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PubMed2001

Neural net classification of REM sleep based on spectral measures as compared to nonlinear measures.

In various studies the implementation of nonlinear and nonconventional measures has significantly improved EEG (electroencephalogram) analyses as compared to using conventional parameters alone. A neural network algorithm well approved in our laboratory for the automatic recognition of rapid eye movement (REM) sleep was investigated in this regard. Originally based on a broad range of spectral power inputs, we additionally supplied the nonlinear measures of the largest Lyapunov exponent and correlation dimension as well as the nonconventional stochastic measures of spectral entropy and entropy of amplitudes. No improvement in the detection of REM sleep could be achieved by the inclusion of the new measures. The accuracy of the classification was significantly worse, however, when supplied with these variables alone. In view of results demonstrating the efficiency of nonconventional measures in EEG analysis, the benefit appears to depend on the nature of the problem.

Adult↗

PubMed1988

Regulation of progesterone receptor messenger ribonucleic acid and protein levels in MCF-7 cells by estradiol: analysis of estrogen's effect on progesterone receptor synthesis and degradation.

The human breast cancer cell line MCF-7 responds to estrogens with increased progesterone receptor (PR) levels. In this study, we use dense amino acid density shift analyses to address directly the question of whether estrogen increases PR levels in MCF-7 cells by altering rates of receptor synthesis and/or degradation. Using different concentrations of estradiol (E2), which achieve PR levels that are half-maximal (3 X 10(-11) M F2) or maximal (6 X 10(-11) M E2), we have done sucrose gradient density shift analyses using dense (15N, 13C, 2H) amino acid incorporation to study rates of PR synthesis and degradation. These studies reveal a nonlinear loss of preexisting normal density receptor with time. From kinetic modeling analyses, equivalent rates of degradation are estimated for PR whether maximal or half-maximal levels are maintained, indicating that the major effect of E2 on PR content is to increase the rate of PR synthesis while leaving the degradation rate unaltered. The E2-stimulated increase in PR protein is also associated with increased levels of PR mRNA, as demonstrated by the use of a human PR cDNA probe. These density shift data provide evidence that the increased PR levels after estrogen exposure in MCF-7 cells are the result of an increased rate of receptor synthesis, rather than modulation of the rate of receptor degradation.

Amino Acids↗

PubMed2006

Recurrence plot analyses suggest a novel reference system involved in newborn spontaneous movements.

The movements of newborns have been thoroughly studied in terms of reflexes, muscle synergies, leg coordination, and target-directed arm/hand movements. Since these approaches have concentrated mainly on separate accomplishments, there has remained a clear need for more integrated investigations. Here, we report an inquiry in which we explicitly concentrated on taking such a perspective and, additionally, were guided by the methodological concept of home base behavior, which Ilan Golani developed for studies of exploratory behavior in animals. Methods from nonlinear dynamics, such as symbolic dynamics and recurrence plot analyses of kinematic data received from audiovisual newborn recordings, yielded new insights into the spatial and temporal organization of limb movements. In the framework of home base behavior, our approach uncovered a novel reference system of spontaneous newborn movements.

Biomechanical Phenomena↗

PubMed2004

Effects of nonlinearities and uncorrelated or correlated errors in realistic simulated data on the prediction abilities of augmented classical least squares and partial least squares.

Comparisons of prediction models from the new augmented classical least squares (ACLS) and partial least squares (PLS) multivariate spectral analysis methods were conducted using simulated data containing deviations from the idealized model. The simulated data were based on pure spectral components derived from real near-infrared spectra of multicomponent dilute aqueous solutions. Simulated uncorrelated concentration errors, uncorrelated and correlated spectral noise, and nonlinear spectral responses were included to evaluate the methods on situations representative of experimental data. The statistical significance of differences in prediction ability was evaluated using the Wilcoxon signed rank test. The prediction differences were found to be dependent on the type of noise added, the numbers of calibration samples, and the component being predicted. For analyses applied to simulated spectra with noise-free nonlinear response, PLS was shown to be statistically superior to ACLS for most of the cases. With added uncorrelated spectral noise, both methods performed comparably. Using 50 calibration samples with simulated correlated spectral noise, PLS showed an advantage in 3 out of 9 cases, but the advantage dropped to 1 out of 9 cases with 25 calibration samples. For cases with different noise distributions between calibration and validation, ACLS predictions were statistically better than PLS for two of the four components. Also, when experimentally derived correlated spectral error was added, ACLS gave better predictions that were statistically significant in 15 out of 24 cases simulated. On data sets with nonuniform noise, neither method was statistically better, although ACLS usually had smaller standard errors of prediction (SEPs). The varying results emphasize the need to use realistic simulations when making comparisons between various multivariate calibration methods. Even when the differences between the standard error of predictions were statistically significant, in most cases the differences in SEP were small. This study demonstrated that unlike CLS, ACLS is competitive with PLS in modeling nonlinearities in spectra without knowledge of all the component concentrations. This competitiveness is important when maintaining and transferring models for system drift, spectrometer differences, and unmodeled components, since ACLS models can be rapidly updated during prediction when used in conjunction with the prediction augmented classical least squares (PACLS) method, while PLS requires full recalibration.

Algorithms↗

PubMed1999

Software for population pharmacokinetics and pharmacodynamics.

Pharmacokinetic-pharmacodynamic modelling is being used increasingly as a tool in drug development because often in phase III clinical trials only sparse data are available for analysis and so a nonlinear mixed effects modelling approach has to be adopted. Specialist data analytical techniques and software are required to analyse such data. This article reviews some of the software currently available for performing nonlinear mixed effects modelling. A questionnaire was devised and sent to a number of software producers and the findings are presented and discussed in this paper. The programs could be grouped into 3 main categories: parametric and nonparametric maximum likelihood and Bayesian. It was apparent from the questionnaire that software development for population data analysis is a very active area of investigation. The implementation of methodologies varied widely between the packages: some were self-contained programs, whereas others were written within another application, usually a statistical package. They also varied with respect to their ease of use and level of support offered by the software producers. Although robustness and reliability are important concerns, they were not addressed in the present review. Most of the programs surveyed are in continual development.

Animals↗

PubMed2000

Education and the activation, course, and management of anger.

Using data from the 1996 General Social Survey, I examine education's association with the activation, course, and management of anger. I argue that education--as a source of stratification (status) and as a personal resource (human capital)--organizes the conditions that influence anger-related processes. In analyses of anger activation, education is associated with lower odds of family-related anger. The well educated have fewer children and more income--factors associated with a lower risk of family anger. Conversely, education is associated with higher odds of work-related anger, but income and personal control account for that association. In analyses of the course of anger, I document a nonlinear association between education and anger duration. Adjustment for the sense of control--which is negatively associated with anger duration--sharpens that parabolic association. Education is positively associated with perceived appropriateness of anger and negatively associated with the display of anger. In both cases, adjustment for control accounts for education's effect. The sense of control also suppresses education's significant positive effect on anger processing. In analyses of anger management, education increases the odds of cognitive flexibility and problem solving, but its effect on communication depends on the sense of control. In sum, education organizes personal and social circumstances that influence anger-related processes.

Anger↗

PubMed2002

Prediction of human clearance from animal data and molecular structural parameters using multivariate regression analysis.

The aim of the study reported here was to develop a method for predicting human clearance that can be applied to various kinds of drugs using clearance values for rats and dogs and some molecular structural parameters. The clearance data for rats, dogs, and humans of 68 drugs were obtained from literature. The compounds have various structures, pharmacological activities, and pharmacokinetic characteristics. In addition, molecular weight, c log P, and the number of hydrogen bond acceptors were used as possible descriptors related to the human clearance value for each drug. Three types of regression methods, multiple linear regression (MLR) analysis, partial least squares (PLS) method, and artificial neural network (ANN), were used to predict human clearance, and their predictive performances were compared with allometric approaches, which have been widely used in interspecies scaling. In MLR and PLS analyses, interaction terms were introduced to evaluate the nonlinear relationships. For the data sets used in the present study, MLR and PLS with quadratic terms gave the same equation and the best predictive performance. The value of the squared cross-validated correlation coefficient (q(2)) was 0.682. In conclusion, the MLR method using animal clearance data from only two species and using easily calculated structural parameters can generally predict human clearance better than allometric methods. This approach can be applied to drugs with various characteristics.

Animals↗

PubMed1991

Predictability of human EEG: a dynamical approach.

The electroencephalogram recordings from human scalp are analysed in the framework of recent methods of nonlinear dynamics. Three stages of brain activity are considered: the alpha waves (eyes closed), the deep sleep (stage four) and the Creutzfeld-Jakob coma. Two dynamical parameters of the attractors are evaluated. These are the Lyapunov exponents, which measure the divergence or convergence of trajectories in phase space and the Kolmogorov or metric entropy, whose inverse gives the mean predicting time of a given EEG signal. In all the stages considered, the results reveal the presence of at least two positive Lyapunov exponents, which are the footprints of chaos. This number increases to three positive exponents in the case of alpha waves, indicating that although for very short episodes the alpha waves seem extremely coherent, the variability of the brain increases markedly over larger periods of activity. The degree of entropy/chaos increases from coma to deep sleep and then to alpha waves. The large predicting time observed for deep sleep suggests that these waves are related to a slow rate of information processing. The predicting time of the alpha waves is much smaller, indicating a rapid loss of information. Finally, with the help of the Lyapunov exponents, the attractor's dimensions are evaluated using two different conjectures and compared to values obtained previously by the Grassberger-Procaccia algorithm.

Brain↗

PubMed1993

Effects of concurrent subchronic treatments with desmethylimipramine and propranolol on beta-adrenergic and serotonin2 receptors in rat brain.

The effects of seven consecutive daily injections of desmethylimipramine (DMI 20 mg/kg) and propranolol (PRO 10 mg/kg) on 3H-dihydroalprenolol (3H-DHA) and 3H-ketanserin (3H-KET) binding in rat brain were examined. Analyses of saturation binding data using the iterative, nonlinear curve-fitting program LIGAND revealed that PRO increased, while DMI reduced, 3H-DHA binding site density in cerebral cortex without altering receptor affinity, as previously reported. DMI reduced 3H-KET binding site density without changing affinity, and PRO produced the same effect. In cerebral cortex and probably in hippocampus and striatum, DMI and PRO administered together increased the density of 3H-DHA binding sites (beta-adrenergic receptors) and reduced their affinity. This combination of drugs reduced the density of 3H-KET binding sites (5-HT2 receptors) in cerebral cortex, but did not change their affinity. These findings indicate a need for additional studies on the interactions of DMI and PRO and related drugs because of implications for the treatment of depressed patients with cardiovascular disorders.

Animals↗

PubMed1999

Mechanical and electromotile characteristics of auditory outer hair cells.

The passive and active properties of the cochlear outer hair cell are studied. The outer hair cell is currently considered the major candidate for the active component of mammalian hearing. Understanding of its properties may explain the amplification and sharp frequency selectivity of the ear. To analyse the cell behaviour, a model of a nonlinear anisotropic electro-elastic shell is used. Using the data from three independent experiments, where the mechanical strains of the cell are measured, estimates of the cell wall in-plane Young's moduli and Poisson's ratios are given, as well as estimates of three modes of bending stiffness. Based on these estimates and data from the microchamber experiment, where the cell is under the action of transmembrane potential changes, the characteristics of the outer hair cell active behaviour are found. These characteristics include the coefficients of the active force production per unit of the transmembrane potential change and limiting parameters of the electromotile response for extreme hyperpolarisation and depolarisation of the cell. The obtained estimates provide important information for the modelling of organ-level cochlear mechanics.

Biomechanical Phenomena↗

PubMed2003

Np.OR: an S-Plus function for pointwise nonparametric estimation of odds-ratios of continuous predictors.

Calculating odds ratios (OR) and corresponding confidence intervals (CI) for exposures that have been measured using a continuous scale, presents important limitations in the traditional practice of epidemiology. Our objective is to describe an S-Plus function, that we called np.OR, that allows the computation of the pointwise estimates of the ORs as well as their corresponding CIs of continuous predictors introduced nonlinearly in a generalised model. The function can also be generalised to compute the pointwise estimates of categorical predictors that were introduced nonlinearly. To illustrate usage of the program we analyse the relationship between ambient temperature and total mortality in Barcelona for the period 1991-1995, while controlling for observed and unobserved confounders.

Confidence Intervals↗

PubMed2006

Conformational structure of gaseous 3-chloropropanoyl chloride by electron diffraction, normal coordinate analysis, and ab initio molecular orbital, and density functional theory calculations.

The molecular and conformational structures of 3-chloropropanoyl chloride (CH(2)Cl-CH(2)-C(=O)Cl) have been studied by using gas-phase electron diffraction (GED) data obtained at 22 degrees C (295 K) and ab initio molecular orbital (MO) and density functional theory (DFT) calculations up to the levels of MP4(SDQ) and B3LYP using larger basis sets. Normal coordinate calculations (NCA) taking into account nonlinear vibrational effects were also used in the analyses. The title compound may have up to four low-energy conformers in the gas phase, labeled according to the position of each of the two chlorine atoms in relation to the CCC propanoyl backbone, labeling the carbonyl chlorine torsion angle first: AA, AG, GG, and GA; where A is anti (ideal C-C-C-Cl torsion angle of approximately 180 degrees) and G is gauche (ideal C-C-C-Cl torsion angle of approximately 60 degrees). It has been judged from the experimental GED data and the theoretical calculations, as well as from previously published infrared (IR) studies on the molecule in both the liquid phase and in argon-trapped matrices at 10 K, that the gas phase consists of a mixture of at least three conformers: AA (most stable), AG, and GG, with the possibility of a smaller contribution (<10%) from the higher-energy GA form. The GA conformer cannot be ruled out by the GED experimental data. Relevant structural parameter values obtained from the GED least-squares refinements, with calculated ab initio MO MP2/6-31+G(2d,p) values used as constraints, were as follows (AA values with estimated 2sigma uncertainties): Bond lengths (r(h1)): r(C-C(=O)) = 1.505(4) A, r(C-CH(2)Cl) = 1.520(4) A, r(C=O) = 1.197(4) A, r(C(=O)-Cl) = 1.789(3) A, and r(C-Cl) = 1.782(3) A. Bond angles (angle(h1)): angle CCC = 111.5(11) degrees , angle CCO = 127.0(5) degrees, angle CC(O)Cl = 112.5(3) degrees, and angle CCCl = 110.3(3) degrees. Torsion angles (phi(C-C) = phi(ClCCC)): for AA, phi(1)(C-C(O)) = phi(2)(C-CH(2)Cl) = 180 degrees (assumed for true C(s) symmetry); for AG, phi(1)(C-C(O)) = -140(5) degrees, phi(2)(C-CH(2)Cl) = 76(13) degrees; for GG, phi(1)(C-C(O)) = 46(8) degrees, phi(2)(C-CH(2)Cl) = 77(14) degrees; for GA, phi(1)(C-C(O)) = 67.9 degrees (assumed), phi(2)(C-CH(2)Cl) = 177.8 degrees (assumed). The non-AA conformers all have chiral C(1) symmetry with twice the statistical weight (multiplicity) of C(s). The MP2/6-31+G(2d,p) calculated composition (%) based on the zero-point energy (ZPE) corrected energy differences, and the statistical weights for conformers: AA/AG/GG/GA = 28/35/28/9 was assumed in the final GED refinement. The more recent literature concerning the title molecule, as well as for several related molecules, has been examined and a survey has been attempted in the present article. The new experimental results for 3-chloropropanoyl chloride are discussed and compared with the previously published findings.

Journal Article↗

PubMed2002

Scaling properties of fluctuations in the human electroencephalogram.

The fluctuation properties of the human electroencephalogram time series are studied using detrended fluctuation analysis. For nearly all 128 channels in each of the 28 subjects studied, it is found that the standard deviation of the fluctuations exhibits scaling behaviors in two regions. Topographical plots of the scaling exponents reveal the spatial structure of the nonlinear electrical activities recorded on the scalp. Moment analyses are performed to summarize the global variability across channels. The correlation between the two scaling exponents in each channel is also examined. Two global measures are found that succinctly characterize the overall properties of the fluctuation behaviors of the brain dynamics for each subject. Together they distinguish the stroke subjects from the normal ones with 90% accuracy, suggesting the possibility that this analysis could lead to an effective diagnostic tool.

Brain↗

PubMed2006

Dose selection and population pharmacokinetics of PEG-Intron in patients with chronic myelogenous leukaemia.

AIMS: To assess the dose selection using population pharmacokinetics of Pegylated Intron-alpha2b (PEG-Intron) in patients with chronic myelogenous leukaemia (CML). METHODS: PEG-Intron 3-6 microg kg(-1) was administered subcutaneously once a week and blood samples were collected up to 48 weeks of treatment. A total of 624 samples collected from 137 patients were included in the analysis. Nonlinear mixed-effects modelling was used to analyse the sparsely sampled concentration data from a clinical efficacy trial. Covariates in the analysis included weight, sex, age, race, serum creatinine and estimated creatinine clearance (CLcr). RESULTS: The apparent clearance of PEG-Intron decreased after repeated dosing. The clearance at treatment week 4 was 42.3 l day(-1) (patients with CLcr 120 ml min(-1)) with interpatient variability 30%. At treatment week 48, the clearance value was reduced to 69% of its week 4 value. CLcr, a composite variable calculated from body weight, sex, age and serum creatinine, had a small but statistically significant influence on the clearance of PEG-Intron. The clearance of PEG-Intron in patients with CML was 40% higher than that of hepatitis C virus-infected patients. CONCLUSION: The dose of PEG-Intron 6.0 microg kg(-1) week(-1) appeared appropriate in the treatment of patients with CML.

Adult↗

PubMed2001

Experimental and finite element comparison of various fixation designs in combined loads.

The short- and long-term successes of tibial cementless implants depend on the initial fixation stability often provided by posts and screws. In this work, a metallic plate was fixed to a polyurethane block with either two bone screws, two smooth-surfaced posts, or two novel smooth-surfaced posts with adjustable inclinations. For this last case, inclinations of 0, 1.5, and 3 deg were considered following insertion. A load of 1031 N was eccentrically applied on the plate at an angle of approximately 14 deg, which resulted in a 1000 N axial compressive force and a 250 N shear force. The response was measured under static and repetitive loading up to 4000 cycles at 1 Hz. The measured results demonstrate subsidence under load, lift-off on the unloaded side, and horizontal translation of the plate specially at the loaded side. Fatigue loading increased the displacements, primarily during the first 100 cycles. Comparison of various fixation systems indicated that the plate with screw fixation was the stiffest with the least subsidence and liftoff. The increase in post inclination from 0 to 3 deg stiffened the plate by diminishing the liftoff. All fixation systems demonstrated deterioration under repetitive loads. In general, the finite element predictions of the experimental fixation systems were in agreement with measurements. The finite element analyses showed that porous coated posts (modeled with nonlinear interface friction with and without coupling) generated slightly less resistance to liftoff than smooth-surfaced posts. In the presence of porous coated posts, Coulomb friction greatly overestimated the rigidity by reducing the liftoff and subsidence to levels even smaller than those predicted for the design with screw fixation. The sequence of combined load application also influenced the predicted response. Finally, the finite element model incorporating measured interface friction and pull-out responses can be used for the analysis of cementless total joint replacement systems during the post-operation period.

Biomechanical Phenomena↗

PubMed2002

Population pharmacokinetics of the novel anticancer agent E7070 during four phase I studies: model building and validation.

PURPOSE: N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters. PATIENTS AND METHODS: Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model. RESULTS: The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model. CONCLUSION: A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.

Antineoplastic Agents↗

PubMed2006

Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers.

Radiation exposure at a young age is a strong risk factor for thyroid cancer. We conducted a nested case-control study of 69 thyroid cancer cases and 265 controls from a cohort of 14,054 childhood cancer survivors to evaluate the shape of the radiation dose-response relationship, in particular at high doses, and to assess modification of the radiation effects by patient and treatment characteristics. We considered several types of statistical models to estimate the excess relative risk (ERR), mainly guided by radiobiological models. A two-parameter model with a term linear in dose and a negative exponential in dose squared provided the best parsimonious description with an ERR of 1.3 per gray (95% confidence interval 0.4-4.1) at doses below 6 Gy and a relative decrease in ERR of 0.2% per unit dose squared with increasing dose, that is, decreases in the ERR/Gy of 53% at 20 Gy and 95% at 40 Gy. Further analyses using spline models suggested that the significant nonlinearity at high doses was characterized most appropriately as a true downturn rather than a flattening of the dose-response curve. We found no statistically significant modification of the dose-response relationship by patient characteristics; however, the linear parameter (i.e., the ERR/ Gy at doses less than 6 Gy) did decrease consistently and linearly with increasing age at childhood cancer diagnosis, from 4.45 for 0-1-year-olds to 0.48 for 15-20-year-olds. In summary, we applied models derived from radiobiology to describe the radiation dose-response curve for thyroid cancer in an epidemiological study and found convincing evidence for a downturn in risk at high doses.

Child↗

PubMed2002

Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients.

OBJECTIVE: To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders. DESIGN: Retrospective population pharmacokinetic study. PARTICIPANTS: 218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations. METHODS: Routine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program. RESULTS: The final pharmacokinetic model was CL = 42.4 * (TBW/60)(0.655) * 0.814(AGE> or = 55) * (DOSE/200)(0.236) * 1.32(ANTIEP) and Vd = 34.4 * TBW * 0.336( AGE> or = 65), where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (microg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE > or = 55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE > or = 65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance. CONCLUSION: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.

Adolescent↗