We describe a new and freely available 3D interactive model of the intracranial internal carotid artery (ICA) and the skull base that also allows to display and compare its main segment classifications. High-resolution 3D human angiography (isometric voxel's size 0.36 mm) and Computed Tomography angiography images were exported to Virtual Reality Modeling Language (VRML) format for processing in a 3D software platform and embedding in a 3D Portable Document Format (PDF) document that can be freely downloaded at http://diposit.ub.edu/dspace/handle/2445/112442 and runs under Acrobat Reader on Mac and Windows computers and Windows 10 tablets. The 3D-PDF allows for visualisation and interaction through JavaScript-based functions (including zoom, rotation, selective visualization and transparentation of structures or a predefined sequence view of the main segment classifications if desired). The ICA and its main branches and loops, the Gasserian ganglion, the petrolingual ligament and the proximal and distal dural rings within the skull base environment (anterior and posterior clinoid processes, silla turcica, ethmoid and sphenoid bones, orbital fossae) may be visualized from different perspectives. This interactive 3D-PDF provides virtual views of the ICA and becomes an innovative tool to improve the understanding of the neuroanatomy of the ICA and surrounding structures.

Background and Purpose: Endovascular therapy has become the standard of care for patients with disabling anterior circulation ischemic stroke due to proximal intracranial thrombi. Our aim was to determine whether the beneficial effect of endovascular treatment on functional outcome could be explained by a reduction in posttreatment infarct volume in the Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT) trial., Materials and Methods: The REVASCAT trial was a multicenter randomized open-label trial with blinded outcome evaluation. Among 206 enrolled subjects (endovascular treatment, n = 103; control, n = 103), posttreatment infarct volume was measured in 204 subjects. Posttreatment infarct volumes were compared with treatment assignment and recanalization status. Appropriate statistical models were used to assess the relationship among baseline clinical and imaging variables, posttreatment infarct volume, the 24-hour NIHSS score, and functional status with the 90-day modified Rankin Scale score., Results: The median posttreatment infarct volume in all subjects was 23.7 mL (interquartile range = 68.9 mL) and 16.3 mL (interquartile range = 50.2 mL) in the endovascular treatment arm and 38.6 mL (interquartile range = 74.9 mL) in the control arm ( P = .02 for endovascular treatment versus control subjects). Baseline NIHSS ( P < .01), site of occlusion ( P < .03), baseline NCCT ASPECTS ( P < .01), and recanalization status ( P = .02) were independently associated with posttreatment infarct volume. Baseline NIHSS ( P < .01), time from symptom onset to randomization ( P = .02), treatment type ( P = .04), and recanalization status ( P < .01) were independently associated with the 24-hour NIHSS scores. The 24-hour NIHSS score strongly mediated the relationship between treatment type and 90-day mRS ( P < .01 for indirect effect when adjusted for age), while posttreatment infarct volume did not ( P = .26)., Conclusions: Endovascular treatment saves brain and improves 90-day clinical outcomes primarily through a beneficial effect on the 24-hour stroke severity., (© 2018 by American Journal of Neuroradiology.)

Purpose: To assess the reliability of the Fazekas score on brain CT in acute stroke patients., Methods: Two raters evaluated the Fazekas score in 157 CT scans from consecutive patients with acute stroke., Results: The Fazekas scores on brain CT scans showed consistent (weighted κ, 0.73) and moderate (weighted κ, 0.56) interobserver agreement for periventricular and deep white matter areas, respectively. Intraobserver reliability was substantial for both areas (weighted κ, 0.85 and 0.8)., Conclusion: The Fazekas score on CT can be used to reliably grade white matter changes, and can be a useful tool when MRI is not available., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: The incidence and significance of perfusion abnormalities on brain imaging in patients with lacunar infarct are controversial. We studied the diagnostic yield of CTP and the type of perfusion abnormalities in patients presenting with a lacunar syndrome and in those with MR imaging-confirmed lacunar infarcts., Materials and Methods: A cohort of 33 patients with lacunar syndrome underwent whole-brain CTP on admission. Twenty-eight patients had an acute ischemic lesion at follow-up MR imaging; 16 were classified as lacunar infarcts. Two independent readers evaluated NCCT and CTP to compare their diagnostic yield. In patients with DWI-confirmed lacunar infarcts and visible deficits on CTP, the presence of mismatch tissue was measured by using different perfusion thresholds., Results: The symptomatic acute lesion was seen on CTP in 50% of patients presenting with a lacunar syndrome compared with only 17% on NCCT, and in 62% on CTP compared with 19% on NCCT, respectively, in patients with DWI-confirmed lacunar infarcts. CTP was more sensitive in supratentorial than in infratentorial lesions. In the nonblinded analysis, a perfusion deficit was observed in 12/16 patients with DWI-confirmed lacunar infarcts. The proportion of mismatch tissue was similar in patients with lacunar infarcts or nonlacunar strokes (32% versus 36%, P = .734)., Conclusions: Whole-brain CTP is superior to NCCT in identifying small ischemic lesions, including lacunar infarcts, in patients presenting with a lacunar syndrome. Perfusion deficits and mismatch are frequent in lacunar infarcts, but larger studies are warranted to elucidate the clinical significance of these CTP findings., (© 2015 by American Journal of Neuroradiology.)

Background: We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry., Methods: During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials., Results: Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals., Conclusions: Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

In a recent randomized controlled trial comparing vertebroplasty (VP) versus conservative treatment (CT) in patients with symptomatic vertebral fractures (VF), we observed the development of chronic back pain (CBP) in nearly one-quarter of patients. The aim of this study was to identify the risk factors related to the development of severe CBP in these subjects. We evaluated risk factors including visual analog scale (VAS) at baseline and during the 1-year follow-up, age, gender, symptom onset time, number, type and severity of VF at baseline, number of vertebral bodies treated, incident VF, and antiosteoporotic treatment, among others. CBP was considered in patients with VAS ≥ 7 at 12 months. 91/125 patients completed the 12-months follow-up. CBP was observed in 23% of VP-treated patients versus 23% receiving CT. Patients developing CBP after VP showed a longer symptom onset time (82% ≥ 4 months in VP vs. 40% in CT, P = 0.03). On univariate analysis, female gender (OR 1.52; 95% CI 1.47-1.57, P < 0.0001), multiple acute VF (OR 1.79; 95% CI 1.71-1.87, P < 0.0001), VAS ≥ 7 two months after treatment (OR 11.04; 95% CI 6.71-18.17, P < 0.0001), and type of antiosteoporotic drug (teriparatide) (OR 0.12; 95% CI 0.03-0.60, P = 0.0236) were risk factors of CBP development in both groups. In the multivariate analysis, the main risk factors were baseline and post-treatment VAS ≥ 7, longer symptom onset time, and type of antiosteoporotic treatment. In conclusion, 23% of patients with symptomatic osteoporotic VF developed severe CBP independently of the type of treatment. Symptom onset time before VP and persistence of severe CBP after treatment were the main factors related to CBP with teriparatide treatment decreasing the risk of this complication.

Indocyanine green videoangiography (ICGVA) procedures have become widespread within the spectrum of microsurgical techniques for neurovascular pathologies. We have conducted a review to identify and assess the impact of all of the methodological variations of conventional ICGVA applied in the field of neurovascular pathology that have been published to date in the English literature. A total of 18 studies were included in this review, identifying four primary methodological variants compared to conventional ICGVA: techniques based on the transient occlusion, intra-arterial ICG administration via catheters, use of endoscope system with a filter to collect florescence of ICG, and quantitative fluorescence analysis. These variants offer some possibilities for resolving the limitations of the conventional technique (first, the vascular structure to be analyzed must be exposed and second, vascular filling with ICG follows an additive pattern) and allow qualitatively superior information to be obtained during surgery. Advantages and disadvantages of each procedure are discussed. More case studies with a greater number of patients are needed to compare the different procedures with their gold standard, in order to establish these results consistently.

Validation studies are prerequisites for computational fluid dynamics (CFD) simulations to be accepted as part of clinical decision-making. This paper reports on the 2011 edition of the Virtual Intracranial Stenting Challenge. The challenge aimed to assess the reproducibility with which research groups can simulate the velocity field in an intracranial aneurysm, both untreated and treated with five different configurations of high-porosity stents. Particle imaging velocimetry (PIV) measurements were obtained to validate the untreated velocity field. Six participants, totaling three CFD solvers, were provided with surface meshes of the vascular geometry and the deployed stent geometries, and flow rate boundary conditions for all inlets and outlets. As output, they were invited to submit an abstract to the 8th International Interdisciplinary Cerebrovascular Symposium 2011 (ICS'11), outlining their methods and giving their interpretation of the performance of each stent configuration. After the challenge, all CFD solutions were collected and analyzed. To quantitatively analyze the data, we calculated the root-mean-square error (RMSE) over uniformly distributed nodes on a plane slicing the main flow jet along its axis and normalized it with the maximum velocity on the slice of the untreated case (NRMSE). Good agreement was found between CFD and PIV with a NRMSE of 7.28%. Excellent agreement was found between CFD solutions, both untreated and treated. The maximum difference between any two groups (along a line perpendicular to the main flow jet) was 4.0 mm/s, i.e. 4.1% of the maximum velocity of the untreated case, and the average NRMSE was 0.47% (range 0.28-1.03%). In conclusion, given geometry and flow rates, research groups can accurately simulate the velocity field inside an intracranial aneurysm-as assessed by comparison with in vitro measurements-and find excellent agreement on the hemodynamic effect of different stent configurations.

We have demonstrated that the antagonism of 5-HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by 5-HT1D and 5-HT7 activation. The aim of this work was to determine mechanisms involved in the 5-hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5-HT2 receptor blocker. The blockade of 5-HT2 receptors was induced by orally sarpogrelate treatment (30 mg/kg/day). Two weeks later, animals were anaesthetized and pithed. A bolus injection of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µg/kg), a guanylyl cyclase inhibitor, or indomethacin (2mg/kg), a non-selective COX inhibitor, prior to the infusion of (2S)(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin, AS-19 (5 µg/kg/min) were not able to abolish its inhibitory action. However, i.v. administration of glibenclamide (20mg/kg), a blocker of ATP-sensitive K(+) channels, completely reversed AS-19 sympathoinhibitory action. The inhibitory effect of 2-[5-[3-(4-methylsulfonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3-yl]ethanamine, L-694,247 (5 µg/kg/min) was abolished by indomethacin, whereas pretreatment with ODQ had no effect. Nimesulide (3mg/kg), a COX-2 inhibitor, completely reversed the inhibitory action of L-694,247, whereas 1-[[4,5-bis (4-methoxyphenyl)-2-thiazolyl]carbonyl]-4-methylpiperazine hydrochloride (FR122047) (3mg/kg), a COX-1 inhibitor, partially blocked this action. The sympathoinhibition by 5-HT (20 µg/kg/min) could not be elicited after i.v. treatment with indomethacin plus glibenclamide. In conclusion, these results suggest that in chronic sarpogrelate-treated rats, the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via 5-HT7 and 5-HT1D receptor activation is mediated by KATP channel-mediated smooth muscle hyperpolarization and the COX pathway, respectively., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: A significant proportion of stroke patients presenting with mild symptoms does not have a successful recovery, especially when a large vessel is occluded. IV thrombolysis is safe and may benefit patients presenting with mild symptoms. In this study, we tested whether endovascular therapy (ET) is superior to medical therapy in these patients., Methods: Observational, prospectively collected, multicenter study of 78 consecutive patients admitted from 2009 to 2012 within 6 h of stroke, with NIHSS≤5 at presentation or during initial diagnostic work-up and large vessel occlusion. Data for patients undergoing ET and/or IV thrombolysis were taken from the SONIIA registry of reperfusion therapies in Catalonia, or from our local stroke registry if no reperfusion therapy was delivered. We compared risk factors, clinical course, collateral circulation, revascularization rates, hemorrhagic complications, infarct volume, and the functional outcome at 3 months of patients treated with ET and those not receiving ET. Ordinal regression was used to assess the independent effect of ET on functional outcome., Results: Baseline characteristics were similar for ET (n=34) and medically (n=44) treated patients, except for older age in the latter. The occlusions were located in the terminal internal carotid artery (1%), M1 segment of the middle cerebral artery (33%), M2 segment (30%), posterior circulation (31%), and 5% of the patients had tandem lesions, with no significant differences between groups. Most patients in both treatment groups had good collateral flow. The rate of successful revascularization (91.2 vs. 63.4%; p=0.006) and the risk of symptomatic intracranial hemorrhage (11.8 vs. 0%; p=0.033) were higher in the ET group. The NIHSS scores were similar at hospital arrival, after initial neuroimaging, and at 24 h in both treatment groups and there were no significant differences in the infarct volume in a follow-up MRI. At 3 months, 35.9% of the patients had some disability. The functional outcome was similar in both treatment groups in univariate analysis and also in models adjusted for age and initial NIHSS or for variables associated to functional outcome on univariate comparison. Conversely, IV thrombolysis was associated with significantly greater chances of full recovery after adjusting for baseline differences (OR 3.70, p=0.015)., Conclusions: One third of stroke patients with mild symptoms and large vessel occlusions do not have a successful recovery. ET is effective to recanalize the occluded vessel but increases the risk of serious bleeding significantly without improving the functional outcome, and is therefore not justified routinely in these patients., (© 2014 S. Karger AG, Basel.)

Anatomical labeling of the cerebral arteries forming the Circle of Willis (CoW) enables inter-subject comparison, which is required for geometric characterization and discovering risk factors associated with cerebrovascular pathologies. We present a method for automated anatomical labeling of the CoW by detecting its main bifurcations. The CoW is modeled as rooted attributed relational graph, with bifurcations as its vertices, whose attributes are characterized as points on a Riemannian manifold. The method is first trained on a set of pre-labeled examples, where it learns the variability of local bifurcation features as well as the variability in the topology. Then, the labeling of the target vasculature is obtained as maximum a posteriori probability (MAP) estimate where the likelihood of labeling individual bifurcations is regularized by the prior structural knowledge of the graph they span. The method was evaluated by cross-validation on 50 subjects, imaged with magnetic resonance angiography, and showed a mean detection accuracy of 95%. In addition, besides providing the MAP, the method can rank the labelings. The proposed method naturally handles anatomical structural variability and is demonstrated to be suitable for labeling arterial segments of the CoW.

Computational algorithms modeling the insertion of endovascular devices, such as coil or stents, have gained an increasing interest in recent years. This scientific enthusiasm is due to the potential impact that these techniques have to support clinicians by understanding the intravascular hemodynamics and predicting treatment outcomes. In this work, a virtual coiling technique for treating image-based aneurysm models is proposed. A dynamic path planning was used to mimic the structure and distribution of coils inside aneurysm cavities, and to reach high packing densities, which is desirable by clinicians when treating with coils. Several tests were done to evaluate the performance on idealized and image-based aneurysm models. The proposed technique was validated using clinical information of real coiled aneurysms. The virtual coiling technique reproduces the macroscopic behavior of inserted coils and properly captures the densities, shapes and coil distributions inside aneurysm cavities. A practical application was performed by assessing the local hemodynamic after coiling using computational fluid dynamics (CFD). Wall shear stress and intra-aneurysmal velocities were reduced after coiling. Additionally, CFD simulations show that coils decrease the amount of contrast entering the aneurysm and increase its residence time.

Introduction: Inflammatory bowel disease (IBD) is an independent risk factor for thromboembolic phenomena (TEP). We evaluated the prevalence and the possible risk factors associated with developing TEP in patients with IBD in our center., Material and Methods: Data were retrospectively collected from January 1995 to December 2011 from 23 patients. A total of 61% were diagnosed with Crohn's disease (CD) and 39% with ulcerative colitis (UC) according to routine criteria., Results: When the Montreal classification was used, 58% of the patients with CD had an inflammatory pattern (B1), 25% a stenosing pattern (B2) and 17% a fistulizing pattern (B3). Half the patients had ileocolic involvement (L3), one-third had colonic involvement (L2) and the remainder had ileal involvement (L1). Among patients with UC according to the Montreal classification, 78% had extensive colitis (E3), 11% had left colonic involvement (E2) and 11% had proctocolitis (E1). During the event, almost half the patients with UC had severe inflammatory activity (S3; 44%), 33% had mild-moderate activity (S1: 22%, S2: 11%) and only 22% were in remission (S0). Overall, at the time of the TEP, 48% of the patients had mild-moderate activity and 22% had severe activity. Likewise, 44% were hospitalized at the time of the event. In UC, an increase in the prevalence of TEP was found in admitted patients (66%). None of the patients had a family history of TEP, two patients (9%) had associated thrombophilia and 26% were active smokers. There were no TEP during pregnancy. Only one patient was taking contraceptive pills when the event occurred. The most frequent forms of TEP were deep vein thrombosis of the legs (55%) followed by pulmonary thromboembolism (25%)., Conclusions: TEP are relatively frequent in patients with IBD, with a strong impact on morbidity and mortality. In our series, risk factors for these events were more extensive involvement (any of the groups) and severe inflammatory activity. No significant association between classical risk factors such as the use of contraceptives, pregnancy, coagulation disorders or smoking and the risk of TEP were found., (Copyright © 2012 Elsevier España, S.L. and AEEH y AEG. All rights reserved.)

Background and Purpose: We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke., Methods: We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting <8 hours in the anterior circulation (n=54) or <12 hours in the vertebrobasilar circulation (n=6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms >4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b-3), good outcome (modified Rankin Scale score 0-2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment ≥ 4 points) were prospectively assessed., Results: Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12-22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173-296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45-114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected., Conclusions: The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials.

We investigated the mechanisms involved in the 5-hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in long-term-diabetic pithed rats. Diabetes was induced in rats by alloxan administration. Eight weeks later, the animals were anaesthetized and pithed. The action and mechanisms of 5-HT were analysed based on the pressor responses induced by sympathostimulation. In 8-week-diabetic animals, 5-HT (20 µg/kg/min) inhibits the pressor effect of sympathostimulation which is reproduced by two selective 5-HT(1A) and 5-HT(2) receptor agonists: 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT, 5 µg/kg/min) and α-methyl-5-HT (5 µg/kg/min). A bolus injection of 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 10 µg/kg), or L-arginine HCl, N(ω)-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg), an inhibitor of NO production, prior to the infusion of 8-OH-DPAT (5 µg/kg/min) reversed the inhibitory effect of 8-OH-DPAT. The inhibitory effect of infusion of α-methyl 5-HT (5 µg/kg/min) was abolished in the presence of indomethacin (2 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, or FR 122047 (1.5 mg/kg) or nimesulide (1.5 mg/kg), two selective COX-1 and COX-2 inhibitors, respectively, in long-term-diabetic pithed rats. Our results indicate that 5-HT inhibition of the pressor responses induced by electrical stimulation is mediated both by the NO and COX pathways in long-term-diabetic rats., (Copyright © 2012 S. Karger AG, Basel.)

Background and Purpose: The value of multimodal CT to assist thrombolysis has received little attention in stroke., Methods: We assessed prospectively the impact derived from the routine application of CT perfusion and CTA in patients with acute stroke treated consecutively with alteplase. The safety and efficacy of thrombolytic therapy were compared in 106 patients assisted with CT/CTA/CT perfusion (multimodal CT group) and 262 patients assisted without full multimodal brain imaging (control group) during a 5-year period (2005-2009)., Results: Good outcome (modified Rankin scale score ≤2) at 3 months was increased in the multimodal group compared with controls (adjusted OR, 2.88; 95% CI, 1.50-5.52). Multimodal-assisted thrombolysis yielded superior benefits in patients treated beyond 3 hours (adjusted OR, 4.48; 95% CI, 1.68-11.98) than treated within 3 hours (adjusted OR, 1.31; 95% CI, 0.80-2.16; interaction test P=0.043). Mortality (14% and 15%) and symptomatic hemorrhage (5% and 7%) were similar in both groups., Conclusions: Multimodal CT use in routine clinical practice may heighten the overall efficacy of thrombolytic therapy in acute ischemic stroke. The benefits seem greater in patients treated >3 hours after stroke onset, but further randomized clinical trials are needed to confirm these findings.

We analyzed the modulation of serotonin on the bradycardia induced in vivo by vagal electrical stimulation in alloxan-induced long-term diabetic rats. Bolus intravenous administration of serotonin had a dual effect on the bradycardia induced either by vagal stimulation or exogenous Ach, increasing it at low doses and decreasing it at high doses of 5-hydroxytryptamine (5-HT), effect reproduced by 5-carboxamidotryptamine maleate (5-CT), a 5-HT(1/7) agonist. The enhancement of the bradycardia at low doses of 5-CT was reproduced by 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) and abolished by WAY-100,635, 5-HT(1A) antagonist. Pretreatment with 5-HT(1) antagonist methiothepin blocked the stimulatory and inhibitory effect of 5-CT, whereas pimozide, 5-HT(7) antagonist, only abolished 5-CT inhibitory action. In conclusion, long-term diabetes elicits changes in the subtype of the 5-HT receptor involved in modulation of vagally induced bradycardia. Activation of the 5-HT(1A) receptors induces enhancement, whereas attenuation is due to 5-HT(7) receptor activation. This 5-HT dual effect occurs at pre- and postjunctional levels.

Using several 5-hydroxytryptamine (5-HT) agonists and antagonists, we attempted to characterize the receptor subtypes involved in the contractile response to 5-HT in the in situ autoperfused rat kidney. An intra-arterial (i.a.) bolus injection of 5-HT (0.00000125 to 0.1 microg/kg) increased renal perfusion pressure in a dose-dependent way but did not affect the systemic blood pressure. The selective 5-HT2 receptor agonist alpha-methyl-5-HT (alpha-methyl-5-hydroxytryptamine) and the non-selective 5-HT2C receptor agonist (1-(3-chlorophenyl)piperazine), m-CPP, caused a local vasoconstrictor effect in the autoperfused rat kidney, whereas BW723C86, a selective 5-HT2B receptor agonist, the 5-HT1 receptor agonist 5-carboxamidotryptamine, 5-CT, and the selective 5-HT3 receptor agonist m-CPBG (1-(m-chlorophenyl)-biguanide) did not modify the renal perfusion pressure. The vasoconstrictor effect elicited by alpha-methyl-5-HT and m-CPP was significantly decreased by ritanserin (a 5-HT2 receptor antagonist), SB 206553 (3,5-Dihydro-5-methyl-N-3pyridinylbenzo[1,2.b:4,5-b']dipyrrole(1H)-carboxamide hydrochloride), a selective 5-HT2B/2C receptor antagonist and enalapril, but was not modified by pretreatment with spiperone (a 5-HT2A receptor antagonist). The results of protein expression analyses allow us to postulate that 5HT-SRC (a 5-HT2C receptor protein) is expressed in renal tissue and differentially expressed in renal artery. Our data suggest also that the serotonergic vasoconstrictor response induced in the in situ autoperfused rat kidney would be mediated by local 5-HT2C receptor activation.

1. In the present study, we investigated how alloxan-induced diabetes affects the ability of 5-hydroxytryptamine (5-HT) to modulate bradycardia induced in vivo by electrical stimulation of the vagus nerve in pithed rats. We also analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats with a single injection of alloxan (150 mg/kg, s.c.). Four weeks later, rats were anaesthetized, pretreated with atenolol and pithed. Electrical stimulation (3, 6 and 9 Hz) of the vagus nerve resulted in frequency dependent decreases in heart rate (HR). 3. In diabetic rats, intravenous bolus administration of high doses of 5-HT (100 and 200 microg/kg) increased the bradycardia induced by vagal electrical stimulation. Similarly, low doses (10 microg/kg) of the 5-HT(1/7) receptor agonist 5-carboxamidotryptamine (5-CT), increased vagally induced bradycardia. However, at high doses (50, 100 and 150 microg/kg), 5-CT reduced the bradycardia. Attenuation of the vagally induced bradycardia evoked by the higher doses of 5-CT was reproduced by L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors. Enhancement of the vagally induced bradycardia elicited by low doses of 5-CT was reproduced by the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT; 50 microg/kg). These stimulatory and inhibitory actions on vagal stimulation-induced bradycardia in diabetic rats were also observed after administration of exogenous acetylcholine. 4. Vagally induced bradycardia in diabetic rats was not affected by administration of the selective 5-HT(2) receptor agonist alpha-methyl-5-HT (150 microg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 microg/kg) or the selective 5-HT(1B) receptor agonist CGS-12066B (50 microg/kg). 5. Enhancement of the electrical stimulation-induced bradycardia in diabetic rats caused by 5-CT (10 microg/kg) or 8-OH-DPAT (50 microg/kg) was abolished by the selective 5-HT(2/7) receptor antagonist mesulergine (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 microg/kg), respectively. Similarly, pretreatment with the non-selective 5-HT(1) receptor antagonist methiothepin (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 microg/kg) on the bradycardia induced by vagal electrical stimulation in diabetic rats. BRL-15572 (2 microg/kg), a selective 5-HT(1D) receptor antagonist, inhibited the action of L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors, on the vagally induced bradycardia. 6. In conclusion, in the present study, experimental diabetes evoked changes in both the nature and 5-HT receptor types/subtypes involved in vagally induced bradycardia.

Background: To determine the frequency and predictors of symptomatic intracerebral hemorrhage (SICH) in patients treated with recombinant tissue plasminogen activator (rt-PA)., Methods: We reviewed the databases of 7 tertiary hospitals that treated ischemic stroke patients with intravenous rt-PA. We recorded demographic data, vascular risk factors, time between onset and treatment, dose, the NIHSS score, body temperature, blood pressure, platelet count, blood glucose, antiplatelet treatment, and CT data. We also registered the study protocol used for treatment and deviations from the accepted protocol. A control CT was performed on all patients. SICH was diagnosed if a parenchymal hematoma was detected within the 36 h after rt-PA and was associated with an increase of > or =4 in the NIHSS score. Bivariate analyses were performed followed by a logistic regression analysis., Results: A total of 347 patients were studied, whose mean age was 68 +/- 10.9 years; 56% were men. Thirty-two patients (9.2%) exhibited a parenchymal hematoma, and 8 patients (2.3%) suffered a SICH. Patients with SICH had a higher frequency of previous transient ischemic attack (p = 0.04), early signs of ischemia (p = 0.003), hyperdense arterial sign (p = 0.008), and deviations (p = 0.002). Early signs of ischemia (OR 8.5, 95% CI 1.6-45.4, p = 0.01) and deviation from the protocol (OR 11.1, 95% CI 2.4-50, p = 0.002) were independent predictors of SICH., Conclusions: SICH is infrequent in patients with ischemic stroke treated with rt-PA outside of a clinical trial. Its frequency increases in the presence of early signs of ischemia on the non-contrast CT scan and deviations from the recommended protocol.

We investigated the involvement of the nitric oxide pathway in the inhibitory mechanisms of 5-hydroxytryptamine (5-HT) in the pressor responses induced by stimulation of sympathetic vasopressor outflow in diabetic pithed rats. Diabetes was induced in male Wistar rats by a single s.c. injection of alloxan. Four weeks later, the animals were anaesthetized, pretreated with atropine, and pithed. Electrical stimulation of the sympathetic outflow from the spinal cord (0.1, 0.5, 1 and 5 Hz) resulted in frequency-dependent increases in blood pressure. The inhibition of electrically induced pressor responses by 5-HT (10 microg/kg/min) in diabetic pithed rats could not be elicited after i.v. treatment with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microg/kg), a guanylyl cyclase inhibitor, or N-omega-L-Arginine methyl ester hydrochloride (L-NAME) (10 mg/kg), a nitric oxide synthase (NOS) inhibitor. The inhibitory effect produced by infusion of the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT) (20 microg/kg/min) was abolished in the presence of ODQ (10 microg/kg), or L-NAME (10 mg/kg) in diabetic pithed rats. The administration of L-Arginine (100 mg/kg) 30 min after L-NAME reproduced the inhibitory effect caused by 5-HT (10 microg/kg/min) and 8-OH-DPAT (20 microg/kg/min) on the electrically induced pressor responses, whereas in the presence of D-Arginine (100 mg/kg)+L-NAME the 5-HT or 8-OH-DPAT inhibitory effect on the pressor responses was abolished. In conclusion, in diabetic pithed rats, the inhibition produced by prejunctional 5-HT(1A) activation on electrically induced sympathetic pressor responses is mediated by the NO synthesis/pathway.

1. In the present study, we analysed the effect of different doses of 5-hydroxytryptamine (5-HT; intravenous infusions of 0.001-40 microg/kg per min) in the autoperfused hindquarters of the rat subjected to electrical stimulation (frequencies of 0.5-20 Hz) of the lumbar chains, investigating the relationship between the adrenergic and serotonergic systems in this vascular bed. 2. Because we observed that 5-HT inhibited the increases in perfusion pressure induced by electrical stimulation of the lumbar chains, we used different agonists and antagonists to analyse the mechanism of action of 5-HT. 3. The effect of 5-HT was inhibited by methiothepin (a non-specific 5-HT receptor antagonist), but not by ritanserin (a selective 5-HT2 receptor antagonist). The effects of 5-HT were mimicked by 5-carboxamidotryptamine (a 5-HT1 receptor agonist) and L-694 247 (a selective 5-HT1D receptor agonist), but not by 8-hydroxy-2-dipropylaminotetralin (a 5-HT1A receptor agonist), CGS-12066B (a 5-HT1B receptor agonist), alpha-methyl-5-HT (a 5-HT2 receptor agonist), 1-(3-chlorophenyl) piperazine (a 5-HT2C receptor agonist) or 1-phenylbiguanide (a 5-HT3 receptor agonist). The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibited the effect of the agonist L-694 247. 4. Our data suggest that 5-HT inhibits the increases in perfusion pressure induced by the electrical stimulation of the lumbar chains, acting on presynaptic 5-HT1D receptors and decreasing the release of noradrenaline from the sympathetic nerves in the hindquarter vascular bed of the rat.

In the present work we studied the actions of the intra-arterial administration of meta-chlorophenylpiperazine (m-CPP - a 5-HT(2C) receptor agonist) in the hindquarters of the anesthetized rat. The lowest doses used (0.001, 0.01, 0.1, 0.25 and 0.5 microg/kg) induced vasodilatation whereas the highest doses produced vasoconstriction (1, 6.25, 12.5 and 25 microg/kg). Both vasodilatation and vasoconstriction were inhibited by the 5-HT(1,2 )receptor antagonist methiothepin, whereas the 5-HT(2 )receptor antagonist ritanserin blocked only the vasoconstrictor responses. 1-[4-(1-Adamantanecarboxamido)butyl]-4-(2-methoxyphenyl)piperazine (a 5-HT(1A) receptor antagonist) and ICI 118,551 (a beta(2)-receptor antagonist) failed to modify the vasodilator responses of m-CPP. Both BRL 15572 (a 5-HT(1D) receptor antagonist) and GR 55562 (a 5-HT(1B) receptor antagonist) only partially inhibited this action. Our data reveal that m-CPP induces the 5-HT(1 )and/or non-specific vasodilator effect and 5-HT(2) vasoconstrictor effects in the hindquarter vascular bed of the rat., (Copyright (c) 2005 S. Karger AG, Basel.)

The vasorelaxant effect of two new neo-clerodane diterpenoids, (12R)-12-hydroxycascarillone and 5beta-hydroxy-cis-dehydrocrotonin, in addition to the known cis-dehydrocrotonin and trans-dehydrocrotonin, all them previously isolated by us from Croton schiedeanus Schlecht, was studied in isolated aorta rings contracted by high K+ (80 mM) or phenylephrine (1 microM). According to their IC50 values to KCl induced contraction, the potency order was (12R)-12-hydroxycascarillone > cis-dehydrocrotonin > 5beta-hydroxy-cis-dehydrocrotonin > trans-dehydrocrotonin (0.3, 1.5, 96 and >100 mM, respectively). The possible cooperativity between diterpenoid compounds and the predominant flavonoid (ayanin) was studied. The vasorelaxant activity of cis-dehydrocrotonin and ayanin was increased when both compounds were incorporated simultaneously to the aortic rings precontracted with phenylephrine. These results suggest that Croton schiedeanus induces its effects via the synergistic actions of several vasodilator substances, among which neo-clerodane diterpenoids play an important role.

Our objective was to examine the effect of chronic treatment with amlodipine on blood pressure, left ventricular hypertrophy, and fibrosis in spontaneously hypertensive rats and the persistence of such an effect after drug withdrawal. We investigated the effects of treatment with 2, 8 and 20 mg/kg/day of amlodipine given orally for six months and at three months after drug withdrawal. Systolic blood pressure was measured using the tail-cuff method. At the end of the study period, the heart was excised, the left ventricle was isolated, and the left ventricle weight/body weight ratio was calculated as a left ventricular hypertrophy index. Fibrosis, expressed as collagen volume fraction, was evaluated using an automated image-analysis system on sections stained with Sirius red. Age-matched untreated Wistar-Kyoto and SHR were used as normotensive and hypertensive controls, respectively. Systolic blood pressure was reduced in the treated SHR in a dose-dependent way and after amlodipine withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy was reduced by 8 and 20 mg/kg/day amlodipine, but when treatment was withdrawn only the group treated with 8 mg/kg/day maintained significant differences versus the hypertensive controls. All three doses of amlodipine reduced cardiac fibrosis and this regression persisted with the two highest doses after three months without treatment. We concluded that antihypertensive treatment with amlodipine is accompanied by a reduction in left ventricular hypertrophy and regression in collagen deposition. Treatment was more effective in preventing fibrosis than in preventing ventricular hypertrophy after drug withdrawal., (Copyright 2004 Elsevier Inc.)

In this work we studied the responses and receptors involved in the effects of intra-arterial 5-hydroxytryptamine (5-HT) in the in situ autoperfused hindquarters of spontaneously hypertensive rats (SHR). Intra-arterial administration of the highest doses (50-1,000 ng/kg) produced a vasoconstrictor effect that was inhibited by ritanserin (a selective 5-HT2 receptor antagonist), SB 206553 (a selective 5-HT(2B/2C) receptor antagonist) and spiperone (a nonspecific 5-HT(1/2A) receptor antagonist), and was mimicked by alpha-methyl-5-HT (a selective 5-HT2 receptor agonist) and m-CPP (a selective 5-HT2C receptor agonist), but not by the intra-arterial administration of BW 723C86, a selective 5HT2B receptor agonist. SB 206553 and spiperone inhibited alpha-methyl-5HT-induced vasoconstriction in the hindquarters of SHR. Our data suggest that the vasoconstrictor response induced by 5-HT in the autoperfused hindquarters of SHR is mainly mediated by the activation of 5-HT2A and 5-HT2C receptors., (Copyright 2004 S. Karger AG, Basel)

These studies were conducted to examine the role of the vasoactive mediators nitric oxide (NO) and adrenaline (epinephrine) in the serotonin (5-hydroxytryptamine; 5-HT)-induced vasodilator response in the hindquarter vascular bed of anaesthetized rats. Intra-arterial administration of doses of 5-HT in the range 0.12-25 ng kg(-1) produced a dose-independent vasodilator effect in the hindquarters. The selective 5-HT(1D/1B) receptor agonist, L-694,247 at intra-arterial doses of 0.0012-1000 ng kg(-1), as well as adrenaline (at doses of 0.05-50 ng kg(-1) i.a.), mimicked the dose-independent vasodilator effect induced by intra-arterial administration of 5-HT. Intravenous pre-treatment with the selective beta2-receptor antagonist ICI 118,551 (0.5 mg kg(-1)) blocked the vasodilator effect of 5-HT, adrenaline and L-694,247. Additionally, the inhibitor of NO synthase NG-nitro-L-arginine (L-NAME) (at a dose of 10 mg kg(-1) i.v.) blocked the vasodilator action of acetylcholine 300-3000 ng kg(-1)) but did not modify 5-HT-induced vasodilatation. The vasodilator effect produced by intra-arterial administration of 5-HT in the hindquarters was significantly inhibited both 30 min after denervation of the lumbar sympathetic chains and 1 h after bilateral adrenalectomy. Our data suggest that in the in-situ autoperfused hindquarters of the rat 5-HT-induced vasodilatation is mediated by a local 5-HT(1D) or 5-HT(1D/1B) activation, which in turn mediates the adrenal release of adrenaline, which then produces beta2-activation and vasodilatation.

Two new neo-clerodane type furano diterpenoids were isolated from the aerial part of Croton schiedeanus, besides the clerodane diterpenes cis- and trans-dehydrocrotonin, previously isolated from other species of Croton. Structural elucidation was achieved on basis of extensive NMR experiments, including X-ray diffraction analysis and molecular mechanics calculations. The previously known flavonoids ayanin and quercetin-3,7-dimethyl ether were also obtained from the extract of this plant.