Small Molecule IL-36γ Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis.

IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate. Nevertheless, we performed a small molecule high-throughput screen to identify IL-36 antagonists using a novel TR-FRET binding assay. Several compounds, including 2-oxypyrimidine containing structural analogs of the marketed endothelin receptor A antagonist Ambrisentan, were identified as hits from the screen. A-552 was identified as a the most potent antagonist of human IL-36γ, but not the closely related family member IL-36α, was capable of attenuating IL-36γ induced responses in mouse and human disease models. Additionally, x-ray crystallography studies identified key amino acid residues in the binding pocket present in human IL-36γ that are absent in human IL-36α. A-552 represents a first-in-class small molecule antagonist of IL-36 signaling that could be used as a chemical tool to further investigate the role of this pathway in inflammatory skin diseases such as psoriasis.

Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure-Based Drug Design.

A HTS campaign identified compound 1, an excellent hit-like molecule to initiate medicinal chemistry efforts to optimize a dual ROCK1 and ROCK2 inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with pyrimidine afforded compounds with a clean CYP inhibition profile. Cocrystal structures of an early lead compound were obtained in PKA, ROCK1, and ROCK2. This provided critical structural information for medicinal chemistry to drive compound design. The structural data indicated the preferred configuration at the central benzylic carbon would be ( R), and application of this information to compound design resulted in compound 16. This compound was shown to be a potent and selective dual ROCK inhibitor in both enzyme and cell assays and efficacious in the retinal nerve fiber layer model after oral dosing. This tool compound has been made available through the AbbVie Compound Toolbox. Finally, the cocrystal structures also identified that aspartic acid residues 176 and 218 in ROCK2, which are glutamic acids in PKA, could be targeted as residues to drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine group to the compound series resulted in compound 58, a potent and selective dual ROCK inhibitor with excellent predicted drug-like properties.

Identification of Hostile Hemodynamics and Geometries of Cerebral Aneurysms: A Case-Control Study.

BACKGROUND AND PURPOSE: Hostile hemodynamic conditions and geometries are thought to predispose aneurysms for instability and rupture. This study compares stable, unstable, and ruptured aneurysms while controlling for location and patient characteristics. MATERIALS AND METHODS: The hemodynamics and geometries of 165 stable, 65 unstable, and 554 ruptured aneurysms were compared. Hemodynamics was modeled using image-based computational fluid dynamics. Case-control pairs were selected matching aneurysm location, patient age, and sex. Paired Wilcoxon tests were used to compare hemodynamic and geometric variables among different aneurysm groups. The pairing was repeated 100 times, and the combined P values were calculated and adjusted for multiple testing. RESULTS: Ruptured aneurysms had lower minimum wall shear stress (P = .03), higher maximum wall shear stress (P = .03), more concentrated (P = .03) and mean oscillatory shear stress (P = .03), higher maximum velocity (P = .03), and more complex flows (vortex core-line length, P = .03) than stable aneurysms. Similarly, unstable aneurysms had more concentrated shear stress (P = .04) and more complex flows (vortex core-line length, P = .04) than stable aneurysms. Compared with stable aneurysms, ruptured aneurysms were larger (size ratio, aneurysm size/vessel size, P = .03), more elongated (aspect ratio, P = .03), and irregular (nonsphericity index, P = .03). Similarly, unstable aneurysms were larger (size ratio, P = .04), more elongated (aspect ratio, P = .04), and irregular (bulge location, P = .04; area-weighted Gaussian curvature; P = .04) than stable aneurysms. No significant differences were found between unstable and ruptured aneurysms. CONCLUSIONS: Unstable and ruptured aneurysms have more complex flows with concentrated wall shear stress and are larger, more elongated, and irregular than stable aneurysms, independent of aneurysm location and patient sex and age.

Physicochemical determinants of pH in pectoralis major of three strains of laying hens housed in conventional and furnished cages.

1. Post-mortem decline in muscle pH has traditionally been attributed to glycogenolysis-induced lactate accumulation. However, muscle pH ([H+]) is controlled by complex physicochemical relationships encapsulated in the Stewart model of acid-base chemistry and is determined by three system-independent variables - strong ion difference ([SID]), total concentration of weak acids ([Atot]) and partial pressure of CO2 (PCO2). 2. This study investigated these system-independent variables in post-mortem pectoralis major muscles of Shaver White, Lohmann Lite and Lohmann Brown laying hens housed in conventional cages (CC) or furnished cages (FC) and evaluated the model by comparing calculated [H+] with previously measured [H+] values. 3. The model accounted for 99.7% of the variation in muscle [H+]. Differences in [SID] accounted for most or all of the variations in [H+] between strains. Greater PCO2 in FC was counteracted by greater sequestration of strong base cations. The results demonstrate the accuracy and utility of the Stewart model for investigating determinants of meat [H+]. 4. The housing differences identified in this study suggested that hens housed in FC have improved muscle function and overall health due to the increased opportunity for movement. These findings support past studies showing improved animal welfare for hens housed in FC compared to CC. Therefore, the Stewart model has been identified as an accurate method to assess changes in the muscle at a cellular level that affect meat quality that also detect differences in the welfare status of the research subjects.

Design of Aminobenzothiazole Inhibitors of Rho Kinases 1 and 2 by Using Protein Kinase†A as a Structure Surrogate.

We describe the design, synthesis, and structure-activity relationships (SARs) of a series of 2-aminobenzothiazole inhibitors of Rho kinases (ROCKs) 1 and 2, which were optimized to low nanomolar potencies by use of protein kinase A (PKA) as a structure surrogate to guide compound design. A subset of these molecules also showed robust activity in a cell-based myosin phosphatase assay and in a mechanical hyperalgesia in vivo pain model.

Hemodynamic Characteristics of Ruptured and Unruptured Multiple Aneurysms at Mirror and Ipsilateral Locations.

BACKGROUND AND PURPOSE: Different hemodynamic patterns have been associated with aneurysm rupture. The objective was to test whether hemodynamic characteristics of the ruptured aneurysm in patients with multiple aneurysms were different from those in unruptured aneurysms in the same patient. MATERIALS AND METHODS: Twenty-four mirror and 58 ipsilateral multiple aneurysms with 1 ruptured and the others unruptured were studied. Computational fluid dynamics models were created from 3D angiographies. Case-control studies of mirror and ipsilateral aneurysms were performed with paired Wilcoxon tests. RESULTS: In mirror pairs, the ruptured aneurysm had more oscillatory wall shear stress (P = .007) than the unruptured one and tended to be more elongated (higher aspect ratio), though this trend achieved only marginal significance (P = .03, 1-sided test). In ipsilateral aneurysms, ruptured aneurysms had larger maximum wall shear (P = .05), more concentrated (P < .001) and oscillatory wall shear stress (P < .001), stronger (P < .001) and more concentrated inflow jets (P < .001), larger maximum velocity (P < .001), and more complex flow patterns (P < .001) compared with unruptured aneurysms. Additionally, ruptured aneurysms were larger (P < .001) and more elongated (P < .001) and had wider necks (P < .001) and lower minimum wall shear stress (P < .001) than unruptured aneurysms. CONCLUSIONS: High wall shear stress oscillations and larger aspect ratios are associated with rupture in mirror aneurysms. Adverse flow conditions characterized by high and concentrated inflow jets; high, concentrated, and oscillatory wall shear stress; and strong, complex and unstable flow patterns are associated with rupture in ipsilateral multiple aneurysms. In multiple ipsilateral aneurysms, these unfavorable flow conditions are more likely to develop in larger, more elongated, more wide-necked, and more distal aneurysms.

Angioarchitectures and Hemodynamic Characteristics of Posterior Communicating Artery Aneurysms and Their Association with Rupture Status.

BACKGROUND AND PURPOSE: Intracranial aneurysms originating at the posterior communicating artery are known to have high rupture risk compared with other locations. We tested the hypothesis that different angioarchitectures (ie, branch point configuration) of posterior communicating artery aneurysms are associated with aneurysm hemodynamics, which in turn predisposes aneurysms to rupture. MATERIALS AND METHODS: A total of 313 posterior communicating artery aneurysms (145 ruptured, 168 unruptured) were studied with image-based computational fluid dynamics. Aneurysms were classified into different angioarchitecture types depending on the location of the aneurysm with respect to parent artery bifurcation. Hemodynamic characteristics were compared between ruptured and unruptured aneurysms, as well as among aneurysms with different angioarchitectures. RESULTS: Angioarchitecture was associated with rupture (P = .003). Ruptured aneurysms had higher, more concentrated, and more oscillatory wall shear stress distributions (maximum wall shear stress, P < .001; shear concentration index, P < .001; mean oscillatory shear index, P < .001), stronger and more concentrated inflow jets (represented as Q, P = .01; inflow concentration index, P < .001), and more complex and unstable flow patterns (vortex core length, P < .001; proper orthogonal decomposition entropy, P < .001) compared with unruptured aneurysms. These adverse conditions were more common in aneurysms with bifurcation-type angioarchitectures compared with those with lateral or sidewall angioarchitectures. Interestingly, ruptured aneurysms also had lower normalized mean wall shear stress (P = .02) and minimum wall shear stress (P = .002) than unruptured aneurysms. CONCLUSIONS: High-flow intrasaccular hemodynamic characteristics, commonly found in bifurcation-type angioarchitectures, are associated with the posterior communicating artery aneurysm rupture status. These characteristics include strong and concentrated inflow jets, concentrated regions of elevated wall shear stress, oscillatory wall shear stress, lower normalized wall shear stress, and complex and unstable flow patterns.

Differences in Hemodynamics and Rupture Rate of Aneurysms at the Bifurcation of the Basilar and Internal Carotid Arteries.

BACKGROUND AND PURPOSE: Cerebral aneurysms in the posterior circulation are known to have a higher rupture risk than those in the anterior circulation. We sought to test the hypothesis that differences in hemodynamics can explain the difference in rupture rates. MATERIALS AND METHODS: A total of 117 aneurysms, 63 at the tip of the basilar artery (27 ruptured, 36 unruptured, rupture rate = 43%) and 54 at the bifurcation of the internal carotid artery (11 ruptured, 43 unruptured, rupture rate = 20%) were analyzed with image-based computational fluid dynamics. Several hemodynamic variables were compared among aneurysms at each location and between ruptured and unruptured aneurysms at each location. RESULTS: On average, aneurysms at the basilar tip had more concentrated inflow (P < .001), a larger inflow rate (P < .001), a larger maximum oscillatory shear index (P = .003), more complex flows (P = .033), and smaller areas under low wall shear stress (P < .001) than aneurysms at the bifurcation of the internal carotid artery. In general, ruptured aneurysms had larger inflow concentration (P = .02), larger shear concentration (P = .02), more complex flows (P < .001), and smaller minimum wall shear stress (P = .003) than unruptured aneurysms. CONCLUSIONS: High flow conditions, characterized by large and concentrated inflow jets, complex and oscillatory flow patterns, and wall shear stress distributions with focalized regions of high shear and large regions of low shear, are associated with aneurysm rupture, especially for basilar tip aneurysms. The higher flow conditions in basilar tip aneurysms could explain their increased rupture risk compared with internal carotid bifurcation aneurysms.

Effect of housing environment on laying hen meat quality: Assessing Pectoralis major pH, colour and tenderness in three strains of 80-81 week-old layers housed in conventional and furnished cages.

1. Meat quality is affected by factors such as stress, genetic strain and activity and is determined in part by measures of pH, colour and tenderness. In conventional laying hen cages (CC), lack of physical space and inability to perform highly motivated behaviours leads to stress and inactivity. Furnished cages (FCs) permit expression of highly motivated behaviours, but typically house larger group sizes than CC, thereby contributing to social stress. The objective of this study was to evaluate the effects of CC and FC laying hen housing environments and strain differences on meat quality of 80-81-week-old birds. 2. Pectoralis major meat quality was assessed for two flocks of Shaver White (SH), Lohmann Lite (LL) and Lohmann Brown (LB) hens housed in either 5-hen CC or 40-hen FC. Between 80 and 81 weeks, muscle samples were collected from randomly selected hens and analysed for muscle pH, colour and shear force (SF) using established methods. 3. In both flocks, the combined treatment body weights (BWs) were higher for CC than FC hens and the combined strain BWs were higher for LB than LL and SH hens. Flock 1 LB had lower initial and ultimate pH than SH and LL, and greater pH decline than SH. Muscle redness (a*) was higher for CC SH than FC SH in both flocks. Muscle a* was higher for LL than SH and LB in Flock 1, and higher than SH in Flock 2. Housing differences in muscle SF were absent. In CC, SF was higher for SH than LL and LB in Flock 1, and higher than LB in Flock 2. 4. Lack of housing differences suggests that environmental stressors present in both housing systems similarly affected meat quality. Strain differences for muscle pH, a* and SF indicate increased stress experienced by SH and LL hens. The absence of Flock 2 strain differences is consistent with the cannibalism outbreak that occurred in this flock and most severely impacted LB hens.

Wall Mechanical Properties and Hemodynamics of Unruptured Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Aneurysm progression and rupture is thought to be governed by progressive degradation and weakening of the wall in response to abnormal hemodynamics. Our goal was to investigate the relationship between the intra-aneurysmal hemodynamic conditions and wall mechanical properties in human aneurysms. MATERIALS AND METHODS: A total of 8 unruptured aneurysms were analyzed. Computational fluid dynamics models were constructed from preoperative 3D rotational angiography images. The aneurysms were clipped, and the domes were resected and mechanically tested to failure with a uniaxial testing system under multiphoton microscopy. Linear regression analysis was performed to explore possible correlations between hemodynamic quantities and the failure characteristics and stiffness of the wall. RESULTS: The ultimate strain was correlated negatively to aneurysm inflow rate (P = .021), mean velocity (P = .025), and mean wall shear stress (P = .039). It was also correlated negatively to inflow concentration, oscillatory shear index, and measures of the complexity and instability of the flow; however, these trends did not reach statistical significance. The wall stiffness at high strains was correlated positively to inflow rate (P = .014), mean velocity (P = .008), inflow concentration (P = .04), flow instability (P = .006), flow complexity (P = .019), wall shear stress (P = .002), and oscillatory shear index (P = .004). CONCLUSIONS: In a study of 8 unruptured intracranial aneurysms, ultimate strain was correlated negatively with aneurysm inflow rate, mean velocity, and mean wall shear stress. Wall stiffness was correlated positively with aneurysm inflow rate, mean velocity, wall shear stress, flow complexity and stability, and oscillatory shear index. These trends and the impact of hemodynamics on wall structure and mechanical properties should be investigated further in larger studies.

Measurement of skeletal muscle radiation attenuation and basis of its biological variation.

Skeletal muscle contains intramyocellular lipid droplets within the cytoplasm of myocytes as well as intermuscular adipocytes. These depots exhibit physiological and pathological variation which has been revealed with the advent of diagnostic imaging approaches: magnetic resonance (MR) imaging, MR spectroscopy and computed tomography (CT). CT uses computer-processed X-rays and is now being applied in muscle physiology research. The purpose of this review is to present CT methodologies and summarize factors that influence muscle radiation attenuation, a parameter which is inversely related to muscle fat content. Pre-defined radiation attenuation ranges are used to demarcate intermuscular adipose tissue [from -190 to -30 Hounsfield units (HU)] and muscle (-29 HU to +150 HU). Within the latter range, the mean muscle radiation attenuation [muscle (radio) density] is reported. Inconsistent criteria for the upper and lower HU cut-offs used to characterize muscle attenuation limit comparisons between investigations. This area of research would benefit from standardized criteria for reporting muscle attenuation. Available evidence suggests that muscle attenuation is plastic with physiological variation induced by the process of ageing, as well as by aerobic training, which probably reflects accumulation of lipids to fuel aerobic work. Pathological variation in muscle attenuation reflects excess fat deposition in the tissue and is observed in people with obesity, diabetes type II, myositis, osteoarthritis, spinal stenosis and cancer. A poor prognosis and different types of morbidity are predicted by the presence of reduced mean muscle attenuation values in patients with these conditions; however, the biological features of muscle with these characteristics require further investigation.

Unexpected silent infarctions after embolization of cerebral arteriovenous malformations and fistulas. A diffusion-weighted magnetic resonance imaging study.

We investigated the number and possible causes of clinically silent lesions seen in diffusion-weighted magnetic resonance imaging after embolization of arteriovenous malformations (AVMs) and fistulas using acrylate only or in combination with coils. Included were 19 patients with 18 AVMs and one case of a vein of Galen aneurysm in which 25 interventions were carried out. Results of diffusion-weighted imaging, the appearance of perinidal and distant lesions, were correlated to Spetzler grade, nidus size, flow, number of feeders occluded, rate of nidus occlusion and duration of the intervention. We found seven distant lesions corresponding to non-symptomatic infarcts in the given clinical setting. The only significant correlation between lesion size and parameters analyzed was the degree of nidus occlusion achieved during the intervention. Because most of the lesions presented in cases with a high occlusion rate, they appear to be related to the intention to reach a complete occlusion of the nidus. These results emphasize that the risk involved in eliminating the nidus completely must be reconsidered with special care, particularly in a situation where most high-flow feeders have been occluded.

Effects of perianeurysmal environment during the growth of cerebral aneurysms: a case study.

BACKGROUND AND PURPOSE: The natural history of cerebral aneurysms is thought to be governed by multifactorial processes involving hemodynamics, biomechanics, mechanobiology, and perianeurysmal environment. The purpose of this study was to highlight the importance of considering the influence of contacts with perianeurysmal environment structures on the hemodynamics and geometric evolution of intracranial aneurysms. MATERIALS AND METHODS: A large aneurysm of the basilar artery in contact with bone and observed to grow during a 4-year follow-up period was selected for study. Anatomic models were constructed from longitudinal CTA images acquired at 1-year intervals during the observation period. Computational fluid dynamics simulations were carried out under pulsatile flow conditions to analyze the blood flow pattern and WSS distribution in the aneurysm during its evolution. RESULTS: The aneurysm was observed to grow against the bone, resulting in a geometric change of the proximal parent artery, which, in turn, induced substantial changes in the aneurysm hemodynamics. In particular, a region of elevated WSS created by the inflow streams was observed to shift locations around the place where the aneurysm enlarged in contact with the bone as the aneurysm progressed. In addition, a "notch" near the distal end of the aneurysm, away from the bone and subject to relatively high WSS, was observed to grow and, later, completely disappear. CONCLUSIONS: Contacts with perianeurysmal structures need to be considered and analyzed to assess whether they could exert a significant influence on the geometric evolution of each individual intracranial aneurysm and its hemodynamics.

Comparative analysis of inactivated-state block of N-type (Ca(v)2.2) calcium channels.

OBJECTIVE: The aim of this study was to compare a diverse set of peptide and small-molecule calcium channel blockers for inactivated-state block of native and recombinant N-type calcium channels using fluorescence-based and automated patch-clamp electrophysiology assays. METHODS: The pharmacology of calcium channel blockers was determined at N-type channels in IMR-32 cells and in HEK cells overexpressing the inward rectifying K(+) channel Kir2.1. N-type channels were opened by increasing extracellular KCl. In the Kir2.1/N-type cell line the membrane potential could be modulated by adjusting the extracellular KCl, allowing determination of resting and inactivated-state block of N-type calcium channels. The potency and degree of state-dependent inhibition of these blockers were also determined by automated patch-clamp electrophysiology. RESULTS: N-type-mediated calcium influx in IMR-32 cells was determined for a panel of blockers with IC(50) values of 0.001-7 µM and this positively correlated with inactivated-state block of recombinant channels measured using electrophysiology. The potency of several compounds was markedly weaker in the state-dependent fluorescence-based assay compared to the electrophysiology assay, although the degree of state-dependent blockade was comparable. CONCLUSIONS: The present data demonstrate that fluorescence-based assays are suitable for assessing the ability of blockers to selectively interact with the inactivated state of the N-type channel.

Aneurysm rupture following treatment with flow-diverting stents: computational hemodynamics analysis of treatment.

BACKGROUND AND PURPOSE: Flow-diverting approaches to intracranial aneurysm treatment had many promising early results, but recent apparently successful treatments have been complicated by later aneurysm hemorrhage. We analyzed 7 cases of aneurysms treated with flow diversion to explore the possible rupture mechanisms. MATERIALS AND METHODS: CFD analysis of pre- and posttreatment conditions was performed on 3 giant aneurysms that ruptured after treatment and 4 successfully treated aneurysms. Pre- and posttreatment hemodynamics were compared including WSS, relative blood flows, vascular resistances, and pressures, to identify the effects of flow-diverter placements. RESULTS: Expected reductions in aneurysm velocity and WSS were obtained, indicating effective flow diversion from the sac into the parent artery, consistent with periprocedural observations. In each case with postaneurysm rupture, the result of flow diversion led to an increase in pressure within the aneurysm. This pressure increase is related to larger effective resistance in the parent artery from placement of the devices and, in 2 cases, the reduction of a preaneurysm stenosis. CONCLUSIONS: Flow-diversion devices can cause intra-aneurysmal pressure increases, which can potentially lead to rupture, especially for giant aneurysms. This relates both to changes in the parent artery configuration, such as reduction of a proximal stenosis, and to the flow diversion into higher resistance parent artery pathways combined with cerebral autoregulation, leading to higher pressure gradients. These may be important effects that should be considered when planning interventions. Potentially dangerous cases could be identified with angiography and/or patient-specific CFD models.

Quantitative characterization of the hemodynamic environment in ruptured and unruptured brain aneurysms.

BACKGROUND AND PURPOSE: Hemodynamics are thought to play an important role in the mechanisms of aneurysm pathogenesis, progression, and rupture. The purpose of this study was to define quantitative measures related to qualitative flow characteristics previously analyzed and to investigate their relationship to aneurysm rupture. MATERIALS AND METHODS: The hemodynamic environments in 210 cerebral aneurysms were analyzed by using image-based CFD under different flow conditions. Quantitative hemodynamic variables were defined and extracted from the simulation results. A statistical analysis of the relationship to the previous history of aneurysm rupture was performed, and the variability with flow conditions was assessed. RESULTS: Ruptured aneurysms were more likely to have larger inflow concentrations, larger MWSS, larger shear concentrations, and lower viscous dissipation ratios than unruptured aneurysms. Areas under low WSS and measures of abnormally low shear force distributions of ruptured and unruptured aneurysms were not statistically different. Although the values of hemodynamic quantities changed with different flow conditions, the statistical differences or ratios between their mean values over the ruptured and unruptured groups were maintained, for both pulsatile and steady flows. CONCLUSIONS: Concentrated inflow streams and WSS distributions with elevated levels of MWSS and low aneurysmal viscous dissipation are statistically associated with a clinical history of prior aneurysm rupture. In contrast, the area and total viscous shear force applied in the aneurysm region subjected to abnormally low WSS levels are not. This study highlights the potential for image-based CFD for investigating aneurysm-evolution mechanisms and for clinical assessment of aneurysm risks.

Association of hemodynamic characteristics and cerebral aneurysm rupture.

BACKGROUND AND PURPOSE: Hemodynamic factors are thought to play an important role in the initiation, growth, and rupture of cerebral aneurysms. This report describes a study of the associations between qualitative intra-aneurysmal hemodynamics and the rupture of cerebral aneurysms. MATERIALS AND METHODS: Two hundred ten consecutive aneurysms were analyzed by using patient-specific CFD simulations under pulsatile flow conditions. The aneurysms were classified into categories by 2 blinded observers, depending on the complexity and stability of the flow pattern, size of the impingement region, and inflow concentration. A statistical analysis was then performed with respect to the history of previous rupture. Interobserver variability analysis was performed. RESULTS: Ruptured aneurysms were more likely to have complex flow patterns (83%, P < .001), stable flow patterns (75%, P = .0018), concentrated inflow (66%, P = <.0001), and small impingement regions (76%, P = .0006) compared with unruptured aneurysms. Interobserver variability analyses indicated that all the classifications performed were in very good agreement-that is, well within the 95% CI. CONCLUSIONS: A qualitative hemodynamic analysis of cerebral aneurysms by using image-based patient-specific geometries has shown that concentrated inflow jets, small impingement regions, complex flow patterns, and unstable flow patterns are correlated with a clinical history of prior aneurysm rupture. These qualitative measures provide a starting point for more sophisticated quantitative analysis aimed at assigning aneurysm risk of future rupture. These analyses highlight the potential for CFD to play an important role in the clinical determination of aneurysm risks.

Wall motion estimation in intracranial aneurysms.

The quantification of wall motion in cerebral aneurysms is becoming important owing to its potential connection to rupture, and as a way to incorporate the effects of vascular compliance in computational fluid dynamics simulations. Most of papers report values obtained with experimental phantoms, simulated images or animal models, but the information for real patients is limited. In this paper, we have combined non-rigid registration with signal processing techniques to measure pulsation in real patients from high frame rate digital subtraction angiography. We have obtained physiological meaningful waveforms with amplitudes in the range 0 mm-0.3 mm for a population of 18 patients including ruptured and unruptured aneurysms. Statistically significant differences in pulsation were found according to the rupture status, in agreement with differences in biomechanical properties reported in the literature.

Blood-flow characteristics in a terminal basilar tip aneurysm prior to its fatal rupture.

BACKGROUND AND PURPOSE: The development and validation of methods to stratify the risk of rupture of cerebral aneurysms is highly desired because current treatment risks can exceed the natural risk of rupture. Because unruptured aneurysms are typically treated before they rupture, it is very difficult to connect the proposed risk indices to the rupture of an individual aneurysm. The purpose of this case study was to analyze the hemodynamic environment of a saccular aneurysm of the terminal morphology subtype that was imaged just before its rupture and to test whether the hemodynamic characteristics would designate this particular aneurysm as at high risk. MATERIALS AND METHODS: A patient-specific CFD model was constructed from 3DRA images acquired just hours before the aneurysm ruptured. A pulsatile flow calculation was performed, and hemodynamic characteristics previously connected to rupture were analyzed. RESULTS: It was found that the aneurysm had a concentrated inflow stream, small impingement region, complex intra-aneurysmal flow structure, asymmetric flow split from the parent vessel to the aneurysm and daughter branches, and high levels of aneurysmal WSS near the impaction zone. CONCLUSIONS: The hemodynamic characteristics observed in this aneurysm right before its rupture are consistent with previous studies correlating aneurysm rupture and hemodynamic patterns in saccular and terminal aneurysms. This study supports the notion that hemodynamic information may be used to help stratify the rupture risk of cerebral aneurysms.