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At least 235 records · Page 13

Evaluating the Influence of Hemorheological Parameters on Circulating Tumor Cell Trajectory and Simulation Time

Extravasation of circulating tumor cells (CTCs) occurs primarily in the microvasculature, where flow and cell interactions significantly affect the blood rheology. Capturing cell trajectory at this scale requires the coupling of several interaction models, leading to increased computational cost that scales as more cells are added or the domain size is increased. In this work, we focus on micro-scale vessels and study the influence of certain hemorheological factors, including the presence of red blood cell aggregation, hematocrit level, microvessel size, and shear rate, on the trajectory of a circulating tumor cell. We determine which of the aforementioned factors significantly affect CTC motion and identify those which can potentially be disregarded, thus reducing simulation time. We measure the effect of these elements by studying the radial CTC movement and runtime at various combinations of these hemorheological parameters. To accurately capture blood flow dynamics and single cell movement, we perform high-fidelity hemodynamic simulations at a sub-micron resolution using our in-house fluid dynamics solver, HARVEY. We find that increasing hematocrit increases the likelihood of tumor cell margination, which is exacerbated by the presence of red blood cell aggregation. As microvessel diameter increases, there is no major CTC movement towards the wall; however, including aggregation causes the CTC to marginate quicker as the vessel size increases. Finally, as the shear rate is increased, the presence of aggregation has a diminished effect on tumor cell margination.

Roychowdhury, Sayan↗

Ultrasonic Doppler measurement of renal artery blood flow

An extensive evaluation of the practical and theoretical limitations encountered in the use of totally implantable CW Doppler flowmeters is provided. Theoretical analyses, computer models, in-vitro and in-vivo calibration studies describe the sources and magnitudes of potential errors in the measurement of blood flow through the renal artery, as well as larger vessels in the circulatory system. The evaluation of new flowmeter/transducer systems and their use in physiological investigations is reported.

Freund, W. R.↗

Responses of heart rate and blood pressure to KC-135 hyper-gravity

Many investigators have clarified the effects of hyper gravitational-inertial forces (G) upon the cardiovascular system, using the centrifugal apparatus with short rotating radius. We investigated the cardiovascular responses to KC-135 hyper-G flight with negligibly small angular velocity. Six normal, healthy subjects 29 to 40 years old (5 males and 1 female) took part in this experiment. Hyper gravitational-inertial force was generated by the KC-135 hyper-G flight, flown in a spiral path with a very long radius of 1.5 miles. Hyper-G was sustained for 3 minutes with 1.8 +Gz in each session and was repeatedly exposed to very subject sitting on a chair 5 times. The preliminary results of blood pressure and R-R interval are discussed. An exposure of 1.8 +Gz stress resulted in a remarkable increase of systolic and diastolic blood pressure, while the pulse pressure did not change and remained equal to the control level regardless of an exposure of hyper-G. These results in blood pressure indicate an increase of resistance in the peripheral vessels, when an exposure of hyper-G was applied. The R-R interval was calculated from ECG. R-R interval in all subjects was changed but not systematically, and R-R interval became obviously shorter during the hyper-G period than during the 1 +Gz control period although R-R interval varied widely in some cases. The coefficient of variation of R-R interval was estimated to determine the autonomic nerve activity, but no significant change was detectable.

Satake, Hirotaka↗

Fluid dynamics in flexible tubes: An application to the study of the pulmonary circulation

Based on an analysis of unsteady, viscous flow through distensible tubes, a lumped-parameter model for the dynamics of blood flow through the pulmonary vascular bed was developed. The model is nonlinear, incorporating the variation of flow resistance with transmural pressure. Solved using a hybrid computer, the model yields information concerning the time-dependent behavior of blood pressures, flow rates, and volumes in each important class of vessels in each lobe of each lung in terms of the important physical and environmental parameters. Simulations of twenty abnormal or pathological situations of interest in environmental physiology and clinical medicine were performed. The model predictions agree well with physiological data.

Kuchar, N. R.↗

Effects of aging on vasoconstrictor and mechanical properties of rat skeletal muscle arterioles

Exercise capacity and skeletal muscle blood flow during exercise are reduced with advancing age. This reduction in blood flow capacity may be related to increased reactivity of skeletal muscle resistance vessels to vasoconstrictor stimuli. The purpose of this study was to test the hypothesis that aging results in increased vasoconstrictor responses of skeletal muscle resistance arterioles. First-order (1A) arterioles (90-220 microm) from the gastrocnemius and soleus muscles of young (4 mo) and aged (24 mo) Fischer-344 rats were isolated, cannulated, and pressurized via hydrostatic reservoirs. Vasoconstriction in response to increases in norepinephrine (NE; 1 x 10(-9)-1 x 10(-4) M) and KCl (20-100 mM) concentrations and increases in intraluminal pressure (10-130 cmH(2)O) were evaluated in the absence of flow. Responses to NE and KCl were similar in both soleus and gastrocnemius muscle arterioles from young and aged rats. In contrast, active myogenic responses to changes in intraluminal pressure were diminished in soleus and gastrocnemius arterioles from aged rats. To assess whether alterations in the mechanical properties of resistance arterioles underlie altered myogenic responsiveness, passive diameter responses to pressure and mechanical stiffness were evaluated. There was no effect of age on the structural behavior (passive pressure-diameter relationship) or stiffness of arterioles from either the soleus or gastrocnemius muscles. These results suggest that aging does not result in a nonspecific decrease in vasoconstrictor responsiveness of skeletal muscle arterioles. Rather, aging-induced adaptations of vasoreactivity of resistance arterioles appear to be limited to mechanisms that are uniquely involved in the signaling of the myogenic response.

NASA Discipline Musculoskeletal↗

Instantaneous stroke volume by PDE during and after constant LBNP (-50 torr)

Six male subjects were exposed to -50 torr lower body negative pressure (LBNP) for 10 min while stroke volume was recorded beat by beat at regular intervals before, during and after release of LBNP. Stroke volume was calculated from the systolic velocity integral in the ascending aorta by pulsed Doppler echocardiography (PDE) and the cross sectional area of the vessel by M mode echocardiography. Changes in leg volume were recorded continuously and blood pressure was taken every minute. Stroke volume dropped by 51% of the control in the first 33 sec of LBNP and continued to decline slowly to -62% toward the end. Heart rate increased by 15% in the first 10 sec and was 22% above control at the end of exposure. The resulting cardiac output closely followed the course of stroke volume (-47% at 33 sec, -53% at 8 min) showing that the modest increase in heart rate did little to offset the drop in stroke volume. Leg volume increased markedly within the first 10 sec with a more gradual rise reaching +3.5% at the end. Upon sudden release of LBNP, leg volume dropped significantly during the first 3 sec simultaneously with an increase in stroke volume followed by a substantial decline in heart rate below the baseline.

Source record↗

Renin-Angiotensin System (RAS) in Hematopoietic Stem/Progenitor Cells (HS/PC) Predicts Vaso-Reparative Dysfunction and Progression of Diabetic Retinopathy (DR)

Purpose: We tested the hypothesis that loss of angiotensin converting enzyme 2 (ACE2) within diabetic HS/PCs (Hematopoietic Stem/Progenitor Cells) would be detrimental to HS/PC reparative function, and alter their ability to contribute to vascular remodeling in human subjects and rodent models of DR (Diabetic Retinopathy). Methods: Subjects (n52) were recruited as controls (n13) or diabetics (n39) with either no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR or proliferative DR (PDR). Fluorescein angiograms were analyzed using Vessel Generation Analysis (VESGEN) software in a cohort of subjects. CD34+ HS/PCs were isolated from peripheral blood. RAS (Renin-Angiotensin System) gene expression and migration was measured. Diabetic ACE2 knockout (KO)C57BL6-Ins2 (Akita) mice at 3, 6 and 9 months of diabetes were compared to age-matched controls. Bone marrow HS/PC populations were analyzed by flow cytometry and migration and proliferation studies performed. Results: ACE2 gene expression in human CD34+ cells from diabetics without DR was increased compared to controls (p0.0437). Mas receptor mRNA was also increased in diabetics without DR, but reduced with the onset of NPDR (p0.0002), suggesting a loss of compensation. DR was associated with CD34+ cell migratory dysfunction. By VESGEN analysis, vessel density measured by several confirming parameters in early NPDR (n3) was greater than in normal retina (n6) in both arteries and veins, which suggests active retinal remodeling. ACE2KO-Akita and Akita cohorts showed reduced retinal thickness by OCT (Optical Coherence Tomography) at 9 months of diabetes. Absence of ACE2 in 9-month Akita mice led to an accelerated increase in acellular capillaries compared to diabetic alone. Electroretinogram (ERG) in ACE2KO-Akita mice resulted in persistent deterioration of the neural retina. Reparative function studies showed that ACE2KO exacerbated diabetes-induced impairment of LK (Low Potassium) cell migration and proliferative functions as early as 3-month of diabetes (p0.0019). Conclusions: Retinopathy and adverse vascular remodeling in subjects with diabetes was associated with a loss of the protective arm of RAS in HS/PCs. Loss of ACE2 exacerbated vascular dysfunction in diabetic mice.

retina↗

Autoregulation of cerebral blood circulation under orthostatic tests

Autoregulation of cerebral blood flow (ACBF) under orthostatic tests (OT) was estimated in acute experiments on rabbits and cats under local anesthesia according to changes of perfusion pressure (PP) in carotid arteries, cerebral blood flow, pressure in the venous system of the brain, and resistance of cerebral vessels. The OT were conducted by turning a special table with the animal fastened to it from a horizontal to a vertical (head up or head down) position at 40 to 80 deg. In most experiments ACBF correlated with the changes of PP. Different variations of ACBF and its possible mechanisms are discussed.

Gayevyy, M. D.↗

Lymphocyte trafficking and HIV infection of human lymphoid tissue in a rotating wall vessel bioreactor

The pathogenesis of HIV infection involves a complex interplay between both the infected and noninfected cells of human lymphoid tissue, the release of free viral particles, the de novo infection of cells, and the recirculatory trafficking of peripheral blood lymphocytes. To develop an in vitro model for studying these various aspects of HIV pathogenesis we have utilized blocks of surgically excised human tonsils and a rotating wall vessel (RWV) cell culture system. Here we show that (1) fragments of the surgically excised human lymphoid tissue remain viable and retain their gross cytoarchitecture for at least 3 weeks when cultured in the RWV system; (2) such lymphoid tissue gradually shows a loss of both T and B cells to the surrounding growth medium; however, this cellular migration is reversible as demonstrated by repopulation of the tissue by labeled cells from the growth medium; (3) this cellular migration may be partially or completely inhibited by embedding the blocks of lymphoid tissue in either a collagen or agarose gel matrix; these embedded tissue blocks retain most of the basic elements of a normal lymphoid cytoarchitecture; and (4) both embedded and nonembedded RWV-cultured blocks of human lymphoid tissue are capable of productive infection by HIV-1 of at least three various strains of different tropism and phenotype, as shown by an increase in both p24 antigen levels and free virus in the culture medium, and by the demonstration of HIV-1 RNA-positive cells inside the tissue identified by in situ hybridization. It is therefore reasonable to suggest that gel-embedded and nonembedded blocks of human lymphoid tissue, cocultured with a suspension of tonsillar lymphocytes in an RWV culture system, constitute a useful model for simulating normal lymphocyte recirculatory traffic and provide a new tool for testing the various aspects of HIV pathogenesis.

Tissue Culture/instrumentation/methods↗

Direct measurement of capillary blood pressure in the human lip

In this study, we developed and tested a new procedure for measuring microcirculatory blood pressures above heart level in humans. Capillary and postcapillary venule blood pressures were measured directly in 13 human subjects by use of the servonulling micropressure technique adapted for micropuncture of lip capillaries. Pressure waveforms were recorded in 40 separate capillary vessels and 14 separate postcapillary venules over periods ranging from 5 to 64 s. Localization and determination of capillary and postcapillary vessels were ascertained anatomically before pressure measurements. Capillary pressure was 33.2 +/- 1.5 (SE) mm Hg in lips of subjects seated upright. Repeated micropunctures of the same vessel gave an average coefficient of variation of 0.072. Postcapillary venule pressure was 18.9 +/- 1.6 mm Hg. This procedure produces a direct and reproducible means of measuring microvascular blood pressures in a vascular bed above heart level in humans.

Parazynski, S. E.↗

Impact of The Protective Renin-Angiotensin System (RAS) on The Vasoreparative Function of CD34+ CACs in Diabetic Retinopathy

Purpose: In diabetes, the impaired vasoreparative function of Circulating Angiogenic Cells (CACs) is believed to contribute to the progression of diabetic retinopathy (DR). Accumulating evidence suggests that the protective arm of renin-angiotensin system (RAS) ACE2 Angiotensin-(1-7) Mas plays an important role in restoring the function of diabetic CACs. We examined the protective RAS in CACs in diabetic individuals with different stages of retinopathy. Methods: Study subjects (n43) were recruited as controls or diabetics with either no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR or proliferative DR (PDR). Fundus photography and fluorescein angiograms were analyzed using Vessel Generation Analysis (VESGEN) software in a cohort of subjects. CD34+ CACs were isolated from peripheral blood of diabetics and control subjects. RAS gene expressions in CACs were measured by qPCR. The vasoreparative function of CACs was assessed by migration ability toward CXCL12 using the QCM 5M 96-well chemotaxis cell migration assay. Results: ACE2 gene is a key enzyme converting the deleterious Angiotensin II to the beneficial Angiotensin-(1-7). ACE2 expression in CACs from diabetic subjects without DR was increased compared to controls, suggestive of compensation (p0.0437). The expression of Mas (Angiotensin-(1-7) receptor) in CACs was also increased in diabetics without DR, while was reduced in NPDR compared to controls (p0.0002), indicating a possible loss of compensation of the protective RAS at this stage of DR. The presence of even mild NPDR was associated with CD34+ CAC migratory dysfunction. When pretreating CACs of DR subjects with Angiotensin-(1-7), migratory ability to a chemoattractant CXCL12 was restored (p0.0008). By VESGEN analysis, an increase in small vessel density was observed in NPDR subjects when compared with the controls. Conclusions: These data suggest the protective RAS axis within diabetic CACs may help maintain their vasoreparative potential. The VESGEN analysis supports the presence of retinal repair in small vessels. The loss of the protective arm of RAS may predict the progression of DR.

diabetes↗

Stress, and pathogen response gene expression in modeled microgravity

Purpose: Immune suppression in microgravity has been well documented. With the advent of human exploration and long-term space travel, the immune system of the astronaut must be optimally maintained. It is important to investigate the expression patterns of cytokine genes, because they are directly related to immune response. Heat shock proteins (HSPs), also called stress proteins, are a group of proteins that are present in the cells of every life form. These proteins are induced when a cell responds to stressors such as heat, cold and oxygen deprivation. Microgravity is another stressor that may regulate HSPs. Heat shock proteins trigger immune response through activities that occur both inside the cell (intracellular) and outside the cell (extracellular). Knowledge about these two gene groups could lead to establishment of a blueprint of the immune response and adaptation-related genes in the microgravity environment. Methods: Human peripheral blood cells were cultured in 1g (T flask) and modeled microgravity (MMG, rotating-wall vessel) for 24 and 72 hours. Cell samples were collected and subjected to gene array analysis using the Affymetrix HG_U95 array. Data was collected and subjected to a two-way analysis of variance. The genes related to immune and stress responses were analyzed. Results and Conclusions: HSP70 was up-regulated by more than two fold in microgravity culture, while HSP90 was significantly down-regulated. HSP70 is not typically expressed in all kinds of cells, but it is expressed at high levels in stress conditions. HSP70 participates in translation, protein translocation, proteolysis and protein folding, suppressing aggregation and reactivating denatured proteins. Increased serum HSP70 levels correlate with a better outcome for heat-stroke or severe trauma patients. At the same time, elevated serum levels of HSP70 have been detected in patients with peripheral or renal vascular disease. HSP90 has been identified in the cytosol, nucleus and endoplasmic reticulum, and exists in many tissue types. HSP90 associates with actin filaments in certain conditions and aids cell motility. The down-regulation of HSP90 could lead to deleterious effects in the lymphocytes, thereby contributing to suppressed immune function in microgravity. Interleukins such as IL 1 alpha, IL11 receptor chain alpha, IL7R, and IL4R were significantly down regulated in modeled microgravity. Further analysis of the genes involved in immune response at the protein level may provide a basis for prophylactic and countermeasure strategies to augment the human immune system for space exploration.

Sundaresan, Alamelu↗

Influence of Gravity on Blood Volume and Flow Distribution

In our previous experiments during NASA Shuttle flights SLS 1 and 2 (9-15 days) and EUROMIR flights (30-90 days) we observed that pulmonary blood flow (cardiac output) was elevated initially, and surprisingly remained elevated for the duration of the flights. Stroke volume increased initially and then decreased, but was still above 1 Gz values. As venous return was constant, the changes in SV were secondary to modulation of heart rate. Mean blood pressure was at or slightly below 1 Gz levels in space, indicating a decrease in total peripheral resistance. It has been suggested that plasma volume is reduced in space, however cardiac output/venous return do not return to 1 Gz levels over the duration of flight. In spite of the increased cardiac output, central venous pressure was not elevated in space. These data suggest that there is a change in the basic relationship between cardiac output and central venous pressure, a persistent "hyperperfusion" and a re-distribution of blood flow and volume during space flight. Increased pulmonary blood flow has been reported to increase diffusing capacity in space, presumably due to the improved homogeneity of ventilation and perfusion. Other studies have suggested that ventilation may be independent of gravity, and perfusion may not be gravity- dependent. No data for the distribution of pulmonary blood volume were available for flight or simulated microgravity. Recent studies have suggested that the pulmonary vascular tree is influenced by sympathetic tone in a manner similar to that of the systemic system. This implies that the pulmonary circulation is dilated during microgravity and that the distribution of blood flow and volume may be influenced more by vascular control than by gravity. The cerebral circulation is influenced by sympathetic tone similarly to that of the systemic and pulmonary circulations; however its effects are modulated by cerebral autoregulation. Thus it is difficult to predict if cerebral perfusion is increased and if there is edema in space. Anecdotal evidence suggests there may be cerebral edema early in flight. Cerebral artery velocity has been shown to be elevated in simulated microgravity. The elevated cerebral artery velocity during simulated microgravity may reflect vasoconstriction of the arteries and not increased cerebral blood flow. The purpose of our investigations was to evaluate the effects of alterations in simulated gravity (+/-), resulting in changes in cardiac output (+/-), and on the blood flow and volume distribution in the lung and brain of human subjects. The first hypothesis of these studies was that blood flow and volume would be affected by gravity, but their distribution in the lung would be independent of gravity and due to vasoactivity changing vascular resistance in lung vessels. The vasodilitation of the lung vasculature (lower resistance) along with increased "compliance" of the heart could account for the absence of increased central venous pressure in microgravity. Secondly, we postulate that cerebral blood velocity is increased in microgravity due to large artery vasoconstriction, but that cerebral blood flow would be reduced due to autoregulation.

Pendergast, D.↗

Orthostatic stress is necessary to maintain the dynamic range of cardiovascular control in space

In the upright position, gravity fills the low-pressure systems of human circulation with blood and interstitial fluid in the sections below the diaphragm. Without gravity one pressure component in the vessels disappears and the relationship between hydrostatic pressure and oncotic pressure, which regulates fluid passage across the capillary endothelium in the terminal vascular bed, shifts constantly. The visible consequences of this are a puffy face and "bird" legs. The plasma volume shrinks in space and the range of cardiovascular control is reduced. When they stand up for the first time after landing, 30-50% of astronauts suffer from orthostatic intolerance. It remains unclear whether microgravity impairs cardiovascular reflexes, or whether it is the altered volume status that causes the cardiovascular instability following space flight. Lower body negative pressure was used in several space missions to stimulate the cardiovascular reflexes before, during and after a space flight. The results show that cardiovascular reflexes are maintained in microgravity. However, the astronauts' volume status changed in space, towards a volume-retracted state, as measurements of fluid-regulating hormones have shown. It can be hypothesized that the control of circulation and body fluid homeostasis in humans is adapted to their upright posture in the Earth's gravitational field. Autonomic control regulates fluid distribution to maintain the blood pressure in that posture, which most of us have to cope with for two-thirds of the day. A determined amount of interstitial volume is necessary to maintain the dynamic range of cardiovascular control in the upright posture; otherwise orthostatic intolerance may occur more often.

manned↗

VEGFA165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss

Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging and often associated with loss of pericytes. Pericytes populate the small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, in turn leading to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show that pericytes, signaled by VEGF isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1–mediated (AAV1–mediated) VEGFA165 viral vector to pericyte-depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. The restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.

60 APPLIED LIFE SCIENCES↗

Assessing blood brain barrier dynamics or identifying or measuring selected substances or toxins in a subject by analyzing Raman spectrum signals of selected regions in the eye

A non-invasive method for analyzing the blood-brain barrier includes obtaining a Raman spectrum of a selected portion of the eye and monitoring the Raman spectrum to ascertain a change to the dynamics of the blood brain barrier. Also, non-invasive methods for determining the brain or blood level of an analyte of interest, such as glucose, drugs, alcohol, poisons, and the like, comprises: generating an excitation laser beam (e.g., at a wavelength of 600 to 900 nanometers); focusing the excitation laser beam into the anterior chamber of an eye of the subject so that aqueous humor, vitreous humor, or one or more conjunctiva vessels in the eye is illuminated; detecting (preferably confocally detecting) a Raman spectrum from the illuminated portion of the eye; and then determining the blood level or brain level (intracranial or cerebral spinal fluid level) of an analyte of interest for the subject from the Raman spectrum. In certain embodiments, the detecting step may be followed by the step of subtracting a confounding fluorescence spectrum from the Raman spectrum to produce a difference spectrum; and determining the blood level and/or brain level of the analyte of interest for the subject from that difference spectrum, preferably using linear or nonlinear multivariate analysis such as partial least squares analysis. Apparatus for carrying out the foregoing methods are also disclosed.

Lambert, James L.↗

Measurement of Acute Changes in Choroid Thickness in Healthy Eyes During Posture Change Using Optical Coherence Tomography

The Visual Impairment and Intracranial Pressure (VIIP) syndrome affects 60% of astronauts returning from long-duration missions and is characterized by structural and functional changes of the eye (3). Upon entry into weightlessness, approximately two liters of fluid translocates from the lower body to the thorax and cephalad regions, potentially contributing to elevated intracranial and intraocular pressures. The choroid is the vasculature that supplies blood flow to the posterior part of the retina and has limited autoregulation. As a consequence these vessels may engorge during a cephalad fluid shift, contributing to structural changes in the retina. The purpose of this experiment was to quantify changes in choroid thickness during a fluid shift. In order to fulfill this objective, it was also necessary to improve the measurement technique for assessing choroid thickness.

Ferguson, Connor R.↗