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Drug-eluting stents are accepted as mainstream endovascular therapy, yet concerns for their safety may be under-appreciated. While failure from restenosis has dropped to below 5%, the risk of stent thrombosis and associated mortality remain relatively high. Further optimization of drug release is required to minimize thrombosis risk while maintaining therapeutic dose. The complex three-dimensional geometry of deployed stents together with the combination of diffusive and advective drug transport render an intuitive understanding of the situation exceedingly difficult. In situations such as this, computational modeling has proven essential, helping define the limits of efficacy, determine the mode and mechanism of drug release, and identify alternatives to avoid toxicity. A particularly challenging conformation is encountered in coronary arteries with overlapping stents. To study hemodynamics and drug deposition in such vessels we combined high-resolution, multi-scale ex vivo computed tomography with a flow and mass transfer computational model. This approach ensures high geometric fidelity and precise, simultaneous calculation of blood flow velocity, shear stress and drug distribution. Our calculations show that drug uptake by the arterial tissue is dependent both on the patterns of flow disruption near the wall, as well as on the relative positioning of drug-eluting struts. Overlapping stent struts lead to localized peaks of drug concentration that may increase the risk of thrombosis. Such peaks could be avoided by anisotropic stent structure or asymmetric drug release designed to yield homogeneous drug distribution along the coronary artery and, at the least, suggest that these issues need to remain in the forefront of consideration in clinical practice., National Institutes of Health (U.S.) (Grant R01 GM 49039)

Despite the observed severe effects of microgravity on mammalian cells, many astronauts have completed long term stays in space without suffering from severe health problems. This raises questions about the cellular capacity for adaptation to a new gravitational environment. The International Space Station (ISS) experiment TRIPLE LUX A, performed in the BIOLAB laboratory of the ISS COLUMBUS module, allowed for the first time the direct measurement of a cellular function in real time and on orbit. We measured the oxidative burst reaction in mammalian macrophages (NR8383 rat alveolar macrophages) exposed to a centrifuge regime of internal 0 g and 1 g controls and step-wise increase or decrease of the gravitational force in four independent experiments. Surprisingly, we found that these macrophages adapted to microgravity in an ultra-fast manner within seconds, after an immediate inhibitory effect on the oxidative burst reaction. For the first time, we provided direct evidence of cellular sensitivity to gravity, through real-time on orbit measurements and by using an experimental system, in which all factors except gravity were constant. The surprisingly ultra-fast adaptation to microgravity indicates that mammalian macrophages are equipped with a highly efficient adaptation potential to a low gravity environment. This opens new avenues for the exploration of adaptation of mammalian cells to gravitational changes.

Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L-leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B(0)AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB(0,+) and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity.

BACKGROUND Postural changes are related to changes in cerebrospinal fluid (CSF) dynamics. While sitting up leads to a decrease in cranial CSF pressure, it also causes shifts in the craniospinal CSF volume and compliance distribution. We hypothesized that jugular vein collapse in upright posture is a major contributor to these shifts in CSF volume and compliance. METHODS To test this hypothesis, we implemented a mathematical lumped-parameter model of the CSF system and the relevant parts of the cardiovascular system. In this model, the CSF and the venous system are each divided into a cranial and a spinal part. The pressures in these cranial and spinal portions differ by the posture-dependent hydrostatic pressure columns in the connecting vessels. Jugular collapse is represented by a reduction of the hydrostatic pressure difference between cranial and spinal veins. The CSF pressure-volume relationship is implemented as a function of the local CSF to venous pressure gradient. This implies that an increase in CSF volume leads to a simultaneous displacement of blood from adjacent veins. CSF pulsations driven by the cardiovascular system are introduced through a pulsating cranial arterial volume. RESULTS In upright posture, the implemented CSF pressure-volume relationship shifts to lower cranial CSF pressures compared to the horizontal position, leading to a decrease in cranial CSF pressure when sitting up. Concurrently, the compliance of the spinal compartment decreases while the one of the cranial compartment increases. With this, in upright posture only 10% of the CSF system's compliance is provided by the spinal compartment compared to 35% in horizontal posture. This reduction in spinal compliance is accompanied by a caudal shift of CSF volume. Also, the ability of the spinal CSF compartment to compensate for cerebral arterial volume pulsations reduces in upright posture, which in turn reduces the calculated craniospinal CSF flow pulsations. CONCLUSION The mathematic

Reduced intracranial compliance is a key manifestation common to a number of pathological conditions of the brain. It is encountered in, but not limited to, traumatic brain injury, cerebral edema, and hydrocephalus. There are no clinically accepted methods to measure intracranial compliance available to date. Intracranial pressure (ICP) waveform analysis is seeing a revival driven by advances in our understanding of cerebrospinal fluid and pressure dynamics. Its translation to widespread clinical use is dependent on the possibility to derive relevant metrics such as intracranial compliance reliably and non-invasively. The B-wave is one of the features of the ICP waveform, reflecting vasogenic activity of cerebral autoregulation. B-waves were originally defined to occupy the 0.5 to 2 cycles per minute frequency range. Recently renamed and redefined as slow waves with an extended range of 0.33 to 3 cycles per minute, specific changes in their pattern of occurrence are considered to be indicative of reduced intracranial compliance. With the still unmet need for a clinically acceptable method for acquiring intracranial compliance, and the revival of ICP waveform analysis, B-waves are moving back into the research focus. Herein we provide a concise review of the literature on B-waves, including a critical assessment of non-invasive methods for obtaining B-wave surrogates.

Observations of fast transport of fluorescent tracers in mouse brains have led to the hypothesis of bulk water flow directed from arterial to venous paravascular spaces (PVS) through the cortical interstitium. At the same time, there is evidence for interstitial solute transport by diffusion rather than by directed bulk fluid motion. It has been shown that the two views may be consolidated by intracellular water flow through astrocyte networks combined with mainly diffusive extracellular transport of solutes. This requires the presence of a driving force that has not been determined to date, but for which arterial pulsation has been suggested as the origin. Here we show that arterial pulsation caused by pulse wave propagation is an unlikely origin of this hypothetical driving force. However, we further show that such pulsation may still lead to fast para-arterial solute transport through dispersion, that is, through the combined effect of local mixing and diffusion in the para-arterial space.

The aim of this study was to evaluate whether possible preglomerular arterial-to-venous oxygen shunting is affected by the interaction between renal preglomerular carbon dioxide and oxygen transport. We hypothesized that a reverse (venous-to-arterial) shunting of carbon dioxide will increase partial pressure of carbon dioxide and decrease pH in the arteries and thereby lead to increased oxygen offloading and consequent oxygen shunting. To test this hypothesis, we employed a segment-wise three-dimensional computational model of coupled renal oxygen and carbon dioxide transport, wherein coupling is achieved by shifting the oxygen-hemoglobin dissociation curve in dependence of local changes in partial pressure of carbon dioxide and pH. The model suggests that primarily due to the high buffering capacity of blood, there is only marginally increased acidity in the preglomerular vasculature compared to systemic arterial blood caused by carbon dioxide shunting. Furthermore, effects of carbon dioxide transport do not promote but rather impair preglomerular oxygen shunting, as the increase in acidity is higher in the veins compared to that in the arteries. We conclude that while substantial arterial-to-venous oxygen shunting might take place in the postglomerular vasculature, the net amount of oxygen shunted at the preglomerular vasculature appears to be marginal.

GOAL The development of increasingly sophisticated cerebrospinal fluid (CSF) shunts calls for test beds that can reproduce an ever larger range of physiologic and pathophysiologic behaviors. In particular, upcoming smart and active devices will require extensive testing under complex dynamic conditions. Herein, we describe a test bed that allows for fast, cost effective, and realistic in vitro testing of active and passive, gravitational and nongravitational CSF shunts based on the hardware-in-the-loop principle. METHODS The shunt to be tested is placed in a dynamic in vitro setup that interfaces with a mathematical model of the patient's relevant physiology, which is evaluated numerically in real time. The model parameters can be identified using standard clinical tests. The test bed accounts for posture-dependent behavior and viscoelastic effects. RESULTS Simulations of infusion tests, of intracranial pressure modulation by cardiovascular action, and of the effects of postural changes show good agreement with published results. Evaluation of valves without and with gravitational units show in modeled sitting patients the expected behavior of overdrainage and avoidance thereof, respectively. Finally, a 24-h test cycle based on recorded patient data elucidates the interaction between patient and shunt system expressed by drainage rate and intracranial pressure during typical daily activities. CONCLUSION We envision this test bed as a tool to quantify a shunt's performance within a realistic yet reproducible testing environment. SIGNIFICANCE The test bed can improve our understanding of the complex interaction between patient and shunt system and may catalyze the development of active shunts, while reducing the number of necessary in vivo experiments.

Purpose: To investigate the impact of continuous positive airway pressure (CPAP) applied by a full-face fitted mask at 15 cmH2O on total cerebral blood flow (tCBF), jugular venous flow (tJVF) and cerebrospinal fluid (CSF) flow. Materials and methods: Axial 2D phase-contrast MRI measurements were acquired at the C2–C3 vertebral level for 23 healthy male awake subjects at baseline (without) and with CPAP applied. CSF flow was quantified within the spinal subarachnoid space and tCBF was quantified based on the summation of blood flow within the left and right internal carotid and vertebral arteries. tJVF was quantified based on the summation of blood flow within the left and right jugular veins. Heart rate, transcutaneous carbon dioxide (PtcCO2) and oxygen saturation were continuously monitored during the MR protocol. Results: CPAP decreased the pulse amplitude (PtPPA) of tJVF by 21% (p = 0.004). CSF stroke volume (SV) and PtPPA also decreased by 20% (p = 0.003) and 15% (p = 0.005), respectively. Change in tCBF SV and PtPPA was not significant. However, the timing of maximum systolic tCBF occurred significantly earlier under CPAP. CSF flow and tJVF waveforms showed significant spatial and temporal differences in waveform feature points, and spectral analysis revealed a decrease in the first harmonic of tJVF under CPAP (p = 0.001). Under CPAP, a 5% decrease in PtcCO2 (p = 0.003) and 9% increase in HR (p = 0.006) were measured. However, these HR and PtcCO2 changes were not correlated with any changes in arterial, venous or CSF flow dynamics. Conclusion: Application of CPAP via a full-fitted mask at 15 cm H2O was found to have a significant effect on intracranial venous outflow and spinal CSF flow at the C2 vertebral level in healthy adult-age awake volunteers. CPAP can be used to non-invasively provoke changes in intracranial and CSF flow dynamics.

“What is the O2 concentration in a normoxic cell culture incubator?” This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level.

The brain possesses an intricate network of interconnected fluid pathways that are vital to the maintenance of its homeostasis. With diffusion being the main mode of solute transport in cerebral tissue, it is not clear how bulk flow through these pathways is involved in the removal of metabolites. In this computational study, we show that networks of astrocytes may contribute to the passage of solutes between tissue and paravascular spaces (PVS) by serving as low resistance pathways to bulk water flow. The astrocyte networks are connected through aquaporin-4 (AQP4) water channels with a parallel, extracellular route carrying metabolites. Inhibition of the intracellular route by deletion of AQP4 causes a reduction of bulk flow between tissue and PVS, leading to reduced metabolite clearance into the venous PVS or, as observed in animal studies, a reduction of tracer influx from arterial PVS into the brain tissue.