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PubMed2005

Optimal blood sampling time windows for parameter estimation using a population approach: design of a phase II clinical trial.

The objective of this paper is to determine optimal blood sampling time windows for the estimation of pharmacokinetic (PK) parameters by a population approach within the clinical constraints. A population PK model was developed to describe a reference phase II PK dataset. Using this model and the parameter estimates, D-optimal sampling times were determined by optimising the determinant of the population Fisher information matrix (PFIM) using PFIM_ _M 1.2 and the modified Fedorov exchange algorithm. Optimal sampling time windows were then determined by allowing the D-optimal windows design to result in a specified level of efficiency when compared to the fixed-times D-optimal design. The best results were obtained when K(a) and IIV on K(a) were fixed. Windows were determined using this approach assuming 90% level of efficiency and uniform sample distribution. Four optimal sampling time windows were determined as follow: at trough between 22 h and new drug administration; between 2 and 4 h after dose for all patients; and for 1/3 of the patients only 2 sampling time windows between 4 and 10 h after dose, equal to [4 h-5 h 05] and [9 h 10-10 h]. This work permitted the determination of an optimal design, with suitable sampling time windows which was then evaluated by simulations. The sampling time windows will be used to define the sampling schedule in a prospective phase II study.

Administration, Oral↗

PubMed2004

Parameters influencing augmentation of cerebral blood flow by cervical spinal cord stimulation.

BACKGROUND: Cervical spinal cord stimulation (SCS) has been shown to augment cerebral blood flow (CBF) and protect the brain from focal ischemia. However, the application of SCS in the treatment of cerebral ischemia requires a better understanding of the limits of the cerebrovascular effect and the optimal stimulation parameters. In the present study, we investigated the effects of various stimulation parameters on CBF augmentation, as well as the issue of tachyphylaxis of the CBF response. METHODS: SCS was performed in adult Sprague Dawley rats, and CBF was assessed using cortical laser Doppler flowmetry (LDF). In separate experimental series, stimulation amplitude, frequency, and pulse width were varied, and the effect on the LDF response was recorded. Finally, using the stimulation parameters found to elicit the strongest LDF response, we examined the effect of lengthening the period of SCS. FINDINGS: SCS elicited a robust increase in cortical LDF values as previously demonstrated. The magnitude of the response varied in a dose-dependent fashion with the stimulation amplitude. LDF values increased by more than 80% over baseline with an amplitude of 1.5 mA. The optimal pulse width and frequency of the stimulation were 0.25 ms and 50 Hz, respectively. Lengthening the stimulation period up to 20 minutes resulted in a persistent increase in cerebral LDF values during the entire stimulation period, although the magnitude of this effect diminished to approximately 50% over the baseline after 10 minutes. CONCLUSIONS: SCS elicits a robust augmentation in CBF, which lasts the entire stimulation duration. Stimulation parameters required for optimal cerebrovascular response are within normally used therapeutic ranges in the clinical settings. These results provide further evidence that SCS may provide a novel therapeutic strategy for the treatment of cerebral ischemia.

Animals↗

PubMed2006

Simultaneous detection of resolved glutamate, glutamine, and gamma-aminobutyric acid at 4 T.

A new approach is introduced to simultaneously detect resolved glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA) using a standard STEAM localization pulse sequence with the optimized sequence timing parameters. This approach exploits the dependence of the STEAM spectra of the strongly coupled spin systems of Glu, Gln, and GABA on the echo time TE and the mixing time TM at 4 T to find an optimized sequence parameter set, i.e., {TE, TM}, where the outer-wings of the Glu C4 multiplet resonances around 2.35 ppm, the Gln C4 multiplet resonances around 2.45 ppm, and the GABA C2 multiplet resonance around 2.28 ppm are significantly suppressed and the three resonances become virtual singlets simultaneously and thus resolved. Spectral simulation and optimization were conducted to find the optimized sequence parameters, and phantom and in vivo experiments (on normal human brains, one patient with traumatic brain injury, and one patient with brain tumor) were carried out for verification. The results have demonstrated that the Gln, Glu, and GABA signals at 2.2-2.5 ppm can be well resolved using a standard STEAM sequence with the optimized sequence timing parameters around {82 ms,48 ms} at 4 T, while the other main metabolites, such as N-acetyl aspartate (NAA), choline (tCho), and creatine (tCr), are still preserved in the same spectrum. The technique can be easily implemented and should prove to be a useful tool for the basic and clinical studies associated with metabolism of Glu, Gln, and/or GABA.

Algorithms↗

PubMed2003

Effect of instrument tuning on the detectabilityof biopolymers in electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry of multiply charged biopolymer ions of different molecular size revealed a strong influence of tuning parameters on their detectability in quadrupole ion trap and triple quadrupole mass spectrometers. Hence, after optimizing the ion optical parameters with the signal of the 4- charge state of (dT)(24) (low charge state tuning), a tenfold increase in the signal-to-noise ratio for a mixture of oligodeoxythymidylic acids (n = 12-18) was obtained compared with the results achieved with tune parameters optimized with a synthetic 80-mer oligodeoxynucleotide. By contrast, a detection limit in the upper femtomole region could only be reached for a 104-mer oligodeoxynucleotide utilizing the 24- charge state of the 80-mer (high charge state tuning). The same effect was observed for proteins investigated in the positive ion mode using low and high charge states of cytochrome c and carbonic anhydrase, respectively, for instrument tuning. By comparing the settings for low and high charge state tuning, it became obvious that the most significant difference was observed in the potential applied to the heated metal capillary used to transfer ions from the atmospheric pressure to the vacuum region of the ion source. Taking advantage of the optimized tuning procedure, the molecular mass of a 61 base pair product of polymerase chain reaction was accurately determined by electrospray ionization mass spectrometry on-line interfaced to ion-pair reversed-phase high-performance liquid chromatography.

Base Sequence↗

PubMed2005

Optimization of Fenton's oxidation of chemical laboratory wastewaters using the response surface methodology.

Establishing a treatment process for practical and economic disposal of laboratory wastewaters has become an urgent environmental concern of the Department of Chemical Engineering of the Universidade Estadual de Maringá (State University of Maringá), Brazil. Fenton and related reactions are potentially useful oxidation processes for destroying toxic organic compounds in water. In these reactions, hydrogen peroxide is combined with ferrous or ferric iron in the presence or absence of light to generate hydroxyl radicals (.OH). The feasibility of Fenton's reagent to treat waste chemicals from an academic research laboratory was investigated in this study. A response surface methodology was applied to optimize the Fenton oxidation process conditions using chemical oxygen demand (COD) removal as the target parameter to optimize, and the reagent concentrations, as related to the initial concentration of organic matter in the effluent, and pH as the control factors to be optimized. Maximal COD removal (92.3%) was achieved when wastewater samples were treated at pH 4 in the presence of hydrogen peroxide and iron in the ratios [COD]:[H2O2]=1:9 and [H2O2]:[Fe2+]=4.5:1. Under these conditions, it was possible to obtain simultaneously maximal COD removal and minimal chemical sludge after treatment, which is a residue that needs further processing.

Brazil↗

PubMed1987

Time hierarchy in enzymatic reaction chains resulting from optimality principles.

Several optimality principles reasonable for the evolution of enzyme reaction chains are formulated, considering the kinetic parameters of the enzymes to be variables. The solutions of these parametric programming problems are studied for the case of linear kinetics and turn out to be not unique in every case. The investigations are confined to stationary states. The net flux through the chain is considered a fixed parameter. The optimality criteria concern the osmotic pressure caused by the intermediates, various relaxation times, largest time scale, and controllability. They all yield distinct time hierarchies. The influence of a constraint concerning the sum of intermediate concentrations is studied. Various combinations of the single criteria are treated as multiobjective programming problems.

Biological Evolution↗

PubMed2003

Effect of hydrophilic polymers on the release of diltiazem hydrochloride from elementary osmotic pumps.

Diltiazem hydrochloride (DLTZ) is a freely water-soluble drug, because of its higher aqueous solubility, the suitability of the drug with elementary osmotic pumps is restricted. Plain DLTZ elementary osmotic pump had shown higher release rate. Drug entrapment in polymer matrix or addition of release retardant materials (various polymers) can reduce the release rate of drug. In present study, effect of appropriate hydrophilic polymers (HP) on the release pattern was investigated. Ingredients of the system were optimized for parameters like drug:polymer ratio and amount of osmogent, for the desired release pattern. Two optimized formulations were selected for further characterization. Theoretical release rate of the formulations were also determined and compared. Different dissolution models were applied to drug release data in order to establish release mechanism and kinetics. Criteria for selecting the most appropriate model were based on best goodness of fit and smallest sum of squared residuals.

Calcium Channel Blockers↗

PubMed2005

Integral equation theory for atactic polystyrene melt with a coarse-grained model.

In this work, an integral equation approach to investigate the atactic polystyrene (aPS) melt based on polymer reference interaction site model (PRISM) theory is proposed. The intramolecular structure factors, required as input to PRISM theory, are obtained from the semiflexible chain model. With a novel coarse-graining procedure and the explicit-atom molecular-dynamics (MD) simulations for aPS, the parameters needed for the coarse-grained model are obtained by using an automatic simplex optimization. These parameters can be used to describe the structure and thermodynamic properties of the complex aPS melt and good agreement is obtained between the theory and MD simulations. The proposed integral equation approach provides a basis for describing the structure and properties of PS nanocomposites where the application of molecular simulation is difficult.

Algorithms↗

PubMed2004

Solid-state fluoroscopic imager for high-resolution angiography: parallel-cascaded linear systems analysis.

Cascaded linear systems based modeling techniques have been used in the past to predict important system parameters that have a direct impact on image quality. Such models are also useful in optimizing system parameters to improve image quality. In this work, detailed analysis of a solid-state fluoroscopic imaging system intended for high-resolution angiography is presented with the use of such a model. The imaging system analyzed through this model uses four 8 x 8 cm three-side buttable interlined charge-coupled devices (CCDs) specifically designed for high-resolution angiography and tiled in a seamless fashion to achieve a field of view (FOV) of 16 x 16 cm. Larger FOVs can be achieved by tiling more CCDs in a similar manner. The system employs a CsI:Tl scintillator coupled to the CCDs by straight (nontapering) fiberoptics and can potentially be operated in 78, 156, or 234 microm pixel pitch modes. The system parameters analyzed through this model include presampling modulation transfer function, noise power spectrum, and detective quantum efficiency (DQE). The results of the simulations performed indicate that DQE(0) in excess of 0.6 is achievable, with the imager operating at 156 microm pixel pitch, 30 frames/s, and employing a 450-microm-thick CsI:Tl scintillator, even at a low fluoroscopic exposure rate of 1 microR/frame. Further, at a nominal fluoroscopic exposure rate of 2.5 microR/frame there was no noticeable degradation of the DQE even at the 78 microm pixel pitch mode suggesting that it is feasible to perform high-resolution angiography hitherto unattainable in clinical practice.

Angiography↗

PubMed1995

Bayesian image estimation of digital chest radiography: interdependence of noise, resolution, and scatter fraction.

Previously, it has been shown that Bayesian image estimation (BIE) can reduce the effects of scattered radiation and improve contrast-to-noise ratios (CNR) in digital radiographs of anthropomorphic chest phantoms by improving contrast while constraining noise. Here, the use of BIE as a noise reduction technique is reported. An anthropomorphic phantom was imaged with a previously calibrated photostimulable phosphor system using standard bedside chest radiography protocols. The Bayesian technique was then used to process this image. BIE incorporates a radial exponential convolution scatter model with two adjustable parameters. In previous reports, these parameters were optimized to reduce the residual fraction of scattered radiation in the processed image. Here, the parameters were adjusted to evaluate the potential of BIE to reduce image noise. While the full width at half maximum of the scatter model was held constant, the magnitude was varied. Evaluation was based on residual scatter fractions and CNR. The magnitude of the kernel in the scatter model was varied from 0.0 to 2.5 in steps of 0.5. Previously, it was found that an "ideal" scatter kernel magnitude of 2.33 provided a minimum residual scatter fraction. This magnitude corresponds to the average scatter-to-primary ratio in the chest radiograph. As the magnitude was increased, the residual scatter fraction decreased and the CNR increased in both the lungs and the mediastinum. However, as the magnitude was decreased, the percent noise also decreased; therefore, a lower magnitude kernel reduces noise. By varying the magnitude of the kernel used, differing amounts of noise reduction and contrast enhancement can be obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Bayes Theorem↗

PubMed2001

SIM--simultaneous inverse filtering and matching of a glottal flow model for acoustic speech signals.

A new method "simultaneous inverse filtering and model matching" (SIM) is proposed that allows one to calculate voice source measures without any user interaction. It is based on the discrete all-pole modeling (DAP) technique for inverse filtering (IF), which is modified to include a model of the glottal flow as integral part [LF model, Fant et al., STL-QPSR (Stockholm) 4/1985, 1-13 (1986)]. As the correct LF parameters are initially unknown, they are estimated in an iterative procedure using multi-dimensional optimization techniques that are initialized according to the results of an exhaustive search. The error criteria applied reflect how well the IF is performed after the spectral contribution of the glottal flow has been removed. The resulting optimal LF parameter constellation serves as the basis to calculate 11 voice source measures. The performance was evaluated using synthesized signals and recordings of natural utterances. For the synthesized signals, the accuracy to reproduce the original parameters was high (correlations exceeding 0.88) for measures where the starting point of the glottal cycle did not enter explicitly. Errors were smaller compared to conventional estimation methods where the measures were estimated from the IF signal. The analysis of natural utterances indicates that problems still exist with regard to robustness, but that under advantageous conditions the open quotient, the speed quotient, the closing quotient, the parabolic spectral parameter, and the negative peak amplitude of the glottal flow derivative can indeed be determined automatically by the SIM method.

Fourier Analysis↗

PubMed1995

[Therapeutic drug monitoring and the pharmacokinetics of carbamazepine in children with a convulsive syndrome].

An analysis of maximal and minimal serum concentrations of carbamazepine was performed in 40 children with convulsive syndrome. All the patients received the drug for a long period. Considerable case-to-case differences of serum concentrations in spite of practically equal doses were revealed. Serum drug concentrations were therapeutically optimal (6-8 mg/ml) only in one third of children. On the basis of pharmacokinetic parameters, mean optimal dosages sufficient for maintenance of effective and safe carbamazepine concentrations were calculated. As the child grows general clearance of carbamazepine decreases. Over the age of 9 years it is significantly lower in girls than in boys of the same age. Speed of carbamazepine elimination was higher in cases of combined treatment than in cases of monotherapy. Indications and optimal time for therapeutic drug monitoring of carbamazepine are determined and clinical illustrations are presented.

Adolescent↗

PubMed2006

Bias in error estimation when using cross-validation for model selection.

BACKGROUND: Cross-validation (CV) is an effective method for estimating the prediction error of a classifier. Some recent articles have proposed methods for optimizing classifiers by choosing classifier parameter values that minimize the CV error estimate. We have evaluated the validity of using the CV error estimate of the optimized classifier as an estimate of the true error expected on independent data. RESULTS: We used CV to optimize the classification parameters for two kinds of classifiers; Shrunken Centroids and Support Vector Machines (SVM). Random training datasets were created, with no difference in the distribution of the features between the two classes. Using these "null" datasets, we selected classifier parameter values that minimized the CV error estimate. 10-fold CV was used for Shrunken Centroids while Leave-One-Out-CV (LOOCV) was used for the SVM. Independent test data was created to estimate the true error. With "null" and "non null" (with differential expression between the classes) data, we also tested a nested CV procedure, where an inner CV loop is used to perform the tuning of the parameters while an outer CV is used to compute an estimate of the error. The CV error estimate for the classifier with the optimal parameters was found to be a substantially biased estimate of the true error that the classifier would incur on independent data. Even though there is no real difference between the two classes for the "null" datasets, the CV error estimate for the Shrunken Centroid with the optimal parameters was less than 30% on 18.5% of simulated training data-sets. For SVM with optimal parameters the estimated error rate was less than 30% on 38% of "null" data-sets. Performance of the optimized classifiers on the independent test set was no better than chance. The nested CV procedure reduces the bias considerably and gives an estimate of the error that is very close to that obtained on the independent testing set for both Shrunken Centroids and SVM classifiers for "null" and "non-null" data distributions. CONCLUSION: We show that using CV to compute an error estimate for a classifier that has itself been tuned using CV gives a significantly biased estimate of the true error. Proper use of CV for estimating true error of a classifier developed using a well defined algorithm requires that all steps of the algorithm, including classifier parameter tuning, be repeated in each CV loop. A nested CV procedure provides an almost unbiased estimate of the true error.

Algorithms↗

PubMed2000

Improved secondary metabolite production in the genus Streptosporangium by optimization of the fermentation conditions.

The cultivation of strains of the genus Streptosporangium in batch fermentations demonstrated that the optimal conditions for secondary metabolite production are completely different to those of the closely related genus Streptomyces. The dissolved oxygen tension (pO(2)) was identified as an important parameter for optimal production of secondary metabolites in submerged cultures. Extreme variations of this parameter by changes in aeration (gas flow), agitation system and stirrer speed showed a tremendous impact in production yields of all investigated strains. Finally, a 20-fold increase in productivity was observed by conditions of controlled oxygen excess compared to optimal fermentation conditions for Streptomyces strains.

Actinomycetales↗

PubMed2004

Optimal sampling time selection for parameter estimation in dynamic pathway modeling.

Systems Biology is an emerging research area, which considers mathematical representations of inter- and intra-cellular dynamics. Among the many research problems that have been addressed, dynamic modeling of signal transduction pathways has received increasing attention. The usual approach to represent intra-cellular dynamics are nonlinear, usually ordinary, differential equations. The purpose of the models is to test and generate hypothesis of specific pathways and it is therefore required to estimate model parameters from experimental data. The experiments to generate data are complex and expensive, as a consequence of which the time series available are usually rather short, with few if any replicates. Almost certainly, not all variables one would like to include in a model can be measured. Parameter estimation is therefore an important research problem in Systems Biology and the focus of this paper. In particular, we are interested in optimizing the sampling time selection in order to minimize the variance of the parameter estimation error. With few sampling time points feasible, their selection is of practical importance in experimental design. Finally, the theoretical results are supported with an application.

Computer Simulation↗

PubMed2005

Artifact and noise suppression in GRAPPA imaging using improved k-space coil calibration and variable density sampling.

A parallel imaging technique, GRAPPA (GeneRalized Auto-calibrating Partially Parallel Acquisitions), has been used to improve temporal or spatial resolution. Coil calibration in GRAPPA is performed in central k-space by fitting a target signal using its adjacent signals. Missing signals in outer k-space are reconstructed. However, coil calibration operates with signals that exhibit large amplitude variation while reconstruction is performed using signals with small amplitude variation. Different signal variations in coil calibration and reconstruction may result in residual image artifact and noise. The purpose of this work was to improve GRAPPA coil calibration and variable density (VD) sampling for suppressing residual artifact and noise. The proposed coil calibration was performed in local k-space along both the phase and frequency encoding directions. Outer k-space was acquired with two different reduction factors. Phantom data were reconstructed by both the conventional GRAPPA and the improved technique for comparison at an acceleration of two. Under the same acceleration, optimal sampling and calibration parameters were determined. An in vivo image was reconstructed in the same way using the predetermined optimal parameters. The performance of GRAPPA was improved by the localized coil calibration and VD sampling scheme.

Algorithms↗

PubMed2006

A novel calcium silicate based microspheres of repaglinide: in vivo investigations.

The objective of the present investigation was to evaluate gastro-retentive performance and pharmacokinetic parameters of optimized floating microspheres (RgFMCS4) consisting of (i) calcium silicate (CS) as porous carrier; (ii) repaglinide (Rg), an oral hypoglycemic agent; and (iii) Eudragit S (ES) as polymer. The optimized formulation demonstrated favorable in-vitro-floating and drug release characteristics. The gastro-retentive behavior of this optimized formulation was compared with non-floating microspheres (RgNFM) prepared from the identical polymer. Stability test of (99m)Tc-labeled formulations were carried out using appropriate standard buffer solutions of pH 2.0, 6.8 and 7.4. The organ distribution study was performed in albino rats in order to measure labeling efficiency of the formulation with (99m)Tc. The gamma scintigraphy of the formulations was carried out in albino rabbits to monitor the transit of RgFMCS4 and RgNFM in the gastrointestinal (GI) tract. Prolonged gastric residence time (GRT) of over 6 h was achieved in all animals for calcium silicate based floating microspheres of Rg. Rg loaded optimized formulation was orally administered to albino rabbits and blood samples were used to determine pharmacokinetic parameters of Rg from floating microspheres, which were compared with pharmacokinetic parameters of the marketed tablet formulation. The relative bioavailability of Rg loaded floating microspheres was found to be increased about 3.17 times in comparison to that of the marketed tablet. The enhanced bioavailability and eliminated half-lives of Rg formulation observed in the present study are attributed to the floating nature of the designed formulations.

Animals↗

PubMed2003

Application of single-drop microextraction and comparison with solid-phase microextraction and solid-phase extraction for the determination of alpha- and beta-endosulfan in water samples by gas chromatography-electron-capture detection.

Water contamination due to the wide variety of pesticides used in agriculture practices is a global environmental pollution problem. The 98/83 European Directive requires the measurement of pesticides residues at a target concentration of 1.0 microg/l in surface water and 0.1 microg/l in drinking water. In order to reach the level of detection required, efficient extraction techniques are necessary. The application of a new extraction technique: single-drop microextraction (SDME), followed by gas chromatography with electron-capture detection, was assessed for determining alpha-endosulfan and beta-endosulfan in water samples. Experimental parameters which control the performance of SDME, such as selection of microextraction solvent and internal standard, optimization of organic drop volume, effects of sample stirring, temperature and salt addition, and sorption time profiles were studied. Once SDME was optimized, analytical parameters such as linearity, precision, detection and quantitation limits, plus matrix effects were evaluated. The SDME method was compared with solid-phase microextraction and solid-phase extraction with the aim of selecting the most appropriate method for a certain application.

Chromatography, Gas↗