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Biomedical subjects

G M Saidel

Publications and source records attributed to G M Saidel.

At least 19 recordsLinked to original sources
PubMed2001

Temperature and perfusion responses of muscle and lung tissue during chronic heating in vivo.

For the first time, both temperature and perfusion responses have been obtained from in vivo studies of chronically heated lung and muscle tissue of calves. In each tissue, the spatial temperature distribution was measured by thermistors placed in needles at several distances from an implanted heated disc. A perfusion parameter was defined for a bioheat transfer model that describes temperature dynamics with distance from the heated disc. Estimates of perfusion were obtained by a least-squares fit of the model output to a step change in heat flux. Except for short transient experiments several times a week, a constant heat flux of 0.04, 0.06 or 0.08 Wcm(-2) was maintained at the disc surface for up to seven weeks. At the higher heat fluxes, the steady-state tissue temperature decreased with heating duration. Also, the characteristic time constants of the tissues decreased with heating duration. Muscle perfusion showed a statistically significant increase during chronic heating. Tissue adapts to chronic heating above 42 degrees C by allowing more capillary blood flow that increases heat loss to reduce tissue temperature.

Adaptation, Physiological↗
PubMed2000

Iterative optimal design of PET experiments for estimating beta-adrenergic receptor concentration.

To estimate in vivo myocardial beta-adrenergic receptor concentration with sufficient precision and to reduce the experimental complexities in positron emission tomography (PET), an iterative optimal design method is applied. An initial three-injection protocol, utilising [F-18]-labelled (R)- and (S)-fluorocarazolol and unlabelled (S)-fluorocarazolol, is optimised for ligand dosages and administration times to maximise the precision of all model parameters using the D-optimal criterion. Using this experimental protocol, PET data are collected in porcine studies, and model parameters are estimated. All model parameters are identified with satisfactory precision. The in vivo myocardial beta-receptor concentration is 7.5+/-0.6 pmol x ml(-1), which corresponds to the in vitro result of 10.1+/-1.3 pmol x ml(-1). With more accurate parameter values, a simplified two-injection protocol is optimally designed, utilising only radiolabelled and unlabelled (S)-fluorocarazolol, based on a new criterion to maximise the precision of the beta-receptor concentration. This revised optimum design predicts that the in vivo beta-receptor concentration can be estimated with good precision but reduced experiment complexity.

Adrenergic beta-Antagonists↗
PubMed1999

A model analysis of lactate accumulation during muscle ischemia.

PURPOSE: The mechanistic basis of the relationship between tissue [O2] and tissue or blood lactate (LA) concentration during tissue hypoxia are not fully understood. However, blood and tissue lactate accumulation are still used as indicators of tissue hypoxia in critically ill patients. To investigate this relationship, we applied a previously developed mathematical model of human bioenergetics to simulate the integrated responses (cellular, tissue, and whole body) to moderate (10% to 45%) and severe (50% to 80%) reductions in muscle blood flow. MATERIALS AND METHODS: Model simulations of muscle ischemia predicted metabolite concentration changes in muscle, splanchnic bed, and other tissues, and were compared with experimental data in humans for model validation. RESULTS: In general, simulations closely predicted the pattern of change in substrates and control metabolites to that observed experimentally. Specifically, simulations showed that most of the increase in muscle LA production during moderate ischemia was due to an increase in pyruvate (PY) and notto the change in redox state induced by a small decrease in O2 consumption. However, during severe ischemia, changes in [LA]/[PY] ratio in venous blood corresponded very closely to changes in tissue redox state. Because both blood [LA] and [LA]/[PY] tracked changes in tissue redox state very well, these can be used reliably as indices of tissue hypoxia during severe muscle ischemia. CONCLUSIONS: Based on the simulations, the commonly used threshold value for venous [LA]/[PY] = 14 as evidence of tissue hypoxia seems appropriate during severe ischemia.

Computer Simulation↗
PubMed1999

Lactate metabolism during exercise: analysis by an integrative systems model.

To provide a framework for quantitative analysis of metabolic and transport processes associated with ATP production during exercise, we adapted a recently developed model that links cellular metabolism and its control to whole body responses at rest. The enhanced model is based on dynamic mass balances for glycogen, glucose, pyruvate (PY), lactate (LA), O(2), and CO(2) and is solved numerically to simulate responses to acute (<20 min), moderate exercise (i.e., below the LA threshold, less than approximately 60% maximal rate of O(2) uptake). Simulations of responses to a step change in muscle ATP turnover predict substrate changes in muscle, splanchnic, and other tissues compartments, as well as changes in other metabolites (e.g., NADH, ADP) whose reactions are coupled to the main reactions. Even a significant (64%) decrease in muscle O(2) concentration (C(m, O(2))) did not affect muscle O(2) consumption. Model simulations of moderate exercise show that 1) muscle oxygenation is sufficient (C(m, O(2)) >2 mM) even during the transient state; 2) transient increases in concentration of muscle LA and arterial concentration of LA are associated with increases in glycolysis from increases in ADP/ATP and in LA production associated with a rise in NADH/NAD; 3) muscle ADP/ATP reaches a higher steady state that stimulates glycolysis, glycogenolysis, and oxidative phosphorylation to match the ATP demand; and 4) muscle NADH/NAD reaches a lower steady state that stimulates LA oxidation. It is suggested that the continuous stimulation of ATP synthesis processes during moderate exercise is mainly due to a higher ADP/ATP, not to a higher NADH/NAD. Critical measurements needed to quantify metabolic control mechanisms are identified.

Adenosine Triphosphate↗
PubMed1998

System for dynamic measurements of membrane capacitance in intact epithelial monolayers.

Dynamic measurements of exocytosis have been difficult to perform in intact epithelial monolayers. We have designed a system that estimates with +/-1% accuracy (99% confidence) the total membrane capacitance of monolayers represented by a lumped model. This impedance measurement and analysis system operates through a conventional transepithelial electrophysiology clamp, performing all signal measurements as frequently as every 5 s. Total membrane capacitance (the series combination of apical and basolateral membranes) is the inverse of one of three unique coefficients that describe the monolayer impedance. These coefficients are estimated using a weighted, nonlinear, least-squares algorithm. Using the estimated coefficients, solution ranges for individual membrane parameters are calculated, frequently providing results within +/-20% of true values without additional electrophysiological measurements. We determined the measurement system specifications and statistical significance of estimated parameters using 1) analytical testing with circuit simulation software and equation-generated data; 2) a system noise analysis combined with Monte Carlo simulations; and 3) analog model circuits for calibration of the electronic system and to check equation-generated results. Finally, the time course of capacitance changes associated with purinergically stimulated mucin exocytosis are quantified in monolayers of the colonic goblet cell-like cell line HT29-CI.16E.

Algorithms↗
PubMed1998

A mechanistic model of plasma filtration.

A model describing the sieving and transmembrane pressure behavior of plasma filtration is developed and numerically simulated. The model assumes a mechanistic criteria for particle passage through a membrane with cylindrical pores. The initial pore diameter distribution and porosity are assumed to be known. Model inputs include the particle diameter distribution, concentration and total flow rate of the permeate plasma solution. Outputs of the model include transmembrane pressure, the time-averaged sieving coefficients, and size distributions of the deposited particles and accumulated filtrate particles. Optimal filtration is characterized by high, stable sieving coefficients for desired particles, high retention of larger particles and relatively small increases in transmembrane pressure. These characteristics are realized for membranes with mean pore diameters equal to or slightly larger than mean permeate particle diameters. Simulations demonstrate that the incorporation of membrane properties into models of plasma filtration is both significant and readily possible.

Biophysical Phenomena↗
PubMed1998

Characterization of tissue morphology, angiogenesis, and temperature in the adaptive response of muscle tissue to chronic heating.

Previous investigations on the in vivo effects of chronic heat on tissue suggest a response whereby heated tissue temperatures decrease over time. This response occurred in conjunction with localized angiogenesis, which possibly contributed to the temperature decreases by increasing local perfusion and enhancing tissue heat transfer. Our own studies were the first to use a chronic heat source to heat tissue at initial interfacial temperatures between 40 degrees C and 46 degrees C. Initial temperatures above 45.3+/-2.2 degrees C caused necrosis of adjacent tissue. Through an adaptive response, the necrosis was removed by 7 weeks and replaced by a highly vascularized tissue capsule at 41.8+/-0.5 degrees C. The present study sought to characterize the spatial distribution, number of capillaries, and temperatures associated with this adaptive response. Heated and control muscle tissue sections were removed after 2, 4, and 7 weeks of heating at 0.08 W/cm2. Tissue layer thicknesses and capillary densities were measured and correlated with corresponding tissue temperatures. Necrosis was present adjacent to the heat source at 2 and 4 weeks; however by 7 weeks, a highly vascularized fibrous tissue capsule had replaced nearly all necrosis. Capillary densities, particularly near the heat source, were significantly greater at 7 weeks than at either 2 or 4 weeks. Capillary densities in heated tissue capillary fronts tripled from 2 to 7 weeks (106.4+/-14.3 caps/mm2 versus 39.1+/-18.5 caps/mm2). Furthermore, a mean temperature of 41.7+/-0.9 degrees C was measured in heated tissue capillary fronts at all durations, suggesting that this may be a threshold temperature for heat-induced angiogenesis or endothelial cell survival. These findings more completely characterize the perfusion component of the current mathematical model for heat transfer in tissue and will help to establish guidelines for the functional heat loss that an implantable, heat-producing device may allow.

Acclimatization↗
PubMed1997

Sensitivity analysis of one-dimensional heat transfer in tissue with temperature-dependent perfusion.

Design criteria for implantable heat-generating devices such as the total artificial heart require the determination of safe thresholds for chronic heating. This involves in-vivo experiments in which tissue temperature distributions are obtained in response to known heat sources. Prior to experimental studies, simulation using a mathematical model can help optimize the design of experiments. In this paper, a theoretical analysis of heat transfer is presented that describes the dynamic, one-dimensional distribution of temperature from a heated surface. Loss of heat by perfusion is represented by temperature-independent and temperature-dependent terms that can reflect changes in local control of blood flow. Model simulations using physiologically appropriate parameter values indicate that the temperature elevation profile caused by a heated surface adjacent to tissue may extend several centimeters into the tissue. Furthermore, sensitivity analysis indicates the conditions under which temperature profiles are sensitive to changes in thermal diffusivity and perfusion parameters. This information provides the basis for estimation of model parameters in different tissues and for prediction of the thermal responses of these tissues.

Body Temperature Regulation↗
PubMed1997

Macromolecular transport in the arterial intima: comparison of chronic and acute injuries.

Hypertension is a known risk factor for the development of atherosclerosis, which is characterized by the abnormal accumulation of low-density lipoprotein and other plasma-borne macromolecules. The goal of this study was to measure accumulation of a plasma-borne macromolecular marker, horseradish peroxidase (HRP; 44 kDa), in the aortic intima and media of chronically hypertensive rats. HRP transport in 2-yr-old spontaneously hypertensive rats (SHR) was compared with that in age-matched Wistar-Kyoto rats (WKY) under conditions in which blood pressures were not significantly different during the 15-min HRP circulation. Intimal accumulation and medial HRP concentration profiles were obtained from methacrylate-embedded sections after reaction with 3,3'-diaminobenzidine and H2O2. Data were analyzed using a mathematical model of macromolecular transport to quantify the permeabilities of endothelium and internal elastic lamina (IEL). Chronic hypertension increased endothelial permeability without a change in IEL permeability. An apparent convective flux of HRP into the intima of SHR raised intimal HRP to a concentration higher than that of HRP in the plasma. Our results suggest that the intimal accumulation of plasma-borne macromolecules from pressure-driven convection is normally minimized by an intact endothelium. Similar changes resulted from acute injury by lipopolysaccharide, suggesting endothelial injury could account for transport changes associated with hypertension. After either chronic or acute endothelial damage, transport of macromolecules into the intima increases, but the IEL continues to retard transport of macromolecules beyond the intima, resulting in increased intimal accumulation.

Animals↗
PubMed1997

Exogenous oxidized low-density lipoprotein injures and alters the barrier function of endothelium in rats in vivo.

Oxidation converts low-density lipoprotein (LDL) into a cytotoxin in vitro. Oxidized LDL exists in vivo in atherosclerotic lesions and possibly in plasma. Many cell functions are altered in vitro by oxidized LDL, but few have been examined in vivo. To test whether oxidized LDL could injure endothelial cells and alter endothelial permeability to macromolecules in vivo, we infused oxidized LDL, native LDL, or their solvent intravenously into rats. Subsequently, endothelial cell injury and proliferation were measured, and the transport into the aorta wall of the macromolecule horseradish peroxidase (HRP) was quantified. Transport data were analyzed using mathematical models of macromolecular transport; parameters were estimated by optimally fitting model-predicted HRP concentrations to experimental data. Compared with native LDL or solvent control infusion, oxidized LDL infusion increased (1) the number of injured aortic endothelial cells fivefold to sixfold at 36 hours, (2) proliferation of endothelial cells at 48 hours, (3) intimal and medial accumulations of HRP twofold to threefold at 48 hours, and (4) the permeability coefficient of the endothelium to HRP fourfold to fivefold at 48 hours. Hence, oxidized LDL administered in vivo can injure the endothelium, despite the presence of endogenous antioxidants, compromising the function of the endothelium as a permeability barrier.

Animals↗
PubMed1996

Effects of willful ventilatory control on respiratory sensation during hypercapnia.

Remarkable augmentation of breathing discomfort has been noted when ventilation is constrained to the steady state level during progressive hypercapnia. However, the effect of willful enhancement of ventilation on breathing discomfort remains to be evaluated. The present study examined the effects of moderate willful increases or decreases in ventilation during progressive hypercapnia on breathing discomfort in 12 subjects. There were a total of 5 rebreathing trials. In the first (F1) and the fifth trials the subjects rebreathed freely. In the other trials subjects breathed by tracking a target to achieve hypercapnic ventilatory responses that were the same (HCVR-S), 25% higher (HCVR-H) and 25% lower (HCVR-L) than in the F1 trial. Breathing discomfort was assessed every 30 s by a 150-mm visual analog scale (VAS). The sensational response (dVAS/dPCO2) during HCVR-S [3.8 +/- (SE) 0.8 mm/Torr] was significantly smaller (p < 0.01) than that during the F1 (6.3 +/- 0.8 mm/Torr) trial. HCVR-H resulted in a further decrease in dVAS/dPCO2 to 3.1 +/- 0.7 mm/Torr as compared to HCVR-S (p < 0.05). HCVR-L significantly increased dVAS/dPCO2 to 4.9 +/- 0.7 mm/Torr compared to HCVR-S (p < 0.05). The final free rebreathing ventilatory response was significantly larger than the initial free rebreathing response (2.7 +/- 0.5 as compared to 2.1 +/- 0.4 liters/min/Torr, p < 0.01). However, the sensational response did not change (6.3 +/- 0.8 vs. 5.8 +/- 0.7 mm/Torr). These rebreathing studies indicate that willful control of respiration decreases respiratory sensation even at comparable levels of ventilation. In particular, moderate willful increases in ventilation produce an ameliorating effect on the sensation of breathing discomfort.

Adult↗
PubMed1995

Model of respiratory sensation and wilful control of ventilation.

A mathematical model has been developed that includes sensations of breathlessness and a dynamic CO2 respiratory controller. Breathing sensations, which are represented as a discomfort index, are assumed to depend on arterial PCO2 level, automatic and wilful motor commands and mechanoreceptor feedback. Wilful control is assumed to arise from cortical centres of the brain and is independent of the reflex control system. The bulbopontine respiratory controller produces the automatic motor command, which is determined by chemical and mechanical feedback. Simulations demonstrate how the controller output and breathing sensations change when wilful motor commands disturb spontaneous breathing. Simulations include isocapnic hyper- and hypoventilation and deliberate hypoventilation during CO2 rebreathing. Simulations are compared with experimental data from human subjects. Simulations predict that the discomfort index intensifies when ventilation is either voluntarily raised or lowered from the optimal level; and discomfort is greater when ventilation is lowered than when it is raised at a given level of PCO2. The simulated results agree with those obtained experimentally. The simulations suggest that respiratory drive integration may depend not only on the direct effects of chemical and mechanical feedback, but also on the perceptual consequences of these stimuli.

Carbon Dioxide↗
PubMed1995

Estimation of cerebral blood flow from thermal measurement.

A thermal method has been developed to quantify continuous perfusion changes with self-calibration. A dynamic, one-dimensional bio-heat transfer model of the thermal probe and tissue describes the system response to either continuous or transient heating. A nonlinear least-squares fit of the model to experimental data yields estimates of the baseline perfusion and other model parameters. With a partial analytical solution of the model, the optimal estimation procedure is two orders of magnitude more efficient than with a total numerical solution of the model system. Experimental data is used to estimate the operating relations between perfusion and the temperature measurement. A new procedure has also been presented to obtain the dynamic response of the system for continuous measurement of perfusion.

Animals↗
PubMed1994

Thermal method for continuous measurement of cerebral perfusion.

A new thermal system using constant heating power for continuous measurement of cerebral perfusion is presented. It is designed and implemented for optimal perfusion sensitivity and dynamic response based on heat-transfer analysis of perfused brain tissue with thermistors on the cortical surface. Two matched thermistors are used, one to serve as a perfusion sensor and the other to compensate for the base-line temperature changes. To improve the signal-to-noise ratio of the measurement system, lock-in amplifiers are used to minimise long-term drift and low-frequency noise. Errors in the measurement caused by electrical and thermal fluctuations are tested and analysed. In vitro tests show that the measurement accuracy of temperature change is better than 10(-3) degrees C, and the temperature resolution is even greater. In vivo evaluation confirms that the system is responsive to cerebral perfusion changes associated with sudden changes in mean arterial blood pressure caused by bolus injection of norepinephrine, blood withdrawal and blood infusion. The dynamic response of the system is sufficient to detect the autoregulatory perfusion changes in response to arterial blood pressure alteration and the oscillations of cerebral blood flow.

Animals↗
PubMed1994

CO2 control of breathing: parameter estimation and stability evaluation.

A method is developed to evaluate system stability for the CO2 control of breathing in individuals by using data from the dynamics of CO2 rebreathing and elimination. The theoretical basis of the method is a physiological model of the CO2 respiratory control system and an explicit stability index (SI). The SI is algebraically related to the model parameters: system volume (Vs), cardiac output (Q), circulatory transit time (ts), and controller gain (G). A sequential optimization scheme is shown to yield estimates of the model parameters by comparing the alveolar ventilation and PCO2 of the model output with corresponding experimental data. Model simulation of CO2 rebreathing and elimination with different parameter values demonstrate that all parameters except ts have significant effect on the outputs. Least-squares estimation of the parameters using model-generated data with added noise showed good precision for all parameters (except ts). This analysis is performed with parameter values chosen to produce overdamped and underdamped responses that would occur in normal and abnormal respiratory control systems, respectively. It is anticipated that SI values of the (overdamped) normal and (underdamped) abnormal systems differ by much more than the variation produced by imprecision of the parameter estimates. For this circumstance, the method is expected to be sensitive enough to distinguish normal from abnormal CO2 respiratory control of individual subjects.

Carbon Dioxide↗
PubMed1994

Mathematical model of acetylcholine kinetics in neuroeffector junctions.

Acetylcholine (ACh) kinetics in neuroeffector junctions (NEJ) of the sinus node plays a key role in vagal control of heart rate. Prior studies have shown that the concentration of ACh ([ACh]) in NEJ appears to follow first-order linear kinetics. To find out the reason why, we examine mathematically diffusion, degradation, and receptor binding of ACh in NEJ. We identify seven conditions that potentially influence ACh kinetics. Because these conditions are satisfied for NEJ in the sinus node, 1) the nonlinearity of ACh binding to muscarinic receptors has little effect on [ACh]; 2) [ACh] does not depend on the distribution of acetylcholinesterase between the interstitial space and the pacemaker cells; 3) the interval from trough to subsequent peak [ACh] at the pacemaker cells is negligible; 4) the mean [ACh] at the pacemaker cells is proportional to the frequency of vagal activity multiplied by the amount of ACh released per vagal stimulus and divided by the rate coefficient of ACh degradation; and 5) [ACh] at pacemaker cells nearly follows first-order linear kinetics but does not at other sites in the NEJ. We conclude that earlier studies showed that [ACh] follows first-order linear kinetics, because they predicted [ACh] only at pacemaker cells. ACh kinetics at other sites in the NEJ, such as at nerve endings, is different.

Acetylcholine↗
PubMed1994

Relative significance of endothelium and internal elastic lamina in regulating the entry of macromolecules into arteries in vivo.

A role for the internal elastic lamina (IEL), which separates the intima and media of an artery wall, as a restrictive barrier to macromolecular movement has been suggested in atherosclerotic lesion development or restenosis during angioplasty. The permeability coefficient of the IEL, however, has never been quantified in unperturbed vessels in vivo. Using a newly developed technique, we measured the concentration distributions in both intima and media of cationic (pI approximately 8.5) and anionic (pI approximately 6.3) isozymes of the 44-kD macromolecule horseradish peroxidase (HRP). Two mathematical models of arterial wall transport differing in their resolution of the intima were required to simulate the concentration distribution data and to estimate the parameters of interest. Optimal estimates of the permeability coefficients of the endothelium (PE) and IEL (PIEL) to HRP were determined by the best least-squares fit of the two models to experimental data. These estimates (anionic: PE = 0.050 +/- 0.021 microns/min, PIEL = 0.146 +/- 0.082 microns/min, n = 8; cationic: PE = 0.034 +/- 0.018 microns/min, PIEL = 0.110 +/- 0.047 microns/min, n = 8) indicate that the IEL is responsible for approximately 25% (anionic, 26 +/- 9%; cationic, 25 +/- 13%) of the resistance to HRP transport from the blood into the arterial media. Although both parameters were less for the cationic preparation, the differences were not significant, and the relative role of the IEL was similar for both molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗