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PubMedDate not supplied

Population kinetics and conditional assessment of the optimal dosage regimen using the P-PHARM software package.

The adjustment of individual dosage regimen is an adaptive control process based upon an individual response to a pharmacokinetic model. To attain this objective, it is very helpful to know the characteristics of the population to which the subject belongs, in terms of mean parameters and interindividual variability. Usually the available information consists of incomplete and sparse data. For this reason it is essential to employ a computational methodology based on non-linear mixed-effect procedures in order to obtain a population parameter estimate. A Bayesian methodology can then be applied from the population parameters to the specific data for the individual requiring a dosage adjustment (such data includes drug concentration(s) of the active drug, demographic data, etc). The result of the Bayesian calculation supplies the required individual pharmacokinetic parameters. An optimal dosage regimen can be defined on the basis of therapeutical criteria (concentration ranges) as well as practical constraints such as: the size of available unitary drug dosages, feasible drug intake times, penalties associated with expected concentrations falling outside the therapeutic concentration ranges. In this paper we present the methodology and results obtained using the P-Pharm software tool. P-Pharm implements a non-linear mixed-effect population parameter estimation algorithm based on the EM algorithm. This method allows the inclusion of explicit variables into the calculations, it implements an individual Bayesian parameter estimation procedure and also an algorithm for the conditional assessment of the optimal dosage regimen given a list of practical constraints.

Algorithms↗

PubMedDate not supplied

Touch-screen computerized education for patients with brain injuries.

The use of computer technology for patient education has increased in recent years. This article describes a study that measures the attitudes and perceptions of healthcare professionals and laypeople regarding the effectiveness of a multimedia computer, the Brain Injury Resource Center (BIRC), as an educational tool. The study focused on three major themes: (a) usefulness of the information presented, (b) effectiveness of the multimedia touch-screen computer methodology, and (c) the appropriate time for making this resource available. This prospective study, conducted in an acute care medical center, obtained healthcare professionals' evaluations using a written survey and responses from patients with brain injury and their families during interviews. The findings have yielded excellent ratings as to the ease of understanding and usefulness of the BIRC. By using sight, sound, and touch, such a multimedia learning center has the potential to simplify patient and family education.

Attitude of Health Personnel↗

PubMed1996

Thermomechanical analysis of shape memory devices.

Shape memory alloys (SMA) are being increasingly used in various industrial applications as actuators, connectors, or damping materials. In the medical field, superelastic devices such as eyeglass frames, stents or guide catheters have come to market in the recent years. The design of SMA devices has usually been based on trial and error, since until recently no general simulation model was available to assist application engineers. The purpose of this article is to describe the computational methodology developed, validated and used for several industrial projects at Ecole Polytechnique of Montréal to simulate the thermomechanical behavior of shape memory materials. This new approach includes three main stages: experimental characterization, construction of a nonlinear material law based on dual kriging interpolation and finally, calculation of the thermomechanical response of SMA devices. For complex geometry, finite element analysis is used, but for simple devices such as springs or electrically activated SMA wires, simplified calculation methods are satisfactory. Validation results recently obtained will also be presented, and examples of industrial applications briefly reviewed.

Algorithms↗

PubMed1996

From electron density and sequence to structure: integrating protein image analysis and threading for structure determination.

This paper presents a computational methodology for integrating techniques from protein image interpretation and protein sequence threading, applied to the problem of structure determination from experimental X-ray crystallographic electron density maps. In the proposed architecture, image interpretation of an electron density map produces candidate structural segments; threading is applied to evaluate these hypothesized segments and thus to constrain the set of possible image interpretations. We present the results of experiments designed to test ability of the threading module to discriminate between correct and incorrect alignments of protein sequences onto structural models derived from protein image interpretation. The long-term goal of this research is to improve our ability to determine protein structures from crystallographic data, and to further our understanding of the underlying relationship between sequence and structure.

Algorithms↗

PubMed1994

Non-covalent DNA groove-binding by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

The cooked meat mutagen 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) is metabolized in vivo to electrophilic intermediates that covalently bind to DNA guanines. Here we address the mechanism of PhIP's non-covalent interaction with DNA by using spectroscopic and computational methodologies. NMR methodologies indicated that upon addition of DNA, PhIP aromatic protons underwent a small, 0.11-0.12 p.p.m. upfield shift. DNA phosphorus resonances of non-covalent PhIP-DNA complexes broadened and slightly shifted upfield, while DNA base imino proton resonances shifted slightly downfield relative to DNA alone. UV and fluorescence spectra of PhIP titrated with DNA showed no detectable shifting and hypochromism of absorbance or fluorescence bands. In the presence of DNA, PhIP fluorescence was efficiently quenched by acrylamide, but not by silver ion. Further, the NMR spectra suggest that PhIP is in fast exchange with the DNA, and is slightly specific for adenine-thymine (A-T) sequences. Finally, structural arguments based on quantum chemistry calculations suggested that PhIP and its metabolites are unlikely to intercalate into DNA. These data collectively indicate that PhIP non-covalently binds in a groove of DNA.

Computer Simulation↗

PubMed1990

Three-dimensional autoradiographic localization of quench-corrected glycine receptor specific activity in the mouse brain using 3H-strychnine as the ligand.

The autoradiographic analysis of neurotransmitter receptor distribution is a powerful technique that provides extensive information on the localization of neurotransmitter systems. Computer methodologies are described for the analysis of autoradiographic material which include quench correction, 3-dimensional display, and quantification based on anatomical boundaries determined from the tissue sections. These methodologies are applied to the problem of the distribution of glycine receptors measured by 3H-strychnine binding in the mouse CNS. The most distinctive feature of this distribution is its marked caudorostral gradient. The highest densities of binding sites within this gradient were seen in somatic motor and sensory areas; high densities of binding were seen in branchial efferent and special sensory areas. Moderate levels were seen in nuclei related to visceral function. Densities within the reticular formation paralleled the overall gradient with high to moderate levels of binding. The colliculi had low and the diencephalon had very low levels of binding. No binding was seen in the cerebellum or the telencephalon with the exception of the amygdala, which had very low levels of specific binding. This distribution of glycine receptors correlates well with the known functional distribution of glycine synaptic function. These data are illustrated in 3 dimensions and discussed in terms of the significance of the analysis techniques on this type of data as well as the functional significance of the distribution of glycine receptors.

Animals↗

PubMedDate not supplied

[Application of multifactorial statistical calculation in research for a correlation between lipid soluble vitamins and cancer].

The aim of this work was to combine computer methodology applied to multi-factorial statistical calculations with liquid chromatography results on the analysis of serum levels of retinol, bêta-carotene and tocopherols in healthy subjects and in patients with various cancers associated with certain tumor markers. Our results show that the serum levels of the vitamins studied differed in cancer patients in comparison to healthy controls. These results also confirm published data showing that serum variations are generally not characteristic of a specific tumor localization, without indicating if these variations are a cause or an effect of tumor development. Computerized multifactorial analysis taking into account the levels of all vitamins and tumor markers chosen, however, enabled us to classify the different tumors in five groups: cancers of the nervous system, urogenital tract cancers, laryngo-pulmonary cancers and two groups of digestive system cancers. This new approach may lead to the constitution of a data bank on the localization of tumors, as well as a reference system for all analyses of serum levels of vitamins associated with tumor markers.

Adult↗

PubMed1995

Methodologic aspects of computed microtomography to monitor the development of osteoporosis in gastrectomized rats.

RATIONALE AND OBJECTIVES: We investigated the methodologic development of computed microtomography (CMT) for monitoring the development of osteoporosis in male Sprague-Dawley rats. METHODS: Eight rats were gastrectomized and eight rats were sham operated. Femurs, tibias, and tails were prepared, and CMT scans with spatial resolutions of 5-500 microns were made. Bone diameters, bone areas, and moments of inertia were determined from the CMT scans. Optimal slice position and the need for spatial resolution and energy optimization for future in vivo applications were investigated. RESULTS: Gastrectomy caused dramatic changes in the bone architecture of the tibia and the femur. The main features were vacuolization of the bone and reduced amounts of compact bone. Although the outer diameters of tubular bones (femur and tibia) were largely unaffected, their inner diameters were greatly increased following gastrectomy. Relative bone area and moment of inertia were greatly reduced. The optimal photon energy was 12 keV. CONCLUSION: It is possible to monitor gastrectomy-evoked changes in bone morphology at various sites in rats using CMT scanning. The changes are suggestive of osteoporosis. By optimizing the energy spectrum and spatial resolution, as well as choosing the proper slice position, it should be possible to keep absorbed doses low enough to avoid acute radiation injury in repeated in vivo measurements.

Animals↗

PubMed1993

A microsatellite-based multipoint index map of human chromosome 22.

Utilizing the CEPH (Centre d'Etude du Polymorphism Humain) reference panel and genotyping data for 24 simple tandem repeat polymorphism (STRP) markers, we have constructed a 15-locus multipoint genetic framework map of human chromosome 22. The markers form a continuous linkage group of 51 cM in males and 81 cM in females. Likely genetic locations are provided for 9 additional STRP sequences. The map was constructed employing the CRIMAP computational methodology to build the multipoint map via a stepwise algorithm. The quality of the framework map was evaluated using a battery of statistical diagnostics that suggest a typing error frequency of 0.1% for markers within the map.

Base Sequence↗

PubMed1991

Separation of o-phthalaldehyde-mercaptoethanol derivatives of amino acids from blood plasma on reversed-phase Nova-Pak C18 cartridges.

A separation of 25 o-phthalaldehyde-mercaptoethanol derivatives of primary amino acids in plasma prepared from human blood has been developed for Waters 10 cm x 0.8 cm I.D., 4-microns Nova-Pak C18 Radial-Pak cartridges. A binary gradient system with solvent-switching capability for the A pump is required. Computer methodologies have been utilized to develop mobile phase mixtures of phosphate buffer (pH 6.9), water, methanol and tetrahydrofuran. Advantages of the method include simple sample preparation, fast turnover time (67 min including the pre-column Autotag derivatization procedure) and exceptional column durability (several hundred analyses).

Amino Acids↗

PubMed1990

A detailed multipoint gene map of chromosome 1q.

Utilizing genotyping data for 23 markers, we have constructed a 21-locus multipoint genetic map of the long arm of chromosome 1. Five new RFLPs are reported. The map integrates anonymous loci from previous primary linkage maps and incorporates markers for 10 coding sequences. These markers form a continuous linkage group of 85 cM in males and 141 cM in females. The map was constructed employing the LINKAGE and CRIMAP computational methodologies via a stepwise algorithm.

Algorithms↗

PubMed1994

Combining rule-based reasoning and mathematical modelling in diabetes care.

A prototype computer system utilising a model of carbohydrate metabolism linked to an expert system is described. The prototype which integrates quantitative and qualitative computational methodologies can be used to predict blood glucose profiles and adjust insulin doses in insulin-dependent (type I) diabetic subjects. A feedback loop insulin-dosage optimisation procedure which allows quantitative advice to be generated is also described. Possible clinical applications for the system, which is intended for educational use and clinically as a research tool to try and attain normoglycaemia, are discussed.

Algorithms↗

PubMed1997

The Hofmeister series: salt and solvent effects on interfacial phenomena.

Advances in experimental and computational methodologies have led to a recent renewed interest in the Hofmeister series and its molecular origins. New results are surveyed and assessed. Insights into the underlying mechanisms have been gained, although deeper molecular understanding still seems to be elusive. The principal reason appears to be that the Hofmeister series emerges from a combination of a general effect of cosolutes (salts, etc.) on solvent structure, and of specific interactions between the cosolutes and the solute (protein or other biopolymer). Hence every system needs to be studied individually in detail, a state of affairs which is likely to continue for some time. A deeper understanding of the Hofmeister series can be an extraordinarily valuable guide to designing experiments, including not only those probing the series per se, but also those designed to elucidate the adsorption, aggregation and stabilization phenomena which underlie so many biological events. The aim of this review is to provide an up-to-date framework to guide such understanding, consolidating recent advances in the many fields on which the Hofmeister series impinges.

Biophysical Phenomena↗

PubMed1991

Computation of ionic distributions around charged biomolecular structures: results for right-handed and left-handed DNA.

We introduce an efficient computational methodology employing the potentials of mean force approach for estimating the detailed three-dimensional ionic distributions around arbitrarily complex charged biomolecular structures for all monovalent salt concentrations of practical interest (e.g., 0.1-5.0 M NaCl). Such distributions are required for specifying thermodynamic and structure-specific features of ion-mediated interactions of charged proteins, DNA and RNA, membranes, and macromolecular assemblies. As a first application, we present results for distributions around the B and ZI conformers of the DNA oligomer d(C-G)18.d(C-G)18. The ionic microenvironment depends strongly on the DNA conformation, sequence, and bulk salt concentrations.

DNA↗

PubMed2024

Structural modelling and preventive strategy targeting of WSSV hub proteins to combat viral infection in shrimp Penaeus monodon.

White spot syndrome virus (WSSV) presents a considerable peril to the aquaculture sector, leading to notable financial consequences on a global scale. Previous studies have identified hub proteins, including WSSV051 and WSSV517, as essential binding elements in the protein interaction network of WSSV. This work further investigates the functional structures and potential applications of WSSV hub complexes in managing WSSV infection. Using computational methodologies, we have successfully generated comprehensive three-dimensional (3D) representations of hub proteins along with their three mutual binding counterparts, elucidating crucial interaction locations. The results of our study indicate that the WSSV051 hub protein demonstrates higher binding energy than WSSV517. Moreover, a unique motif, denoted as "S-S-x(5)-S-x(2)-P," was discovered among the binding proteins. This pattern perhaps contributes to the detection of partners by the hub proteins of WSSV. An antiviral strategy targeting WSSV hub proteins was demonstrated through the oral administration of dual hub double-stranded RNAs to the black tiger shrimp, Penaeus monodon, followed by a challenge assay. The findings demonstrate a decrease in shrimp mortality and a cessation of WSSV multiplication. In conclusion, our research unveils the structural features and dynamic interactions of hub complexes, shedding light on their significance in the WSSV protein network. This highlights the potential of hub protein-based interventions to mitigate the impact of WSSV infection in aquaculture.

Animals↗

PubMed1992

[Application of multifactorial statistical calculation searching for a correlation between fat soluble vitamins and cancer].

The aim of this work was to combine computer methodology applied to multi-factorial statistical calculations with liquid chromatography results on the analyses of serum levels of retinol, bêta-carotene and tocopherols in healthy subjects and in patients with various cancers associated with certain tumor markers. Our results show that the serum levels of the vitamins studied differed in cancer patients in comparison to healthy controls. These results also confirm published data showing that serum variations are generally not characteristic of a specific tumor localization, without indicating if these variations are a cause or an effect of tumor development. Computerized multifactorial analysis taking into account the levels of all vitamins and tumor markers chosen, however, enabled us to classify the different tumors in five groups: cancers of the nervous system, urogenital tract cancers, laryngo-pulmonary cancers and two groups of digestive system cancers. This new approach may lead to the constitution of a data bank on the localization of tumors, as well as a reference system for all analyses of serum levels of vitamins associated with tumor markers.

Adult↗

PubMed1991

A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates.

Utilizing the CEPH reference panel and genotypic data for 53 markers, we have constructed a 20-locus multipoint genetic map of human chromosome 4. New RFLPs are reported for four loci. The map integrates a high-resolution genetic map of 4p16 into a continuous map extending to 4q31 and an unlinked cluster of three loci at 4q35. The 20 linked markers form a continuous linkage group of 152 cM in males and 202 cM in females. Likely genetic locations are provided for 25 polymorphic anonymous sequences and 28 gene-specific RFLPs. The map was constructed employing the LINKAGE and CRIMAP computational methodologies to build the multipoint map via a stepwise algorithm. A detailed 10-point map of the 4p16 region constructed from the CEPH panel provides evidence for heterogeneity in the linkage maps constructed from families segregating for Huntington disease (HD). It additionally provides evidence for position-specific recombination frequencies in the telomeric region of 4p.

Chromosome Mapping↗

PubMed1986

Interfacial reaction dynamics and acyl-enzyme mechanism for lipoprotein lipase-catalyzed hydrolysis of lipid p-nitrophenyl esters.

The fatty acyl (lipid) p-nitrophenyl esters p-nitrophenyl caprylate, p-nitrophenyl laurate and p-nitrophenyl palmitate that are incorporated at a few mol % into mixed micelles with Triton X-100 are substrates for bovine milk lipoprotein lipase. When the concentration of components of the mixed micelles is approximately equal to or greater than the critical micelle concentration, time courses for lipoprotein lipase-catalyzed hydrolysis of the esters are described by the integrated form of the Michaelis-Menten equation. Least square fitting to the integrated equation therefore allows calculation of the interfacial kinetic parameters Km and Vmax from single runs. The computational methodology used to determine the interfacial kinetic parameters is described in this paper and is used to determine the intrinsic substrate fatty acyl specificity of lipoprotein lipase catalysis, which is reflected in the magnitude of kcat/Km and kcat. The results for interfacial lipoprotein lipase catalysis, along with previously determined kinetic parameters for the water-soluble esters p-nitrophenyl acetate and p-nitrophenyl butyrate, indicate that lipoprotein lipase has highest specificity for the substrates that have fatty acyl chains of intermediate length (i.e. p-nitrophenyl butyrate and p-nitrophenyl caprylate). The fatty acid products do not cause product inhibition during lipoprotein lipase-catalyzed hydrolysis of lipid p-nitrophenyl esters that are contained in Triton X-100 micelles. The effects of the nucleophiles hydroxylamine, hydrazine, and ethylenediamine on Km and Vmax for lipoprotein lipase catalyzed hydrolysis of p-nitrophenyl laurate are consistent with trapping of a lauryl-lipoprotein lipase intermediate. This mechanism is confirmed by analysis of the product lauryl hydroxamate when hydroxylamine is the nucleophile. Hence, lipoprotein lipase-catalyzed hydrolysis of lipid p-nitrophenyl esters that are contained in Triton X-100 micelles occurs via an interfacial acyl-lipoprotein lipase mechanism that is rate-limited by hydrolysis of the acyl-enzyme intermediate.

Animals↗