Effect of convection in capillaries on oxygen removal from arterioles in striated muscle

Based on experimental data that show the presence of significant oxygen saturation gradients in precapillary arterioles, it has been suggested that the in vivo permeability to oxygen of resting striated muscle may be significantly higher than the corresponding in vitro value obtained in unperfused tissue samples (Popel et al., 1989b, Adv. expl. Med. Biol. 247, 215). The present study performs two analyses to further compare theoretical predictions with experimental data obtained under control conditions and during hemodilution and hemoconcentration. First, it is shown that, in principle, a capillary-perfused tissue layer with a thickness of a few hundred microns is necessary to convectively carry the experimentally determined amount of oxygen released by precapillary arterioles under control and hemodiluted conditions. This capacity to convect oxygen depends strongly on the resting tissue oxygen tension. Second, a more general version of a previous model (Weerappuli & Popel, 1989, J. Biomech. Eng. 111, 24) is used to examine whether changes made in the model parameters within the physiological range of values can explain the experimentally measured flux. The results show that the theoretical predictions can be made compatible with experimental observations if the in vivo permeability of perfused tissue to oxygen is assumed to be one to two orders of magnitude higher than the in vitro value. Furthermore, the predicted in vivo permeability for perfused tissue surrounding an arteriole varies with the arteriolar luminal oxygen tension and flow. This may be due to simplifying approximations made in the model or possible experimental artifacts. Alternatively, it could also be speculated that this variability indicates the flow dependency of the permeability of perfused tissue to oxygen.     

Computational modeling of progressive damage and rupture in fibrous biological tissues: application to aortic dissection

This study analyzes the lethal clinical condition of aortic dissections from a numerical point of view. On the basis of previous contributions by Gültekin et al. (Comput Methods Appl Mech Eng 312:542–566, 2016 and 331:23–52, 2018), we apply a holistic geometrical approach to fracture, namely the crack phase-field, which inherits the intrinsic features of gradient damage and variational fracture mechanics. The continuum framework captures anisotropy, is thermodynamically consistent and is based on finite strains. The balance of linear momentum and the crack evolution equation govern the coupled mechanical and phase-field problem. The solution scheme features the robust one-pass operator-splitting algorithm upon temporal and spatial discretizations. Based on experimental data of diseased human thoracic aortic samples, the elastic material parameters are identified followed by a sensitivity analysis of the anisotropic phase-field model. Finally, we simulate an incipient propagation of an aortic dissection within a multi-layered segment of a thoracic aorta that involves a prescribed initial tear. The finite element results demonstrate a severe damage zone around the initial tear and exhibit a rather helical crack pattern, which aligns with the fiber orientation. It is hoped that the current contribution can provide some directions for further investigations of this disease.

     

Frequency dispersions of human skin dielectrics.

The electrical properties of many biological materials are known to exhibit frequency dispersions. In the human skin, the impedance measured at various frequencies closely describes a circular locus of the Cole-Cole type in the complex impedance plane. In this report, the formative mechanisms responsible for the anomalous circular-arc behavior of skin impedance were investigated, using data from impedance measurements taken after successive strippings of the skin. The data were analyzed with respect to changes in the parameters of the equivalent Cole-Cole model after each stripping. For an exponential resistivity profile (Tregear, 1966, Physical Functions of Skin; Yamamoto and Yamamoto, 1976, Med. Biol. Eng., 14:151--158), the profile of the dielectric constant was shown to be uniform across the epidermis. Based on these results, a structural model has been formulated in terms of the relaxation theory of Maxwell and Wagner for inhomogeneous dielectric materials. The impedance locus obtained from the model approximates a circular are with phase constant alpha = 0.82, which compares favorably with experimental data. At higher frequencies a constant-phase, frequency-dependent component having the same phase constant alpha is also demonstrated. It is suggested that an approximately rectangular distribution of the relaxation time over the epidermal dielectric sheath is adequate to account for the anomalous frequency characteristics of human skin impedance.     

Large deforming buoyant embolus passing through a stenotic common carotid artery: a computational simulation

Arterial embolism is responsible for the death of lots of people who suffers from heart diseases. The major risk of embolism in upper limbs is that the ruptured particles are brought into the brain, thus stimulating neurological symptoms or causing the stroke. We presented a computational model using fluid-structure interactions (FSI) to investigate the physical motion of a blood clot inside the human common carotid artery. We simulated transportation of a buoyant embolus in an unsteady flow within a finite length tube having stenosis. Effects of stenosis severity and embolus size on arterial hemodynamics were investigated. To fulfill realistic nonlinear property of a blood clot, a rubber/foam model was used. The arbitrary Lagrangian-Eulerian formulation (ALE) and adaptive mesh method were used inside fluid domain to capture the large structural interfacial movements. The problem was solved by simultaneous solution of the fluid and the structure equations. Stress distribution and deformation of the clot were analyzed and hence, the regions of the embolus prone to lysis were localized. The maximum magnitude of arterial wall shear stress during embolism occurred at a short distance proximal to the throat of the stenosis. Through embolism, arterial maximum wall shear stress is more sensitive to stenosis severity than the embolus size whereas role of embolus size is more significant than the effect of stenosis severity on spatial and temporal gradients of wall shear stress downstream of the stenosis and on probability of clot lysis due to clot stresses while passing through the stenosis.     

Studies on the filtration properties of isolated renal basement membranes.

1. The filtration properties of films of renal basement membrane were studied in vitro using pressure filtration chambers. 2. Retention of cytochrome c by the films was found to be dependent upon the filtration pressure indicating that it was transferred across the films by convective as well as diffusive flow. In contrast, serum albumin was transferred by diffusive movement only. 3. When solutions containing both cytochrome c and IgG were filtered it was found that increasing the filtration pressure reduced the flux of cytochrome c across the films. A similar phenomenon occurred when serum was filtered, less protein passed through the films at high filtration pressures. These phenomena are explained by concentration-polarisation effects. 4. The flux of cytochrome c through the films was found to decrease in a non-linear manner as the films thickness was increased. With thin films, the flux of cytochrome c increased in a non-linear manner as the concentration of the protein in the overstanding solution was increased. With thicker films the flux was linearly dependent on concentration. These findings are interpreted as supporting the view that movement of cytochrome c occurs, at least in part, by convective flow.     

Implications of different classes of sensorimotor disturbance for cerebellar-based motor learning models

The exact role of the cerebellum in motor control and learning is not yet fully understood. The structure, connectivity and plasticity within cerebellar cortex has been extensively studied, but the patterns of connectivity and interaction with other brain structures, and the computational significance of these patterns, is less well known and a matter of debate. Two contrasting models of the role of the cerebellum in motor adaptation have previously been proposed. Most commonly, the cerebellum is employed in a purely feedforward pathway, with its output contributing directly to the outgoing motor command. The cerebellum must then learn an inverse model of the motor apparatus in order to achieve accurate control. More recently, Porrill et al. (Proc Biol Sci 271(1541):789–796, 2004) and Porrill et al. (PLoS Comput Biol 3:1935–1950, 2007a) and Porrill et al. (Neural Comput 19(1), 170–193, 2007b) have highlighted the potential importance of these recurrent connections by proposing an alternative architecture in which the cerebellum is embedded in a recurrent loop with brainstem control circuitry. In this framework, the feedforward connections are not necessary at all. The cerebellum must learn a forward model of the motor apparatus for accurate motor commands to be generated. We show here how these two models exhibit contrasting yet complimentary learning capabilities. Central to the differences in performance between architectures is that there are two distinct kinds of disturbance to which a motor system may need to adapt (1) changes in the relationship between the motor command and the observed outcome and (2) changes in the relationship between the stimulus and the desired outcome. The computational distinction between these two kinds of transformation is subtle and has therefore often been overlooked. However, the implications for learning turn out to be significant: learning with a feedforward architecture is robust following changes in the stimulus-desired outcome mapping but not necessarily the motor command-outcome mapping, while learning with a recurrent architecture is robust under changes in the motor command-outcome mapping but not necessarily the stimulus-desired outcome mapping. We first analyse these differences theoretically and through simulations in the vestibulo-ocular reflex (VOR), then illustrate how these same concepts apply more generally with a model of reaching movements.     

Modelling the impact of clot fragmentation on the microcirculation after thrombectomy

Many ischaemic stroke patients who have a mechanical removal of their clot (thrombectomy) do not get reperfusion of tissue despite the thrombus being removed. One hypothesis for this ‘no-reperfusion’ phenomenon is micro-emboli fragmenting off the large clot during thrombectomy and occluding smaller blood vessels downstream of the clot location. This is impossible to observe in-vivo and so we here develop an in-silico model based on in-vitro experiments to model the effect of micro-emboli on brain tissue. Through in-vitro experiments we obtain, under a variety of clot consistencies and thrombectomy techniques, micro-emboli distributions post-thrombectomy. Blood flow through the microcirculation is modelled for statistically accurate voxels of brain microvasculature including penetrating arterioles and capillary beds. A novel micro-emboli algorithm, informed by the experimental data, is used to simulate the impact of micro-emboli successively entering the penetrating arterioles and the capillary bed. Scaled-up blood flow parameters–permeability and coupling coefficients–are calculated under various conditions. We find that capillary beds are more susceptible to occlusions than the penetrating arterioles with a 4x greater drop in permeability per volume of vessel occluded. Individual microvascular geometries determine robustness to micro-emboli. Hard clot fragmentation leads to larger micro-emboli and larger drops in blood flow for a given number of micro-emboli. Thrombectomy technique has a large impact on clot fragmentation and hence occlusions in the microvasculature. As such, in-silico modelling of mechanical thrombectomy predicts that clot specific factors, interventional technique, and microvascular geometry strongly influence reperfusion of the brain. Micro-emboli are likely contributory to the phenomenon of no-reperfusion following successful removal of a major clot.     

Estimates for the acoustical stimulation and heating of multiphase biotissue

Low-intensity, unfocused, ultrasound-induced diathermy can produce undesired temperature increases at the interface of adjacent tissues within the body; particularly, at the interface of soft tissue and bone. This study provides a computational framework for predicting an upper bound on the temperature profile within a multiphase system composed of gel pad (water), tissue and bone from an input of acoustic energy, at frequencies and power levels consistent with applications of therapeutic hyperthermia. The model consists of solving a (one-dimensional) spatially discretized bioheat transfer equation via finite-difference method and updating the solution in time with a forward-Euler scheme. Simulations are then compared to experimental data to determine the energy-to-heat conversion factors within each constituent material using thermocouple-embedded, tissue-mimicking phantom material, with and without bone. Viscous heating artifacts from the presence of the thermocouples in the experimental phantom tissue are accounted for via additional experimental methods similar to those described by Morris et al. (Phys Med Biol 53:4759, 2008). Finally, an example application of the model is presented via prediction of the maximum temperature at the tissue–bone interface, as well as the peak temperatures in the composite structure at the end of a prescribed 2-min sonication, of blood-perfused, human soft-tissue at 1, 2 and 3 MHz frequencies and a spatial peak temporally averaged intensity of \(1.0 \ W/cm^{2}\). The results of this simulation are then related to comparable experimental studies in the literature.     

Hydroxyl radicals is not a significant intermediate in the vanadate-stimulated oxidation of NAD(P)H by O2

The vanadate-stimulated oxidation of NADH by an enzymatic flux of O2- is inhibited by superoxide dismutase, but not by catalase. Keller et al. (1989, Free Radical Biol. Med. 6, 15-22) observed inhibition by catalase presumably because they used a commercial preparation contaminated with superoxide dismutase. Their proposal, that H2O2 and hydroxyl radical play significant roles in vanadate-stimulation of NAD(P)H oxidation, may be discounted on the basis of these and of previously reported results.     

A two-barrier compartment model for volume flow across amphibian skin

The amphibian skin has long been used as a model tissue for the study of ion transport and osmotic water movement across tight epithelia. To understand the mechanism of water uptake across amphibian skin, we model the skin as a well-stirred compartment bounded by an apical barrier and a tissue barrier. The compartment represents the lateral intercellular space between cells in the stratum granulosum. The apical barrier represents the stratum corneum, the principal/mitochondria-rich cells, and the junctional area between cells. This barrier is hypothesized to have the ability to actively transport solutes through Na+-K+-ATPase. The actively transported solute flux is assumed to satisfy the Michaelis-Menten relationship. The tissue barrier represents a composite barrier comprising the stratum spinosum, the stratum germinativum, the basal lamina, and the dermis. Our model shows that 1) the predicted rehydration rates from apical bathing solutions are in good agreement with the experiment results in Hillyard and Larsen (J Comp Physiol 171: 283-292, 2001); 2) under their experimental conditions, there is a substantial volume flux coupled to the active solute flux and this coupled volume flux is nearly constant when the osmolality of the apical bathing solution is >100 mosmol/kgH2O; 3) the molar ratio of the actively transported solute flux to the coupled water flux is about 1:160, which is the same as that reported in Nielsen (J Membr Biol 159: 61-69, 1997).     

Blood Clot Formation Does Not Affect Metastasis Formation or Tumor Growth in a Murine Model of Breast Cancer

Cancer is associated with increased fracture risk, due either to metastasis or associated osteoporosis. After a fracture, blood clots form. Because proteins of the coagulation cascade and activated platelets promote cancer development, a fracture in patients with cancer often raises the question whether it is a pathologic fracture or whether the fracture itself might promote the formation of metastatic lesions. We therefore examined whether blood clot formation results in increased metastasis in a murine model of experimental breast cancer metastasis.For this purpose, a clot was surgically induced in the bone marrow of the left tibia of immundeficient mice. Either one minute prior to or five minutes after clot induction, human cancer cells were introduced in the circulation by intracardiac injection. The number of cancer cells that homed to the intervention site was determined by quantitative real-time PCR and flow cytometry. Metastasis formation and longitudinal growth were evaluated by bioluminescence imaging.The number of cancer cells that homed to the intervention site after 24 hours was similar to the number of cells in the opposite tibia that did not undergo clot induction. This effect was confirmed using two more cancer cell lines. Furthermore, no difference in the number of macroscopic lesions or their growth could be detected. In the control group 72% developed a lesion in the left tibia. In the experimental groups with clot formation 79% and 65% developed lesions in the left tibia (p = ns when comparing each experimental group with the controls). Survival was similar too.In summary, the growth factors accumulating in a clot/hematoma are neither enough to promote cancer cell homing nor support growth in an experimental model of breast cancer bone metastasis. This suggests that blood clot formation, as occurs in traumatic fractures, surgical interventions, and bruises, does not increase the risk of metastasis formation.     

Mechanisms for the formation and transport of ion fluxes in the plasma of a high-current vacuum spark

The processes of ion flux formation in the plasma of a high-current vacuum spark were investigated experimentally. It is shown that multicharged ions are generated in the neck formed in the erosion products of the inner electrode. The plasma escaping from the neck region plays a role of a piston dragging particles of the cold peripheral plasma into ambient space. As the discharge current increases, the flux of the evaporated electrode material grows, the degree of ionization of the plasma produced decreases, and the efficiency of plasma heating caused by the pinching effect is reduced.     

Human albumin prevents 6-hydroxydopamine-induced loss of tyrosine hydroxylase in in vitro and in vivo

Human albumin has recently been demonstrated to protect brain neurons from injury in rat ischemic brain. However, there is no information available about whether human albumin can prevent loss of tyrosine hydroxylase (TH) expression of dopaminergic (DA) neurons induced by 6-hydroxydopamine (6-OHDA) toxicity that is most commonly used to create a rat model of Parkinson's disease (PD). In the present study, two microliters of 1.25% human albumin were stereotaxically injected into the right striatum of rats one day before or 7 days after the 6-OHDA lesion in the same side. D-Amphetamine-induced rotational asymmetry was measured 7 days, 3 and 10 weeks after 6-OHDA lesion. We observed that intrastriatal administration of human albumin significantly reduced the degree of rotational asymmetry. The number of TH-immunoreactive neurons present in the substantia nigra was greater in 6-OHDA lesioned rats following human albumin-treatment than non-human albumin treatment. TH-immunoreactivity in the 6-OHDA-lesioned striatum was also significantly increased in the human albumin-treated rats. To examine the mechanisms underlying the effects of human albumin, we challenged PC12 cells with 6-OHDA as an in vitro model of PD. Incubation with human albumin prevented 6-OHDA-induced reduction of cell viability in PC12 cell cultures, as measured by MTT assay. Furthermore, human albumin reduced 6-OHDA-induced formation of reactive oxygen species (ROS) and apoptosis in cultured PC12 cells, as assessed by flow cytometry. Western blot analysis showed that human albumin inhibited 6-OHDA-induced activation of JNK, c-Jun, ERK, and p38 mitogen-activated protein kinases (MAPK) signaling in PC12 cultures challenged with 6-OHDA. Human albumin may protect against 6-OHDA toxicity by influencing MAPK pathway followed by anti-ROS formation and anti-apoptosis.     

Skeletal muscle mitochondrial beta-oxidation. A study of the products of oxidation of [U-14C]hexadecanoate by h.p.l.c. using continuous on-line radiochemical detection.

Well-coupled mitochondrial fractions were prepared from rat skeletal muscle without the use of proteolytic enzymes. The products of [U-14C]hexadecanoate oxidation by rat skeletal muscle mitochondrial fractions were analysed by h.p.l.c. with on-line radiochemical detection. In the presence of 1 mM-carnitine, 70% of the products is acetylcarnitine. In agreement with Veerkamp et al. [Veerkamp, van Moerkerk, Glatz, Zuurveld, Jacobs & Wagenmakers (1986) Biochem. Med. Metab. Biol. 35, 248-259] 14CO2 release is shown to be an unreliable estimate of flux through beta-oxidation in skeletal muscle mitochondrial fractions. The flux through beta-oxidation is recorded unambiguously polarographically in the presence of 1 mM-carnitine and the absence of citrate cycle intermediates.     

Estimation of Cell Proliferation Dynamics Using CFSE Data

Advances in fluorescent labeling of cells as measured by flow cytometry have allowed for quantitative studies of proliferating populations of cells. The investigations (Luzyanina et al. in J. Math. Biol. 54:57–89, 2007; J. Math. Biol., 2009; Theor. Biol. Med. Model. 4:1–26, 2007) contain a mathematical model with fluorescence intensity as a structure variable to describe the evolution in time of proliferating cells labeled by carboxyfluorescein succinimidyl ester (CFSE). Here, this model and several extensions/modifications are discussed. Suggestions for improvements are presented and analyzed with respect to statistical significance for better agreement between model solutions and experimental data. These investigations suggest that the new decay/label loss and time dependent effective proliferation and death rates do indeed provide improved fits of the model to data. Statistical models for the observed variability/noise in the data are discussed with implications for uncertainty quantification. The resulting new cell dynamics model should prove useful in proliferation assay tracking and modeling, with numerous applications in the biomedical sciences.     

Factors influencing lesion formation during radiofrequency catheter ablation

In radiofrequency (RF) ablation, the heating of cardiac tissue is mainly resistive. RF current heats cardiac tissue and in turn the catheter electrode is being heated. Consequently, the catheter tip temperature is always lower--or ideally equal--than the superficial tissue temperature. The lesion size is influenced by many parameters such as delivered RF power, electrode length, electrode orientation, blood flow and tissue contact. This review describes the influence of these different parameters on lesion formation and provides recommendations for different catheter types on selectable parameters such as target temperatures, power limits and RF durations.     

Metabolic model of autoregulation in the Circle of Willis

The Circle of Willis (CoW) is a ringlike structure of blood vessels found at the base of the brain. Its main function is to distribute oxygen-rich arterial blood to the cerebral mass. In a previous study, a one-dimensional (1D) model of the CoW was created to simulate a series of possible clinical scenarios such as occlusions in afferent arteries, absent or stringlike circulus vessels, or arterial infarctions (Moorhead et al., 2004, Comput. Methods Biomech. Biomed. Eng., 7(3), pp. 121-130). The model captured cerebral haemodynamic autoregulation by using a proportional-integral-derivative (PID) controller to modify efferent artery resistances. Although some good results and correlations were achieved, the model was too simple to capture all the transient dynamics of autoregulation. Hence a more physiologically accurate model has been created that additionally includes the oxygen dynamics that drive the autoregulatory response. Results very closely match accepted physiological response and limited clinical data. In addition, a set of boundary conditions and geometry is presented for which the autoregulated system cannot provide sufficient perfusion, representing a condition with increased risk of stroke and highlighting the importance of modeling the haemodynamics of the CoW. The system model created is computationally simple so it can be used to identify at-risk cerebral arterial geometries and conditions prior to surgery or other clinical procedures.     

Relatively simple, precise methods to analyze temperature transients in ectotherms

Relatively complex core-shell models have been used to precisely characterize times and temperatures for ectotherms. There is a simpler method using a second-order analysis of heat flux. We derive the method from an equivalent mechanical system, correct some previously published inaccuracies, and show how to use the method by analyzing thermal transients for House Wren eggs under natural conditions.     

Dynamics of initial L-cell adhesion. II. Competition of albumin and serum activating factor

The initial attachment process of L cells is studied by the combined action of serum and albumin. Both the substances are added jointly in the Eagle medium or one of them was adsorbed on the substrate previously. The results show that there are two factors in the serum: one depressing the cell attachment, like albumin, and the other being just opposite. The simple kinetical competition model is suggested to describe the experimental dependence of final level of attachment on the concentrations of serum and albumin. The examination of the thermal resistance of the serum factor is made; the previous heating to 60-100 degrees C increases the depressing effect of serum and albumin.