Biomedical subjects

Gerald M Saidel

Publications and source records attributed to Gerald M Saidel.

16 recordsLinked to original sources

PubMed2006

Multi-organ system model of O2 and CO2 transport during isocapnic and poikilocapnic hypoxia.

A multi-organ systems model of O(2) and CO(2) transport is developed to analyze the control of ventilation and blood flow during hypoxia. Among the aspects of the control processes that this model addressed are possible mechanisms responsible for the second phase of the ventilatory hypoxic response to mild hypoxia, i.e., hypoxic ventilatory decline (HVD). Species mass transport processes are described by compartmental mass balances in brain, heart, skeletal muscle, and "other tissues" connected in parallel via the circulation. In pulmonary and systemic capillaries and in the vasculature connecting the systemic tissues, species transport processes are represented by a one-dimensional, convection-dispersion model. The effects of bicarbonate acid-base buffering, hemoglobin, and myoglobin on the transport processes are included. The model incorporates feedback control mechanisms through a cardiorespiratory control system in which peripheral and central chemoreceptors sense O(2) and CO(2) partial pressures. Model simulations of the ventilatory responses to isocapnic and poikilocapnic hypoxia show two phases with distinct dynamics. A fast phase is discernable immediately after switching from normoxic to hypoxic conditions, while a delayed slow phase (HVD) typically becomes manifested after several minutes. Model simulations allow quantitative evaluation of several proposed mechanisms to account for HVD. Under isocapnic hypoxia, simulations indicate that an increase in brain blood flow has no effect on HVD, but that HVD can be entirely described by central ventilatory depression (CVD). Under poikilocapnic hypoxia, the hypocapnia caused by hypoxic hyperventilation has no effect on HVD.

Algorithms↗

PubMed2006

Multi-scale computational model of fuel homeostasis during exercise: effect of hormonal control.

A mathematical model of the whole-body metabolism is developed to predict fuel homeostasis during exercise by using hormonal control over cellular metabolic processes. The whole body model is composed of seven tissue compartments: brain, heart, liver, GI (gastrointestinal) tract, skeletal muscle, adipose tissue, and "other tissues". Each tissue compartment is described by dynamic mass balances and major cellular metabolic reactions. The glucagon-insulin controller is incorporated into the whole body model to predict hormonal changes during exercise. Moderate [150 W power output at 60% of peak oxygen consumption (VO(2max))] exercise for 60 min was implemented by increasing ATP utilization rates in heart and skeletal muscle. Arterial epinephrine level was given as an input function, which directly affects heart and skeletal muscle metabolism and indirectly other tissues via glucagon-insulin controller. Model simulations were validated with experimental data from human exercise studies. The exercise induced changes in hormonal signals modulated metabolic flux rates of different tissues in a coordinated way to achieve glucose homeostasis, demonstrating the efficacy of hormonal control over cellular metabolic processes. From experimental measurements of whole body glucose balance and arterial substrate concentrations, this model could predict the dynamic changes of hepatic glycogenolysis and gluconeogenesis, which are not easy to measure experimentally, suggesting the higher contribution of glycogenolysis ( approximately 75%). In addition, it could provide dynamic information on the relative contribution of carbohydrates and lipids for fuel oxidation in skeletal muscle. Model simulations indicate that external fuel supplies from other tissue/organ systems to skeletal muscle become important for prolonged exercise emphasizing the significance of interaction among tissues. In conclusion, this model can be used as a valuable complement to experimental studies due to its ability to predict what is difficult to measure directly, and usefulness to provide information about dynamic behaviors.

Adaptation, Physiological↗

PubMed2006

Effects of synchronized cardiac assist device on cardiac energetics.

A novel physiological cardiac assist device (PCAD), the LEV RAM assist device, which is synchronized with the failing heart ejection, was developed to improve the failing heart systolic and diastolic functions and cardiac energetics. The PCAD uses a single short cannula, which is inserted into the beating left ventricle (LV) by means of a specially designed device. Blood is ejected from the PCAD into the LV after the opening of the aortic valve and augments the cardiac stroke work. The same amount of blood is withdrawn from the LV into the PCAD, through the same cannula, during the diastole. The study aims to test the effects of the PCAD on cardiac energetics and coronary blood flow. Adult normal sheep were anesthetized and the heart was exposed by left thoracotomy. Pressures transducers (Millar Instruments, Inc., Houston, TX) were inserted into the LV and aorta. LV volume was measured by sonocrystals (Sonometrics Corp., London, Ontario, Canada) and impedance catheter (CD Lycom, Argonstrat 116 Zoetermeer, 2718 SP The Netherlands). Flowmeters (transonic) measured the cardiac output (CO) and the coronary arteries (left anterior descending (LAD) and circumflex) flows. A thin cannula was inserted into the coronary sinus and the oxygen content of the LV and the coronary sinus were determined (AVOXimeter-1000). Pressure-volume loops, myocardial energetics, and coronary flow were measured. The displaced PCAD volume was 11 mL. Four different levels of assist were studied by changing the frequency of the assist: (1) assist beat after three successive regular beats [1:4], (2) assist every third beat [1:3], (3) alternate assist and normal beat [1:2], and (4) continuous assist [1:1]. Cardiac output (CO) and stroke volume (SV) increased proportionally with increasing frequency of assist. Systolic mechanical efficiency of the PCAD was above 90%. Simultaneously, the PCAD decreased the end-diastolic volume (EDV; diastolic unloading). The PCAD increased coronary flow and decreased cardiac arterial-venous O(2) difference. We conclude that the PCAD efficiently augments CO and stroke work, decreases preload, and decreases the coronary arterial-venous O(2) difference; all these may expedite cardiac reverse remodeling, and promote recovery of function and eventual easy explanation of the device.

Animals↗

PubMed2005

Regulation of lactate production at the onset of ischaemia is independent of mitochondrial NADH/NAD+: insights from in silico studies.

Ischaemia decreases mitochondrial NADH oxidation, activates glycolysis, increases the NADH/NAD+ ratio, and causes lactate production. The mechanisms that regulate anaerobic glycolysis and the NADH/NAD+ ratio during ischaemia are unclear. Although continuous measurements of metabolic fluxes and NADH/NAD+ in cytosol and mitochondria are not possible in vivo with current experimental techniques, computational models can be used to predict these variables by simulations with in silico experiments. Such predictions were obtained using a mathematical model of cellular metabolism in perfused myocardium. This model, which distinguishes cytosolic and mitochondrial domains, incorporates key metabolic species and processes associated with energy transfer. Simulation of metabolic responses to mild, moderate and severe ischaemia in large animals showed that mitochondrial NADH/NAD+ was rapidly reset to higher values in proportion to the reduced O2 delivery and myocardial oxygen consumption . Cytosolic NADH/NAD+, however, showed a biphasic response, with a sharp initial increase that was due to activation of glycogen breakdown and glycolysis, and corresponded with lactate production. Whereas the rate of glycolysis and the malate-aspartate shuttle had a significant effect on the cytosolic NADH/NAD+, their effects on the mitochondrial NADH/NAD+ were minimal. In summary, model simulations of the metabolic response to ischaemia showed that mitochondrial NADH/NAD+ is primarily determined by O2 consumption, while cytosolic NADH/NAD+ is largely a function of glycolytic flux during the initial phase, and is determined by mitochondrial NADH/NAD+ and the malate-aspartate shuttle during the steady state.

Animals↗

PubMed2005

Alterations in internal elastic lamina permeability as a function of age and anatomical site precede lesion development in apolipoprotein E-null mice.

Early atherosclerosis is characterized by the accumulation of plasma-borne macromolecules (eg, low-density lipoproteins) in the arterial intima, which is bordered by endothelial cells (EC) and the internal elastic lamina (IEL). This accumulation is believed to be secondary to increased EC permeability. We hypothesized that a decrease in IEL permeability may precede lesion development and contribute to macromolecular accumulation. To test this hypothesis, we quantified EC and IEL permeability in lesion-free areas of the thoracic and abdominal aortas of chow-fed C57BL/6 control and atherosclerotic-prone apolipoprotein E (apoE)-null mice at 3 and 5 months of age. Between 3 and 5 months of age, apoE-null mice begin to develop atherosclerotic lesions in the thoracic aorta. No significant differences in EC and IEL permeability were observed at either time in C57BL/6 control mice. In contrast, 78% and 19% decreases in IEL permeability of the thoracic aorta and abdominal aorta, respectively, were observed between 3 to 5 months of age in apoE-null mice (thoracic: 2.05+/-1.33 and 0.44+/-0.15 microm/min, P<0.001; abdominal: 1.13+/-0.58 and 0.93+/-0.44 microm/min, P<0.05). To further determine whether decreased IEL permeability is linked with atherosclerotic lesion development, we quantified IEL permeability in the greater and lesser curvature of the aortic arch. In apoE-null mice, the lesser curvature of the aortic arch develops lesions before the greater curvature. We found a significant and sustained decrease (59%) in IEL permeability in the lesser curvature of the aortic arch compared with the greater curvature. These data suggest that atherogenesis involves the pathological remodeling of the IEL, not the endothelium before lesion development. This remodeling may be attributable to local responses of the endothelium and smooth muscle cells to hyperlipidemia.

Age Factors↗

PubMed2005

Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia.

A new multidomain mathematical model of cardiac cellular metabolism was developed to simulate metabolic responses to reduced myocardial blood flow. The model is based on mass balances and reaction kinetics that describe transport and metabolic processes of 31 key chemical species in cardiac tissue. The model has three distinct domains (blood, cytosol, and mitochondria) with interdomain transport of chemical species. In addition to distinguishing between cytosol and mitochondria, the model includes a subdomain in the cytosol to account for glycolytic metabolic channeling. Myocardial ischemia was induced by a 60% reduction in coronary blood flow, and model simulations were compared with experimental data from anesthetized pigs. Simulations with a previous model without compartmentation showed a slow activation of glycogen breakdown and delayed lactate production compared with experimental results. The addition of a subdomain for glycolysis resulted in simulations showing faster rates of glycogen breakdown and lactate production that closely matched in vivo experimental data. The dynamics of redox (NADH/NAD+) and phosphorylation (ADP/ATP) states were also simulated. These controllers are coupled to energy transfer reactions and play key regulatory roles in the cytosol and mitochondria. Simulations showed a similar dynamic response of the mitochondrial redox state and the rate of pyruvate oxidation during ischemia. In contrast, the cytosolic redox state displayed a time response similar to that of lactate production. In conclusion, this novel mechanistic model effectively predicted the rapid activation of glycogen breakdown and lactate production at the onset of ischemia and supports the concept of localization of glycolysis to a subdomain of the cytosol.

Computer Simulation↗

PubMed2005

Macromolecular transport in the arterial wall: alternative models for estimating barriers.

Early atherosclerosis, or atherogenesis, is characterized by the abnormal accumulation of plasma-borne macromolecules (e.g., LDL) in the arterial intima. The change of barrier characteristics of tissue in the arterial wall requires evaluation of macromolecular transport across the endothelial cell layer (ECL) and internal elastic lamina (IEL), the luminal and abluminal boundaries of the arterial intima, respectively. In this study, alternative mathematical models are derived from dynamic mass balances to describe macromolecular transport across the arterial wall. One model considers each medial layer as a spatially lumped compartment, whereas another model consists of a spatially lumped intima and spatially distributed media. Model simulations of a tracer concentration distribution in the arterial wall are compared with concentration distributions of horseradish peroxidase (HRP) after i.v. injection in mice. For each model, optimal parameter values are obtained that yield model outputs matching the data well for two different HRP circulation times. The model parameter estimates show that the ECL is the major barrier for macromolecular transport across the normal arterial wall. Sensitivity analysis indicates that the parameter estimates of the transport coefficients of the ECL and IEL are well determined. Optimal circulation times are determined and expected to yield improved precision of parameter estimates in future experiments to reflect disease progression.

Animals↗

PubMed2005

Regulation of cardiac energetics: role of redox state and cellular compartmentation during ischemia.

The heart is capable of altering its metabolic rate during exercise or ischemia. Under most state transitions, the heart maintains the concentration of adenosine triphosphate (ATP) at relatively constant values, in spite of large fluctuations in metabolic rate or in the delivery of fuels and oxygen. However, the mechanisms responsible for the regulation of cardiac energetics under conditions of increased demand or reduced supply are still under debate. To improve quantitative understanding of the regulation of glycolysis and oxidative phosphorylation under physiological and pathological conditions, it is essential to assess the dynamics of cytosolic and mitochondrial nicotinamide adenine dinucleotide (NAD(+)) and its reduced form (NADH) during stress (e.g., ischemia, exercise). However, at present there are no reliable methods to measure the dynamics of redox state in vivo in these subcellular compartments. In the present study, computer simulations with a mathematical model of myocardial energy metabolism are used to investigate the role of cytosolic and mitochondrial redox states in regulating cardiac energetics during reduced myocardial blood flow.

Cell Compartmentation↗

PubMed2004

Comparison of doxorubicin concentration profiles in radiofrequency-ablated rat livers from sustained- and dual-release PLGA millirods.

PURPOSE: To evaluate and compare the local pharmacokinetics of doxorubicin in radiofrequency (rf)-ablated rat livers after interstitial delivery from sustained- and dual-release poly(D,L-lactide-co-glycolide) (PLGA) millirods. METHODS: PLGA millirods with sustained- and dual-release kinetics (burst followed by sustained release) of doxorubicin were implanted in rf-ablated rat livers. Doxorubicin release kinetics in vivo were measured from explanted millirods by UV-Vis spectrophotometer over 8 days. Spatial distribution of doxorubicin in liver tissues was measured by fluorescence imaging. RESULTS: In the initial 24 h after millirod implantation, dual-release millirods released significantly more doxorubicin into liver tissues than the sustained millirods. Subsequently, both types of millirods provided comparable sustained-release kinetics over 8 days. With dual-release millirods, doxorubicin concentration and penetration distance in liver tissue increased more rapidly. To reach 30 microg/g doxorubicin concentration at the ablation boundary (targeted site of action), the time required was 6 days and 1.5 days for sustained- and dual-release millirods, respectively. CONCLUSIONS: Compared with sustained-release millirods, dual-release millirods provide a quick concentration elevation and sustaining of the drug concentration at the ablation boundary. Additionally, the steady-state drug concentration agrees well with model predictions based on previously determined transport parameters, which demonstrates the feasibility of rational design of drug formulations in polymer millirods.

Animals↗

PubMed2003

Quantification of in vivo doxorubicin transport from PLGA millirods in thermoablated rat livers.

The objective of this research was to quantify the key parameters governing the drug transport processes in radiofrequency (RF) thermoablated and non-ablated liver tissues. Experimentally, doxorubicin-containing polymer millirods were implanted in the ablated rat livers and spatial distribution of doxorubicin was measured by fluorescence imaging from 1 to 96 h after millirod implantation. At all time points, doxorubicin had significantly higher tissue penetration and retention in ablated tissues than in non-ablated tissues. A mathematical model was developed to quantitatively describe the transport processes in ablated and non-ablated rat livers. Based on the experimental data and mathematical models, the optimal estimates of apparent drug diffusivities in ablated and non-ablated tissues were 1.1 x 10(-7) and 6.7 x 10(-7) cm(2) s(-1), respectively, and the apparent drug elimination rate coefficient was 9.6 x 10(-4) s(-1) in non-ablated tissues. Results from this study contribute to the fundamental understanding of in vivo drug transport in liver tissues and provide the quantitative parameters for the rational design of polymer millirods for liver cancer treatment.

Algorithms↗

PubMed2003

Distributed versus compartment models for PET receptor studies.

Although distributed models are generally accepted as being more realistic than compartment models, use of simpler compartment models is pervasive in nuclear medicine applications, particularly in positron emission tomography (PET). Here, we report on comparisons made between distributed and compartment model outputs to address the question of whether differences between them are sufficient to justify distributed models for analysis of PET receptor experiments. For both two- and three-injection experiments, "data" sets were obtained by simulation using a distributed model and a wide range of parameter values. Optimal fits of the compartment model output to these "data" were achieved with three strategies in which values of different groups of parameter were estimated. Compartment model outputs yielded good fits to all the distributed model outputs and the values of the corresponding parameters were in close agreement. Given the temporal resolution typically available with PET, the use of a distributed model has no advantage over a compartment model for PET receptor quantification.

Computer Simulation↗

PubMed2003

Model analysis of tissue responses to transient and chronic heating.

Thermal models are used to analyze responses of muscle and lung tissue to transient (30-45 min) and chronic (4-7 week) heating in vivo. The general bioheat model, which describes one-dimensional temperature dynamics, incorporates heat conductance and perfusion. In general, perfusion changes with time and distance from a heated surface. One of the main objectives of this study was to analyze long-term perfusion change, which reflects tissue adaptation associated with angiogenesis. The database for these models was obtained using heated disks implanted in calves for up to seven weeks. Tissue temperature distributions were obtained repeatedly from thermistors protruding 1 to 10 mm from the heated disk surface. The perfusion parameter was estimated from the transient experiments at least several times each week by nonlinear, least-squares fitting of the model predicted temperature to the measured temperature response. Chronic heating at a heat flux 0.08 W/cm2 caused perfusion of muscle tissue to increase with postimplant day (PID). Under the same conditions, lung tissue perfusion increased with chronic heating from early to late PID, but less than that for muscle tissue. During chronic heating above 42 degrees C and below 50 degrees C, a decrease in tissue temperature is associated with higher perfusion that develops with time. Over seven weeks, perfusion of muscle tissue near the heated disk surface increased by about 70% at 0.08 W/cm2 and 40% at 0.06 W/cm2. Furthermore, the model can be used to predict tissue and perfusion changes continuously over weeks for heat fluxes around 0.08 W/cm2.

Animals↗

PubMed2003

Concentration of solutes in the renal inner medulla: interstitial hyaluronan as a mechano-osmotic transducer.

Although the concentrating process in the renal outer medulla is well understood, the concentrating mechanism in the renal inner medulla remains an enigma. The purposes of this review are fourfold. 1) We summarize a theoretical basis for classifying all possible steady-state inner medullary countercurrent concentrating mechanisms based on mass balance principles. 2) We review the major hypotheses that have been proposed to explain the axial osmolality gradient in the interstitium of the renal inner medulla. 3) We summarize and expand on the Schmidt-Nielsen hypothesis that the contractions of the renal pelvocalyceal wall may provide an important energy source for concentration in the inner medulla. 4) We discuss the special properties of hyaluronan, a glycosaminoglycan that is the chief component of a gel-like renal inner medullary interstitial matrix, which may allow it to function as a mechano-osmotic transducer, converting energy from the contractions of the pelvic wall to an axial osmolality gradient in the medulla. These considerations set the stage for renewed experimental investigation of the urinary concentrating process and a new generation of mathematical models of the renal concentrating mechanism, which treat the inner medullary interstitium as a viscoelastic system rather than a purely hydraulic system.

Animals↗

PubMed2002

Combined modeling and experimental approach for the development of dual-release polymer millirods.

This paper describes a combined modeling and experimental approach for the design and development of a polymer device to provide local drug therapy to thermally ablated solid tumors. The polymer device, in the shape of cylindrical millirod, will be implanted via image-guided procedures into the center of the ablated tumor. Drug released from the millirod aims to eliminate residual cancer cells at the boundary of the normal and ablated tissue following thermal ablation to provide an effective treatment of the total tumor volume. The design of the millirod release kinetics is based on a mathematical model of drug transport in the ablated tumor and the surrounding normal tissue. The optimal release kinetics consists of a dual-release process-a burst release followed by sustained release-to provide the most optimal drug pharmacokinetics at the ablation boundary. Model analysis leads to a quantitative correlation of burst dose and release rates to the ablation size and the drug concentration at the ablation boundary. A three-layer polymer millirod is produced by a dip-coating method, and in vitro study demonstrates the dual-release kinetics in which a burst release occurs within 2 h followed by a sustained release over 7 -10 days. Independent control of the burst and sustained release rates is achieved by varying the structural composition of the outer and middle layers of the millirods, respectively. Results from this study provide the rational basis and experimental feasibility of dual-release millirods for further efficacy studies in solid tumors.

Antineoplastic Agents↗

PubMed2002

Mechanistic model of myocardial energy metabolism under normal and ischemic conditions.

A moderate reduction in coronary blood flow results in decreased myocardial oxygen consumption, accelerated glycolysis, decreased pyruvate oxidation, and lactate accumulation. To quantitatively understand cardiac metabolism during ischemia, we have developed a mechanistic, mathematical model based on biochemical mass balances and reaction kinetics in cardiac cells. By numerical solution of model equations, computer simulations showed the dynamic responses in glucose, fatty acid, glucose-6-phosphate, glycogen, triglyceride, pyruvate, lactate, acetyl-CoA, and free-CoA as well as CO2, O2, phosphocreatine/creatine, nicotinamide adenine dinucleotide (reduced form)/nicotinamide adenine dinucleotide (oxidized form) (NADH/NAD+), and adenosine diphosphate/adenosine triphosphate (ADP/ATP). When myocardial ischemia was simulated by a 60% reduction in coronary blood flow, the model generated myocardial concentrations, uptakes, and fluxes that were consistent with experimental data from in vivo pig studies. After 60 min of ischemia the concentrations of glycogen, phosphocreatine, and ATP were decreased by 60%, 75%, and 50%, respectively. With the onset of ischemia, myocardial lactate concentration increased and the myocardium switched from net consumer to net producer of lactate. Our model predicted a rapid 13-fold increase in NADH/NAD+, but only a twofold increase in the ratio of acetyl-CoA to free-CoA. These findings are consistent with the concept that pyruvate oxidation is inhibited during ischemia partially by the rise in NADH/NAD+.

Adenosine Diphosphate↗

PubMed2002

Thermal model for fast simulation during magnetic resonance imaging guidance of radio frequency tumor ablation.

Thermal ablation of a tumor with radio frequency (rf) energy from a small probe inserted into the solid tumor can be accomplished with minimal invasiveness under guidance with magnetic resonance imaging (MRI). A theoretical study is presented of 3D temperature distribution dynamics in tissue with rf heating to show the feasibility of fast numerical solution for repeated simulations during an ablation procedure. Model simulations are intended to be used during an ablation treatment together with temperature field images obtained by MR to predict the effect of alternative strategies of source heating and placement. A feature of the model is that it incorporates a heat source term that varies with distance from the rf probe to avoid the need for solving electric field equations. The effects of perfusion and internal cooling of the rf probe on the temperature distribution are simulated to show the model flexibility. Using a personal computer (PC), numerical solution of the model equations required 10 s to 2 min depending on the perfusion-temperature relationship. The results show the feasibility of using thermal model simulations in an iterative manner with MR images to help guide thermal ablation procedures in the clinical setting.

Biomedical Engineering↗