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Objective: It is commonly believed that in intrathecal (IT) drug delivery, agent distribution is confined to a narrow region close to the injection site, thereby undermining the efficacy of the method. Methods: To test the claim, multimodal in vivo imaging was used to experimentally observe the effects of IT infusion in cynomolgus monkey, looking at cerebrospinal fluid flow, anatomy, and dispersion of a radiolabeled tracer. Results: At high infusion rates, the tracer reached the cervical region after only 2 h, demonstrating rapid and wide distribution. The same in vivo nonhuman primate imaging data also provided evidence in support of a computational fluid dynamic model for the prediction of drug distribution following IT injection. Tracer dispersion was predicted in two specimens matching the distribution acquired with positron emission tomography (PET). For the third specimen, tracer dispersion simulations were conducted as a blind study: predictions were made before in vivo biodistribution data was known. In all cases, the computational fluid dynamics (CFD) predictions of drug dispersion after IT administration showed close spatio-temporal agreement with tracer biodistribution in vivo . Conclusion: Validation by in vivo nonhuman primate data confirms our ability to predict the biodistribution of intrathecally administered agents in subject-specific models of the central nervous system from first principles. Significance: The experiments reinstate IT delivery as a viable administration method when targeting molecules to the whole spine or the brain. The proposed computational methodology enables rational design of novel therapies for neurological diseases that require reliable, efficient, and safe delivery of therapeutic agents to specific target sites in the central nervous system.

BackgroundTraditionally, there is a widely held belief that drug dispersion after intrathecal (IT) delivery is confined locally near the injection site. We posit that high volume infusions can overcome this perceived limitation of IT administration.MethodsTo test our hypothesis, subject-specific deformable phantom models of the human central nervous system were manufactured so that tracer infusion could be realistically replicated in vitro over the entire physiological range of pulsating cerebrospinal fluid (CSF) amplitudes and frequencies. Dispersion of IT injected tracers was studied systematically with high-speed optical methods to determine the relative impact of injection parameters including infusion volume, flow rate, catheter configurations and natural CSF oscillations.ResultsOptical imaging analysis of high-volume infusion experiments showed that tracer spreads quickly throughout the spinal subarachnoid space (SAS), reaching the cervical region in less than ten minutes. The experimentally observed biodispersion is much faster than suggested by prior theories (Taylor-Aris-Watson TAW dispersion). Our experiments indicate that micro-mixing patterns induced by oscillatory CSF flow around microanatomical features such as nerve roots significantly accelerate solute transport. Strong micro mixing effects due to anatomical features in the spinal subarachnoid space were found to be active in intrathecal drug administration but were not considered in prior dispersion theories. Their omission explains why prior models developed in the engineering community are poor predictors for IT delivery.ConclusionOur experiments support the feasibility of targeting large sections of the neuroaxis or brain utilizing high-volume IT injection protocols. The experimental tracer dispersion profiles acquired with an in vitro human CNS analog informed a new predictive model of tracer dispersion as a function of physiological CSF pulsations and adjustable infusion parameters. The ability to predict spatiotemporal dispersion patterns is an essential prerequisite for exploring new indications of IT drug delivery that targets specific regions in the central nervous system (CNS) or the brain.

This paper presents a mathematical model of the global, arterio-venous circulation in the entire human body, coupled to a refined description of the cerebrospinal fluid (CSF) dynamics in the craniospinal cavity. The present model represents a substantially revised version of the original Müller-Toro mathematical model. It includes one-dimensional (1D), non-linear systems of partial differential equations for 323 major blood vessels and 85 zero-dimensional, differential-algebraic systems for the remaining components. Highlights include the myogenic mechanism of cerebral blood regulation; refined vasculature for the inner ear, the brainstem and the cerebellum; and viscoelastic, rather than purely elastic, models for all blood vessels, arterial and venous. The derived 1D parabolic systems of partial differential equations for all major vessels are approximated by hyperbolic systems with stiff source terms following a relaxation approach. A major novelty of this paper is the coupling of the circulation, as described, to a refined description of the CSF dynamics in the craniospinal cavity, following Linninger et al. The numerical solution methodology employed to approximate the hyperbolic non-linear systems of partial differential equations with stiff source terms is based on the Arbitrary DERivative Riemann problem finite volume framework, supplemented with a well-balanced formulation, and a local time stepping procedure. The full model is validated through comparison of computational results against published data and bespoke MRI measurements. Then we present two medical applications: (i) transverse sinus stenoses and their relation to Idiopathic Intracranial Hypertension; and (ii) extra-cranial venous strictures and their impact in the inner ear circulation, and its implications for Ménière's disease.

Objective Indications for the treatment of cerebral aneurysms with flow diversion stents are expanding. The current aneurysm occlusion rate at six months ranges between 60 and 80%. Predictability of complete vs. partial aneurysm occlusion is poorly defined. Here, we evaluate the angiographic contrast time-density as a predictor of aneurysm occlusion rate at six months’ post-flow diversion stents. Methods Patients with unruptured cerebral aneurysms proximal to the internal carotid artery terminus treated with single flow diversion stents were included. 2D parametric parenchymal blood flow software (Siemens-Healthineers, Forchheim, Germany) was used to calculate contrast time-density within the aneurysm and in the proximal adjacent internal carotid artery. The area under the curve ratio between the two regions of interests was assessed at baseline and after flow diversion stents deployment. The area under the curve ratio between completely vs. partially occluded aneurysms at six months’ follow-up was compared. Results Thirty patients with 31 aneurysms were included. Mean aneurysm diameter was 8 mm (range 2–28 mm). Complete occlusion was obtained in 19 aneurysms. Younger patients ( P = 0.006) and smaller aneurysms ( P = 0.046) presented higher chance of complete obliteration. Incomplete occlusion of the aneurysm was more likely if the area under the curve contrast time-density ratio showed absolute ( P = 0.001) and relative percentage ( P = 0.001) decrease after flow diversion stents deployment. Area under ROC curve was 0.85. Conclusion Negative change in the area under the curve ratio indicates less contrast stagnation in the aneurysm and lower chance of occlusion. These data provide a real-time analysis after aneurysm treatment. If validated in larger datasets, this can prompt input to the surgeon to place a second flow diversion stents.

BACKGROUND: The development of venous outflow stenosis in cerebral arteriovenous malformation (AVM) is poorly understood. OBJECTIVE: The location of stenosis within the AVM-draining vein in relation to the adjacent venous sinus and the hypothesis that the ratio of draining vein to adjacent sinus diameter might predict the development of venous stenosis were explored. METHODS: Patients with supratentorial AVMs (1997–2018) were reviewed (n=290). AVM-draining vein and adjacent venous sinus diameters, degree of draining vein stenosis, and distance from the maximal stenotic point to the junction of the adjacent draining sinus were recorded. Correlation between percentage of AVM-draining vein stenosis and the ratio of AVM-draining vein to venous sinus diameters was analyzed. RESULTS: 360 draining veins in 243 AVM with complete angiographic data were measured. Venous stenosis (in 131 draining veins) was observed within 20mm of the junction to the adjacent draining sinus in 85% of our sample. The ratio of draining vein to adjacent sinus diameter correlated positively with the percentage of venous stenosis (P1.0 showed significant tighter stenosis compared to the ratio ≤0.5 (25.9% and 28.9% vs. 10.0% respectively, P0.5. This may be related to more turbulent flow at the junction of the draining vein and venous sinus, especially in larger draining veins, which causes venous stenosis to develop over time.

Cerebral autoregulation, the physiological capability to regulate cerebral blood flow, may be assisted by short-term mean arterial pressure control via baroreflex, which, among several effects, modulates total peripheral resistance. It is unclear, however, whether the resistance of the head and neck vasculatures is also affected by baroreflex and whether these extracranial vessels assist autoregulation. Since sensing technologies such as functional Near-Infrared Spectroscopy and noninvasive intracranial pressure monitoring by strain gauge may be influenced by superficial tissue, it is clinically relevant to understand the relations between intracranial and extracranial hemodynamics. Therefore, we created an autoregulation model consisting of arteries and arterioles regulated by the intralumial pressure and microcirculation regulated by local blood flow. As the first critical step to quantify the signal deterioration introduced by the extracranial circulation on superficial sensors, the extracranial peripheral circulation of the head and neck and baroreflex regulation of the peripheral vasculature and of heart rate were also included. During simulations of a bout of acute hypotension, the model predicts a rapid return of cerebral blood flow to baseline levels and a prolonged suppression of the blood flow to the external carotid vasculature, in accordance with experimental evidence. The inclusion of peripheral control via baroreflex at the external carotid vasculature did not assist cerebral autoregulation, thus we raise the hypothesis that baroreflex may act on the head and neck vasculatures but this action has negligible effects on regulation of cerebral blood flow. When autoregulation is impaired, results suggest that the blood flow of the brain and of the head and neck present similar dynamics, while they are weakly coupled when autoregulation is intact. The model also provides a mechanistic explanation of the protection brought by cerebral autoregulation to the microvasculature and to the brain parenchyma. Our model forms the foundation for predicting the interference introduced by the superficial tissue to nonivasive sensors.

Recent developments in optical microscopy, applicable for large-scale and longitudinal imaging of cortical activity in behaving animals, open unprecedented opportunities to gain a deeper understanding of neurovascular and neurometabolic coupling during different brain states. Future studies will leverage these tools to deliver foundational knowledge about brain state-dependent regulation of cerebral blood flow and metabolism, as well as regulation as a function of brain maturation and aging. This knowledge is of critical importance to interpret hemodynamic signals observed with functional magnetic resonance imaging (fMRI).

Recent advancements in multiphoton imaging and vascular reconstruction algorithms have increased the amount of data on cerebrovascular circulation for statistical analysis and hemodynamic simulations. Experimental observations offer fundamental insights into capillary network topology but mainly within a narrow field of view typically spanning a small fraction of the cortical surface (less than 2%). In contrast, larger-resolution imaging modalities, such as computed tomography (CT) or magnetic resonance imaging (MRI), have whole-brain coverage but capture only larger blood vessels, overlooking the microscopic capillary bed. To integrate data acquired at multiple length scales with different neuroimaging modalities and to reconcile brain-wide macroscale information with microscale multiphoton data, we developed a method for synthesizing hemodynamically equivalent vascular networks for the entire cerebral circulation. This computational approach is intended to aid in the quantification of patterns of cerebral blood flow and metabolism for the entire brain. In part I, we described the mathematical framework for image-guided generation of synthetic vascular networks covering the large cerebral arteries from the circle of Willis through the pial surface network leading back to the venous sinuses. Here in part II, we introduce novel procedures for creating microcirculatory closure that mimics a realistic capillary bed. We demonstrate our capability to synthesize synthetic vascular networks whose morphometrics match empirical network graphs from three independent state-of-the-art imaging laboratories using different image acquisition and reconstruction protocols. We also successfully synthesized twelve vascular networks of a complete mouse brain hemisphere suitable for performing whole-brain blood flow simulations. Synthetic arterial and venous networks with microvascular closure allow whole-brain hemodynamic predictions. Simulations across all length scales will potentially illuminate organ-wide supply and metabolic functions that are inaccessible to models reconstructed from image data with limited spatial coverage.

Magnetophoresis is an important physical process with application to drug delivery, biomedical imaging, separation, and mixing. Other than empirically, little is known about how the magnetic field and magnetic properties of a solution affect the flux of magnetic particles. A comprehensive explanation of these effects on the transport of magnetic particles has not been developed yet. Here we formulate a consistent, constitutive equation for the magnetophoretic flux of magnetic nanoparticles suspended in a medium exposed to a stationary magnetic field. The constitutive relationship accounts for contributions from magnetic diffusion, magnetic convection, residual magnetization, and electromagnetic drift. We discovered that the key physical properties governing the magnetophoresis are magnetic diffusion coefficient, magnetic velocity, and activity coefficient, which depend on relative magnetic energy and the molar magnetic susceptibility of particles. The constitutive equation also reveals previously unknown ballistic and diffusive limits for magnetophoresis wherein the paramagnetic particles either aggregate near the magnet or diffusive away from the magnet, respectively. In the diffusive limit, the particle concentration is linearly proportional to the relative magnetic energy of the suspension of paramagnetic particles. The region of the localization of paramagnetic particles near the magnet decreases with increasing the strength of the magnet. The dynamic accumulation of nanoparticles, measured as the thickness of the nanoparticle aggregate, near the magnet compares well with the theoretical prediction. The effect of convective mixing on the rate of magnetophoresis is also discussed for the magnetic targeting applications.

Abstract: Dental amalgam has been used for more than 150 years due to its beneficial mechanical properties and durability in dentistry. In the past and to date, many questions about amalgam restorations have arisen, especially regarding the mercury content, which has been the subject of global disputes. By presenting the past and present of the ‘amalgam issue’, the aim of our paper is to display the current position of international literature. This summary is based on the publications in the PubMed database, the guidelines of the Council of European Dentists. Although the use of dental amalgam is widespread, concerns have been raised about the adverse effect on human health and the environment, focusing on its heavy metal pollution during waste treatment. In 2017, the European Union (EU) adopted the so-called Mercury Regulation, based on the United Nations Minamata Convention on Mercury, the recommendations of which are presented in the present review. This Regulation includes the requirement for EU Member States to develop a national action plan for the phase-down of amalgam. The feasibility plan for complete phase-out may be guaranteed by 2030. The authors discuss the advantages and disadvantages of possible amalgam alternatives by presenting glass-ionomers and resin-based composites. In the future, more material research programmes and long-term follow-up studies are necessary. In addition to several global health organizations, the Council of European Dentists also draws attention to prevent dental caries, expecting to reduce the number of restorations. Orv Hetil. 2018; 159(42): 1700–1709.

Accurate subject-specific vascular network reconstruction is a critical task for the hemodynamic analysis of cerebroarterial circulation. Vascular skeletonization and computational mesh generation for large sections of cerebrovascular trees from magnetic resonance angiography (MRA) is an error-prone, operator-dependent, and very time-consuming task. Validation of reconstructed computational models is essential to ascertain their accuracy and precision, which directly relates to the confidence of CFD computations performed on these meshes. The aim of this study is to generate an imaging segmentation pipeline to validate and quantify the spatial accuracy of computational models of subject-specific cerebral arterial trees. We used a recently introduced parametric structured mesh (PSM) generation method to automatically reconstruct six subject-specific cerebral arterial trees containing 1364 vessels and 571 bifurcations. By automatically extracting sampling frames for all vascular segments and bifurcations, we quantify the spatial accuracy of PSM against the original MRA images. Our comprehensive study correlates lumen area, pixel-based statistical analysis, area overlap and centerline accuracy measurements. In addition, we propose a new metric, the pointwise offset surface distance metric (PSD), to quantify the spatial alignment between dimensions of reconstructed arteries and bifurcations with in-vivo data with the ability to quantify the over- and under-approximation of the reconstructed models. Accurate reconstruction of vascular trees can a practical process tool for morphological analysis of large patient data banks, such as medical record files in hospitals, or subject-specific hemodynamic simulations of the cerebral arterial circulation.

BACKGROUND: Among diffusely infiltrative gliomas in adults, 20%–30% contain a point mutation in isocitrate dehydrogenase 1 (IDH1(mut)), which increases production of D-2-hydroxyglutarate (D2HG). This is so efficient that D2HG often reaches 30 mM within IDH1(mut) gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1(mut) glioma patients, the exposure of nonneoplastic cells within and surrounding an IDH1(mut) glioma to D2HG is unknown and difficult to measure directly. METHODS: Conditioned medium from patient-derived wild type IDH1 (IDH1(wt)) and IDH1(mut) glioma cells was analyzed for D2HG by liquid chromatography–mass spectrometry (LC-MS). Mathematical models of D2HG release and diffusion around an IDH1(mut) glioma were independently generated based on fluid dynamics within the brain and on previously reported intratumoral and cerebrospinal D2HG concentrations. RESULTS: LC-MS analysis indicates that patient-derived IDH1(mut) glioma cells release 3.7–97.0 pg D2HG per cell per week. Extrapolating this to an average-sized tumor (30 mL glioma volume and 1 × 10(8) cells/mL tumor), the rate of D2HG release by an IDH1(mut) glioma (S(A)) is estimated at 3.2–83.0 × 10(−12) mol/mL/sec. Mathematical models estimate an S(A) of 2.9–12.9 × 10(−12) mol/mL/sec, within the range of the in vitro LC-MS data. In even the most conservative of these models, the extracellular concentration of D2HG exceeds 3 mM within a 2 cm radius from the center of an IDH1(mut) glioma. CONCLUSIONS: The microenvironment of an IDH1(mut) glioma is likely being exposed to high concentrations of D2HG, in the low millimolar range. This has implications for understanding how D2HG affects nonneoplastic cells in an IDH1(mut) glioma.

The job demands-resources model (JD-R model; Bakker & Demerouti, 2014) is well established in occupational research, and the proposed processes it posits have been replicated numerous times. Thus, the JD-R model provides an excellent framework for explaining the occupational well-being of beginning teachers—an occupation associated with particularly high levels of strain and consequently, high attrition rates. However, the model’s assumptions have to date mostly been tested piecewise, and seldom on the basis of longitudinal models. With a series of longitudinal autoregressive SEM models (N = 1,700) we tested all assumptions of the JD-R model simultaneously in one model with an applied focus on beginning teachers. We assessed self-reports of beginning teachers at three time waves: at the beginning and end (one and a half to two years later) of their preservice period, and again, one year later. Results revealed significant direct effects of resources (self-efficacy) on engagement, of demands (classroom disturbances) on strain (emotional exhaustion), and a significant reverse path of engagement on self-efficacy. Additionally, the results showed two moderation effects: Self-efficacy buffered the demands-strain relationship, while self-efficacy also predicted engagement, especially when disturbances were high. Thus, self-efficacy in classroom management plays an important role in the teachers’ stress development process, as it will, in case of high classroom disturbances, not only buffer the strain-enhancing effects, but also boost engagement. Commitment was predicted directly by emotional exhaustion and engagement, but indirectly only by self-efficacy (via engagement). Thus, we provide strong empirical support for the JD-R model. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

In this paper, we present a novel technique for automatic parametric mesh generation of subject-specific cerebral arterial trees. This technique generates high-quality and anatomically accurate computational meshes for fast blood flow simulations extending the scope of 3D vascular modeling to a large portion of cerebral arterial trees. For this purpose, a parametric meshing procedure was developed to automatically decompose the vascular skeleton, extract geometric features and generate hexahedral meshes using a body-fitted coordinate system that optimally follows the vascular network topology. To validate the anatomical accuracy of the reconstructed vasculature, we performed statistical analysis to quantify the alignment between parametric meshes and raw vascular images using receiver operating characteristic curve. Geometric accuracy evaluation showed an agreement with area under the curves value of 0.87 between the constructed mesh and raw MRA data sets. Parametric meshing yielded on-average, 36.6% and 21.7% orthogonal and equiangular skew quality improvement over the unstructured tetrahedral meshes. The parametric meshing and processing pipeline constitutes an automated technique to reconstruct and simulate blood flow throughout a large portion of the cerebral arterial tree down to the level of pial vessels. This study is the first step towards fast large-scale subject-specific hemodynamic analysis for clinical applications. Display Omitted Automated parametric mesh generation technique to reconstruct subject-specific cerebral arterial tree.The parametric meshing technique extends hemodynamic analysis from few segments to large-scale modeling.CFD hemodynamic studies in subject-specific arterial trees are facilitated by the automated parametric mesh generation.

Intrathecal drug delivery is an attractive option to circumvent the blood-brain barrier for pain management through its increased efficacy of pain relief, reduction in adverse side effects, and cost-effectiveness. Unfortunately, there are limited guidelines for physicians to choose infusion or drug pump settings to administer therapeutic doses to specific regions of the spine or the brain. Although empiric trialing of intrathecal drugs is critical to determine the sustained side effects, currently there is no inexpensive in vitro method to guide the selection of spinal drug delivery parameters. The goal of this study is to demonstrate current computational capabilities to predict drug biodistribution while varying 3 parameters: (1) infusion settings, (2) drug chemistry, and (3) subject-specific anatomy and cerebrospinal fluid dynamics. We will discuss strategies to systematically optimize these 3 parameters to administer drug molecules to targeted tissue locations in the central nervous system.We acquired anatomical data from magnetic resonance imaging (MRI) and velocity measurements in the spinal cerebrospinal fluid with CINE-MRI for 2 subjects. A bench-top surrogate of the subject-specific central nervous system was constructed to match measured anatomical dimensions and volumes. We generated a computational mesh for the bench-top model. Idealized simulations of tracer distribution were compared with bench-top measurements for validation. Using reconstructions from MRI data, we also introduced a subject-specific computer model for predicting drug spread for the human volunteer.MRI velocity measurements at 3 spinal regions of interest reasonably matched the simulated flow fields in a subject-specific computer mesh. Comparison between the idealized spine computations and bench-top tracer distribution experiments demonstrate agreement of our drug transport predictions to this physical model. Simulated multibolus drug infusion theoretically localizes drug to the cervical and thoracic region. Continuous drug pump and single bolus injection were successful to target the lumbar spine in the simulations. The parenchyma might be targeted suitably by multiple boluses followed by a flush infusion. We present potential guidelines that take into account drug specific kinetics for tissue uptake, which influence the speed of drug dispersion in the model and potentially influence tissue targeting.We present potential guidelines considering drug-specific kinetics of tissue uptake, which determine the speed of drug dispersion and influence tissue targeting. However, there are limitations to this analysis in that the parameters were obtained from an idealized healthy patient in a supine position. The proposed methodology could assist physicians to select clinical infusion parameters for their patients and provide guidance to optimize treatment algorithms. In silico optimization of intrathecal drug delivery therapies presents the first steps toward a possible care paradigm in the future that is specific to personalized patient anatomy and diseases.

Large cerebral aneurysms are considered more dangerous than their smaller counterparts, with higher risk of subarachnoid hemorrhage. Understanding the hemodynamics of large aneurysms has potential to predict their response to treatment. Digital subtraction angiography images for patients with intracranial aneurysms over a seven-year period were reviewed. Unruptured solitary aneurysms of the internal carotid artery (ICA) proximal to the terminus and posterior communicating artery were included. Contrast intensity over time was analyzed at the center of the M1 segment of the middle cerebral artery distal to the aneurysm and compared to the contralateral side. Analysis included time to peak (TP)10%–100% (time needed for contrast to change from 10% intensity to 100%), washout time (WT)100%–10% (time for 100% intensity to 10%), and quartile time (QT)25%–25% (time for 25% intensity during vessel filling to 25% during emptying). Fifty patients met the inclusion criteria. Analysis over the ipsilateral M1 segment revealed a significant increase in QT25%–25% (8.5 vs 7.6 seconds, p = 0.006) compared to the contralateral side. There was a correlation between TP10%–100% and QT25%–25% with aneurysm size (Pearson’s r = 0.37, p = 0.007 and r = 0.43, p = 0.001, respectively). Larger ICA aneurysms were associated with delayed contrast intensity times . A plausible mechanism is that large aneurysms act as a capacitance chamber (Windkessel effect) that slow the arrival of contrast distal to the aneurysm. This may be of significance for large aneurysms after treatment, where the loss of the Windkessel effect places the distal circulation at greater risk for hemorrhage, and warrants further study.

Current image processing techniques capture large vessels reliably but often fail to preserve connectivity in bifurcations and small vessels. Imaging artifacts and noise can create gaps and discontinuity of intensity that hinders segmentation of vascular trees. However, topological analysis of vascular trees require proper connectivity without gaps, loops or dangling segments. Proper tree connectivity is also important for high quality rendering of surface meshes for scientific visualization or 3D printing. We present a fully automated vessel enhancement pipeline with automated parameter settings for vessel enhancement of tree-like structures from customary imaging sources, including 3D rotational angiography, magnetic resonance angiography, magnetic resonance venography, and computed tomography angiography. The output of the filter pipeline is a vessel-enhanced image which is ideal for generating anatomical consistent network representations of the cerebral angioarchitecture for further topological or statistical analysis. The filter pipeline combined with computational modeling can potentially improve computer-aided diagnosis of cerebrovascular diseases by delivering biometrics and anatomy of the vasculature. It may serve as the first step in fully automatic epidemiological analysis of large clinical datasets. The automatic analysis would enable rigorous statistical comparison of biometrics in subject-specific vascular trees. The robust and accurate image segmentation using a validated filter pipeline would also eliminate operator dependency that has been observed in manual segmentation. Moreover, manual segmentation is time prohibitive given that vascular trees have more than thousands of segments and bifurcations so that interactive segmentation consumes excessive human resources. Subject-specific trees are a first step toward patient-specific hemodynamic simulations for assessing treatment outcomes. Automated vesselness filter with adjustable parameters for various imaging modality.Vessel contrast enhancement enables accurate modeling of cerebral vasculature.CFD studies in subjectspecific arterial trees are facilitated by the automated filter.

Nanoparticles offer several applications in the field of medicine such as targeted drug delivery, controlled drug release, and imaging applications. The central nervous system (CNS), in particular, has remained a challenge for drug delivery. This is mainly due to barriers such as the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), which hinder drug molecules from reaching the brain and spinal cord tissue. Although researchers have mainly focused on applying nanotechnology in the brain, there is an increase in applications of nanomaterials in the spine as well. This chapter focuses on the potential of nanomedicine for medical applications in the spine, including unique drug delivery systems and gene therapy applications, and for enhancement of medical imaging. We look at the problems and recent advances in the development of nanoparticles for spine-related applications and provide a comprehensive review on recent research work.

Nanoparticles offer several applications in the field of medicine such as targeted drug delivery, controlled drug release, and imaging applications. The central nervous system (CNS), in particular, has remained a challenge for drug delivery. This is mainly due to barriers such as the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), which hinder drug molecules from reaching the brain and spinal cord tissue. Although researchers have mainly focused on applying nanotechnology in the brain, there is an increase in applications of nanomaterials in the spine as well. This chapter focuses on the potential of nanomedicine for medical applications in the spine, including unique drug delivery systems and gene therapy applications, and for enhancement of medical imaging. We look at the problems and recent advances in the development of nanoparticles for spine-related applications and provide a comprehensive review on recent research work.

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BackgroundThe hemodynamic evaluation of cerebral arteriovenous malformations (AVMs) using DSA has not been validated against true flow measurements.ObjectiveTo validate AVM hemodynamics assessed by DSA using quantitative magnetic resonance angiography (QMRA).Materials and methodsPatients seen at our institution between 2007 and 2016 with a supratentorial AVM and DSA and QMRA obtained before any treatment were retrospectively reviewed. DSA assessment of AVM flow comprised AVM arterial-to-venous time (A-Vt) and iFlow transit time. A-Vt was defined as the difference between peak contrast intensity in the cavernous internal carotid artery and peak contrast intensity in the draining vein. iFlow transit times were determined using syngo iFlow software. A-Vt and iFlow transit times were correlated with total AVM flow measured using QMRA and AVM angioarchitectural and clinical features.Results33 patients (mean age 33 years) were included. Nine patients presented with hemorrhage. Mean AVM volume was 9.8 mL (range 0.3–57.7 mL). Both A-Vt (r=−0.47, p=0.01) and iFlow (r=−0.44, p=0.01) correlated significantly with total AVM flow. iFlow transit time was significantly shorter in patients who presented with seizure but A-Vt and iFlow did not vary with other AVM angioarchitectural features such as venous stenosis or hemorrhagic presentation.ConclusionsA-Vt and iFlow transit times on DSA correlate with cerebral AVM flow measured using QMRA. Thus, these parameters may be used to indirectly estimate AVM flow before and after embolization during angiography in real time.

Cerebral vascular disease is responsible for nearly 800 000 hospital admissions annually with a total healthcare cost of $34 billion. Neuro-interventional surgery is at the forefront of fast-response assessment and intervention to assess patients' health using digital subtraction angiography (DSA). Unfortunately, cerebral blood flow cannot be reliably measured with DSA during intervention. In this study, we introduced a novel inversion-based method to quantify blood flow from DSA intensity profiles. This technique yields absolute volumetric flow rates in major cerebral arteries comparable in accuracy to QMRA measurements. This remarkable outcome was achieved by incorporating patient-specific anatomical data as well as flow physics into the image analysis. The inversion-based flow assessment is a promising approach to render absolute flow measurements with traditional DSA. We also discuss the precision of several methods for assessing cerebral blood flow before and after intervention in DSA were investigated. Angiographic intensity data in four patients with cerebral vascular diseases were analyzed to compute time-to-peak index (TTPi) and relative cerebral angiographic blood flow index (RCABi). Flow indices were compared with quantitative magnetic resonance angiography acquired pre- and post-intervention. The results suggest that individual intensity- based flow indices do not always reflect blood flow improvements after intervention; two- dimensional index maps showed the improvements more robustly.

Classical reaction kinetics based on deterministic rates laws are not valid for the description of cellular events in which the small number of molecules introduces stochasticity with discrete instead of continuous state transitions. Stochastic models are suitable for simulating transcriptional and translational events inside biological cells, but are impractical for solving inverse problems, which aim to estimate unknown reaction propensities from experimental observations. We introduce a new mathematical framework of Ito stochastic differential equations for the modeling of discrete cellular events and the robust and consistent parameter estimation of cellular dynamics where classical reaction kinetics is invalid. The results supported by case studies on gene expression in B. subtilis cells and viral gene transcription and translation inside non-lytic viral cells demonstrate that the proposed methodology performs as reliable as the gold standard Gillespie algorithm for simulating cellular events. More importantly, the new Ito process framework is ideal for estimating unknown reaction propensities from data as readily as in deterministic parameter estimation by using the novel ‘SPE – simulation free parameter estimation’ approach. Also, the computation time for the stochastic differential equation models is significantly low when compared to discrete event simulations.

OBJECT The use of digital subtraction angiography (DSA) for semiquantitative cerebral blood flow(CBF) assessment is a new technique. The aim of this study was to determine whether patients with aneurysmal subarachnoid hemorrhage (aSAH) with higher Hunt and Hess grades also had higher angiographic contrast transit times (TTs) than patients with lower grades. METHODS A cohort of 30 patients with aSAH and 10 patients without aSAH was included. Relevant clinical information was collected. A method to measure DSA TTs by color-coding reconstructions from DSA contrast-intensity images was applied. Regions of interest (ROIs) were chosen over major cerebral vessels. The estimated TTs included time-to-peak from 0% to 100% (TTP0–100), TTP from 25% to 100% (TTP25–100), and TT from 100% to 10% (TT100–10) contrast intensities. Statistical analysis was used to compare TTs between Group A (Hunt and Hess Grade I-II), Group B (Hunt and Hess Grade III-IV), and the control group. The correlation coefficient was calculated between different ROIs in aSAH groups. RESULTS There was no difference in demographic factors between Group A (n = 10), Group B (n = 20), and the control group (n = 10). There was a strong correlation in all TTs between ROIs in the middle cerebral artery (M1, M2) and anterior cerebral artery (A1, A2). There was a statistically significant difference between Groups A and B in all TT parameters for ROIs. TT100–10 values in the control group were significantly lower than the values in Group B. CONCLUSIONS The DSA TTs showed significant correlation with Hunt and Hess grades. TT delays appear to be independent of increased intracranial pressure and may be an indicator of decreased CBF in patients with a higher Hunt and Hess grade. This method may serve as an indirect technique to assess relative CBF in the angiography suite.

Microcirculation plays a significant role in cerebral metabolism and blood flow control, yet explaining and predicting functional mechanisms remains elusive because it is difficult to make physiologically accurate mathematical models of the vascular network. As a precursor to the human brain, this paper presents a computational framework for synthesizing anatomically accurate network models for the cortical blood supply in mouse. It addresses two critical deficiencies in cerebrovascular modeling. At the microscopic length scale of individual capillaries, we present a novel synthesis method for building anatomically consistent capillary networks with loops and anastomoses (=microcirculatory closure). This overcomes shortcomings in existing algorithms which are unable to create closed circulatory networks. A second critical innovation allows the incorporation of detailed anatomical features from image data into vascular growth. Specifically, computed tomography and two photon laser scanning microscopy data are input into the novel synthesis algorithm to build the cortical circulation for the entire mouse brain in silico. Computer predictions of blood flow and oxygen exchange executed on synthetic large-scale network models are expected to elucidate poorly understood functional mechanisms of the cerebral circulation.

There is a growing research interest in quantifying blood flow distribution for the entire cerebral circulation to sharpen diagnosis and improve treatment options for cerebrovascular disease of individual patients. We present a methodology to reconstruct subject-specific cerebral blood flow patterns in accordance with physiological and fluid mechanical principles and optimally informed by in vivo neuroimage data of cerebrovascular anatomy and arterial blood flow rates. We propose an inverse problem to infer blood flow distribution across the visible portion of the arterial network that best matches subject-specific anatomy and a given set of volumetric flow measurements. The optimization technique also mitigates the effect of uncertainties by reconciling incomplete flow data and by dissipating unavoidable acquisition errors associated with medical imaging data.

Dental amalgam has been used for more than 150 years due to its beneficial mechanical properties and durability in dentistry. In the past and to date, many questions about amalgam restorations have arisen, especially regarding the mercury content, which has been the subject of global disputes. By presenting the past and present of the 'amalgam issue', the aim of our paper is to display the current position of international literature. This summary is based on the publications in the PubMed database, the guidelines of the Council of European Dentists. Although the use of dental amalgam is widespread, concerns have been raised about the adverse effect on human health and the environment, focusing on its heavy metal pollution during waste treatment. In 2017, the European Union (EU) adopted the so-called Mercury Regulation, based on the United Nations Minamata Convention on Mercury, the recommendations of which are presented in the present review. This Regulation includes the requirement for EU Member States to develop a national action plan for the phase-down of amalgam. The feasibility plan for complete phase-out may be guaranteed by 2030. The authors discuss the advantages and disadvantages of possible amalgam alternatives by presenting glass-ionomers and resin-based composites. In the future, more material research programmes and long-term follow-up studies are necessary. In addition to several global health organizations, the Council of European Dentists also draws attention to prevent dental caries, expecting to reduce the number of restorations. Orv Hetil. 2018; 159(42): 1700-1709.Absztrakt: Az amalgámot már több mint 150 éve alkalmazzák a fogászatban kedvező mechanikai tulajdonságai és tartóssága miatt. Az amalgámtöméssel kapcsolatban számos kérdés merült fel a múltban, elsősorban higanytartalma kapcsán, amely globális viták tárgyát képezte. Az „amalgámkérdés” múltjának és jelenének bemutatásával közleményünk célja a nemzetközi irodalom jelenlegi álláspontjának ismertetése. A jelen összefoglaló a PubMed adatbázisban lévő publikációk, az Európai Fogorvosok Tanácsának irányelvei és a Szakmai Kollégium Fog- és Szájbetegségek Tagozatának ajánlásán alapul. Bár a fogászati amalgám használata széles körben elterjedt, és sok előnnyel jár, aggályok merültek fel az emberi egészségre és a környezetre való káros hatása miatt, amelyben a legfőbb problémát a higanynak a csatornahálózatba való bejutása jelenti a hulladékkezelés során. Az Európai Parlament és Tanács 2017 tavaszán fogadta el a Minamata-egyezményen alapuló, higanyra vonatkozó rendeletét, amelynek a fogászati amalgámot érintő pontjait részletesen taglalja a közlemény. Az Európai Unió tagállamainak nemzeti tervet kell készíteniük az amalgám kivezetésére, amelynek előkészítése minden országban egyéni sajátosságokra épül. Az ötvözet teljes kivezetése lassan, 2030-ig valósul meg a szabályzat szerint. A szerzők az üvegionomer cementek és a műgyanta bázisú, esztétikus kompozitok ismertetése kapcsán tárgyalják a lehetséges amalgámalternatívák előnyös és hátrányos tulajdonságait. A jövőben számos anyagtani kutatás és hosszú távú követéses vizsgálat szükséges az ideális tömőanyag kifejlesztésére. Több egészségügyi világszervezet mellett az Európai Fogorvosok Tanácsa is felhívja a figyelmet a fogszuvasodás megelőzését elősegítő programokra, amelyek a restaurációk számának csökkentését javasolják. Orv Hetil. 2018; 159(42): 1700–1709.

Objective: Proximal obstruction due to cellular material is a major cause of shunt failure in hydrocephalus management. The standard approach to treat such cases involves surgical intervention which unfortunately is accompanied by inherent surgical risks and a likelihood of future malfunction. We report a prototype design of a proximal ventricular catheter capable of noninvasively clearing cellular obstruction. Methods: In-vitro cell-culture methods show that low-intensity ac signals successfully destroy a cellular layer in a localized manner by means of Joule heating induced hyperthermia. A detailed electrochemical model for determining the temperature distribution and ionic current density for an implanted ventricular catheter supports our experimental observations. Results: In-vitro experiments with cells cultured in a plate as well as cells seeded in mock ventricular catheters demonstrated that localized heating between 43 °C and 48 °C caused cell death. This temperature range is consistent with hyperthermia. The electrochemical model verified that Joule heating due to ionic motion is the primary contributor to heat generation. Conclusion: Hyperthermia induced by Joule heating can clear cellular material in a localized manner. This approach is feasible to design a noninvasive self-clearing ventricular catheter system. Significance: A shunt system capable of clearing cellular obstruction could significantly reduce the need for future surgical interventions, lower the cost of disease management, and improve the quality of life for patients suffering from hydrocephalus.

Purpose An image filter designed for reconstructing cerebrovascular trees from MR images is described. Current imaging techniques capture major cerebral vessels reliably, but often fail to detect small vessels, whose contrast is suppressed due to limited resolution, slow blood flow rate, and distortions around bifurcations or nonvascular structures. An incomplete view of angioarchitecture limits the information available to physicians. Methods A novel Hessian-based filter for contrast-enhancement in MR angiography and venography for blood vessel reconstruction without introducing dangling segments is presented. We quantify filter performance with receiver-operating-characteristic and dice-similarity-coefficient analysis. Total extracted vascular length, number-of-segments, volume, surface-to-distance, and positional error are calculated for validation. Results Reconstruction of cerebrovascular trees from MR images of six volunteers show that the new filter renders more complete representations of subject-specific cerebrovascular networks. Validation with phantom models shows the filter correctly detects blood vessels across all length scales without failing at bifurcations or distorting diameters. Conclusion The novel filter can potentially improve the diagnosis of cerebrovascular diseases by delivering metrics and anatomy of the vasculature. It also facilitates the automated analysis of large datasets by computing biometrics free of operator subjectivity. The high quality reconstruction enables computational mesh generation for subject-specific hemodynamic simulations. Magn Reson Med, 2016. © 2016 Wiley Periodicals, Inc.

Cerebrospinal fluid (CSF) is not stagnant but displays fascinating oscillatory flow patterns inside the ventricular system and reversing fluid exchange between the cranial vault and spinal compartment. This review provides an overview of the current knowledge of pulsatile CSF motion. Observations contradicting classical views about its bulk production and clearance are highlighted. A clinical account of diseases of abnormal CSF flow dynamics, including hydrocephalus, syringomyelia, Chiari malformation type 1, and pseudotumor cerebri, is also given. We survey medical imaging modalities used to observe intracranial dynamics in vivo. Additionally, we assess the state of the art in predictive models of CSF dynamics. The discussion addresses open questions regarding CSF dynamics as they relate to the understanding and management of diseases.

Extracranial cerebrospinal fluid (CSF) shunt obstruction is one of the most important problems in hydrocephalus patient management. Despite ongoing research into better shunt design, robust and reliable detection of shunt malfunction remains elusive. The authors present a novel method of correlating degree of tissue ingrowth into ventricular CSF drainage catheters with internal electrical impedance. The impedance based sensor is able to continuously monitor shunt patency using intraluminal electrodes. Prototype obstruction sensors were fabricated for in-vitro analysis of cellular ingrowth into a shunt under static and dynamic flow conditions. Primary astrocyte cell lines and C6 glioma cells were allowed to proliferate up to 7 days within a shunt catheter and the impedance waveform was observed. During cell ingrowth a significant change in the peak-to-peak voltage signal as well as the root-mean-square voltage level was observed, allowing the impedance sensor to potentially anticipate shunt malfunction long before it affects fluid drainage. Finite element modeling was employed to demonstrate that the electrical signal used to monitor tissue ingrowth is contained inside the catheter lumen and does not endanger tissue surrounding the shunt. These results may herald the development of “next generation” shunt technology that allows prediction of malfunction before it affects patient outcome.

Currently, anatomically consistent segmentation of vascular trees acquired with magnetic resonance imaging requires the use of multiple image processing steps, which, in turn, depend on manual intervention. In effect, segmentation of vascular trees from medical images is time consuming and error prone due to the tortuous geometry and weak signal in small blood vessels. To overcome errors and accelerate the image processing time, we introduce an automatic image processing pipeline for constructing subject specific computational meshes for entire cerebral vasculature, including segmentation of ancillary structures, the grey and white matter, cerebrospinal fluid space, skull, and scalp. To demonstrate the validity of the new pipeline, we segmented the entire intracranial compartment with special attention of the angioarchitecture from magnetic resonance imaging acquired for two healthy volunteers. The raw images were processed through our pipeline for automatic segmentation and mesh generation. Due to partial volume effect and finite resolution, the computational meshes intersect with each other at respective interfaces. To eliminate anatomically inconsistent overlap, we utilized morphological operations to separate the structures with a physiologically sound gap spaces. The resulting meshes exhibit anatomically correct spatial extent and relative positions without intersections. For validation, we computed critical biometrics of the angioarchitecture, the cortical surfaces, ventricular system, and cerebrospinal fluid (CSF) spaces and compared against literature values. Volumina and surface areas of the computational mesh were found to be in physiological ranges. In conclusion, we present an automatic image processing pipeline to automate the segmentation of the main intracranial compartments including a subject-specific vascular trees. These computational meshes can be used in 3D immersive visualization for diagnosis, surgery planning with haptics control in virtual reality. Subject-specific computational meshes are also a prerequisite for computer simulations of cerebral hemodynamics and the effects of traumatic brain injury.

This paper presents two studies adding validity evidence to the assessment of educational knowledge (EK) measured by a recently developed test. The first study compared the test scores of a large sample of graduates from academic teacher education with those of a sample of first-semester teacher students. Results indicate higher scores for graduates in the majority of the test’s six domains. Additionally, we gained validity evidence based on response processes by conducting 46 cognitive interviews in Study 2. Participants with different professional backgrounds stated their response strategies while taking the knowledge test. Among other results, analyses revealed that graduates and advanced students in teacher education were often familiar with item topics and solved items mostly by retrieving academic knowledge from memory. Overall, results add to previously gained evidence suggesting that test scores can be taken to measure EK mainly gained by university studies.

Purpose The aim of this prospective multicenter study was to determine 50:50% perceptibility threshold (PT) and 50:50% acceptability threshold (AT) of dental ceramic under simulated clinical settings. Materials and Methods The spectral radiance of 63 monochromatic ceramic specimens was determined using a non-contact spectroradiometer. A total of 60 specimen pairs, divided into 3 sets of 20 specimen pairs (medium to light shades, medium to dark shades, and dark shades), were selected for psychophysical experiment. The coordinating center and seven research sites obtained the Institutional Review Board (IRB) approvals prior the beginning of the experiment. Each research site had 25 observers, divided into five groups of five observers: dentists—D, dental students—S, dental auxiliaries—A, dental technicians—T, and lay persons—L. There were 35 observers per group (five observers per group at each site ×7 sites), for a total of 175 observers. Visual color comparisons were performed using a viewing booth. Takagi–Sugeno–Kang (TSK) fuzzy approximation was used for fitting the data points. The 50:50% PT and 50:50% AT were determined in CIELAB and CIEDE2000. The t-test was used to evaluate the statistical significance in thresholds differences. Results The CIELAB 50:50% PT was ΔEab = 1.2, whereas 50:50% AT was ΔEab = 2.7. Corresponding CIEDE2000 (ΔE00) values were 0.8 and 1.8, respectively. 50:50% PT by the observer group revealed differences among groups D, A, T, and L as compared with 50:50% PT for all observers. The 50:50% AT for all observers was statistically different than 50:50% AT in groups T and L. Conclusion A 50:50% perceptibility and ATs were significantly different. The same is true for differences between two color difference formulas ΔE00/ΔEab. Observer groups and sites showed high level of statistical difference in all thresholds. Clinical Significance Visual color difference thresholds can serve as a quality control tool to guide the selection of esthetic dental materials, evaluate clinical performance, and interpret visual and instrumental findings in clinical dentistry, dental research, and subsequent standardization. The importance of quality control in dentistry is reinforced by increased esthetic demands of patients and dental professionals.

Convection-enhanced delivery (CED) is an emerging field focused on administering therapeutic drugs directly to the brain to treat a multitude of pathologies ranging from malignant tumors to degenerative diseases. CED methods include direct administration of therapeutics using a catheter to the target site or using other vectors, such as nanoparticles or retroviruses to localize the therapy. In this chapter, the authors review landmark in vitro experiments, including catheter design and brain phantom models, and address contemporary challenges in catheter design, including the backflow problem. Prominent animal studies are next discussed, including tumor, epilepsy, and degenerative models, and vectors for drug delivery, including nanocarriers, liposomes, antibodies, and viral vectors are explored. Contemporary clinical trials are then outlined, including current brain tumor, neurodegenerative, and metabolic disorder initiatives. The chapter concludes with a discussion of ongoing challenges and future directions in CED which systems engineering can advance.

Intrathecal delivery of opiates directly into the cerebrospinal fluid (CSF) is the oldest technique for the delivery of anesthetics to the central nervous system (CNS). Despite the long empirical experience with spinal anesthetics, the relationships between CSF dynamics and biodistribution of intrathecally delivered drugs are complex and the mechanisms that lead to this complex distribution are poorly understood. First-principle models of fluid mechanics have been created to elucidate complex flow patterns in subject-specific computations. It has also been shown that complex CSF flow patterns are responsible for the vigorous mixing effects that govern the biodistribution of intrathecally delivered drugs. This chapter aims to link CSF flow patterns to expected drug dispersion. However, predicting the biodistribution of drugs is not an easy task. Due to the difficulty of access to the CNS, computational analysis capable of interpreting spatial and temporally distributed imaging data plays a vital role in elucidating pharmacokinetics and pharmacodynamics of intrathecal drug delivery. We review progress in our lab as well as the open literature to give a snapshot of this very active field. The chapter aims to understand better the relationship between infusion parameters and achievable drug distribution. In the near future we expect that the integration of imaging data with first-principle computational models such as those described here will enable us to design more effective drug administration strategies so that specific cells and tissue in any point of the CNS can be more effectively targeted than is the case with existing methods. We close by pointing out research directions that will pave the way for these imminent developments.