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Influence of simulated weightlessness on the pharmacokinetics of acetaminophen administered by the oral route: a study in the rat.

During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal-models such as the Morey-Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible 'stress effect' caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high-performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow.

Acetaminophen↗

Survival of spacecraft-associated microorganisms under simulated martian UV irradiation.

Spore-forming microbes recovered from spacecraft surfaces and assembly facilities were exposed to simulated Martian UV irradiation. The effects of UVA (315 to 400 nm), UVA+B (280 to 400 nm), and the full UV spectrum (200 to 400 nm) on the survival of microorganisms were studied at UV intensities expected to strike the surfaces of Mars. Microbial species isolated from the surfaces of several spacecraft, including Mars Odyssey, X-2000 (avionics), and the International Space Station, and their assembly facilities were identified using 16S rRNA gene sequencing. Forty-three Bacillus spore lines were screened, and 19 isolates showed resistance to UVC irradiation (200 to 280 nm) after exposure to 1,000 J m(-2) of UVC irradiation at 254 nm using a low-pressure mercury lamp. Spores of Bacillus species isolated from spacecraft-associated surfaces were more resistant than a standard dosimetric strain, Bacillus subtilis 168. In addition, the exposure time required for UVA+B irradiation to reduce the viable spore numbers by 90% was 35-fold longer than the exposure time required for the full UV spectrum to do this, confirming that UVC is the primary biocidal bandwidth. Among the Bacillus species tested, spores of a Bacillus pumilus strain showed the greatest resistance to all three UV bandwidths, as well as the total spectrum. The resistance to simulated Mars UV irradiation was strain specific; B. pumilus SAFR-032 exhibited greater resistance than all other strains tested. The isolation of organisms like B. pumilus SAFR-032 and the greater survival of this organism (sixfold) than of the standard dosimetric strains should be considered when the sanitation capabilities of UV irradiation are determined.

Bacillus↗

Effects of transmural electrical heterogeneities and electrotonic interactions on the dispersion of cardiac repolarization and action potential duration: A simulation study.

It has been shown in the literature that myocytes isolated from the ventricular walls at various intramural depths have different action potential durations (APDs). When these myocytes are embedded in the ventricular wall, their inhomogeneous properties affect the sequence of repolarization and the actual distribution of the APDs in the entire wall. In this article, we implement a mathematical model to simulate the combined effect of (a) the non-homogeneous intrinsic membrane properties (in particular the non-homogeneous APDs) and (b) the electrotonic currents that modulate the APDs when the myocytes are embedded in the ventricular myocardium. In particular, we study the effect of (a) and (b) on the excitation and repolarization sequences and on the distribution of APDs in the ventricles. We implement a Monodomain tissue representation that includes orthotropic anisotropy, transmural fiber rotation and homogeneous or heterogeneous transmural intrinsic membrane properties, modeled according to the phase I Luo-Rudy membrane ionic model. Three-dimensional simulations are performed in a cartesian slab with a parallel finite element solver employing structured isoparametric trilinear finite elements in space and a semi-implicit adaptive method in time. Simulations of excitation and repolarization sequences elicited by epicardial or endocardial pacing show that in a homogeneous slab the repolarization pathways approximately follow the activation sequence. Conversely, in the heterogeneous cases considered in this study, we observed two repolarization wavefronts that started from the epi and the endocardial faces respectively and collided in the thickness of the wall and in one case an additional repolarization wave starting from an intramural site. Introducing the heterogeneities along the transmural epi-endocardial direction affected both the repolarization sequence and the APD dispersion, but these effects were clearly discernible only in transmural planes. By contrast, in planes parallel to epi- and endocardium the APD distribution remained remarkably similar to that observed in the homogeneous model. Therefore, the patterns of the repolarization sequence and APD dispersion on the epicardial surface (or any other intramural surface parallel to it) do not reveal the uniform transmural heterogeneity.

Action Potentials↗

Models and molecular approaches to assessing the effects of the microgravity environment on vertebrate development.

The extent to which gravity, and especially the lack thereof, can affect normal development in higher organisms is poorly understood. Underlying this question is the assumption that normal development depends on the embryo's ability to maintain a programmed temporal and spatial coordination of morphogenetic events. There are several reports documenting the apparently normal development of several vertebrate species, including mammals, under conditions of exposure to space flight during various periods of the development process. Evidence to the contrary also exists and it is therefore likely that some alterations in morphology do occur in a microgravity environment. Although subsequent development may appear overtly normal, more subtle abnormalities result. In all studies, the evaluation is restricted by the few numbers of specimens that can be examined and the relatively insensitive techniques for assessing potentially subtle effects. In the present discussion, we summarize some observations of mammalian development made in microgravity and consider which stages might be expected to be differentially sensitive to altered gravity conditions. While we emphasize mammalian development, we discuss the suitability of another model system for examining such effects in a cross-species context. Furthermore, we consider recent developments in our understanding of the molecular genetic program regulating embryogenesis that could serve as markers for assessing perturbations of development.

Animals↗

Convergence in peptide folding simulation: multiple trajectories of a potential AIDS pharmacophore.

To examine the conformational properties in aqueous solution of a 15-residue peptide that is a potential pharmacophore for AIDS vaccine development, molecular dynamics simulations were performed in water starting from structures determined experimentally in three different organic solvents. Convergence characteristics of the simulation are examined in Cartesian and conformational spaces. In addition, novel analysis tools are employed including a multidimensional scaling method to represent the distance between trajectory frames. As these methods are based on a variety of physical parameters, they provide a useful cross-check on the structural convergence. Theoretical two-dimensional (2D) 1H-NMR spectra are also generated. These are superficially quite different in appearance, demonstrating that backbone similarities difficult to identify by visual inspection of 2D NMR data can be revealed using the methods described here.

AIDS Vaccines↗

Dual wavelength spectrophotometry as a diagnostic test of the pulp chamber contents.

The purpose of this in vitro study was to determine the feasibility of using dual wavelength spectrophotometry to identify teeth with pulp chambers that are either empty, filled with fixed pulp tissue, or filled with oxygenated blood. In phase I of the experiment, a human third molar was prepared so that its pulp space could be filled with oxygenated blood and later emptied. In phase II, the lower jaw of a beagle dog was removed and placed in formalin, thereby fixing the pulps of the teeth. The pulp of the right canine was removed via an apical approach, and attachments were placed in a similar position to those on the human tooth, to allow filling and emptying of the pulp space. Cavit was placed over the exposed fixed pulp in the left canine. Ten readings, which were separated by light source and detector removal and replacement, were taken of the right canine pulp space when it was empty or filled with oxygenated blood, or the left canine pulp space when it was filled with fixed tissue. Distinct and reproducible changes were measured for pulp spaces filled with air, tissue, or oxygenated blood. In phase III, simulated pulp testing on a dog tooth model was performed. Blood was introduced into the root canal space, the chamber was rinsed with water and replaced with air, according to a predetermined code. Spectrophotometer readings were recorded. The identification of pulpal contents was correctly determined in all 20 of the predetermined conditions. The findings indicate that continuous wave spectrophotometry may become a useful pulp testing method.

Animals↗

Assessment of a new multileaf collimator concept using GEANT4 Monte Carlo simulations.

The aim of the work was to investigate in advance the dosimetric properties of a new multileaf collimator (MLC) concept with the help of Monte Carlo (MC) simulations prior to the production of a prototype. The geometrical design of the MLC was implemented in the MC code GEANT4. For the simulation of a 6 MV treatment beam, an experimentally validated phase space and a virtual spatial Gaussian-shaped model placed in the origin were used. For the simulation of the geometry in GEANT4, the jaws and the two leaf packages were implemented with the help of computer-aided design data. First, transmission values for different tungsten alloys were extracted using the simulation codes GEANT4 and BEAMnrc and compared to experimental measurements. In a second step, high-resolution simulations were performed to detect the leakage at depth of maximum dose. The 20%-80% penumbra along the travel direction of the leaves was determined using 10 x 10 cm2 fields shifted along the x- and y-axis. The simulated results were compared with measured data. The simulation of the transmission values for different tungsten alloys showed a good agreement with the experimental measurements (within 2.0%). This enabled an accurate estimation of the attenuation coefficient for the various leaf materials. Simulations with varying width of the spatial Gaussian distribution showed that the leakage and the penumbra depend very much on this parameter: for instance, for widths of 2 and 4 mm, the interleaf leakage is below 0.3% and 0.75%, respectively. The results for the leakage and the penumbra (4.7+/-0.5 mm) are in good agreement with the measurements. This study showed that GEANT4 is appropriate for the investigation of the dosimetric properties of a multileaf collimator. In particular, a quantification of the leakage, the penumbra, and the tongue-and-groove effect and an evaluation of the influence of the beam parameters such as the width of the Gaussian distribution was possible.

Body Burden↗

The spatial arrangement of L and M cones in the peripheral human retina.

The spatial arrangement of L and M cones in the human peripheral retina was estimated from red-green color naming of small test flashes (0.86 min of arc, 555 nm, constant intensity) presented at different locations (grid with 1.5 min of arc steps) centered at 17 degrees temporal eccentricity. Simulated red-green color naming ratings were generated by a model based on an ideal observer for all possible patterns of placement and relative numerosities of L and M cones, constrained by the anatomical data on the statistics of cone spacing at this retinal location. The best matching simulated performance as compared to the human observer's data determined the cone array most likely to produce that observer's color naming results. The mosaics for two color normal observers showed L and M cones randomly arrayed over this retinal region. Consequences of random cone placements for spectral sampling and color opponency are discussed.

Color Perception↗

Design and prioritization of plates for high-throughput screening.

A general algorithm for the prioritization and selection of plates for high-throughput screening is presented. The method uses a simulated annealing algorithm to search through the space of plate combinations for the one that maximizes some user-defined objective function. The algorithm is robust and convergent, and permits the simultaneous optimization of multiple design objectives, including molecular diversity, similarity to known actives, predicted activity or binding affinity, and many others. It is shown that the arrangement of compounds among the plates may have important consequences on the ability to design a well-targeted and cost-effective experiment. To that end, two simple and effective schemes for the construction of homogeneous and heterogeneous plates are outlined, using a novel similarity sorting algorithm based on one-dimensional nonlinear mapping.

Algorithms↗

A novel method for the 3-dimensional simulation of orthognathic surgery by using a multimodal image-fusion technique.

INTRODUCTION: The aim of this study was to establish a novel method for simulating orthognathic surgery in 3-dimensional (3D) space. METHODS: This system mainly consists of 6 procedures: (1) reconstruction of a virtual skull model (VS) from presurgical computed tomography scans; (2) reconstruction of virtual dentition models from 3D surface scanning of dental casts occluded at presurgical and postsurgical intercuspal positions (VD1 and VD2, respectively); (3) reconstruction of a preliminary fusion model of VS and VD1 by an initial intermodality registration; (4) reconstruction of another preliminary fusion model of VS, VD1, and VD2 by a second intramodality registration; (5) repositioning of bony segments by a third intramodality registration and reconstruction of final fusion models at presurgery and postsurgery; and (6) 3D analysis of the movement of bony segments. To test this system, 2 patients with severe skeletal deformities, who had undergone presurgical orthodontic treatment, were used as models. Registration accuracy was determined by the root mean squared distance between the corresponding fiducial markers in a set of 2 images. RESULTS AND CONCLUSIONS: The sum of the root mean squared error of the 3 registration processes was less than 0.4 mm in both patients. This simulation system could be used to precisely realize the presurgical and postsurgical occlusal relationships and craniofacial morphology of a patient with severe skeletal deformities, and to quantitatively describe the movement of a given anatomical point of bony segments. It is assumed that there could be significant benefits in sharing visual and quantitative 3D information from this simulation system among orthodontists and surgeons.

Adult↗

Interlayer expansion and mechanisms of anion sorption of Na-montmorillonite modified by cetylpyridinium chloride: a Monte Carlo study.

To study the change of interlayer structure of a Wyoming-type Na-montmorillonite as a result of the replacement of interlayer Na+ ions by cetylpyridinium (CP+) ions, a series of NPT Monte Carlo simulations of the clay mineral with different contents of CP+, Na+, Cl- ions and water in its interlayer space is carried out. In agreement with conclusions from experimental studies, the simulations show that the CP+ ions form monomolecular, bimolecular, and pseudotrimolecular layers with increasing interlayer contents. Calculated potential energies reveal that clay-organic interactions are stronger than organic-organic interactions in CP+-modified montmorillonite, which is in conformity with observations of earlier thermogravimetric experiments. The simulation results indicate that the pseudotrimolecular arrangement of CP+ ions is a prerequisite for the experimentally observed interlayer sorption of inorganic anions. Furthermore, in the interlayer space with a pseudotrimolecular layer, chloride ions favor the formation of pairs with inorganic rather than organic cations. On the basis of these findings and available experimental data, we propose that the interlayer sorption of inorganic anions from the pore space of an organically modified montmorillonite may occur not only in pairs with organic cations, as suggested earlier, but also in pairs with inorganic cations, which represents a so-far unconsidered and maybe more important mechanism of anion sorption on clay minerals.

Journal Article↗

Scrotal ultrasonography with emphasis on the extratesticular space: anatomy, embryology, and pathology.

Sonography is the imaging modality of choice in detecting and characterizing pathologic conditions affecting the extratesticular space. Although most abnormalities are benign, many may simulate or represent malignant processes. Accurate diagnosis is therefore essential and must be based not only on the sonographic findings but also on accurate clinical history and physical examination findings. This article reviews the anatomy, embryologic development, and pathologic conditions affecting the extratesticular space.

Journal Article↗

Optimization of rib surgery parameters for the correction of scoliotic deformities using approximation models.

BACKGROUND: As opposed to thoracoplasty (a cosmetic surgical intervention used to reduce the rib hump associated with scoliosis), experimental scoliosis has been produced or reversed on animals by rib shortening or lengthening. In a prior work (J. Orthop. Res., 20, pp. 1121-1128), a finite element modeling (FEM) of rib surgeries was developed to study the biomechanics of their correction mechanisms. Our aims in the present study were to investigate the influence of the rib surgery parameters and to identify optimal configurations. Hence, a specific objective of this study was to develop a method to find surgical parameters maximizing the correction by addressing the issue of high computational cost associated with FEM. METHOD OF APPROACH: Different configurations of rib shortening or lengthening were simulated using a FEM of the complete torso adapted to the geometry of six patients. Each configuration was assessed using objective functions that represent different correction objectives. Their value was evaluated using the rib surgery simulation for sample locations in the design space specified by an experimental design. Dual kriging (interpolation technique) was used to fit the data from the computer experiment. The resulting approximation model was used to locate parameters minimizing the objective function. RESULTS: The overall coverage of the design space and the use of an approximation model ensured that the optimization algorithm had not found a local minimum but a global optimal correction. The interventions generally produced slight immediate modifications with final geometry presenting between 95-120% of the initial deformation in about 50% of the tested cases. But in optimal cases, important loads (500-2000 N mm) were generated on vertebral endplates in the apical region, which could potentially produce the long-term correction of vertebral wedging by modulating growth. Optimal parameters varied among patients and for different correction objectives. CONCLUSIONS: Approximation models make it possible to study and find optimal rib surgery parameters while reducing computational cost.

Adolescent↗

Structure of a cyclic peptide with a catalytic triad, determined by computer simulation and NMR spectroscopy.

We report the design of a cyclic, eight-residue peptide that possesses the catalytic triad residues of the serine proteases. A manually built model has been relaxed by 0.3 ns of molecular dynamics simulation at room temperature, during which no major changes occurred in the peptide. The molecule has been synthesised and purified. Two-dimensional NMR spectroscopy provided 35 distance and 7 torsion angle constraints, which were used to determine the three-dimensional structure. The experimental conformation agrees with the predicted one at the beta-turn, but deviates in the arrangement of the disulphide bridge that closes the backbone to a ring. A 1.2 ns simulation at 600 K provided extended sampling of conformation space. The disulphide bridge reoriented into the experimental arrangement, producing a minimum backbone rmsd from the experimental conformation of 0.8 A. At a later stage in the simulation, a transition at Ser3 produced more pronounced high-temperature behaviour. The peptide hydrolyses p-nitrophenyl acetate about nine times faster than free histidine.

Amino Acid Sequence↗

Detection of temporal changes in the spatial distribution of cancer rates using local Moran's I and geostatistically simulated spatial neutral models.

This paper presents the first application of spatially correlated neutral models to the detection of changes in mortality rates across space and time using the local Moran's I statistic. Sequential Gaussian simulation is used to generate realizations of the spatial distribution of mortality rates under increasingly stringent conditions: 1) reproduction of the sample histogram, 2) reproduction of the pattern of spatial autocorrelation modeled from the data, 3) incorporation of regional background obtained by geostatistical smoothing of observed mortality rates, and 4) incorporation of smooth regional background observed at a prior time interval. The simulated neutral models are then processed using two new spatio-temporal variants of the Morany's I statistic, which allow one to identify significant changes in mortality rates above and beyond past spatial patterns. Last, the results are displayed using an original classification of clusters/outliers tailored to the space-time nature of the data. Using this new methodology the space-time distribution of cervix cancer mortality rates recorded over all US State Economic Areas (SEA) is explored for 9 time periods of 5 years each. Incorporation of spatial autocorrelation leads to fewer significant SEA units than obtained under the traditional assumption of spatial independence, confirming earlier claims that Type I errors may increase when tests using the assumption of independence are applied to spatially correlated data. Integration of regional background into the neutral models yields substantially different spatial clusters and outliers, highlighting local patterns which were blurred when local Moran's I was applied under the null hypothesis of constant risk.

Journal Article↗

Propagation in cardiac tissue adjacent to connective tissue: two-dimensional modeling studies.

The conditions for activation transmission across a region of extracellular space was demonstrated in two-dimensional preparations with results consistent with those previously seen in the one-dimensional fiber studies. In addition, one sees changes in action potential morphology which occur in the tissue nearest the connective-tissue border as well as changes in conduction velocity along the border. These results hinge on an adequate representation of the connective-tissue region achieved by careful implementation of the boundary conditions in the intracellular and interstitial spaces and the expansion of the connective-tissue discretization to a "double-tier network" description. Through a series of simulations, a clear dependence on fiber orientation is illustrated in the efficacy to transmit activation. The collision of a front with an embedded connective-tissue region was also examined. The results revealed that fibers aligned normal to a planar stimulus would more greatly disrupt the advancement of a planar front. Such pronounced disruptions have been shown to be proarrhythmic in the literature. The increasing evidence of the ability of connective tissue to transmit activation has implications in understanding spread of activation through infarcted tissues and through the healthy ventricular wall in the presence of connective-tissue sheets.

Action Potentials↗

Melanin granule models for the processes of laser-induced thermal damage in pigmented retinal tissues. I. Modeling of laser-induced heating of melanosomes and selective thermal processes in retinal tissues.

The computer modeling was applied for investigation of the processes of laser-induced tissue damage. The melanin granule models for the processes of laser-induced thermal damage and the results of computer modeling of the optical, thermophysical, and thermochemical processes during selective laser interaction with melanoprotein granules (melanosomes) in retinal pigment epithelium are presented in this paper. Physical-mathematical model and system of equations are formulated which describe thermal interaction processes for "short" laser pulses of duration t (p)<10(-6) s and for " long' pulses of duration t(p) > 10(-6) s. Results of numerical simulation of the processes give the space-time distributions of temperature and degrees of thermodenaturation of the protein molecules inside and around melanosomes and in the volume of irradiated tissues. Energy absorption, heat transfer and thermochemical (thermodenaturation, coagulation) processes occurring during the interaction of laser pulses with pigmented spherical and spheroidal granules in heterogeneous tissues are theoretically investigated. The possibility for selective interaction of short laser pulses with pigmented granules is discussed which results in the formation of denaturation microregions inside and near the pigmented granules (granular thermodenaturation) without origination of a continuous macroscopic thermodenaturation lesion in tissue. Analytical model of heating of single spherical and spheroidal granule under laser pulse is presented. Simple equations for time dependencies of particle temperature are obtained. The presented results are of essential interest for laser applications in and can be used for investigation of laser interaction with pigmented tissues in different fields of laser medicine.

Computer Simulation↗

A procedure for benchmarking laboratory exposures with 1 A GeV iron ions.

A new version of the HZETRN code capable of simulating HZE ions with either laboratory or space boundary conditions is under development. The computational model consists of combinations of physical perturbation expansions based on the scales of atomic interaction, multiple scattering, and nuclear reactive processes with use of asymptotic/Neumann expansions with non-perturbative corrections. The code contains energy loss with straggling, nuclear attenuation, nuclear fragmentation with energy dispersion and downshifts, and off-axis dispersion with multiple scattering under preparation. The present benchmark is for a broad directed beam for 1 A GeV iron ion beams with 2 A MeV width and four targets of polyethylene, polymethyl metachrylate, aluminum, and lead of varying thickness from 5 to 30 g/cm2. The benchmark quantities will be dose, track averaged LET, dose averaged LET, fraction of iron ion remaining, and fragment energy spectra after 23 g/cm2 of polymethyl metachrylate.

Aluminum↗