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Results for “nonlinear analyses”

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PubMed1997

Nonlinear mathematical analysis of the hemodynamic parameters during left ventricular assistance with oscillated blood flow.

For the development of a totally implantable ventricular assist system (VAS), we have been developing the vibrating flow pump (VFP), which can generate oscillated blood flow with a relatively high frequency (10-50 Hz) for a totally implantable system. In this study, effects of left ventricular assistance with this unique oscillated blood flow were analyzed by nonlinear mathematics for evaluation as the entire circulatory regulatory system, not as a separate part of the system. Left heart bypasses using VFPs from the left atriums to the descending aortas were performed in chronic animal experiments using healthy adult goats. Electrocardiogram (ECG), arterial blood pressure, VFP pump flow, and flow of the descending aorta data taken while the goats were awake were recorded in the data recorder and analyzed in the personal computer system through the AD convertor. Using nonlinear mathematics, time series data were embedded into the phase space, and the Lyapunov numerical method, fractal dimension analysis, and power spectrum analysis were performed to evaluate the nonlinear dynamics. During left ventricular assistance with the VFP, Mayer wave fluctuations were decreased in the power spectrum, the fractal dimension of the hemodynamics was significantly decreased, and peripheral vascular resistance was significantly decreased. These results suggest that nonlinear dynamics, which mediate the cardiovascular dynamics, may be affected during LV bypass with oscillated flow. Decreased power of the Mayer wave in the spectrum caused the limit cycle attractor of the hemodynamics and decreased the peripheral resistance. Decreased sympathetic discharges may be the origin of the decreased Mayer wave and fractal dimension. These nonlinear dynamical analyses may be useful to design the optimal VAS control.

Animals↗

PubMed1999

Chaotic dynamics in circulation with Tohoku University vibrating flow pump.

For the development of a totally implantable ventricular assist system (VAS), we have been developing the vibrating flow pump (VFP), which can generate oscillated blood flow with a relative high frequency (10-50 Hz) for a totally implantable system. In this study, the effects of left ventricular assistance with this unique oscillated blood flow were analyzed by the use of nonlinear mathematics for evaluation as the whole circulatory regulatory system, not as the decomposed parts of the system. Left heart bypasses using the VFP from the left atrium to the descending aorta were performed in chronic animal experiments using healthy adult goats. The ECG, arterial blood pressure, VFP pump flow, and the flow of the descending aorta were recorded in the data recorder during awake conditions and analyzed in a personal computer system through an A-D convertor. By the use of nonlinear mathematics, time series data were embedded into the phase space, the Lyapunov numerical method, fractal dimension analysis, and power spectrum analysis were performed to evaluate nonlinear dynamics. During left ventricular assistance with the VFP, Mayer wave fluctuations were decreased in the power spectrum, the fractal dimension of the hemodynamics was significantly decreased, and peripheral vascular resistance was significantly decreased. These results suggest that nonlinear dynamics, which mediate the cardiovascular dynamics, may be affected during left ventricular (LV) bypass with oscillated flow. The decreased power of the Mayer wave in the spectrum caused the limit cycle attractor of the hemodynamics and decreased peripheral resistance. Decreased sympathetic discharges may be the origin of the decreased Mayer wave and fractal dimension. These nonlinear dynamic analyses may be useful to design optimal VAS control.

Analog-Digital Conversion↗

PubMed2006

Nonlinear time series analysis of food intake in the dab and the rainbow trout.

Evidence suggests that dab and rainbow trout are able to quickly adjust their food intake to an appropriate level when offered novel diets. In addition day-to-day and meal-to-meal food intake varies greatly and meal timing is plastic. Why this is the case is not clear: Food intake in fish is influenced by many factors, however the hierarchy and mechanisms by which these interact is not yet fully understood. A model of food intake may be helpful to understand these phenomena; to determine model type it is necessary to understand the qualitative nature of food intake. Food intake can be regarded as an autoregressive (AR) time series, as the amount of food eaten at time t will be influenced by previous meals, and this allows food intake to be considered using time series analyses. Here, time series data were analysed using nonlinear techniques to obtain qualitative information from which evidence for the hierarchy of mechanisms controlling food intake may be drawn. Time series were obtained for a group of dab and individuals and a group of rainbow trout for analysis. Surrogate data sets were generated to test several null hypotheses describing linear processes and all proved significantly different to the real data, suggesting nonlinear dynamics. Examination of topography and recurrence diagrams suggested that all series were deterministic and non-stationary. The point correlation dimension (PD2i) suggested low-dimensional dynamics. Our findings suggest therefore that any model of appetite should create output that is deterministic, non-stationary, low-dimensional and having nonlinear dynamics.

Animals↗

PubMed2001

Origin of deficits in the flicker electroretinogram of the cone system in X-linked retinoschisis as derived from response nonlinearities.

The aim of this study was to identify the origin of a high-frequency attenuation in the flicker electroretinogram (ERG) of patients with X-linked retinoschisis (XLRS) through an analysis of nonlinearities in the ERG response. The ERGs of six patients with XLRS and six age-similar control subjects were recorded in response to stimuli that consisted of pairs of sinusoids that had varying temporal frequencies and that differed by either 8 or 16 Hz. Compared with the control subjects, the patients with XLRS showed a significant reduction in the amplitude of the difference frequency to high-frequency stimuli that paralleled the high-frequency attenuation of their ERG response fundamental. This result indicates that a response attenuation at an initial linear filter, most likely photoreceptoral, was a major determinant of the reduced ERG amplitude of the XLRS patients at high temporal frequencies. Additional analyses of nonlinearities in the ERG responses provided evidence of a postreceptoral component to the flicker ERG deficits of the XLRS patients, as well.

Adult↗

PubMed1992

Nonlinear pharmacokinetics of hepatobiliary transport of rose bengal in rats after i.v. bolus administration with varying doses.

To investigate the nonlinear kinetics in the hepatobiliary transport of rose bengal (RB), the time profiles of plasma concentration and biliary excretion rate after its i.v. administration at various doses were measured in rats. The total body clearance decreased remarkably with increased dose. The hepatic uptake clearance also showed a similar dose dependency, and saturation of hepatic uptake at least partly accounts for the dose-dependent change in total body clearance. The peak biliary excretion rate approached the transport maximum (approximately 150 nmol min-1 kg-1) with increased dose. To further clarify which process in RB hepatobiliary transport has nonlinearity, we analysed thus obtained data based on a three-compartment model. The hepatic uptake and sequestration rate constants decreased remarkably with increased dose. The initial hepatic uptake rates assessed from the plasma disappearance rate during the early phase fit well to the Michaelis-Menten equation with a saturable and a nonsaturable component. The maximum uptake velocity and Michaelis constant were 4.7 mumol min-1 kg-1 and 360 microM, respectively. That hepatic uptake has a much higher capacity (about 30 fold) than biliary excretion suggests that biliary excretion can be a rate-determining process in the overall hepatobiliary transport of RB. We conclude that the saturation of both hepatic uptake and biliary excretion could be the main causes for the nonlinear pharmacokinetics of hepatobiliary transport of RB.

Animals↗

PubMed2003

Changes in muscle proteins and spermidine content in response to unloading and clenbuterol treatment.

Anabolic agents such clenbuterol (Cb) are useful tools for probing the mechanisms by which muscles respond to disuse. Cb was examined under different loading conditions with respect to its effects on muscle mass, protein (myofibrillar and cytosolic), and spermidine content in mature male rats. Compared with control treatment, Cb significantly increased loaded and unloaded soleus, plantaris, and extensor digitorum longus (EDL) mass. Likewise, Cb significantly increased loaded and unloaded soleus (24.8 and 21.6%, respectively), plantaris (12.1 and 22.9%, respectively), and EDL (22.4 and 13.3%, respectively) myofibrillar protein content. After unloading, cytosolic proteins significantly increased in the EDL but decreased in the soleus and plantaris. Cb significantly increased cytosolic protein levels in all loaded muscles, while only causing increases in unloaded soleus. When compared with controls, unloading caused significant reductions in spermidine levels in the soleus (40.4%) and plantaris (35.9%) but caused increases in the EDL (54.8%). In contrast, Cb increased spermidine levels in unloaded soleus (42.9%), plantaris (102.8%), and EDL (287%). In loaded muscles, Cb increased spermidine levels in all three muscles, but to a lesser degree than under unloading conditions. Nonlinear regression analyses indicated that the plantaris behaves like a slow-twitch muscle under unloading conditions and like a fast-twitch muscle when loaded. This suggests that the responses of these muscles to unloading and (or) Cb treatment might be influenced by factors beyond fiber type alone.

Adrenergic beta-Agonists↗

PubMed2001

Derived fuzzy knowledge model for estimating the depth of anesthesia.

Reliable and noninvasive monitoring of the depth of anesthesia (DOA) is highly desirable. Based on adaptive network-based fuzzy inference system (ANFIS) modeling, a derived fuzzy knowledge model is proposed for quantitatively estimating the DOA and validate it by 30 experiments using 15 dogs undergoing anesthesia with three different anesthetic regimens (propofol, isoflurane, and halothane). By eliciting fuzzy if-then rules, the model provides a way to address the DOA estimation problem by using electroencephalogram-derived parameters. The parameters include two new measures (complexity and regularity) extracted by nonlinear quantitative analyses, as well as spectral entropy. The model demonstrates good performance in discriminating awake and asleep states for three common anesthetic regimens (accuracy 90.3 % for propofol, 92.7 % for isoflurane, and 89.1% for halothane), real-time feasibility, and generalization ability (accuracy 85.9% across the three regimens). The proposed fuzzy knowledge model is a promising candidate as an effective tool for continuous assessment of the DOA.

Algorithms↗

PubMed1999

Effects of crystalline form on the tableting compression mechanism of phenobarbital polymorphs.

The effects of the polymorphic form on the compression mechanism of forms A, B, and F of phenobarbital were investigated using a compression simulator, mercury porosimetry, X-ray diffraction analysis, BET gas absorption method, and scanning electron microscopic (SEM) photography. The order of tablet hardness obtained from all phenobarbital polymorphs was form A > form B > form F in accordance with that of the specific surface area. The Cooper and Eaton method was applied to evaluate two individual compression processes: particle rearrangement (phase I) and fragmentation and/or deformation (phase II). The parameters for compression processes were calculated using a nonlinear regression analyses program, and the compression energies of phases I and II were calculated from these parameters. The relationship between specific surface area after compression and compression energy at phase I showed a good linear correlation, but their ratio did not. In contrast, the specific surface area ratio showed a linear relationship with the compression energy on phase II, but again the ratio of these two parameters did not. The tablet hardness showed a linear relationship with the specific surface area ratio, but not with the specific surface area. Again, the ratio of these two parameters did not show a linear relationship.

Anticonvulsants↗

PubMed1998

Integrated pharmacokinetic-pharmacodynamic model for acetaminophen, ibuprofen, and placebo antipyresis in children.

A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic-pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (microgram/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and Sigmoid Emax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlax, k alpha, beta, T1/2 beta, AUC0-infinity, Vd/F, and Clp/F) were not different than those reported previously, except the APAP k alpha was significantly lower. The link component yielded keos of 0.58 +/- 0.06 (mean +/- SE), 0.70 +/- 0.11 and 0.57 +/- 0.11 hr-1 for APAP, IBU05, and IBU10, respectively; the Sigmoid Emax component yielded EC50s (microgram/ml) and sigmoidicity (gamma) of 4.63 +/- 0.39 and 3.98 +/- 0.42 for APAP, 11.33 +/- 1.35 and 3.97 +/- 0.58 for IBU05 and 12.83 +/- 1.89 and 4.27 +/- 0.63 for IBU10. On visual inspection of the efficacy-time profiles of the febrile children, a number of them had an apparent linear function (slope; delta degree C/hr) and/or a sinusoidal cyclic function "confounding" standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (delta degree C/hr) and/or a sinusoidal cyclic function to the Sigmoid Emax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual delta degree Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBU AUC0-infinity was confirmed; doubling the dose from 5 to 10 mg/kg increased the AUC0-->infinity by only 1.5-fold. The confounding effect of initial temperature (Tempi) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p = 0.03) contribution of Tempi (but not age) on the value of the slope function was found. There was no consistent effect of age or Tempi on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age and Tempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, and Tempi interacted with beta in a significant multiple linear relationship with AUC0-infinity. The effects of IBU dose, age, and Tempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified Sigmoid Emax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition to Tempi. A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.

Acetaminophen↗

PubMed1998

Pharmacodynamics of topoisomerase I inhibition: Western blot determination of topoisomerase I and cleavable complex in patients with upper gastrointestinal malignancies treated with topotecan.

Analogues of camptothecins are specific inhibitors of eukaryotic DNA topoisomerase I (topo I) that lead to DNA damage and, eventually, cellular cytotoxicity. Camptothecin analogues bind to this target enzyme in the course of its normal function and stabilize the DNA-enzyme adduct to form a "cleavable complex." Preclinical experiments using Western blot analyses have shown cleavable complex formation to be the key intermediate step in topo I inhibition. In this series of experiments, it was our goal to convert this laboratory technique into a useful clinical assay, allowing measurement of the target enzyme and detection of the key intermediate in clinical specimens taken from patients being treated with the topo I inhibitor topotecan. Because available antibodies were not sufficiently sensitive at the start of this project, we identified a highly specific human SCL-70 antibody from a patient with scleroderma, which allowed quantitative determination of topo I copy number in HeLa and HT-29 cell lines. Additional refinements of the Western blot technique were accomplished to improve signal:noise ratio. In surgical tumor specimens, we found the median topo I level to be 30.1 x 10(5) copies/cell for gastric adenocarcinomas, compared to 18.4 x 10(5) copies/cell for normal gastric mucosae in the same samples. For lung adenocarcinoma, the median protein level was 21.5 x 10(5) copies/cell, compared with the normal tissue counterpart protein level of 12.7 x 10(5) copies/cell. The median tumor:normal ratios from paired samples of these tumor types were 1.51 and 1.84, respectively. As part of a Phase II study evaluating the efficacy of topotecan (1.5-2.0 mg/m2 daily for 5 days) in upper gastrointestinal malignancies, we obtained tumor and normal mucosa biopsies in 11 patients with gastric or esophageal cancer, 30 min after administration on day 4 or 5. Three patients with gastric adenocarcinoma had stable disease as their best response, with the remainder of patients progressing. Improvement in Western blotting methodology allowed the quantitation of topo I levels in these gastric and esophageal cancer biopsies, which could be augmented by brief heating to release complexed topo I. We were also able to directly visualize high molecular weight topo I-containing bands, which were shown to be cleavable complexes by heat reversal, with restoration of the topo I Mr 100,000 band. Using this heat reversal technique, we determined the presence of cleavable complex in a total of 7 of 11 patient biopsy samples (5 tumors and 2 normal mucosae). In patients treated with topotecan on this dose and schedule, we determined that a median of 73% of the total tumor topo I was involved in cleavable complex (range, 18.3-91%). The intensity of the Mr 100,000 topo I band in biopsy specimens of patients receiving topotecan represented "free" or noncomplexed topo I. The median copy number for the residual, noncomplexed topo I (n = 11) was 7.36 x 10(5) copies/cell, significantly less than the median of 30.1 x 10(5) copies/cell for random tumor specimens from patients with gastric adenocarcinomas (P < 0.001). Pharmacodynamic analysis demonstrated a negative correlation between the noncomplexed topo I copy number and topotecan area under the curve (Spearman rank test: r(s) = -0.81, P = 0.003). Nonlinear regression analyses of these data were best fit with an inhibitory maximum effect model, yielding parameter estimates for Emax and EC50 of 29.3 x 10(5) copies/cell (coefficient of variation = 22%) and 43.1 ng x h/ml (coefficient of variation = 27%), respectively. Through a series of careful modifications and refinements, we have improved the Western blot assay for topo I for use in clinical monitoring. We have demonstrated the ability to directly visualize cleavable complex in patients being treated with topo I inhibitor therapy and have directly quantitated free topo I, as well as the key topo I intermediate (cleavable complex), in biopsy specimens obtained from pat

Adenoma, Islet Cell↗

PubMed2000

Elastic and physicochemical relationships within cortical bone.

The purpose of this study was to examine the relationships that exist between the elastic properties and the physicochemical properties of cortical bone in two groups of experimental animals. The animal model was the immature mutant dwarf rat, and the groups consisted of rats treated and not treated with recombinant human growth hormone (rhGH). The objective was to establish and broaden the quantifiable link between the three-dimensional form and function of bone beyond the typical unidirectional measures. This study was based on previously reported work that refined the ultrasonic elasticity technique for use with small specimens (<1.0 mm) and determined that the administration of rhGH can counter the degenerative effects produced by hormone-suppressed downregulation on the elastic and physicochemical characteristics of cortical bone. Ultrasonic wave propagation and density measurements were used previously to determine the three-dimensional (orthotropic) material properties of rat femoral cortical bone. X-ray powder diffraction, microscopic, morphometric, and biochemical analysis techniques have been used to describe physicochemical properties, including mineral crystal size, cortical porosity, mineral and nonmineral content, and microstructural characteristics. In this study, mathematical relationships between the local physicochemical (independent variable) and elastic (dependent variable) properties were formulated via linear and nonlinear regression analyses. In general, apparent density was found to have the highest level of correlation with most of the longitudinal and shear moduli (R(2) = 0.300 to 0.800). Concomitantly, mineral crystal width and cortical porosity offered the best correlations with the Poisson's ratios (R(2) up to 0.600). Wilcoxon t tests verified a significant decrease in the elastic properties in dwarf rat cortical bone after rhGH treatments (p < 0.05). Physicochemical measures of bone quality (density, crystal size) generally decreased while measures of bone quantity (cortical area, moments of inertia) generally increased (p < 0.05) after rhGH treatments. Some mineral and nonmineral properties were unchanged. This study presents a quantifiable link between cortical bone elasticity and its composite construction as measured across two dramatically different experimental groups.

Animals↗

PubMed2004

Biodegradation kinetics of volatile hydrophobic organic compounds in cultures with variable fractional volumes.

An extension of the models developed by Guha and Jaffé (Biotechnol Bioeng [1996] 50:693-699) to describe the phenanthrene biodegradation kinetics for the cultures with variable fractional volumes is presented. Batch experiments were conducted with a culture capable of degrading the phenanthrene using a single culture vessel from which samples were withdrawn over time to monitor the disappearance of phenanthrene. For accurate measurement of phenanthrene concentrations, a sampling procedure designed for quantifying the sorption of phenanthrene onto glassware was also introduced. The Monod parameters were estimated by nonlinear regression analyses of simultaneous solutions to the substrate utilization/volatilization and Monod equations for growth of the cell mass. The results demonstrate that the models were able to be extended to phenanthrene-degrading cultures with variable fractional volumes. When the ratio between sampling volume and volume of the culture medium was relatively small, the parameters obtained were similar to those which would be obtained using constant fractional volumes of culture medium. It was also found that the model's fit to the phenanthrene disappearance data in this study were better than those obtained by Guha and Jaffé, implying that the sorption process of phenanthrene during the sampling period could significantly affect the measurement of phenanthrene concentrations. Failing to account for these losses led to less accurate measurements of substrate concentrations, which in turn resulted in a poor estimation of the parameters. The findings of this study reduce considerably the experimental work necessary in the estimation of Monod kinetic parameters for the purpose of modeling.

Biodegradation, Environmental↗

PubMed1986

Chloride-dependent binding sites for L-[3H]glutamate on dendrodendritic synaptosomal membranes of rat olfactory bulb.

Dendrodendritic synapses occur between granule cell dendrites and secondary dendrites of mitral cells within the olfactory bulb and are attainable in a subcellular fraction (DDS). Since the mitral cells are thought to utilize an excitatory amino acid as a neurotransmitter, we determined the pharmacologic specificity of Na+-independent L-[3H]glutamate binding to fresh membranes of DDS in 50 mM Tris-HCl, pH 7.1. Binding of L-glutamate to membranes of DDS was specific, Cl(-)-dependent, and saturable. Scatchard plots were analyzed by nonlinear regression analyses using the computer program LIGAND, and the data was best-fitted to a one-site model with KD of 0.56 +/- 0.04 microM and an apparent Bmax of 48 +/- 5 pmol/mg protein. Hill plots also indicated the presence of one site and no cooperativity (nH = 0.99 +/- 0.03). However, the relative effectiveness of several compounds in inhibiting L-glutamate binding to membranes of DDS clearly demonstrated the presence of more than one site. Electrophysiological studies suggest that 2-amino-4-phosphonobutyrate (APB) is a potent antagonist of evoked responses elicited by stimulation of mitral cell axons and that quisqualate is a potent agonist; both of these compounds were highly effective inhibitors of L-glutamate binding to DDS membranes. APB displaced about 70% of the sites labeled with 200 nM L-glutamate with a KI of 1.6 microM, whereas quisqualate inhibition of L-glutamate binding yielded a line that was curvilinear in the Scatchard plot and was resolved into two sites of relatively high affinity (KI values of 0.02 and 0.65 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminobutyrates↗

PubMed1994

Substituent contributions to the transport of substituted p-toluic acids across lipid bilayer membranes.

The fluxes of p-toluic acid and seven alpha-methylene-substituted analogs have been determined as a function of pH across planar egg lecithin/decane bilayers to construct a set of well-isolated polar functional group contributions to the free energy of transfer from water to the bilayer transport barrier domain. Nonlinear regression analyses of flux-pH profiles using a model which accounts for unstirred layer effects yielded membrane permeability coefficients (PRX) that varied from 1.1 cm/s for p-toluic acid to 4.1 x 10(-5) cm/s for the alpha-carbamoyl-p-toluic acid. Bulk organic solvent/water partition coefficients (KRX) were obtained for the same set of permeants using four solvent systems to identify a bulk solvent which closely resembles the chemical nature of the bilayer barrier microenvironment for these permeants. The slopes of plots of log PRX vs log KRX were 0.85, 0.91, 0.99, and 2.4, respectively, for hexadecane/water, hexadecene/water, 1,9-decadiene/water, and octanol/water with the best model solvent being that which yielded a slope closest to unity. A significant deviation in the slope from 1, as observed in the correlation with octanol/water partition coefficients, reveals that this relatively polar, hydrogen-bonding solvent is a poor model solvent for describing the barrier microenvironment for these permeants. Thus, the polar interfacial regions occupied by phospholipid head groups are not the barrier domain for the transport of the series examined in this study. The incremental group contributions to the free energy of transfer to the barrier domain (cal/mol) for the functional groups, CI, OCH3, CN, OH, COOH, and CONH2, were found to be 325, 687, 2170, 3860, 5170, and 6060, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzoates↗

PubMed2001

Method dependence of apparent stoichiometry in the binding of salicylate ion to human serum albumin: a comparison between equilibrium dialysis and fluorescence titration.

The binding of salicylate ion to human serum albumin (HSA) was studied in 100 mM potassium phosphate buffer (pH 7.4, 25 degrees C), using equilibrium dialysis and fluorescence titration methods. The protein samples tested were (a) dialyzed human plasma and (b) a commercial preparation of HSA, essentially free of globulin and fatty acids. Independent of the analytical method used, Scatchard and nonlinear regression analyses of the data pointed to a single class of high-affinity salicylate binding sites. On the other hand, the binding parameters were found to be method dependent. K(d) ranged between 25 +/- 2.4 and 62 +/- 15 microM in equilibrium dialysis and between 10 +/- 1.3 and 40 +/- 3.0 microM in fluorescence titration. (The higher limits refer to plasma samples at high [HSA]). Following the same pattern, the apparent stoichiometry of binding (though independent of sample identity and concentration) was higher in equilibrium dialysis (n(app) = 3.2 +/- 0.10) than in fluorescence titration (n(app) 1.9 +/- 0.30). The difference between the two methods could be reconciled by invoking two distinct classes of binding sites (I and II), which had identical (or marginally different) K(d) values, while differing in the magnitude of the fluorescence signal (Deltaf) generated upon ligand binding (Deltaf, PL(I) = Deltaf(I); Deltaf, PL(II) = 0). Further, it was assumed that the state of occupation of class II sites affected the fluorescence efficiency of class I sites, such that Deltaf, PL(I,II) = betaDeltaf(I) (beta = interaction factor). A random binding scheme involving P, PL(I), PL(II), and PL(I,II) was formulated. The model adequately predicted the behavior of the system when monitored through the change in protein fluorescence: Taking K(d) = 25 microM and n(T) = 3, the interaction factor beta was found to be 0.62 +/- 0.10. It was concluded that the correct parameters for the binding of salicylate ion to HSA are K(d) = 25 +/- 2.4 microM and n(T) = 3.2 +/- 0.10, as indicated by equilibrium dialysis of purified HSA. Besides updating information relating to the salicylate binding potential of HSA, this study serves to illustrate a likely complication in the study of protein-ligand interactions by fluorometric methods.

Chromatography, Gel↗

PubMed1986

Effects of bucumolol, nadolol and nifenalol on maximum upstroke velocity of action potential in guinea pig papillary muscles.

The effects of bucumolol (BUC), nadolol (NAD) and nifenalol (NIF) on contractile forces and on action potentials (APs) were investigated in isolated guinea pig atrial and papillary muscles, respectively. Log 1/ED40 values for the negative inotropic effects of these drugs were 0.097, 10 and 0.74 mmol/l in this order. BUC (50 mumol/l), NAD (0.5 mmol/l) and NIF (0.2 mmol/l) produced about 60, 20 and 20% reduction of Vmax at 1 Hz. The frequency-dependent reductions at these and higher concentrations were greatest for BUC, intermediate for NAD and least for NIF. These potencies at certain frequencies were, as a whole, consistent with log P-potency relationship established in our previous papers (Harada et al. 1981; Ban et al. 1985). The reductions of Vmax in APs in response to premature stimuli during basic stimuli at the rate of 0.25 or 0.027 Hz decayed exponentially during diastolic intervals (DI). The time constants of these decay process (tau) estimated by linear and nonlinear regression analyses and by eye were 12.2-9.6 s for BUC (50-100 mumol/l) and 2.9-4.8 s for NAD (1-2 mmol/l) and 57-87 ms for NIF (0.2-1 mmol/l). In terms of the molecular weight (MW)-log tau relationship (Ban et al. 1985), these tau values are within the 95% fiducial limit for BUC and NAD and deviated from the lower fiducial limit for NIF. The frequency-dependent reductions of Vmax by these drugs were explained in terms of a function of tau and the intercept Ao. Based on the study made by Cohen et al.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed2005

A cartilage growth mixture model for infinitesimal strains: solutions of boundary-value problems related to in vitro growth experiments.

A cartilage growth mixture (CGM) model is linearized for infinitesimal elastic and growth strains. Parametric studies for equilibrium and nonequilibrium boundary-value problems representing the in vitro growth of cylindrical cartilage constructs are solved. The results show that the CGM model is capable of describing the main biomechanical features of cartilage growth. The solutions to the equilibrium problems reveal that tissue composition, constituent pre-stresses, and geometry depend on collagen remodeling activity, growth symmetry, and differential growth. Also, nonhomogeneous growth leads to nonhomogeneous tissue composition and constituent pre-stresses. The solution to the nonequilibrium problem reveals that the tissue is nearly in equilibrium at all time points. The results suggest that the CGM model may be used in the design of tissue engineered cartilage constructs for the repair of cartilage defects; for example, to predict how dynamic mechanical loading affects the development of nonuniform properties during in vitro growth. Furthermore, the results lay the foundation for future analyses with nonlinear models that are needed to develop realistic models of cartilage growth.

Biomechanical Phenomena↗

PubMed1994

Nonlinear stress analysis of the whole lumbar spine in torsion--mechanics of facet articulation.

The response of the whole ligamentous lumbar spine in axial torsion is studied. Attention is focused on the inter-segmental variations, role of articular facets, presence of coupled movements, intervertebral stresses and the effects of a structural alteration at a level on the response. A detailed three-dimensional finite element model (L1-S1) was used for nonlinear stress analyses under torques of up to 15 N m. In right axial torque, extra cases of larger gap limit for more effective articulation, of loss of L4-L5 disc fluid content, and of removal of L4-L5 compression facet were also studied. The intersegmental results varied from one level to the next. The facet contact occurred at the lateral posterior regions of articular surfaces. The interference gap distance between facet articular surfaces, and not the orientation of articular surfaces, was the primary factor in the relative effectiveness of facets in resisting torsion. Coupled motions of upward translation and flexion rotation were noted at all levels under torques in both left and right directions. Loss of disc fluid content at the L4-L5 level resulted in larger facet contact force and axial rotation at the same level. Removal of the L4-L5 compression facet substantially increased the axial rotation, intradiscal pressure, maximum fibre strain, and strains in capsular ligaments at the same L4-L5 level. In axial torque, the disc failure appeared to be unlikely. Relatively large facet forces were generated that further increased with a loss in disc fluid content.

Aged↗