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Background and Purpose: Aneurysm hemodynamics play an important role in aneurysm growth and subsequent rupture. Within the available hemodynamic characteristics, particle residence time (PRT) is relatively unexplored. However, some studies have shown that PRT is related to thrombus formation and inflammation. The goal of this study is to evaluate the association between PRT and aneurysm rupture and morphology.Methods: We determined the PRT for 113 aneurysms (61 unruptured, 53 ruptured) based on computational fluid dynamic models. Virtual particles were injected into the parent vessel and followed during multiple cardiac cycles. PRT was defined as the time needed for 99% of the particles that entered an aneurysm to leave the aneurysm. Subsequently, we evaluated the association between PRT, rupture, and morphology (aneurysm type, presence of blebs, or multiple lobulations).Results: PRT showed no significant difference between unruptured (1.1 seconds interquartile range [IQR .39-2.0 seconds]) and ruptured aneurysms (1.2 seconds [IQR .47-2.3 seconds]). PRT was influenced by aneurysm morphology. Longer PRTs were seen in bifurcation aneurysms (1.3 seconds [IQR .54-2.4 seconds], P = .01) and aneurysms with blebs or multiple lobulations (1.92 seconds [IQR .94-2.8 seconds], P < .001). Four of five partially thrombosed aneurysms had a long residence time (>1.9 seconds).Conclusions: Our study shows an influence of aneurysm morphology on PRT. Nevertheless, it suggests that PRT cannot be used to differentiate unruptured and ruptured aneurysms. [ABSTRACT FROM AUTHOR]

An experimental system designed for the study of the effects of diagnostic or therapeutic ultrasound exposure on isolated blood vessels in the presence or absence of intraluminal contrast agent is described. The system comprised several components. A microscope was used to monitor vessel size (and thus vessel functionality), and potential leakage of intraluminal 70 kDa FITC-dextran fluorescence marker. A vessel chamber allowed the mounting of an isolated vessel whilst maintaining its viability, with pressure regulation for the control of intraluminal pressure and induction of flow for the infusion of contrast microbubbles. A fibre-optic hydrophone sensor mounted on the vessel chamber using a micromanipulator allowed pre-exposure targeting of the vessel to within 150 µm, and monitoring of acoustic cavitation emissions during exposures. Acoustic cavitation was also detected using changes in the ultrasound drive voltage and by detection of audible emissions using a submerged microphone. The suitability of this system for studying effects in the isolated vessel model has been demonstrated using a pilot study of 6 sham exposed and 18 high intensity focused ultrasound exposed vessels, with or without intraluminal contrast agent (SonoVue) within the vessels. [ABSTRACT FROM AUTHOR]

While matrix remodeling plays a key role in vascular physiology and pathology, the underlying mechanisms have remained incompletely understood. We studied the remodeling of collagen matrices by individual vascular smooth muscle cells (SMCs), clusters and monolayers. In addition, we focused on the contribution of transglutaminase 2 (TG2), which plays an important role in the remodeling of small arteries. Single SMCs displaced fibers in collagen matrices at distances up to at least 300 μm in the course of 8-12 h. This process involved both 'hauling up' of matrix by the cells and local matrix compaction at a distance from the cells, up to 200 μm. This exceeded the distance over which cellular protrusions were active, implicating the involvement of secreted enzymes such as TG2. SMC isolated from TG2 KO mice still showed compaction, with changed dynamics and relaxation. The TG active site inhibitor L682777 blocked local compaction by wild type cells, strongly reducing the displacement of matrix towards the cells. At increasing cell density, cells cooperated to establish compaction. In a ring-shaped collagen matrix, this resulted in preferential displacement in the radial direction, perpendicular to the cellular long axis. This process was unaffected by inhibition of TG2 cross-linking. These results show that SMCs are capable of matrix remodeling by prolonged, gradual compaction along their short axis. This process could add to the 3D organization and remodeling of blood vessels based on the orientation and contraction of SMCs. [ABSTRACT FROM AUTHOR]

In this study, the effect of polymer materials with different polarity, namely low density polyethylene (LDPE) and ethylene vinyl acetate (EVA), on the migration behaviour of α -tocopherol from active packaging was investigated. The antioxidant was also adsorbed onto silica materials, namely SBA-15 (Santa Barbara-15) and Syloblock, in order to protect the antioxidant during extrusion and to ensure a controlled and sufficient release during the shelf-life of the food product. Migration experiments were performed at 7.0 ± 0.5°C and 95% ethanol was used as fatty food simulant. All films contained a high concentration of α -tocopherol, ∼ 2000 mg kg -1 , to obtain an active packaging. Polymer matrix had a small influence on the migration profile. The migration of 80% of total migrated amount of antioxidant was retarded for 2.4 days by using LDPE instead of EVA. When α -tocopherol was adsorbed onto both silica materials, the migration of 80% of total migrated amount of antioxidant was retarded for 3.4 days in comparison to pure α -tocopherol. No difference was seen between the migration profiles of α -tocopherol adsorbed onto both silica materials. In the case of pure α-tocopherol, 82% of the initial amount of α -tocopherol in the film migrated into the food simulant at a rather fast migration rate. In the case of adsorption on silica materials, a total migration was observed. These antioxidative films can have positive food applications. [ABSTRACT FROM AUTHOR]

Microelectrode impalement of human macrophages evokes a transient hyperpolarizing response (HR) of the membrane potential. This HR was found to be dependent on the extracellular concentration of K+ but not on that of Na+ or Cl-. It was not influenced by low temperature (12 degrees C) or by 0.2 mM ouabain, but was blocked by 0.2 mM quinine or 0.2 mM Mg2+-EGTA. These findings indicate that the HR in human macrophages is caused by the activation of a K+ (Ca2+) conductance. Two types of ionic channels were identified in intact cells by use of the patch-clamp technique in the cell-attached-patch configuration, low and high-conductance voltage-dependent K+ channels. The low-conductance channels had a mean conductance of 38 pS with Na+-saline and 32 pS with K+-saline in the pipette. The high-conductance channels had a conductance of 101 and 114 pS with Na+- and K+-saline in the pipette, respectively. Cell-attached patch measurements made during evocation of an HR by microelectrode penetration showed enhanced channel activity associated with the development of the HR. These channels were also high-conductance channels (171 pS with Na+- and 165 pS K+-saline in the pipette) and were voltage dependent. They were, however, active at less positive potentials than the high-conductance K+ channels seen prior to the microelectrode-evoked HR. It is concluded that the high-conductance voltage-dependent ionic channels active during the HR in human macrophages contribute to the development of the HR. [ABSTRACT FROM AUTHOR]

Introduction Endovascular treatment with detachable coils has become an established technique for patients with intracranial aneurysms, the drawback being recurrence due to coil compaction or enlargement of a remnant. The contribution of hemodynamics to recurrence is at present unknown. The aim of this study was to explore the relationship between blood flow into the aneurysm and area of recurrence. We hypothesized that the location of the recurrence at first follow-up overlaps with the location of the inflow jet into the original untreated aneurysm. Materials and methods Out of 270 patients who received endovascular treatment for an intracranial aneurysm, 19 patients with a recurrence at first follow-up were included. Five patients with a recurrence were excluded because imaging was unsuitable for processing. Virtual surface models of the original untreated aneurysms and surrounding vessels were segmented with the Vascular Modeling ToolKit (VMTK) using three-dimensional imaging obtained before treatment. Recurrence areas were identified on 6 month follow-up three-dimensional time of flight MR angiography. Virtual surface models were also segmented of the lumen of the recurrences. Both surface models were matched using the Iterative Closest Point registration already available in VMTK (). Match between the surface models of the untreated aneurysm and the luminal recurrence. Case No 01001. After post-processing of the flow, it was possible to visualize the exact location of blood flowing into the aneurysm. This flow profile was matched with the location of the recurrence, with the untreated aneurysm neck as a reference frame. This match allowed for calculation of the overlap between area of recurrence and area of inflow (). Two-dimensional slice perpendicular through the aneurysm neck. Dark grey: blood outflow zone before treatment. Light grey: blood inflow zone before treatment. Black outline: the luminal recurrence. Black area: overlapping zone of original inflow and later recurrence. Overlap: 15.3%. Case No 01005. Results The area of recurrence did not show a strong correlation with the initial inflow jet area in the aneurysm. The mean area of overlap of the inflow area and recurrence area as a percentage of the total recurrence area was only 35.45% (CI 22.83 to 48.07). Two cases did not show any overlap and none of the cases had a complete overlap. The range of overlap area was 0.00–96.35%. Conclusion Our model, construction using high quality geometry and CFD simulations using Fluent, were accurate. The results in this small sample do not support a relation between location of inflow in an untreated aneurysm and location of recurrence after treatment with coils. [ABSTRACT FROM PUBLISHER]

Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. McKerracher is CEO of BioAxone BioSciences, Inc. and hold an ownership interest in the company and has a significant competing interest. The data for this article were collected while Drs. Abbinanti, Woller, Ruschel and Rosen were employed at BioAxone BioSciences, and they have a modest conflict of interest. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Neurelis, Inc. acquired the rights to BA-1049 (now referred to as NRL-1049) from BioAxone in June 2021. Ayata is on the scientific advisory board of Neurelis, Inc. and declares sponsored research agreements with Praxis and Takeda Pharmaceutical Company. Mulder declares a past sponsored research agreement with BioAxone BioSciences, Inc. (concerning work not included in this manuscript). The other authors declare no conflict of interest. No writing assistance was utilized in the production of this manuscript.

Pulsed dye lasers are used effectively in the treatment of psoriasis with long remission time and limited side effects. It is, however, not completely understood which biological processes underlie its favorable outcome. Pulsed dye laser treatment at 585-595 nm targets hemoglobin in the blood, inducing local hyperthermia in surrounding blood vessels and adjacent tissues. While the impact of destructive temperatures on blood vessels has been well studied, the effects of lower temperatures on the function of several cell types within the blood vessel wall and its periphery are not known. The aim of our study is to assess the functionality of isolated blood vessels after exposure to moderate hyperthermia (45 to 60°C) by evaluating the function of endothelial cells, smooth muscle cells, and vascular nerves. We measured blood vessel functionality of rat mesenteric arteries (n=19) by measuring vascular contraction and relaxation before and after heating vessels in a wire myograph. To this end, we elicited vascular contraction by addition of either high potassium solution or the thromboxane analogue U46619 to stimulate smooth muscle cells, and electrical field stimulation (EFS) to stimulate nerves. For measurement of endothelium-dependent relaxation, we used methacholine. Each vessel was exposed to one temperature in the range of 45-60°C for 30 seconds and a relative change in functional response after hyperthermia was determined by comparison with the response per stimulus before heating. Non-linear regression was used to fit our dataset to obtain the temperature needed to reduce blood vessel function by 50% (Half maximal effective temperature, ET50). Our findings demonstrate a substantial decrease in relative functional response for all three cell types following exposure to 55°C-60°C. There was no significant difference between the ET50 values of the different cell types, which was between 55.9°C and 56.9°C (P>0.05). Our data show that blood vessel functionality decreases significantly when exposed to temperatures between 55°C-60°C for 30 seconds. The results show functionality of endothelial cells, smooth muscle cells, and vascular nerves is similarly impaired. These results help to understand the biological effects of hyperthermia and may aid in tailoring laser and light strategies for selective photothermolysis that contribute to disease modification of psoriasis after pulsed dye laser treatment., (© 2024. The Author(s).)

The early management of transferred patients with a large vessel occlusion (LVO) stroke could be improved by identifying patients who are likely to recanalize early. We aim to predict early recanalization based on patient clinical and thrombus imaging characteristics. We included 81 transferred anterior-circulation LVO patients with an early recanalization, defined as the resolution of the LVO or the migration to a distal location not reachable with endovascular treatment upon repeated radiological imaging. We compared their clinical and imaging characteristics with all (322) transferred patients with a persistent LVO in the MR CLEAN Registry. We measured distance from carotid terminus to thrombus (DT), thrombus length, density, and perviousness on baseline CT images. We built logistic regression models to predict early recanalization. We validated the predictive ability by computing the median area-under-the-curve (AUC) of the receiver operating characteristics curve for 100 5-fold cross-validations. The administration of intravenous thrombolysis (IVT), longer transfer times, more distal occlusions, and shorter, pervious, less dense thrombi were characteristic of early recanalization. After backward elimination, IVT administration, DT and thrombus density remained in the multivariable model, with an AUC of 0.77 (IQR 0.72-0.83). Baseline thrombus imaging characteristics are valuable in predicting early recanalization and can potentially be used to optimize repeated imaging workflow., Competing Interests: N. Arrarte Terreros is co-founder of inSteps, a start-up that focuses on in-silico stroke models. D.W.J. Dippel reports unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences and Health, and Thrombolytic Science, LLC for research, paid to institution. H.A. Marquering is co-founder of inSteps and Nico.lab, a company that focuses on the use of artificial intelligence for medical image analysis. C.B.L.M. Majoie reports grants from the European Commission during the conducting of the study; grants from CVON/Dutch Heart Foundation, TWIN Foundation, Healthcare Evaluation Netherlands and Stryker, outside the submitted work; and is a shareholder of Nico.lab. The remaining 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.

Drug development for neurological diseases is greatly impeded by the presence of the blood-brain barrier (BBB). We and others previously reported on extravasation of micrometer-sized particles from the cerebral microcirculation - across the BBB - into the brain tissue over the course of several weeks. This mechanism could potentially be used for sustained parenchymal drug delivery after extravasation of biodegradable microspheres. As a first step toward this goal, we set out to evaluate the extravasation potential in the rat brain of three classes of biodegradable microspheres with drug-carrying potential, having a median diameter of 13 µm (80% within 8-18 µm) and polyethylene glycol concentrations of 0%, 24% and 36%. Extravasation, capillary recanalization and tissue damage were determined in a rat cerebral microembolization model at day 14 after microsphere injection. Microspheres of all three classes had the potential to extravasate from the vessel into the brain parenchyma, with microspheres without polyethylene glycol extravasating the fastest. Microembolization with biodegradable microspheres led to impaired local capillary perfusion, which was substantially restored after bead extravasation. We did not observe overt tissue damage after microembolization with any microsphere: we found very limited BBB disruption (IgG extravasation), no microgliosis (Iba1 staining) and no large neuronal infarctions (NeuN staining). In conclusion, biodegradable microspheres with different polymer compositions can extravasate into the brain parenchyma while causing minimal tissue damage.

Background: The effects of thrombus imaging characteristics on procedural and clinical outcomes after ischemic stroke are increasingly being studied. These thrombus characteristics - for eg, size, location, and density - are commonly analyzed as separate entities. However, it is known that some of these thrombus characteristics are strongly related. Multicollinearity can lead to unreliable prediction models. We aimed to determine the distribution, correlation and clustering of thrombus imaging characteristics based on a large dataset of anterior-circulation acute ischemic stroke patients., Methods: We measured thrombus imaging characteristics in the MR CLEAN Registry dataset, which included occlusion location, distance from the intracranial carotid artery to the thrombus (DT), thrombus length, density, perviousness, and clot burden score (CBS). We assessed intercorrelations with Spearman's coefficient (ρ) and grouped thrombi based on 1) occlusion location and 2) thrombus length, density and perviousness using unsupervised clustering., Results: We included 934 patients, of which 22% had an internal carotid artery (ICA) occlusion, 61% M1, 16% M2, and 1% another occlusion location. All thrombus characteristics were significantly correlated. Higher CBS was strongly correlated with longer DT (ρ=0.67, p<0.01), and moderately correlated with shorter thrombus length (ρ=-0.41, p<0.01). In more proximal occlusion locations, thrombi were significantly longer, denser, and less pervious. Unsupervised clustering analysis resulted in four thrombus groups; however, the cohesion within and distinction between the groups were weak., Conclusions: Thrombus imaging characteristics are significantly intercorrelated - strong correlations should be considered in future predictive modeling studies. Clustering analysis showed there are no distinct thrombus archetypes - novel treatments should consider this thrombus variability., Competing Interests: Competing interests: This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST project), and the AMC medical Research BV, Amsterdam UMC, location AMC, under project No 21937. The MR CLEAN registry is partially funded by unrestricted grants from the Applied Scientific Institute for Neuromodulation (Toegepast Wetenschappelijk Instituut voor Neuromodulatie), Erasmus Medical Center, Amsterdam University Medical Center and Maastricht University Medical Center. HAM reports being a co-founder and shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical image analysis. CBLMM reports grants from European Commission during the conduct of the study; grants from CVON/Dutch Heart Foundation, TWIN Foundation, Health Evaluation Netherlands, and Stryker, outside the submitted work; and shareholder of Nicolab. DWJD reports unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences and Health, and Thrombolytic Science, LLC for research, paid to institution. The remaining 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., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Microinfarcts result in a transient loss of the blood-brain barrier (BBB) in the ischemic territory. This leads to the extravasation of blood proteins into the brain parenchyma. It is not clear how these proteins are removed. Here we studied the role of perivascular spaces in brain clearance from extravasated blood proteins. Male and female Wistar rats were infused with microspheres of either 15, 25, or 50 μm in diameter (n = 6 rats per group) via the left carotid artery. We infused either 25,000 microspheres of 15 μm, 5500 of 25 μm, or 1000 of 50 μm. One day later, rats were infused with lectin and hypoxyprobe to label perfused blood vessels and hypoxic areas, respectively. Rats were then euthanized and perfusion-fixed. Brains were excised, sectioned, and analyzed using immunostaining and confocal imaging. Microspheres induced a size-dependent increase in ischemic volume per territory, but the cumulative ischemic volume was similar in all groups. The total volumes of ischemia, hypoxia and infarction affected 1-2 % of the left hemisphere. Immunoglobulins (IgG) were present in ischemic brain tissue surrounding lodged microspheres in all groups. In addition, staining for IgG was found in perivascular spaces of blood vessels nearby areas of BBB disruption. About 2/3 of these vessels were arteries, while the remaining 1/3 of these vessels were veins. The subarachnoid space (SAS) of the affected hemisphere stained stronger for IgG than the contralateral hemisphere in all groups: +27 %, +44 % and +27 % respectively. Microspheres of various sizes induce a local loss of BBB integrity, evidenced by parenchymal IgG staining. The presence of IgG in perivascular spaces of both arteries and veins distinct from the ischemic territories suggests that both contribute to the removal of blood proteins. The strong staining for IgG in the SAS of the affected hemisphere suggests that this perivascular route egresses via the CSF. Perivascular spaces therefore play a previously unrecognized role in tissue clearance of fluid and extravasated proteins after BBB disruption induced by microinfarcts., 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 Inc. All rights reserved.)

Pulsed dye laser (PDL) therapy can be effective in treating psoriasis, with a long duration of remission. Although PDL therapy, albeit on a modest scale, is being used for decades now, the underlying mechanisms responsible for the long-term remission of psoriasis remain poorly understood. The selective and rapid absorption of energy by the blood causes heating of the vascular wall and surrounding structures, like perivascular nerves. Several studies indicate the importance of nerves in psoriatic inflammation. Interestingly, denervation leads to a spontaneous remission of the psoriatic lesion. Among all dermal nerves, the perivascular nerves are the most likely to be affected during PDL treatment, possibly impairing the neuro-inflammatory processes that promote T-cell activation, expression of adhesion molecules, leukocyte infiltration and cytokine production. Repeated PDL therapy could cause a prolonged loss of innervation through nerve damage, or result in a 'reset' of neurogenic inflammation after temporary denervation. The current hypothesis provides strong arguments that PDL treatment affects nerve fibres in the skin and thereby abrogates the persistent and exaggerated inflammatory process underlying psoriasis, causing a long-term remission of psoriasis., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Background and Objective: Mechanical thrombectomy is a minimally invasive procedure that aims at removing the occluding thrombus from the vasculature of acute ischemic stroke patients. Thrombectomy success and failure can be studied using in-silico thrombectomy models. Such models require realistic modeling steps to be effective. We here present a new approach to model microcatheter tracking during thrombectomy., Methods: For 3 patient-specific vessel geometries, we performed finite-element simulations of the microcatheter tracking (1) following the vessel centerline (centerline method) and (2) as a one-step insertion simulation, where the microcatheter tip was advanced along the vessel centerline while its body was free to interact with the vessel wall (tip-dragging method). Qualitative validation of the two tracking methods was performed with the patient's digital subtraction angiography (DSA) images. In addition, we compared simulated thrombectomy outcomes (successful vs unsuccessful thrombus retrieval) and maximum principal stresses on the thrombus between the centerline and tip-dragging method., Results: Qualitative comparison with the DSA images showed that the tip-dragging method more realistically resembles the patient-specific microcatheter-tracking scenario, where the microcatheter approaches the vessel walls. Although the simulated thrombectomy outcomes were similar in terms of thrombus retrieval, the thrombus stress fields (and the associated fragmentation of the thrombus) were strongly different between the two methods, with local differences in the maximum principal stress curves up to 84%., Conclusions: Microcatheter positioning with respect to the vessel affects the stress fields of the thrombus during retrieval, and therefore, may influence thrombus fragmentation and retrieval in-silico thrombectomy., Competing Interests: Declaration of Competing Interest HAM reports co-founder and shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical image analysis. CBLMM reports grants from the European Commission during the conduct of the study; grants from CVON/ Dutch Heart Foundation, TWIN Foundation, Healthcare Evaluation Netherlands, and Stryker, outside the submitted work; and shareholder of Nicolab. The remaining 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 Elsevier B.V. All rights reserved.)

Background: A thrombus in the M1 segment of the middle cerebral artery (MCA) can occlude this main stem only or extend into the M1-M2 bifurcation. The occlusion pattern may affect endovascular treatment (EVT) success, as a bifurcated thrombus may be more prone to fragmentation during retrieval., Objective: To investigate whether bifurcated thrombus patterns are associated with EVT procedural and clinical outcomes., Methods: Occlusion patterns of MCA thrombi on CT angiography from MR CLEAN Registry patients were classified into three groups: main stem occlusion, bifurcation occlusion extending into one M2 branch, and bifurcation occlusion extending into both M2 branches. Procedural parameters, procedural outcomes (reperfusion grade and embolization to new territory), and clinical outcomes (24-48 hour National Institutes of Health Stroke Scale [NIHSS FU ] score, change in NIHSS scores between 24 and 48 hours and baseline ∆ [NIHSS], and 90-day modified Rankin Scale [mRS] scores) were compared between occlusion patterns., Results: We identified 1023 patients with an MCA occlusion of whom 370 (36%) had a main stem occlusion, 151 (15%) a single branch, and 502 (49%) a double branch bifurcation occlusion. There were no statistically significant differences in retrieval method, procedure time, number of retrieval attempts, reperfusion grade, and embolization to new territory between occlusion patterns. Patients with main stem occlusions had lower NIHSS FU scores than patients with single (7 vs 11, p=0.01) or double branch occlusions (7 vs 9, p=0.04). However, there were no statistically significant differences in ∆ NIHSS or in 90-day mRS scores., Conclusions: In our population, EVT procedural and long-term clinical outcomes were similar for MCA bifurcation occlusions and MCA main stem occlusions., Competing Interests: Competing interests: This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST project), and the AMC medical Research BV, Amsterdam UMC, location AMC, under project No 21937. The MR CLEAN registry is partially funded by unrestricted grants from the Applied Scientific Institute for Neuromodulation (Toegepast Wetenschappelijk Instituut voor Neuromodulatie), Erasmus Medical Center, Amsterdam University Medical Center and Maastricht University Medical Center. HAM reports co-founder and shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical image analysis. CBLMM reports grants from European Commission during the conduct of the study; grants from CVON/Dutch Heart Foundation, TWIN Foundation, and Stryker, outside the submitted work; and shareholder of Nicolab. IGHJ reports shareholder of Nicolab. DWJD and AvdL report unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences and Health, and Thrombolytic Science, LLC for research, paid to institution. BvdW received funds from Bayer and LivaNova for consultancy, paid to his institution, and grants from the Dutch Heart Foundation, the Horizon 2020 programme, and Stryker, paid to his institution, all outside the work submitted. The remaining 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., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The microvasculature plays a key role in oxygen transport in the mammalian brain. Despite the close coupling between cerebral vascular geometry and local oxygen demand, recent experiments have reported that microvascular occlusions can lead to unexpected distant tissue hypoxia and infarction. To better understand the spatial correlation between the hypoxic regions and the occlusion sites, we used both in vivo experiments and in silico simulations to investigate the effects of occlusions in cerebral penetrating arteriole trees on tissue hypoxia. In a rat model of microembolisation, 25 μm microspheres were injected through the carotid artery to occlude penetrating arterioles. In representative models of human cortical columns, the penetrating arterioles were occluded by simulating the transport of microspheres of the same size and the oxygen transport was simulated using a Green's function method. The locations of microspheres and hypoxic regions were segmented, and two novel distance analyses were implemented to study their spatial correlation. The distant hypoxic regions were found to be present in both experiments and simulations, and mainly due to the hypoperfusion in the region downstream of the occlusion site. Furthermore, a reasonable agreement for the spatial correlation between hypoxic regions and occlusion sites is shown between experiments and simulations, which indicates the good applicability of in silico models in understanding the response of cerebral blood flow and oxygen transport to microemboli., Competing Interests: The authors have declared that no competing interests exist.

Background: We performed an exploratory analysis to identify patient and thrombus characteristics associated with early recanalization in large-vessel occlusion (LVO) stroke patients transferred for endovascular treatment (EVT) from a primary (PSC) to a comprehensive stroke center (CSC)., Methods: We included patients with an LVO stroke of the anterior circulation who were transferred to our hospital for EVT and underwent repeated imaging between January 2016 and June 2019. We compared patient characteristics, workflow time metrics, functional outcome (modified Rankin Scale at 90 days), and baseline thrombus imaging characteristics, which included: occlusion location, thrombus length, attenuation, perviousness, distance from terminus of intracranial carotid artery to the thrombus (DT), and clot burden score (CBS), between early-recanalized LVO (ER-LVO), and non-early-recanalized LVO (NER-LVO) patients., Results: One hundred and forty-nine patients were included in the analysis. Early recanalization occurred in 32% of patients. ER-LVO patients less often had a medical history of hypertension (31% vs 49%, P=0.04), and more often had clinical improvement between PSC and CSC (ΔNIHSS -5 vs 3, P<0.01), compared with NER-LVO patients. Thrombolysis administration was similar in both groups (88% vs 78%, P=0.18). ER-LVO patients had no ICA occlusions (0% vs 27%, P<0.01), more often an M2 occlusion (35% vs 17%, P=0.01), longer DT (27 mm vs 12 mm, P<0.01), shorter thrombi (17 mm vs 27 mm, P<0.01), and higher CBS (8 vs 6, P<0.01) at baseline imaging. ER-LVO patients had lower mRS scores (1 vs 3, P=0.02)., Conclusions: Early recanalization is associated with clinical improvement between PSC and CSC admission, more distal occlusions and shorter thrombi at baseline imaging, and better functional outcome., Competing Interests: Competing interests: H.A. Marquering is co-founder and shareholder of Nico.lab, a company that focuses on the use of artificial intelligence for medical image analysis. C.B.L.M. Majoie reports grants from the European Commission during the conduct of the study; grants from CVON/Dutch Heart Foundation, TWIN Foundation, and Stryker, outside the submitted work; and is shareholder of Nico.lab. The remaining 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., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Residual blood flow distal to an arterial occlusion in patients with acute ischemic stroke (AIS) is associated with favorable patient outcome. Both collateral flow and thrombus permeability may contribute to such residual flow. We propose a method for discriminating between these two mechanisms, based on determining the direction of flow in multiple branches distal to the occluding thrombus using dynamic Computed Tomography Angiography (dynamic CTA). We analyzed dynamic CTA data of 30 AIS patients and present patient-specific cases that identify typical blood flow patterns and velocities. We distinguished patterns with anterograde (N = 10), retrograde (N = 9), and both flow directions (N = 11), with a large variability in velocities for each flow pattern. The observed flow patterns reflect the interplay between permeability and collaterals. The presented method characterizes distal flow and provides a tool to study patient-specific distal tissue perfusion.

The aim of this work is to propose a methodology for identifying relationships between morphological features of the cerebral vasculature and the outcome of in silico simulations of thrombectomy, the mechanical treatment for acute ischemic stroke. Fourteen patient-specific cerebral vasculature segmentations were collected and used for geometric characterization of the intracranial arteries mostly affected by large vessel occlusions, i.e., internal carotid artery (ICA), middle cerebral artery (MCA) and anterior cerebral artery (ACA). First, a set of global parameters was created, including the geometrical information commonly provided in the clinical context, namely the total length, the average diameter and the tortuosity (length over head-tail distance) of the intracranial ICA. Then, a more exhaustive geometrical analysis was performed to collect a set of local parameters . A total of 27 parameters was measured from each patient-specific vascular configuration. Fourteen virtual thrombectomy simulations were performed with a blood clot with the same length and composition placed in the middle of the MCA. The model of TREVO ProVue stent-retriever was used for all the simulations. Results from simulations produced five unsuccessful outcomes, i.e., the clot was not removed from the vessels. The geometric parameters of the successful and unsuccessful simulations were compared to find relations between the vascular geometry and the outcome. None of the global parameters alone or combined proved able to discriminate between positive and negative outcome, while a combination of local parameters allowed to correctly identify the successful from the unsuccessful simulations. Although these results are limited by the number of patients considered, this study indicates a promising methodology to relate patient-specific geometry to virtual thrombectomy outcome, which might eventually guide decision making in the treatment of acute ischemic stroke., Competing Interests: HM reports co-founder and shareholder of Nico.lab, a company that focuses on the use of artificial intelligence for medical image analysis. CM received funds from the European Commission (related to this project, paid to institution); and from CVON/Dutch Heart Foundation, Stryker, TWIN Foundation, Health Evaluation Program Netherlands (unrelated; all paid to institution). CM is shareholder of Nico.lab, a company that focuses on the use of artificial intelligence for medical imaging analysis. The remaining 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 © 2021 Bridio, Luraghi, Rodriguez Matas, Dubini, Giassi, Maggio, Kawamoto, Moerman, McGarry, Konduri, Arrarte Terreros, Marquering, van Bavel, Majoie and Migliavacca.)

Considering its intolerance to ischemia, it is of critical importance for the brain to efficiently process microvascular occlusions and maintain tissue perfusion. In addition to collateral microvascular flow and enzymatic degradation of emboli, the endothelium has the potential to engulf microparticles and thereby recanalize the vessel, through a process called angiophagy. Here, we set out to study the dynamics of angiophagy in relation to cytoskeletal remodeling in vitro and reperfusion in vivo. We show that polystyrene microspheres and fibrin clots are actively taken up by (brain) endothelial cells in vitro, and chart the dynamics of the actin cytoskeleton during this process using live cell imaging. Whereas microspheres were taken up through the formation of a cup structure by the apical endothelial membrane, fibrin clots were completely engulfed by the cells, marked by dense F-actin accumulation surrounding the clot. Both microspheres and fibrin clots were retained in the endothelial cells. Notably, fibrin clots were not degraded intracellularly. Using an in vivo microembolization rat model, in which microparticles are injected into the common carotid artery, we found that microspheres are transported by the endothelium from the microvasculature into the brain parenchyma. Microembolization with microspheres caused temporal opening of the blood-brain barrier and vascular nonperfusion, followed by microsphere extravasation and restoration of vessel perfusion over time. Taken together, angiophagy is accompanied by active cytoskeletal remodeling of the endothelium, and is an effective mechanism to restore perfusion of the occluded microvasculature in vivo.

Thrombus permeability determines blood flow through the occluding thrombus in acute ischemic stroke (AIS) patients. The quantification of thrombus permeability is challenging since it cannot be directly measured nor derived from radiological imaging data. As a proxy of thrombus permeability, thrombus perviousness has been introduced, which assesses the amount of contrast agent that has penetrated the thrombus on single-phase computed tomography angiography (CTA). We present a method to assess thrombus permeability rather than perviousness. We follow a three-step approach: (1) we propose a theoretical channel-like structure model describing the thrombus morphology. Using Darcy's law, we provide an analytical description of the permeability for this model. According to the channel-like model, permeability depends on the number of channels in the thrombus, the radius of the occluded artery, and the void fraction representing the volume available for the blood to flow; (2) we measure intra-thrombus blood flow and velocity on dynamic CTA; and (3) we combine the analytical model with the dynamic CTA measurements to estimate thrombus permeability. Analysis of dynamic CTA data from 49 AIS patients showed that the median blood velocity in the thrombus was 0.58 (IQR 0.26-1.35) cm/s. The median flow within the thrombus was 3.48 · 10 -3 (IQR 1.71 · 10 -3 -9.21 · 10 -3 ) ml/s. Thrombus permeability was of the order of 10 -3 -10 -5 mm 2 , depending on the number of channels in the thrombus. The channel-like thrombus model offers an intuitive way of modelling thrombus permeability, which can be of interest when studying the effect of thrombolytic drugs., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Antihypertensive drugs are included in the medical therapy of vascular Ehlers-Danlos syndrome (vEDS). The β-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta., Methods and Results: We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment., Conclusions: In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Most common complications of esophagectomy stem from a perfusion deficiency of the gastric conduit at the anastomosis. Fluorescent tracer imaging allows intraoperative visualization of tissue perfusion. Quantitative assessment of fluorescence dynamics has the potential to identify perfusion deficiency. We developed a perfusion model to analyze the relation between fluorescence dynamics and perfusion deficiency. The model divides the gastric conduit into two well-perfused and two anastomosed sites. Hemodynamics and tracer transport were modeled. We analyzed the value of relative time-to-threshold (RTT) as a predictor of the relative remaining flow (RRF). Intensity thresholds for RTT of 20% to 50% of the maximum fluorescence intensity of the well-perfused site were tested. The relation between RTT and RRF at the anastomosed sites was evaluated over large variations of vascular conductance and volume. The ability of RTT to distinguish between sufficient and impaired perfusion was analyzed using c-statistics. We found that RTT was a valuable estimate for low RRF. The threshold of 20% of the maximum fluorescence intensity provided the best prediction of impaired perfusion on the two anastomosed sites (AUC = 0.89 and 0.86). The presented model showed that for low flows, relative time-to-threshold may be used to estimate perfusion deficiency.

Glycosaminoglycans in the skin interstitium and endothelial surface layer have been shown to be involved in local sodium accumulation without commensurate water retention. Dysfunction of heparan sulfate glycosaminoglycans may therefore disrupt sodium and water homeostasis. In this study, we investigated the effects of combined heterozygous loss of heparan sulfate polymerization genes (exostosin glycosyltransferase 1 and 2; Ext1+/-Ext2+/-) on sodium and water homeostasis. Sodium storage capacity was decreased in Ext1+/-Ext2+/- mice as reflected by a 77% reduction in endothelial surface layer thickness and a lower skin sodium-to-glycosaminoglycan ratio. Also, these mice were characterized by a higher heart rate, increased fluid intake, increased plasma osmolality and a decreased skin water and sodium content, suggesting volume depletion. Upon chronic high sodium intake, the initial volume depletion was restored but no blood pressure increase was observed. Acute hypertonic saline infusion resulted in a distinct blood pressure response: we observed a significant 15% decrease in control mice whereas blood pressure did not change in Ext1+/-Ext2+/- mice. This differential blood pressure response may be explained by the reduced capacity for sodium storage and/or the impaired vasodilation response, as measured by wire myography, which was observed in Ext1+/-Ext2+/- mice. Together, these data demonstrate that defective heparan sulfate glycosaminoglycan synthesis leads to abnormal sodium and water homeostasis and an abnormal response to sodium loading, most likely caused by inadequate capacity for local sodium storage., Competing Interests: The authors have declared that no competing interests exist.

Aim: Conduction of vasomotor responses may contribute to long-term regulation of resistance artery function and structure. Most previous studies have addressed conduction of vasoactivity only during very brief stimulations. We developed a novel set-up that allows the local pharmacological stimulation of arteries in vitro for extended periods of time and studied the conduction of vasomotor responses in rat mesenteric arteries under those conditions., Methods: The new in vitro set-up was based on the pressure myograph. The superfusion chamber was divided halfway along the vessel into two compartments, allowing an independent superfusion of the arterial segment in each compartment. Local and remote cumulative concentration-response curves were obtained for a range of vasoactive agents. Additional experiments were performed with the gap junction inhibitor 18β-glycyrrhetinic acid and in absence of the endothelium., Results: Phenylephrine-induced constriction and acetylcholine-induced dilation were conducted over a measured distance up to 2.84 mm, and this conduction was maintained for 5 minutes. Conduction of acetylcholine-induced dilation was inhibited by 18β-glycyrrhetinic acid, and conduction of phenylephrine-induced constriction was abolished in absence of the endothelium. Constriction in response to high K + was not conducted. Absence of remote stimulation dampened the local response to phenylephrine., Conclusion: This study demonstrates maintained conduction of vasoactive responses to physiological agonists in rat mesenteric small arteries likely via gap junctions and endothelial cells, providing a possible mechanism for the sustained functional and structural control of arterial networks., (© 2018 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background and Aim: Quantitative Blush Evaluator (QuBE) is a software application that allows quantifying myocardial perfusion in coronary angiograms after a percutaneous coronary intervention. QuBE has some limitations such as the application of a crude filter to remove large scale structures and the absence of correction for cardiac motion. This study investigates the extent of these limitations and we hypothesize that enhanced image analysis methods can provide improvements., Methods: We calculated QuBE scores of 117 patients from the HEBE Trial and determined its association with the Myocardial Blush Grade (MBG) score. Accuracy of large-structure removal is qualitatively assessed for various sizes of a median filter. The influence of cardiac motion was evaluated by comparing the blush curve and QuBE score of the native QuBE with manually motion-corrected QuBE for 40 patients. The effect of different kernel sizes and motion correction to a potential improvement of the association between QuBE score and MBG was studied., Results: In our population, there was no significant association between QuBE score and MBG ( p = 0.14). Median filters of various kernel sizes were unable to remove large structure related noise. Variations in filters and cardiac movement correction did not result in an improvement in the association with MBG scores (observer 1: p = 0.66; observer 2: p = 0.72)., Conclusions: There was no significant association of QuBE with MBG scores in our population, which suggests that QuBE is not suitable for a quantitative assessment of myocardial perfusion. Alternative kernel sizes for the large structure removal filter and cardiac motion correction did not improve QuBE performance., Relevance for Patients: Further improvements of QuBE to overcome its inherent limitations are necessary in order to establish QuBE as a reliable myocardial perfusion assessment method.

Background and Purpose: Hemodynamics are thought to play a role in intracranial aneurysm growth and rupture. Computational fluid dynamics is frequently performed to assess intra-aneurysmal hemodynamics, using generalized flow waveforms of healthy volunteers as inflow boundary conditions. The purpose of this study was to assess differences in inflow conditions for different aneurysmal parent artery locations and variations of circle of Willis configurations., Materials and Methods: In a series of 96 patients with 103 aneurysms, velocity measurements were acquired using 2D phase-contrast MR imaging perpendicular to the aneurysmal parent arteries in the circle of Willis. Circle of Willis configurations were inspected for variations using multiple overlapping thin-slab-acquisition MRAs. Flow rates, velocity magnitudes, and pulsatility indices were calculated for each parent artery location in subgroups of complete and incomplete circle of Willis configurations., Results: Flow rates, velocity magnitudes, and pulsatility indices were significantly different among aneurysmal parent arteries. Incomplete circle of Willis configurations were observed in 24% of the cases. Significantly lower basilar artery flow rates were observed in configurations with hypoplastic P1 segments. Significantly higher A1 flow rates were observed in configurations with a hypoplastic contralateral A1 segment., Conclusions: Inflow conditions vary substantially between aneurysmal parent arteries and circle of Willis configurations. We have created a collection of parent artery-specific inflow conditions tailored to the patient-specific circle of Willis configuration that can be used in future computational fluid dynamics studies analyzing intra-aneurysmal hemodynamics., (© 2018 by American Journal of Neuroradiology.)

Background and Purpose: Thrombus CT characteristics might be useful for patient selection for intra-arterial treatment. Our objective was to study the association of thrombus CT characteristics with outcome and treatment effect in patients with acute ischemic stroke., Materials and Methods: We included 199 patients for whom thin-section NCCT and CTA within 30 minutes from each other were available in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) study. We assessed the following thrombus characteristics: location, distance from ICA terminus to thrombus, length, volume, absolute and relative density on NCCT, and perviousness. Associations of thrombus characteristics with outcome were estimated with univariable and multivariable ordinal logistic regression as an OR for a shift toward better outcome on the mRS. Interaction terms were used to investigate treatment-effect modification by thrombus characteristics., Results: In univariate analysis, only the distance from the ICA terminus to the thrombus, length of >8 mm, and perviousness were associated with functional outcome. Relative thrombus density on CTA was independently associated with functional outcome with an adjusted common OR of 1.21 per 10% (95% CI, 1.02-1.43; P = .029). There was no treatment-effect modification by any of the thrombus CT characteristics., Conclusions: In our study on patients with large-vessel occlusion of the anterior circulation, CT thrombus characteristics appear useful for predicting functional outcome. However, in our study cohort, the effect of intra-arterial treatment was independent of the thrombus CT characteristics. Therefore, no arguments were provided to select patients for intra-arterial treatment using thrombus CT characteristics., (© 2017 by American Journal of Neuroradiology.)

The purpose of this study was to assess whether there was an agreement between quantitative cerebral blood flow (CBF) and arterial cerebral blood volume (CBVA) measurements by [(15)O]H2O positron emission tomography (PET) and model-free QUASAR MRI. Twelve healthy subjects were scanned within a week in separate MRI and PET imaging sessions, after which quantitative and qualitative agreement between both modalities was assessed for gray matter, white matter and whole brain region of interests (ROI). The correlation between CBF measurements obtained with both modalities was moderate to high (r(2): 0.28-0.60, P < 0.05), although QUASAR significantly underestimated CBF by 30% (P < 0.001). CBVA was moderately correlated (r(2): 0.28-0.43, P < 0.05), with QUASAR yielding values that were only 27% of the [(15)O]H2O-derived values (P < 0.001). Group-wise voxel statistics identified minor areas with significant contrast differences between [(15)O]H2O PET and QUASAR MRI, indicating similar qualitative CBVA and CBF information by both modalities. In conclusion, the results of this study demonstrate that QUASAR MRI and [(15)O]H2O PET provide similar CBF and CBVA information, but with systematic quantitative discrepancies., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Creatine kinase (CK) is a main predictor of blood pressure, and this is thought to largely depend on high resistance artery contractility. We previously reported an association between vascular contractility and CK in normotensive pregnancy, but pregnancy is a strong CK inducer, and data on human hypertension are lacking. Therefore, we further explored CK-dependency of vascular contractility outside the context of pregnancy in normotensive and hypertensive women., Methods and Results: Nineteen consecutive women, mean age 42 years (SE 1.3), mean systolic/diastolic blood pressure respectively 142.6 (SE 5.9)/85.6 (3.4) mm Hg (9 hypertensive), donated an omental fat sample during abdominal surgery. We compared vasodilation after the specific CK inhibitor 2,4-dinitro-1-fluorobenzene (DNFB; 10(-6) mol/l) to sodium nitroprusside (10(-6) mol/l) in isolated resistance arteries using a wire myograph. Additionally, we assessed predictors of vasoconstrictive force. DNFB reduced vascular contractility to 24.3% (SE 4.4), P < 0.001, compared to baseline. Sodium nitroprusside reduced contractility to 89.8% (SE 2.3). Maximum contractile force correlated with DNFB effect as a measure of CK (r = 0.8), and with vessel diameter (r = 0.7). The increase in contractile force was 16.5 mN [9.1-23.9] per unit DNFB effect in univariable and 10.35 mN [2.10-18.60] in multivariable regression analysis., Conclusion: This study extends on our previous findings in pregnant normotensive women of CK-dependent microvascular contractility, indicating that CK contributes significantly to resistance artery contractility across human normotension and primary hypertension outside the context of pregnancy. Further studies should explore the effect of CK inhibitors on clinical blood pressure., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: The utility of computed tomographic perfusion (CTP)-based patient selection for intra-arterial treatment of acute ischemic stroke has not been proven in randomized trials and requires further study in a cohort that was not selected based on CTP. Our objective was to study the relationship between CTP-derived parameters and outcome and treatment effect in patients with acute ischemic stroke because of a proximal intracranial arterial occlusion., Methods: We included 175 patients who underwent CTP in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN). Association of CTP-derived parameters (ischemic-core volume, penumbra volume, and percentage ischemic core) with outcome was estimated with multivariable ordinal logistic regression as an adjusted odds ratio for a shift in the direction of a better outcome on the modified Rankin Scale. Interaction between CTP-derived parameters and treatment effect was determined using multivariable ordinal logistic regression. Interaction with treatment effect was also tested for mismatch (core <70 mL; penumbra core >1.2; penumbra core >10 mL)., Results: The adjusted odds ratio for improved functional outcome for ischemic core, percentage ischemic core, and penumbra were 0.79 per 10 mL (95% confidence interval: 0.71-0.89; P<0.001), 0.82 per 10% (95% confidence interval: 0.66-0.90; P=0.002), and 0.97 per 10 mL (96% confidence interval: 0.92-1.01; P=0.15), respectively. No significant interaction between any of the CTP-derived parameters and treatment effect was observed. We observed no significant interaction between mismatch and treatment effect., Conclusions: CTP seems useful for predicting functional outcome, but cannot reliably identify patients who will not benefit from intra-arterial therapy., (© 2015 American Heart Association, Inc.)

Background: Liquid solder laser-assisted vascular welding using biocompatible polymeric scaffolds (ssLAVW) is a novel technique for vascular anastomoses. Although ssLAVW has pronounced advantages over conventional suturing, drawbacks include low welding strength and extensive thermal damage., Aim: To determine optimal ssLAVW parameters for maximum welding strength and minimal thermal damage., Methods: Substudy 1 compared breaking strength (BS) of aortic strips welded with electrospun poly(ε-caprolactone) (PCL) or poly(lactic-co-glycolic acid) (PLGA) scaffold, 670-nm laser, 50-s single-spot continuous lasing (SSCL), and semi-solid solder (48% bovine serum albumin (BSA)/0.5% methylene blue (MB)/3% hydroxypropylmethylcellulose (HPMC)). Substudy 2 compared the semi-solid solder to 48% BSA/0.5% MB/0.38% genipin and 48% BSA/0.5% MB/3% HPMC/0.38% genipin solder. Substudy 3 compared SSCL to single-spot pulsed lasing (SSPL)., Results: PCL-ssLAVW yielded an acute BS of 248.0 ± 54.0 N/cm 2 and remained stable up to 7d of hydration. PLGA-ssLAVW obtained higher acute BS (408.6 ± 78.8 N/cm 2 ) but revealed structural defects and a BS of 109.4 ± 42.6 N/cm 2 after 14 d of hydration. The addition of HPMC and genipin improved the 14-d BS of PLGA-sLAVW (223.9 ± 19.1 N/cm 2 ). Thermal damage was reduced with SSPL compared with SSCL., Conclusions: PCL-ssLAVW yielded lower but more stable welds than PLGA-ssLAVW. The addition of HPMC and genipin to the solder increased the post-hydration BS of PLGA-ssLAVW. SSPL regimen reduced thermal damage. PLGA-ssLAVW using 48% BSA/0.5% MB/3% HPMC/0.38% genipin solder and SSPL constitutes the most optimal welding modality., Relevance for Patients: Surgical patients requiring vascular anastomoses may benefit from the advantages that ssLAVW potentially offers over conventional sutures (gold standard). These include no needle trauma and remnant suture materials in the patient, reduction of foreign body reaction, immediate liquid-tight sealing, and the possibility of a faster and easier procedure for minimally invasive and endoscopic anastomotic techniques.

Objective: To explore the views and experiences of general practitioners (GPs) in relation to recognition, recording, and treatment of mental health problems of undocumented migrants (UMs), and to gain insight in the reasons for under-registration of mental health problems in the electronic medical records., Design: Qualitative study design with semi-structured interviews using a topic guide., Subjects and Setting: Sixteen GPs in the Netherlands with clinical expertise in the care of UMs., Results: GPs recognized many mental health problems in UMs. Barriers that prevented them from recording these problems and from delivering appropriate care were their low consultation rates, physical presentation of mental health problems, high number of other problems, the UM's lack of trust towards health care professionals, and cultural differences in health beliefs and language barriers. Referrals to mental health care organizations were often seen as problematic by GPs. To overcome these barriers, GPs provided personalized care as far as possible, referred to other primary care professionals such as social workers or mental health care nurses in their practice, and were a little less restrictive in prescribing psychotropics than guidelines recommended., Conclusions: GPs experienced a variety of barriers in engaging with UMs when identifying or suspecting mental health problems. This explains why there is a gap between the high recognition of mental health problems and the low recording of these problems in general practice files. It is recommended that GPs address mental health problems more actively, strive for continuity of care in order to gain trust of the UMs, and look for opportunities to provide mental care that is accessible and acceptable for UMs.

Objective: Characteristics of vortices within intracranial aneurysmal flow patterns have been associated with increased risk of rupture. The classifications of these vortex characteristics are commonly based upon qualitative scores, and are, therefore, subjective to user interpretation. We present a quantitative method for automatic time-resolved characterization of 3-D flow patterns and vortex detection within aneurysms., Methods: Our approach is based upon the combination of kernel deconvolution and Jacobian analysis of the velocity field. The deconvolution approach is accurate in detecting vortex centers but cannot discriminate between vortices and high-shear regions. Therefore, this approach is combined with analysis of the Jacobian of the velocity field. Scale-space theory is used to evaluate aneurysmal flow velocity fields at various scales., Results: The proposed algorithm is applied to computational fluid dynamics and time-resolved 3-D phase-contrast magnetic resonance imaging of aneurysmal flow., Conclusion: Results show that the proposed algorithm efficiently detects, visualizes, and quantifies vortices in intracranial aneurysmal velocity patterns at multiple scales and follows the temporal evolution of these patterns., Significance: Quantitative analysis performed with this method has the potential to reduce interobserver variability in aneurysm classification.

Background: Undocumented migrants (UM) frequently report mental health problems. It is unknown to what extent these migrants seek help for these problems in general practice and how these issues are explored, discussed, registered and treated by GPs., Objective: To gain insight in the registration and treatment of mental health problems in general practice of UM compared to documented migrants (DM)., Methods: A survey study of general practice patient records of UM and DM in nine general practices in the Netherlands. Consultation rates, registration of mental health problems, prescription of psychotropic medication and referrals to mental health care institutions of UM and DM patients were compared., Results: A total of 541 migrants were included (325 UM and 216 DM). UM consulted a GP significantly less than DM (3.1 versus 4.9 times per year). Only 20.6% of the UM had at least one mental health problem diagnosis registered compared to 44.0% of the DM. In both groups, ~10% mentioned at least one main mental health complaint during the consultation that was not coded in the record. No significant differences were found in the prescription of psychotropic medication between the two groups. UM were referred less to mental health care institutions but more often to psychiatrists than to psychologists., Conclusion: UM had less consultations with their GP, and in these consultations, less mental health problems were registered. UM were referred less to psychologists but more often to psychiatrists. GPs are advised to explore and register mental health problems more actively in UM., (© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Attempts have been made to associate intracranial aneurysmal hemodynamics with aneurysm growth and rupture status. Hemodynamics in aneurysms is traditionally determined with computational fluid dynamics by using generalized inflow boundary conditions in a parent artery. Recently, patient-specific inflow boundary conditions are being implemented more frequently. Our purpose was to compare intracranial aneurysm hemodynamics based on generalized versus patient-specific inflow boundary conditions., Materials and Methods: For 36 patients, geometric models of aneurysms were determined by using 3D rotational angiography. 2D phase-contrast MR imaging velocity measurements of the parent artery were performed. Computational fluid dynamics simulations were performed twice: once by using patient-specific phase-contrast MR imaging velocity profiles and once by using generalized Womersley profiles as inflow boundary conditions. Resulting mean and maximum wall shear stress and oscillatory shear index values were analyzed, and hemodynamic characteristics were qualitatively compared., Results: Quantitative analysis showed statistically significant differences for mean and maximum wall shear stress values between both inflow boundary conditions (P < .001). Qualitative assessment of hemodynamic characteristics showed differences in 21 cases: high wall shear stress location (n = 8), deflection location (n = 3), lobulation wall shear stress (n = 12), and/or vortex and inflow jet stability (n = 9). The latter showed more instability for the generalized inflow boundary conditions in 7 of 9 patients., Conclusions: Using generalized and patient-specific inflow boundary conditions for computational fluid dynamics results in different wall shear stress magnitudes and hemodynamic characteristics. Generalized inflow boundary conditions result in more vortices and inflow jet instabilities. This study emphasizes the necessity of patient-specific inflow boundary conditions for calculation of hemodynamics in cerebral aneurysms by using computational fluid dynamics techniques., (© 2014 by American Journal of Neuroradiology.)

Head movement during brain Computed Tomography Perfusion (CTP) can deteriorate perfusion analysis quality in acute ischemic stroke patients. We developed a method for automatic detection of CTP datasets with excessive head movement, based on 3D image-registration of CTP, with non-contrast CT providing transformation parameters. For parameter values exceeding predefined thresholds, the dataset was classified as 'severely moved'. Threshold values were determined by digital CTP phantom experiments. The automated selection was compared to manual screening by 2 experienced radiologists for 114 brain CTP datasets. Based on receiver operator characteristics, optimal thresholds were found of respectively 1.0°, 2.8° and 6.9° for pitch, roll and yaw, and 2.8 mm for z-axis translation. The proposed method had a sensitivity of 91.4% and a specificity of 82.3%. This method allows accurate automated detection of brain CTP datasets that are unsuitable for perfusion analysis.

Background and Purpose: CFD has been proved valuable for simulating blood flow in intracranial aneurysms, which may add to better rupture risk assessment. However, CFD has drawbacks such as the sensitivity to assumptions needed for the model, which may hinder its clinical implementation. 3D PC-MR imaging is a technique that enables measurements of blood flow. The purpose of this study was to compare flow patterns on the basis of 3D PC-MR imaging with CFD estimates., Materials and Methods: 3D PC-MR imaging was performed in 8 intracranial aneurysms. Two sets of patient-specific inflow boundaries for CFD were obtained from a separate 2D PC-MR imaging sequence (2D CFD) and from the 3D PC-MR imaging (3D CFD) data. 3D PC-MR imaging and CFD were compared by calculation of the differences between velocity vector magnitudes and angles. Differences in flow patterns expressed as the presence and strengths of vortices were determined by calculation of singular flow energy., Results: In systole, flow features such as vortex patterns were similar. In diastole, 3D PC-MR imaging measurements appeared inconsistent due to low velocity-to-noise ratios. The relative difference in velocity magnitude was 67.6 ± 51.4% and 27.1 ± 24.9% in systole and 33.7 ± 21.5% and 17.7 ± 10.2% in diastole for 2D CFD and 3D CFD, respectively. For singular energy, this was reduced to 15.5 ± 13.9% at systole and 19.4 ± 17.6% at diastole (2D CFD)., Conclusions: In systole, good agreement between 3D PC-MR imaging and CFD on flow-pattern visualization and singular-energy calculation was found. In diastole, flow patterns of 3D PC-MR imaging differed from those obtained from CFD due to low velocity-to-noise ratios.

Objective: The objective of this study was to investigate the performance of k-t BLAST (Broad-use Linear Acquisition Speed-up Technique) accelerated time-resolved 3D PC-MRI compared to SENSE (SENSitivity Encoding) acceleration in an in vitro and in vivo intracranial aneurysm., Materials and Methods: Non-accelerated, SENSE and k-t BLAST accelerated time-resolved 3D PC-MRI measurements were performed in vivo and in vitro. We analysed the consequences of various temporal resolutions in vitro., Results: Both in vitro and in vivo measurements showed that the main effect of k-t BLAST was underestimation of velocity during systole. In the phantom, temporal blurring decreased with increasing temporal resolution. Quantification of the differences between the non-accelerated and accelerated measurements confirmed that in systole SENSE performed better than k-t BLAST in terms of mean velocity magnitude. In both in vitro and in vivo measurements, k-t BLAST had higher SNR compared to SENSE. Qualitative comparison between measurements showed good similarity., Conclusion: Comparison with SENSE revealed temporal blurring effects in k-t BLAST accelerated measurements.

Increasing evidence shows that sex hormones exert a protective effect on the vasculature, especially in the regulation of the active vasomotor responses. However, whether sex hormones affect vascular remodelling is currently unclear. In the present study, we tested the hypothesis that testosterone in males and β-oestradiol in females prevent inward remodelling, possibly through inhibition of cross-linking activity induced by enzymes of the TG (transglutaminase) family. Small mesenteric arteries were isolated from male and female Wistar rats. Dose-dependent relaxation to testosterone and β-oestradiol was inhibited by the NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester), confirming that these hormones induce NO release. When arteries were cannulated, pressurized and kept in organ culture with ET-1 (endothelin-1) for 3 days we observed strong vasoconstriction and inward remodelling. Remodelling was significantly inhibited by testosterone in males, and by β-oestradiol in females. This preventive effect of sex hormones was not observed in the presence of L-NAME. Inward remodelling was also reduced by the inhibitor of TG L682.777, both in males and females. In arteries from female rats, ET-1 increased TG activity, and this effect was prevented by β-oestradiol. L-NAME induced a significant increase in TG activity in the presence of sex hormones in arteries from both genders. We conclude that testosterone and β-oestradiol prevent constriction-induced inward remodelling. Inward remodelling, both in males and females, depends on NO and TG activity. In females, inhibition of inward remodelling could be mediated by NO-mediated inhibition of TG activity.

Hemodynamics is thought to play a role in the growth and rupture of intracranial aneurysms. In 4 patients, we obtained local pressure and BFV by using a dual-sensor pressure and Doppler velocity wire within and in vessels surrounding unruptured aneurysms. Local BFVs can serve as boundary conditions for computational fluid dynamics, whereas pressure recordings provide direct information on the mechanical load imposed on the aneurysm. Both measurements may thus add to patient-specific rupture-risk assessment.

Background: Inflammation and endothelial dysfunction are prominent in preeclampsia. Microparticles (MPs) may link these processes, as MPs induce the production of pro-inflammatory cytokines by endothelial cells and cause endothelial dysfunction., Aim: To study changes in expression of inflammation-related genes in human endothelial cells in response to MPs from preeclamptic patients., Methods: Human umbilical vein endothelial cells (HUVECs) were incubated for various time intervals in the absence or presence of isolated MP fractions from preeclamptic patients (n = 3), normotensive pregnant women (n = 3), non-pregnant controls (n = 3), and interleukin (IL)-1alpha as a positive control. Total RNA was isolated and used for multiplex ligation-dependent probe amplification (MLPA) and real-time polymerase chain reaction (PCR)., Results: IL-1alpha enhanced the expression of IL-1alpha, IL-2, IL-6, and IL-8; nuclear factor of kappa light chain enhancer in B-cells (NFkappaB)-1, NFkappaB-2, and NFkappaB-inhibitor; cyclin-dependent kinase inhibitor and monocyte chemotactic protein-1; and transiently increased tissue factor expression. RNA expression of inflammation-related genes and genes encoding adhesion receptors, however, were unaffected by any of the MP fractions tested., Conclusion: MLPA is a suitable assay to test the inflammatory status of endothelial cells, because incubation with IL-1alpha triggered substantial changes in RNA expression in endothelial cells. Taken together, it seems unlikely that MPs from preeclamptic patients induce endothelial dysfunction by directly affecting the expression of inflammation-related genes in these cells.

Plugged hexagonal templated silica (PHTS) materials are synthesized using a high TEOS/EO(20)PO(70)EO(20) ratio in the SBA-15 synthesis. This generates internal microporous nanocapsules or plugs in part of the channels, which could be inferred from the two-step desorption branch. These materials exhibit a tunable amount of open and plugged pores and a very high micropore volume (up to 0.24 mL/g) and are more stable than the conventional micellar templated structures known so far. In this study the adsorption properties of PHTS are investigated and compared to those of its plug-free analogue SBA-15. For this purpose nitrogen, n-hexane, n-heptane, c-hexane, 3-methylpentane, 1-hexene, and water were adsorbed on SBA-15 and PHTSs with a different ratio of open and plugged mesopores. The adsorption of n-hexane, c-hexane, n-heptane, and 3-methylpentane on SBA-15 and PHTS-A demonstrated that the presence of the plugs had an effect on the uptake of adsorbate in the low relative pressure region, the position of the capillary condensation step, and the total adsorbed amount of adsorbate. The results showed that n-heptane and 3-methylpentane cannot access part of the micropore system of SBA-15 and PHTS-A. Adsorption of c-hexane and n-hexane on PHTS-A indicated that not only the kinetic diameter but also the shape of the molecule is an important factor for being able to be adsorbed into the micropores or past the plugs. Moreover, these two adsorbates were the most efficient in filling up the available pore volume. From the adsorption of n-hexane on PHTSs with a different ratio of open and plugged pores, it was concluded that the size of the plugs differed, which depends on the synthesis conditions. Water adsorption isotherms proved SBA-15 and PHTS-B to be more hydrophobic than PHTS-A. n-Hexane, 1-hexene, and toluene were adsorbed on SBA-15 and the PHTSs to investigate the influence of the polarity of the adsorbate. The isotherms showed higher uptakes for polar adsorbates on more hydrophobic materials and vice versa.