Thom P Santisakultarm

Cornell University, Ithaca, New York, United States

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Publications (6)21.23 Total impact

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    ABSTRACT: Background Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) that share the JAK2V617F mutation in hematopoietic stem cells, leading to excessive production of predominantly platelets in ET, and predominantly red blood cells (RBCs) in PV. The major cause of morbidity and mortality in PV and ET is thrombosis, including cerebrovascular occlusive disease. Objectives: To identify the effect of excessive blood cells on cerebral microcirculation in ET and PV.Methods We used two-photon excited fluorescence microscopy to examine cerebral blood flow in transgenic mouse models that mimic MPNs.Results and Conclusions We found that flow was “stalled” in an elevated fraction of brain capillaries in ET (18%), PV (27%), mixed MPN (14%), and secondary (non-MPN) erythrocytosis (27%) mice, as compared to controls (3%). The fraction of capillaries with stalled flow increased when hematocrit value exceeded 55% in PV mice, and the majority of stalled vessels contained only stationary RBCs. In contrast, the majority of stalls in ET mice were caused by platelet aggregates. Stalls had a median persistence time of 0.5 and 1 h in ET and PV mice, respectively. Our findings shed new light on potential mechanisms of neurological problems in patients with MPNs.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 09/2014; · 6.08 Impact Factor
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    ABSTRACT: Koh, Hookam, and Leal (JFM, 1994) adapted laser-Doppler anemometry to study velocity and concentration profiles in concentrated suspensions flowing through rectangular channels. To allow measurements inside the concentrated suspensions, indices of refraction of the particles and fluid were closely matched. We report the results of measurements for a similar problem in physiology – the flow of blood, a highly concentrated suspension of red blood cells, in cortical vessels of live, anesthetized rodents. We are especially interested in measuring flow when the hematocrit – the volume fraction occupied by the red cells – exceeds normal physiological values, which are typically around 42%. Our interest stems from observations of flow deficits associated with various myeloproliferative diseases, which are characterized by an overproduction of blood cells. Using a two-photon excited fluorescence (2PEF) microscope as a velocimeter, we have measured red cell velocity profiles inside arterioles, capillaries, and venules, both in healthy animals and in animals with elevated hematocrit (up to 60%) due to myeloproliferative disease. Results demonstrate that the spatial resolution of the method is sufficient to construct detailed velocity profiles, despite the high concentration of red cells that limits other measurement methods. Furthermore, the temporal resolution of 2PEF microscopy is sufficient to determine how local velocity profiles depend on heartbeat and respiration in individual blood vessels and at vessel bifurcations. The data show that velocity profiles are blunted at all times during a cardiac cycle. The time-averaged blood flow speed decreases with vessel diameter in arterioles and in capillaries, and increases in venules. Furthermore, animals with elevated hematocrit show an abnormally large number of “stalled” capillaries that have little or no blood flow. A simple empirical model of capillary networks suggests these capillary stalls start as a result of hemodynamics and rheology. The experiments show that they can persist for long times, which can be a consequence of cell adhesion to the vessel wall. Diminished cerebral blood flow may be a cause of cognitive decline associated with myeoloproliferative disease.
    13 AIChE Annual Meeting; 11/2013
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    ABSTRACT: Subtle alterations in cerebral blood flow can impact the health and function of brain cells and are linked to cognitive decline and dementia. To understand hemodynamics in the three-dimensional vascular network of the cerebral cortex, we applied two-photon excited fluorescence microscopy to measure the motion of red blood cells (RBCs) in individual microvessels throughout the vascular hierarchy in anesthetized mice. To resolve heartbeat- and respiration-dependent flow dynamics, we simultaneously recorded the electrocardiogram and respiratory waveform. We found that centerline RBC speed decreased with decreasing vessel diameter in arterioles, slowed further through the capillary bed, and then increased with increasing vessel diameter in venules. RBC flow was pulsatile in nearly all cortical vessels, including capillaries and venules. Heartbeat-induced speed modulation decreased through the vascular network, while the delay between heartbeat and the time of maximum speed increased. Capillary tube hematocrit was 0.21 and did not vary with centerline RBC speed or topological position. Spatial RBC flow profiles in surface vessels were blunted compared with a parabola and could be measured at vascular junctions. Finally, we observed a transient decrease in RBC speed in surface vessels before inspiration. In conclusion, we developed an approach to study detailed characteristics of RBC flow in the three-dimensional cortical vasculature, including quantification of fluctuations in centerline RBC speed due to cardiac and respiratory rhythms and flow profile measurements. These methods and the quantitative data on basal cerebral hemodynamics open the door to studies of the normal and diseased-state cerebral microcirculation.
    AJP Heart and Circulatory Physiology 01/2012; 302(7):H1367-77. · 4.01 Impact Factor
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    ABSTRACT: Many planar connective tissues exhibit complex anisotropic matrix fiber arrangements that are critical to their biomechanical function. This organized structure is created and modified by resident fibroblasts in response to mechanical forces in their environment. The directionality of applied strain fields changes dramatically during development, aging, and disease, but the specific effect of strain direction on matrix remodeling is less clear. Current mechanobiological inquiry of planar tissues is limited to equibiaxial or uniaxial stretch, which inadequately simulates many in vivo environments. In this study, we implement a novel bioreactor system to demonstrate the unique effect of controlled anisotropic strain on fibroblast behavior in three-dimensional (3-D) engineered tissue environments, using aortic valve interstitial fibroblast cells as a model system. Cell seeded 3-D collagen hydrogels were subjected to cyclic anisotropic strain profiles maintained at constant areal strain magnitude for up to 96 h at 1 Hz. Increasing anisotropy of biaxial strain resulted in increased cellular orientation and collagen fiber alignment along the principal directions of strain and cell orientation was found to precede fiber reorganization. Cellular proliferation and apoptosis were both significantly enhanced under increasing biaxial strain anisotropy (P<0.05). While cyclic strain reduced both vimentin and alpha-smooth muscle actin compared to unstrained controls, vimentin and alpha-smooth muscle actin expression increased with strain anisotropy and correlated with direction (P<0.05). Collectively, these results suggest that strain field anisotropy is an independent regulator of fibroblast cell phenotype, turnover, and matrix reorganization, which may inform normal and pathological remodeling in soft tissues.
    Acta biomaterialia 01/2012; 8(5):1710-9. · 5.68 Impact Factor
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    ABSTRACT: Experimental measurements are reported of blood flow in the microcirculation of the brain cortex. We use two-photon excited fluorescence (2PEF) microscopy to measure cortical blood flow in anesthetized rats. 2PEF is a nonlinear optical technique that allows detection of fluorescence from a point in highly scattering samples such as neural tissue. By rapidly scanning the detection point throughout the sample, an “image” can be detected deep inside the cortex of a live animal. We exploit this technique to track the motion of individual red blood cells inside arterioles, capillaries, and venules in the cortex with precision that is unmatched by other in vivo measurement methods. Furthermore, we correlate the blood cell speed with heartbeat and respiration measurements to extract detailed information about time-dependent blood flow in individual vessels and at vessel bifurcations. Measurements are made in surface vessels and in capillaries deep in the brain tissue. Time-averaged blood flow speed decreases with vessel diameter in arterioles and in capillaries, and increases in venules. Blood flow speed decreases with inspiration by about 20% across all parts of the cardiac cycle. These results show that hemodynamics in the brain cortex can be resolved with high spatial and temporal resolution in vivo, which is a critical step toward identifying and quantifying cerebral blood flow abnormalities associated with a variety of hematological disorders.
    2011 AIChE Annual Meeting; 10/2011
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    Thom P Santisakultarm, Chris B Schaffer
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2011; 31(6):1337-8. · 5.46 Impact Factor