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PubMed2006

Temporal decline in sirolimus elimination immediately after pancreatic islet transplantation.

Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.

Adult↗

PubMed1991

Pharmacokinetic analysis of azelaic acid disodium salt. A proposed substrate for total parenteral nutrition.

Azelaic acid was the first dicarboxylic acid proposed as an alternative energy substrate in total parenteral nutrition. In this study, the pharmacokinetics of azelaic acid were investigated in 12 healthy volunteers, 7 receiving a constant infusion (10g over 90 min) and 5 a bolus dose (1g). The 24h urinary excretion and plasma concentration in blood samples taken at regular intervals were assayed by gas-liquid chromatography. Experimental data were analysed by a 2-compartment nonlinear model that describes both tubular secretion and cellular uptake in Michaelis-Menten terms. A high value of urinary excretion (mean 76.9% of infused dose) and a mean clearance of 8.42 L/h were found, suggesting the presence of tubular secretion. Estimating the population mean of the pharmacokinetic model parameters gave a maximal cellular uptake of 0.657 g/h. The model predicts that 90% of the maximal uptake should be reached in the plateau phase of a constant infusion of 2.2 g/h. The presence of extensive and rapid losses through urinary excretion, and the low estimated value of the maximal cellular uptake, indicate that azelaic acid is not suitable as an energy substrate for total parenteral nutrition.

Adult↗

PubMed2006

Binding characteristics and distribution of lactoferrin receptors in the gut and choroid plexus in newborn calves.

Lactoferrin (Lf), an iron-binding multifunctional glycoprotein, abundantly present in colostrum and milk of different species such as humans, bovines, and mice has been shown that bovine colostral Lf is transported into the CSF via plasma in newborn calves. Specific Lf-receptors (Lf-R) are present in different cells of different species. In the present study, we report for the first time, the presence and distribution of Lf-R in the intestine and choroid plexus in newborn calves. Brush-border membrane vesicles (BBMV) were prepared from the mucosa of duodenum, jejunum, ileum, colon, epithelium overlying Peyer's patches (EOPP) in jejunum (EOPPJ) and ileum (EOPPI), and choroid plexus membranes. Receptor binding assays were carried out using 125I labeled bovine Lf. Specific and saturable Lf-R were found in BBMV of all the intestinal segments and choroid plexus examined. Nonlinear regression and Scatchard plot analyses clearly revealed that EOPP had the highest binding maximal (Bmax), and lowest in colon. The maximum dissociation constant (Kd) 0.7 microM was in colon while, Bmax and Kd in choroid plexus membrane were 16.87 nmol/mg protein and 0.34 microM, respectively. All these findings together strongly suggested that Lf was transported into CSF via plasma through receptor mediated transcytosis.

Animals↗

PubMed2005

Stochastic modeling of nonlinear epidemiology.

The objectives of this paper to analyse, model and simulate the spread of an infectious disease by resorting to modern stochastic algorithms. The approach renders it possible to circumvent the simplifying assumption of linearity imposed in the majority of the past works on stochastic analysis of epidemic processes. Infectious diseases are often transmitted through contacts of those infected with those susceptible; hence the processes are inherently nonlinear. According to the classical model of Kermack and McKendrick, or the SIR model, three classes of populations are involved in two types of processes: conversion of susceptibles (S) to infectives (I) and conversion of infectives to removed (R). The master equations of the SIR process have been formulated through the probabilistic population balance around a particular state by considering the mutually exclusive events. The efficacy of the present methodology is mainly attributable to its ability to derive the governing equations for the means, variances and covariance of the random variables by the method of system-size expansion of the nonlinear master equations. Solving these equations simultaneously along with rates associated influenza epidemic data yields information concerning not only the means of the three populations but also the minimal uncertainties of these populations inherent in the epidemic. The stochastic pathways of the three different classes of populations during an epidemic, i.e. their means and the fluctuations around these means, have also been numerically simulated independently by the algorithm derived from the master equations, as well as by an event-driven Monte Carlo algorithm. The master equation and Monte Carlo algorithms have given rise to the identical results.

Algorithms↗

PubMed2006

Robustness analysis of biochemical network models.

Biological systems that have been experimentally verified to be robust to significant changes in their environments require mathematical models that are themselves robust. In this context, a necessary condition for model robustness is that the model dynamics should not be sensitive to small variations in the model's parameters. Robustness analysis problems of this type have been extensively studied in the field of robust control theory and have been found to be very difficult to solve in general. The authors describe how some tools from robust control theory and nonlinear optimisation can be used to analyse the robustness of a recently proposed model of the molecular network underlying adenosine 3',5'-cyclic monophosphate (cAMP) oscillations observed in fields of chemotactic Dictyostelium cells. The network model, which consists of a system of seven coupled nonlinear differential equations, accurately reproduces the spontaneous oscillations in cAMP observed during the early development of D. discoideum. The analysis by the authors reveals, however, that very small variations in the model parameters can effectively destroy the required oscillatory dynamics. A biological interpretation of the analysis results is that correct functioning of a particular positive feedback loop in the proposed model is crucial to maintaining the required oscillatory dynamics.

Animals↗

PubMed2002

Bio-acoustic thermal lensing and nonlinear propagation in focused ultrasound surgery using large focal spots: a parametric study.

It is well known that the acoustic properties of soft tissue have a dependence on tissue temperature. This is of particular interest in focused ultrasound surgery since the mechanism of action of focused ultrasound surgery is to kill targeted tissue by inducing localized heating by ultrasound absorption, and hence cautery of that tissue. However, the act of localized heating induces a change in the acoustic properties of the targeted tissue and tissue surrounding it. This phenomenon distorts the incoming acoustic wavefront, and has been termed the thermal lens effect for this reason. Furthermore, nonlinear effects in acoustic propagation become non-negligible at the ultrasound intensities required for therapeutic action. This paper examines the importance of the thermal lens effect and nonlinear tissue properties by simulating a variety of clinically applicable phased array transducer configurations that have not yet been appropriately analysed using a full three-dimensional nonlinear treatment of acoustic propagation. The significance of the thermal lens effect is characterized by comparing the simulation of coupled acoustic and thermal propagation with an uncoupled treatment; neglecting thermal lensing typically produces a movement of 1 to 2 mm in the predicted position of the focus towards the transducer. The results also show that the classical methods of acoustic propagation can produce grossly erroneous results under certain clinically relevant transducer configurations and that an acoustic field scan with a hydrophone may not accurately predict therapeutic effect.

Acoustics↗

PubMed1997

Artifactual nonlinearity due to wear grooves and friction in four-point bending experiments of cortical bone.

Experiments and analyses were performed to determine the cause of a nonlinear force-deflection response observed in four-point flexural fatigue of beams of cortical bone machined from the mid-diaphysis of the equine third metacarpus. Observable grooves which formed on the beam surface at supports and load noses were found to be the primary cause of the nonlinearity. An additional geometric nonlinearity at large deflections revealed by finite element modeling may be minimized by using the smallest diameter supports and load noses recommended in ASTM 790. However, frictional constraint of the beams at the load noses and supports can occur at low load levels and should be avoided by using roller-bearing supports and load noses, or some equivalent method.

Animals↗

PubMed1996

A dual-input nonlinear system analysis of autonomic modulation of heart rate.

Linear analyses of fluctuations in heart rate and other hemodynamic variables have been used to elucidate cardiovascular regulatory mechanisms. The role of nonlinear contributions to fluctuations in hemodynamic variables has not been fully explored. This paper presents a nonlinear system analysis of the effect of fluctuations in instantaneous lung volume (ILV) and arterial blood pressure (ABP) on heart rate (HR) fluctuations. To successfully employ a nonlinear analysis based on the Laguerre expansion technique (LET), we introduce an efficient procedure for broadening the spectral content of the ILV and ABP inputs to the model by adding white noise. Results from computer simulations demonstrate the effectiveness of broadening the spectral band of input signals to obtain consistent and stable kernel estimates with the use of the LET. Without broadening the band of the ILV and ABP inputs, the LET did not provide stable kernel estimates. Moreover, we extend the LET to the case of multiple inputs in order to accommodate the analysis of the combined effect of ILV and ABP effect on heart rate. Analyzes of data based on the second-order Volterra-Wiener model reveal an important contribution of the second-order kernels to the description of the effect of lung volume and arterial blood pressure on heart rate. Furthermore, physiological effects of the autonomic blocking agents propranolol and atropine on changes in the first- and second-order kernels are also discussed.

Adult↗

PubMed2001

Kinetic analyses of mitochondrial 75selenium uptake in Trigonella foenum-graecum seedlings exposed to selenium and mimosine.

Uptake of (75Se) added in vitro was followed in mitochondria isolated from Trigonella foenum-graecum seedlings grown under different Se status (0.5-1.0 ppm) and with added mimosine (0.1 mM). Uptake of 75Se followed with added Na2 75SeO3 upto 20 microM in the medium was nonlinear in all the groups. Kinetic analyses of the uptake of 75Se for 1 min were carried out for all the groups. The results indicated a cooperative effect during Se transport. Graphical analyses using the Hill plot and Scatchard plot confirmed the existence of negative cooperativity during 75Se uptake. Scatchard plots were biphasic, suggesting the probable presence of two classes of binding sites. The presence of succinate or ATP in the incubation medium inhibited 75Se uptake by 40%. Studies with mitochondrial respiratory inhibitors indicated the uptake to be energy independent. A decrease in the uptake of 75Se by 40% effected by HgCl2, N-ethyl maleimide, and iodoacetate confirmed the interaction of active thiols in the process. The present study confirms the controlled nature of 75Se uptake by plant mitochondria.

Germination↗

PubMed1996

[Tooth movement by biomechanical technique in orthodontic treatment].

The purpose of this study was to analyze tooth movement by measuring the electric impedance of the wire and by using the nonlinear finite element analysis. In this study, the HP4338A Milliohmmeter was used and the model consisted of a metal tooth, silicone bath, bracket, and orthodontic wire. Then, the two-dimensional finite elements were used and the model consisted of tooth, periodontal ligament, alveolar bone, bracket, and orthodontic wire. There were two analyses. The first was the contact nonlinear finite element analysis of elastic deformation in the displaced tooth at the slide points between the bracket and wire where two gap element areas existed, and the second was the material nonlinear finite element analysis of the stress relaxation in bone at the fixing points between the bracket and wire where two rigid element areas, differing from the gap element areas, existed. The results were as follows: 1. The linear proportion between the electric impedance and the orthodontic wire was found. Therefore very minute tooth movements became measurable with changes of the wire electric impedance. 2. During tooth movement, the stick between the bracket and the wire altered with the slip ones repeatedly. 3. The movement of the displaced tooth at the center of rotation was counterclockwise. 4. The movement of the displaced tooth at the bracket position was clockwise.

Biomechanical Phenomena↗

PubMed2006

Spike-triggered neural characterization.

Response properties of sensory neurons are commonly described using receptive fields. This description may be formalized in a model that operates with a small set of linear filters whose outputs are nonlinearly combined to determine the instantaneous firing rate. Spike-triggered average and covariance analyses can be used to estimate the filters and nonlinear combination rule from extracellular experimental data. We describe this methodology, demonstrating it with simulated model neuron examples that emphasize practical issues that arise in experimental situations.

Action Potentials↗

PubMedDate not supplied

Validation of an approximate approach to compute genetic correlations between longevity and linear traits.

The estimation of genetic correlations between a nonlinear trait such as longevity and linear traits is computationally difficult on large datasets. A two-step approach was proposed and was checked via simulation. First, univariate analyses were performed to get genetic variance estimates and to compute pseudo-records and their associated weights. These pseudo-records were virtual performances free of all environmental effects that can be used in a BLUP animal model, leading to the same breeding values as in the (possibly nonlinear) initial analyses. By combining these pseudo-records in a multiple trait model and fixing the genetic and residual variances to their values computed during the first step, we obtained correlation estimates by AI-REML and approximate MT-BLUP predicted breeding values that blend direct and indirect information on longevity. Mean genetic correlations and reliabilities obtained on simulated data confirmed the suitability of this approach in a wide range of situations. When nonzero residual correlations exist between traits, a sire model gave nearly unbiased estimates of genetic correlations, while the animal model estimates were biased upwards. Finally, when an incorrect genetic trend was simulated to lead to biased pseudo-records, a joint analysis including a time effect could adequately correct for this bias.

Longevity↗

PubMed1987

Mathematical separation of multi-component exponential signals from the u.v. laser excitation of glycogen phosphorylase b.

Laser excitation of the vitamin B6 cofactor of the glycogen phosphorylase enzyme produces a transient absorbance signal at 470 nm. Martin et al. proposed four exponential decays for this complex signal. One component with the largest amplitude and a decay rate constant in the region of 150,000 s-1 results from an excited singlet state, and three successive decays of smaller amplitude with the rate constants in the regions of 700,000 s-1, 30,000 s-1, and 6000 s-1 result from a triplet state. These results were determined through nonlinear least squares regression and residual analyses, with some knowledge of the possible photochemistry of the cofactor by itself. The Fourier transform method, which requires no initial estimates of the parameters or of the number of decays, was selected for further analysis of the data. The results of the Gardner and differential approaches to the method confirm that the predicted four exponential components are in the signal and that the values of the decay rate constants agree with those from the nonlinear regression analysis. These results, presented here, help to demonstrate protein changes at the active site of enzyme catalysis.

Animals↗

PubMed2004

Avoiding the material nonlinearity in an external fixation device.

BACKGROUND: External fixation devices are widely used for treating unstable bone fractures because of their attractive features including minimal invasiveness, maximum tailorability, and extreme versatility. In one type of these devices (i.e., the fine-wire fixators), these unique features are made possible by the use of tensioned wires to support bone fragments. The major problem with these wires is their yielding. Once the wires yield, the fracture healing process will be adversely affected. A recent study showed that the nonlinear behavior observed in these tensioned wires can be geometric and material, and the geometric nonlinearity will stiffen the wires while the material nonlinearity will cause the wires to yield. This study is to investigate if it is possible to avoid the material nonlinearity in order to retain the elastic and repeatable performance for the wires. METHODS: Nonlinear and large deformation finite element analyses were conducted. Models of a bone segment transfixed by pairs of cross-aligned wires subjected to various levels of pre-tension were developed. The bone segment was subjected to a vertical load, and the load-displacement curves, wire tensions and wire tensile stresses were obtained under a full cycle of loading and unloading regime. FINDINGS: Pre-tensioning the wires is beneficial for stiffening a fixation device, but is disadvantageous to maintaining the wire elasticity. By limiting the level of the pre-tension, we can avoid the material nonlinearity. Doing so we will be able to stiffen the fixation device and retain elastic and predictable mechanical performance at the same time. INTERPRETATION: The findings will lead to a new paradigm toward enhancing the performance of external fixation devices.

Bone Wires↗

PubMed2005

Nonlinear dynamics of homeothermic temperature control in skunk cabbage, Symplocarpus foetidus.

Certain primitive plants undergo orchestrated temperature control during flowering. Skunk cabbage, Symplocarpus foetidus, has been demonstrated to maintain an internal temperature of around 20 degrees C even when the ambient temperature drops below freezing. However, it is not clear whether a unique algorithm controls the homeothermic behavior of S. foetidus, or whether such an algorithm might exhibit linear or nonlinear thermoregulatory dynamics. Here we report the underlying dynamics of temperature control in S. foetidus using nonlinear forecasting, attractor and correlation dimension analyses. It was shown that thermoregulation in S. foetidus was governed by low-dimensional chaotic dynamics, the geometry of which showed a strange attractor named the "Zazen attractor." Our data suggest that the chaotic thermoregulation in S. foetidus is inherent and that it is an adaptive response to the natural environment.

Araceae↗

PubMedDate not supplied

Mechanical response of bone under short-term loading of a dental implant with an internal layer simulating the nonlinear behaviour of the periodontal ligament.

We consider a non-standard design for a fixed dental implant, incorporating a soft layer which simulates the presence of the periodontal ligament (PDL). Instead of being aimed at causing an a priori defined stress/strain field within the surrounding bone, upon loading, such a design simply tries to better reproduce the natural tooth-PDL configuration. To do this, the mechanical properties of the internal layer match those of the PDL, determined experimentally to be strongly nonlinear. Three-dimensional finite element analyses show that the presence of such a layer produces (i) a prosthesis mobility very similar to that of a healthy tooth, for several loading conditions, and (ii) a stress/strain distribution substantially different from that arising, upon loading, around a conventional implant. The lack of knowledge of the real mechanical fields existing, under loading, in the bone around a healthy tooth makes it very difficult to state that the stress distribution produced by the modified implant is "better" than that produced by the standard one. Nevertheless, the comparison of the results obtained here, with those of previous refined analyses of the tooth-PDL-bone system, indicates that the modified implant tends to produce a stress distribution in the bone, upon loading, closer to "natural" than that given by the standard one, within the limits imposed by the presence of threads coupling the implant with the bone.

Biomimetic Materials↗

PubMed1994

Simulation for the analysis of distorted pharmacodynamic data.

A simulation study was conducted to compare the performance of alternative approaches for analyzing the distorted pharmacodynamic data. The pharmacodynamic data were assumed to be obtained from the natriurertic peptide-type drug, where the diuretic effect arises from the hyperbolic (Emax) dose-response model and is biased by the dose-dependent hypotensive effect. The nonlinear mixed effect model (NONMEM) method enabled assessment of the effects of hemodynamics on the diuretic effects and also quantification of intrinsic diuretic activities, but the standard two-stage (STS) and naive pooled data (NPD) methods did not give accurate estimates. Both the STS and the NONMEM methods performed well for unbiased data arising from a one-compartment model with saturable (Michaelis-Menten) elimination, whereas the NPD method resulted in inaccurate estimates. The findings suggest that nonlinearity and/or bias problems result in poor estimation by NPD and STS analyses and that the NONMEM method is useful for analyzing such nonlinear and distorted pharmacodynamic data.

Antihypertensive Agents↗

PubMed1991

[Analysis of environmentally-conditioned and genetic influences on the frequency of hip joint dysplasia in German Shepherd dogs].

The importance of environmental and genetic influences on the frequency of hip dysplasia was studied in 10,595 German shepherd dogs. Systematic effects were analysed using mixed linear and mixed nonlinear threshold models. Following effects were regarded in the models applied: sire and mother of the dog as random effects, age at x-raying, sex, birth year and season of the x-rayed dogs, litter size, percentage of x-rayed dogs in each litter and sex ratio of the litter as fixed effects. Sire, mother, sex and age at x-raying showed significant influence on the occurrence of hip dysplasia. The heritability estimates in a hierarchical data design (sire, mother within sire) for the polychotomous trait hip dysplasia were for full sibs h2 = 0.30, for maternal half sibs h2 = 0, 48, and for paternal half sibs h2 = 0.11. Only the heritability estimates of the paternal half sibs seem to be reliable because kennel and breeder effects are confounded with the mother effect. Analysing the frequency of hip dysplasia as all-or-none traits, the heritability estimates were usually lowered by 50%. Selection programmes to reduce frequency of hip dysplasia can be improved if the estimation of breeding values with respect to environmental effects and frequency of hip dysplasia in all relatives will be implemented.

Analysis of Variance↗