Continuous monitoring of blood oxygenation in brain is of great clinical interest. Hyperoxia and hypoxia, even over a short period of time, can lead to irreversible neurological damage. The recent progress in techniques to spectroscopically characterize turbid media has led to new possibilities to determine blood oxygenation by measuring the absorption coefficient of blood-containing biological tissues. In this work the influence of the air-tissue interface on the accuracy of the determination of tissue optical properties is examined. Different theoretical expression derived from diffusion theory under three commonly assumed boundary conditions are compared to each other, to Monte Carlo simulations and to experiments on tissue phantoms. It is shown that a simple fitting algorithm, which is based on the time-resolved diffusion theory with the zero boundary condition, can be used to determine the absorption coefficient of homogeneous tissues with high accuracy. When this algorithm is applied to heterogeneous tissues, the determined absorption coefficient has to be interpreted as an apparent absorption coefficient. For the case of layered tissues it is demonstrated, through simulations and experiments, that in most practical situations the apparent absorption coefficient equals the absorption coefficient of the underlying medium. For example, the skin, the skull and the meninges do not affect the determination of the absorption properties of the deeper located brain tissue. Furthermore, it is established that in the case of tissues with embedded, high-absorbing, blood vessels, the apparent absorption coefficient can be approximated by a volume-weighted sum of the blood absorption and the tissue-background absorption. This finding leads to a correction of commonly applied blood-oxygenation-determination algorithms, which neglect the background absorption. Experiments on tissue phantoms and biological tissues in vivo exemplify the use of the improved algorithm. Finally, it is illustrated how photon density waves can be used to distinguish between life-threatening hemorrhages and less dangerous blood-oxygenation decreases in parts of the brain. An analytical solution for the wave propagation in the present of a spherical optical inhomogeneity is derived and used to estimate the sensitivity and specificity of photon-density-wave based tomography.

The effects of dynamic mechanical stresses on the arachidonic acid (AA) metabolism of human platelets and on the cell growth properties of murine tumor cells were studied. The cells were stressed by suspending them in laminar simple shear flows. Washed human platelet suspensions were stressed at 75 dynes/cm$\sp2$ and 150 dynes/cm$\sp2$ for 5 to 10 min. at 25$\sp\circ$C. The stress stimulated AA metabolism above basal levels. The lipoxygenase metabolite 12-hydroxyeicosatetraenoic acid was preferentially formed, but the cyclooxygenase metabolite thromboxane B$\sb2$ was not detected. Thrombin-stimulated platelets, however, formed cyclooxygenase metabolites in addition to the lipoxygenase metabolites. This result indicates that the physical stresses and chemical agonists (like thrombin) affect platelet AA metabolism differently. Stress effects on tumor cells were studied using high and low metastatic sub-lines of the B16 melanoma and the RAW117 large cell lymphoma. The cells were stressed at 0, 450 and 900 dynes/cm$\sp2$ at 37$\sp\circ$C for 5 min. Damage caused by the stresses was determined by measuring the lysis in the shear field and measuring the relative reduction in cell numbers in stressed cultures compared to unstressed controls. Also, cell growth and lysis in stressed and unstressed cultures were monitored over time. The results could by modeled assuming that a subpopulation of stressed cells was lethally damaged and ultimately died while a second group of stressed cells were only sublethally damaged and grew normally after a brief lag-time. The data indicate that there was not much difference in the damage levels between high and low metastatic sub-lines and that a considerable fraction of stressed cells were not lethally damaged even at bulk shear stresses as high as 900 dynes/cm$\sp2$ for 5 min. Although the stresses applied were higher than normally seen in vivo, the results are in contrast to the accepted view that mechanical stresses developed in the circulation directly cause the destruction of most of the tumor cells during blood-borne metastasis and that highly metastatic cells can resist these stresses more effectively than poorly metastatic cells.

Sickle erythrocytes have previously been demonstrated to be abnormally adhesive to human endothelial cells in both static incubation assays and under venous flow conditions. The extent to which human fibronectin and human von Willebrand factor (vWF) can promote sickle erythrocyte adhesion to human endothelial cells was studied under venous flow conditions in a parallel-plate laminar flow chamber (wall shear stress = 1.0 dyne/cm$\sp2$). The data presented indicate that endothelial cell derived, unusually large, vWF multimers are optimally effective at promoting receptor-mediated sickle erythrocyte adhesion to endothelial cells. vWF appears to bind to erythrocyte surfaces via receptors immunologically identical to the glycoprotein Ib and glycoprotein IIb/IIIa receptors on platelet surfaces. Other cytoadhesive plasma proteins, such as fibronectin and purified plasma vWF multimers, can also promote sickle red cell adhesion to endothelial cells, but to a much lesser extent. Unusually large vWF multimers are also able to mediate the adhesion of young non-sickle red blood cells to endothelial cells. These results indicate that red cell adhesion to endothelial cells is due to an increase in the fraction of light, young erythrocytes in sickle blood and not necessarily to the presence of sickle hemoglobin. Vaso-occlusive crises in sickle cell anemia may be caused, at least in part, by adhesive interactions between the abnormal surfaces of sickle red blood cells and the endothelium after release of unusually large vWF multimeric forms from stimulated or damaged endothelial cells.

This study is concerned with the development of a multiple compartment model of the isolated cerebral artery in rat. The smooth muscle/arterial wall complex is an important component of the circulatory model and serves as a "vasomotor organ", which provides the myogenic mechanism that underlies the phenomenon of the autoregulation of blood flow. We have focused on this myogenic mechanism and have developed a model of the electrophysiological and contractile characteristics of the single smooth muscle cell of the posterior cerebral artery. This cell model is used to interrelate the topics of arterial wall stress, changes in transmembrane potential, intracellular Ca 2+ concentration and contraction. Moreover, the smooth muscle cell model is imbedded in a larger arterial wall model which converts contractile activity into changes in lumen diameter. The complete model consisting of component models of cell, wall, vessel and testing apparatus is used to provide biophysically based explanations of the myogenic mechanisms underlying the autoregulation of cerebral blood flow.

A mathematical model of external respiration integrating component models of airway/lung mechanics, pulmonary circulation and gas exchange is presented. The airway system was lumped into: (1) a conducting zone consisting of a rigid compartment in series with a collapsible segment; and (2) a respiratory zone representing respiratory bronchioles and alveolar sacs. Ventilation of the alveolar space was simulated by driving the airway mechanics model with measured intrapleural pressure waveforms obtained experimentally from human subjects in a clinical Pulmonary Function Laboratory (PFL). Pulmonary circulation was described using a lumped tubular compartment with the variation in capillary blood volume being dependent on the surrounding alveolar pressure and the blood flow rates determined by the applied intrapleural pressure and alveolar volume. Gas exchange was described using a one-dimensional spatially distributed model with transport of gas species between air in the alveoli and blood in the pulmonary capillaries driven by the species partial pressure gradient across the alveolar-capillary barrier. The effects of fluctuation in airflow upon the gas composition in the partitioned airway compartments, as well as within the pulmonary capillary, were simulated under conditions of tidal breathing, panting, and forced-vital capacity maneuvers. Results from the model were compared against experimental data obtained in the PFL from normal subjects, and demonstrate the ability of the model in producing reasonable least-squares fits to data using model parameters obtained from a parameter estimation algorithm. The identified model parameters provide a compact description of airway and lung mechanics for an individual subject and may prove useful in assessing pulmonary function and gas exchange abnormalities.

Our visual world contains both luminance- (first-order) and contrast-defined (second-order) information. Distinct mechanisms underlying the perception of first-order and second-order motion have been proposed from electrophysiological, psychophysical and neurological studies. In this thesis psychophysical and human brain imaging (fMRI) experiments are described that support the notion of distinct mechanisms, but extend the previous studies by providing evidence for a functional dissociation and a relative cortical specialization for first- and second-order motion. / Using psychophysical methods, a directional anisotropy was found for second-order but not first-order motion in peripheral vision. This anisotropy is interpreted as a functional dissociation implicating the second-order mechanism in optic flow processing. / Identification of early visual cortical areas is a prerequisite to any functional assessment of these visual areas. To this aim a novel human brain mapping method has been developed which automatically segments early human retinotopic visual areas. Unlike previous methods this procedure does not depend on a cortical surface reconstruction and thereby greatly simplifies the analysis. / In a combined psychophysical and fMRI study, distinct cortical regions, in occipital and parietal lobes, were preferentially activated by either first- or second-order motion. These results provide evidence for the idea that first-order motion is computed in V1 and second-order motion in later occipital visual areas. In addition the results suggest a functional dissociation of the two kinds of motion beyond the occipital lobe consistent with a role for the second-order mechanism in optic flow analysis.

The purpose of this study was to measure ankle stiffness in stroke patients using system identification, which provides an objective method of separating reflex and intrinsic stiffness components. / We studied twelve (12) stroke patients with clinical evidence of ankle spasticity and compared them with nine (9) gender- and age-matched controls. Subjects lay supine with their foot attached to an electro-hydraulic actuator by a custom-fitted boot. Series of pseudo-random binary sequences were used to rotate the ankle. The position, torque, and EMG recorded during these perturbations were used to separate the reflex and intrinsic contributions of ankle stiffness. / The results of this study showed that ankle stiffness was increased in four (4) stroke patients, mostly due to the increased reflex stiffness component. Furthermore, the changes in reflex stiffness varied with position; ankle stiffness increased in these stroke subjects as the ankle was dorsiflexed. The reflex gain parameter explained the increased reflex stiffness.

Understanding bladder mechanics and the changes caused by bladder outlet obstruction is an important task in urology. In this work, bladder mechanics are examined in terms of bladder hydrodynamics: the relation between a perturbing volume applied to the bladder and the evoked pressure change. A PC-based experimental system was built which can generate a computer-controlled perturbation volume and measure volume and pressure signals. / The bladders of six minipigs, three normal and three obstructed, were subjected to stochastic volume perturbations about different average volume levels and evoked pressure changes were measured. The hydrodynamic stiffness transfer function relating volume and pressure was calculated and described by a second-order, lumped parametric model having inertial, viscous and elastic terms. Estimates of the elastic constant (K) increased linearly with volume in both normal and obstructed animals. The rate of increase was substantially greater in the obstructed animals than in the normals. Consequently, this approach shows promise for distinguishing normal and obstructed bladder mechanics.

The aim of this project was to extend a mathematical model of the cardiovascular circulation, originally built by Burkhoff and Tyberg [6]. The model was implemented in Simulink and consists of 6 lumped vascular compartments interconnected by segments allowing unidirectional blood flow. A set of 6 differential equations describe changes in blood volume in the four systemic and two ventricular compartments as functions of time in terms of the pressure across each compartment and the resistances between them. The model was used to investigate why pulmonary venous pressure rises after the onset of left ventricular dysfunction. Special attention was given to the pericardial and peripheral resistance effects. Sensitivity analysis showed that our parameter values and ratios were more appropriate than those of Burkhoff and Tyberg [6]. We conclude that, although stressed volume has a fundamental role in raising the pulmonary venous pressure, contractile strength and systemic arterial resistance also contribute considerably.

This study focused on the structural genomics of granulin/epithelin modules (GEMs). Expression, purification and NMR studies of 14 out of all known 19 zebrafish GEMs allowed an assessment of the degree of structural diversity in their C-terminal subdomains. Very interestingly, one well-folded zebrafish GEM was obtained, and its three-dimensional structure was determined with high accuracy using NOE, H-bond, dihedral angle and residue dipolar coupling constraints. Solution structure determination and 15N NMR relaxation measurements indicate that one unique proline residue of the zebrafish GEM may confer the well-structured and stable folding property of the stack of all four beta-hairpins in contrast to other members of the GEM protein family.