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Improvement of low-contrast detectability in low-dose hepatic multidetector computed tomography using a novel adaptive filter: evaluation with a computer-simulated liver including tumors.

PURPOSE: The purpose of this study was to investigate how much radiation dose can be reduced without loss of low-contrast detectability with a newly developed adaptive noise reduction filter in hepatic multidetector computed tomography (MDCT) scans by using a computer-simulated liver phantom. MATERIALS AND METHODS: Simulated CT images, including liver and intrahepatic tumors, were mathematically constructed using a computer workstation to evaluate low-contrast detectability by the observer performance test. Milliampere second for construction of simulated images were 60, 80, 100, and 120 mAs (low dose) and 160 mAs (standard dose) at 120 kVp. Images with 60, 80, 100, and 120 mAs were postprocessed with the adaptive noise reduction filter. A total of 432 images were prepared and receiver operating characteristic (ROC) analysis was performed by 5 radiologists. The detectability of simulated tumor by radiologists was estimated with the area under the ROC curves (Az values). In addition, we visually evaluated CT images of 15 patients with chronic liver damage for graininess of the liver parenchyma, sharpness of the liver contour, conspicuity and marginal sharpness of the liver tumors, and overall image quality. RESULTS: The mean Az value at 0.777 (60 mAs), 0.828 (80 mAs), and 0.844 (100 mAs) without filter was significantly lower than that of 160 mAs without filter (P < 0.001, 60 mAs; P = 0.010, 80 mAs; P = 0.040, 100 mAs). There was no statistical difference between the mean Az value at 80 mAs with and 160 mAs without the adaptive noise reduction filter (P = 0.220) and 100 mAs with and 160 mAs without the adaptive noise reduction filter (P = 0.979). In the visual evaluation of patient livers, there was no statistical difference in the graininess and sharpness of the liver, the conspicuity and marginal sharpness of the tumor, and the overall image quality between standard-dose and filtered low-dose images (Wilcoxon signed rank test, P > 0.05). CONCLUSION: The radiation dose can be reduced by 50% without loss of nodule detectability by applying the adaptive noise reduction filter to simulated and patient liver images obtained at MDCT.

Aged↗

Errors in measurements of stroke volume for invasive and echo-Doppler evaluations of valvular regurgitant fractions. Clinical evaluation and computer simulation.

The aim of this study was to compare cardiac catheterization (CATH) with 2D echo-Doppler (ED) in clinically evaluating the stroke volumes (SV) needed to calculate aortic and mitral regurgitant fractions (aortic and mitral SV for the ED method, thermodilution and angiographic SV for the CATH). As there is no 'gold standard' for this kind of measurement, only subjects without valvular regurgitation were considered. In these subjects, though the two SV measurements needed to calculate the regurgitant volume should have been identical, there was, in fact a difference due to the systematic and random errors of the methods. We calculated the mean value and the standard deviation of this difference in a series of patients without valvular regurgitation in order to obtain an estimate of both systematic and random errors. In 20 patients studied by ED a difference of 11.9 +/- 16.7 ml was found. In 36 patients studied by cardiac catheterization the difference was 19.6 +/- 20.1 ml. A significant systematic error was found for both ED and the invasive method; The transmitral SV tended to be larger than the aortic and the angiographic SV larger than that obtained by thermodilution. To try to determine the extent to which the random errors could be attributed to the reproducibility of the measurements, we carried out computer simulations. The SVs of 50 000 hypothetical patients were randomly generated and then attributed a random error calculated on the basis of the variability of the CATH (thermodilution 4%, angiography 10%) and the ED measurements (aortic annulus 6%, mitral annulus 18%, mitral time velocity integral 10%, aortic time velocity integral 8%).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗

Relative activity of structural analogues of amsacrine against human leukemia cell lines containing amsacrine-sensitive or -resistant forms of topoisomerase II: use of computer simulations in new drug development.

Anilino analogues of amsacrine showed increased activity against amsacrine (AMSA)-resistant cell lines when compared with the parent compound, but the mechanisms of amsacrine resistance in these lines were unknown (Finlay, G. J., Baguley, B. C., Snow, K., and Judd, W., J. Natl. Cancer Inst., 82: 662-667, 1990). We tested the cytotoxic and DNA-cleaving activities of two amsacrine analogues which were derivatives of 9-anilinoacridine (1'-methylcarbamate and 1'-benzenesulfonamide) against an amsacrine-resistant human leukemia cell line (HL-60/AMSA) whose resistance is due to an amsacrine-resistant topoisomerase II. Neither agent could overcome the amsacrine resistance of HL-60/AMSA. Neither agent could induce HL-60/AMSA topoisomerase II-mediated cleavage of DNA in an isolated biochemical system, although at high concentrations the two analogues could inhibit HL-60/AMSA topoisomerase II-mediated DNA strand passage. Both analogues were at least as active, if not more active, than amsacrine against amsacrine-sensitive HL-60 and its topoisomerase II. Comparison of the cellular and biochemical results with those from computer simulation of the energy-minimized structures of amsacrine, its inactive isomer o-AMSA, and the two new active analogues suggests the following possibilities: (a) the positioning of the potential topoisomerase II-binding site (1'-anilino group) of the two new drugs resembles the positioning of this site in amsacrine; (b) the HL-60 topoisomerase II has a binding site which interacts with amsacrine and the two anilino analogues but not with o-AMSA, an analogue with altered positioning of the methoxy group; (c) the HL-60/AMSA topoisomerase II interacts with reduced affinity with amsacrine and the two anilino analogues, although HL-60/AMSA topoisomerase II still interacts with the structurally distinct topoisomerase II-reactive nonintercalator, etoposide; (d) because of their higher DNA binding affinity or the greater possible positions of their side groups in comparison to amsacrine, the two analogues can, at high concentrations, inhibit the strand-passing activity of HL-60/AMSA topoisomerase II.

Amsacrine↗

An unusual Z-system in the obliquely striated muscles of crinoids: three-dimensional structure and computer simulations.

The peculiar functional structure of the Z-line in the obliquely striated muscles of some feather stars is described. It is known that cross-striated muscles are characterized by linear and continuous Z-bands, and obliquely striated muscles by disconnected, obliquely aligned Z-elements. Owing to this discontinuous organization, the sarcomere can perform wide active lengthenings, shortenings, and even 'super-elongations' in the helical fibres. In contrast, the obliquely striated fibres of crinoids show markedly continuous and homogeneous oblique Z-lines; such a structure is not compatible with 'super-performances' like sliding and shearing of the sarcomere elements, but instead could allow functions comparable to those characteristic of a cross-striated muscle (quick, short movements, mechanically amplifiable by bone levers). This odd situation, only interpretable in terms of evolutionary constraint, could be considered opposite and symmetrical to that of cross-striated 'super-contracting' muscles, where the Z-line is exceptionally fragmented to allow the sarcomere to super-contract. The possible architecture of a significant parameter such as the Z-line, which determines muscle fibre potential capacities, is analysed in detail: through qualitative-quantitative evaluation of electron micrographs, supported by statistical analysis of the data; and by computer simulations. The data obtained suggest that the most realistic conformation of the whole Z-complex in these muscles consists of a multiple system of continuous, ribbon-like helical planes running in parallel along the fibre from end to end and regularly cutting it with a constant thickness. The proposed model seems morphologically compatible with the experimentally verified situations and functionally compatible with the mechanical requirements for a normal contraction and for a balanced distribution of the involved strengths.

Animals↗

Computer simulation of lipid diffusion in a two-component bilayer. The effect of adsorbing macromolecules.

We have modelled the effects of macromolecular adsorption upon lipid lateral diffusion in a two-component lipid bilayer or monolayer, which is at a temperature above both of the main transition temperatures. One set of lipids (binders, b) can bind to the macromolecules with a free energy of binding, FB, while the other set does not bind (non-binders, nb). We assumed that no phase separation of the lipids occurs in the absence of adsorbed macromolecules. We represented the lipid bilayer/monolayer by a triangular lattice, each site of which is occupied by a lipid molecule. Adsorbed macromolecules were represented by hexagons covering nH sites, and we defined a probability per unit of time, p, that a hexagon attempts to adsorb onto the lattice. We considered two sizes of hexagons, nH = 7 (Size-1) and nH = 19 (Size-2) and disallowed or permitted adsorbed hexagons to move laterally on the lattice. We calculate the lipid relative diffusion coefficients, Dnb, and Db, for three characteristic time-regimes, (i) tau c << tau a, (ii) tau c approximately tau a and (iii) tau c >> tau a, where tau c and tau a are the times for proteins to adsorb/desorb or for lipids to move from site to site, respectively. We obtain analytical expressions for Dnb and Db in the first case and calculate them using computer simulation in the other two cases. We found that (i) D alpha (iii) < or = D alpha (ii) < or = D alpha (i) (alpha = nb, b); (ii) D alpha could display a shoulder as a function of FB for low values of p; (iii) compared to cases in which lateral diffusion was disallowed, the lateral diffusion of absorbed hexagons appeared to have little effect on Dnb, but could cause Db to increase by 50%. (iv) Scatter in the calculated values of D via simulation appeared to be largest for Size-1 hexagons, and could be understood as a consequence of the large interfacial region between areas free of hexagons and areas 'covered' by hexagons. Our results suggest that it is advisable to measure Db, since Dnb might show little change from 1.0 for the values of F and p appropriate to the system being studied.

Adsorption↗

Computer simulation of the effect of the nodal gap resistance on ionic current measurements in the Ranvier node membrane.

Results are presented of a computer simulation of the effect of the irreducible resistance introduced by the nodal gap, in series with the impedance of the axon membrane. A clamp potential is applied to a structure modeled as an electric circuit composed of a resistance in series with the membrane impedance, and modified nerve equations describing membrane currents are solved to predict the effect of nodal series resistance on these currents. These studies reveal changes in the absolute values and kinetics of the ionic currents (errors greater than 10-20%) for selected values of series resistance.

Animals↗

Conduction in bundles of demyelinated nerve fibers: computer simulation.

This study presents a model of action potential propagation in bundles of myelinated nerve fibers. The model combines the single-cable formulation of Goldman and Albus (1967) with a basic representation of the ephaptic interaction among the fibers. We analyze first the behavior of the conduction velocity (CV) under the change of the various conductance parameters and temperature. The main parameter influencing the CV is the fast sodium conductance, and the dependence of CV on the temperature is linear up to 30 degrees C. The increase of myelin thickness above its normal value (5 microm) gives a slight increase in CV. The CV of the single fiber decreases monotonically with the disruption of myelin, but the breakdown is abrupt. There is always conduction until the thickness is larger than 2% of its original value, at which with at this point a sharp transition of CV to zero occurs. Also, the increase of temperature can block conduction. At 5% of the original thickness there is still spike propagation, but an increase of 2 degrees C causes conduction block. These results are consistent with clinical observations. Computer simulations are performed to show how the CV is affected by local damage to the myelin sheath, temperature alterations, and increased ephaptic coupling (i.e., coupling of electrical origin due to the electric neutrality of all the nerve) in the case of fiber bundles. The ephaptic interaction is included in the model. Synchronous impulse transmission and the formation of "condensed" pulse states are found. Electric impulses with a delay of 0.5 ms are presented to the system, and the numerical results show that, for increasing coupling, the impulses tend to adjust their speed and become synchronized. Other interesting phenomena are that spurious spikes are likely to be generated when ephaptic interaction is raised and that damaged axons suffering conduction block can be brought into conduction by the normal functioning fibers surrounding them. This is seen also in the case of a large number of fibers (N=500). When all the fibers are stimulated simultaneously, the conduction velocity is found to be strongly dependent on the level of ephaptic coupling and a sensible reduction is observed with respect to the propagation along an isolated axon even for low coupling level. As in the case of three fibers, spikes tend to lock and form collective impulses that propagate slowly in the nerve. On the other hand, if only 10% of fibers are stimulated by an external input, the conduction velocity is only 2% less than that along a single axon. We found a threshold value for the ephaptic coupling such that for lower values it is impossible to recruit the damaged fibers into conduction, for values of the coupling equal to this threshold only one fiber can be restored by the nondamaged fibers, and for values larger than the threshold an increasing number of fibers can return to normal functioning. We get values of the ephaptic coupling such that 25% of axons can be damaged without change of the collective conduction.

Action Potentials↗

Modification of cell response to insulin by membrane-acting agents in rat white adipocytes: analysis of structural features by computational simulation.

The effect of membrane-acting agents, biscoclaurine alkaloids (cepharanthine, tetrandrine, isotetrandrine), carbobenzoxy-D-Phe-L-Phe-Gly (z-FFG), and tyrphostin AG17, on the insulin-involved fatty acid synthesis by an beta-agonist (e.g., isoproterenol) in adipocytes was examined. The alkaloids dose-dependently enhanced the insulin-involved fatty acid synthesis in rat white adipocytes, stabilized the C(6)-NBD-PC (1-acyl-2-[6-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-caproyl]-sn-glycero-3-phosphatidylcholine) model membrane, and suppressed the phospholipase A(2)-induced phospholipid degradation. In contrast, z-FFG had no effect on the fatty acid synthesis or the membrane stability. Tyrphostin AG17 suppressed insulin action, but promoted the model membrane stabilization. In the same culture conditions as for the fatty acid synthesis assay, cepharanthine, z-FFG and tyrphostin AG17 had no effect on the transcript levels of glucose transporter isoforms (GLUT 1, 4) and hexokinase isozymes (HK I, II) in rat white adipocytes. Thus, these membrane-acting agents modify the insulin action via a change in the cell membrane condition, and do not directly act on the insulin-involved glucose metabolism. Then we analyzed the structural conformation of these membrane-acting agents by computational simulations. The alkaloids had an elliptic macrocyclic structure, and the order of ellipticity (cepharanthine>tetrandrine>isotetrandrine) agreed with that of the modifying ability for insulin action. The distribution of electrostatic potential fields of these alkaloids was essentially equal by turn in surrounding with the dipole moments. Both in z-FFG and tyrphostin AG17, the distribution pattern of electrostatic potential fields was different from that of the alkaloids. Judging from these results, we concluded that the electrostatic potential field is a good index of the modification of insulin action, and the elliptic structure in these alkaloids is regarded with the modification of insulin action.

Adipocytes↗

Computer simulation of metal ion equilibria in biofluids. IV. Plutonium speciation in human blood plasma and chelation therapy using polyaminopolycarboxylic acids.

An investigation by computer simulation into the nature of Pu(IV) binding to low-molecular ligands in human blood plasma is described. Particular consideration is given to the interactions of various chelating agents which have been or might be used for treating plutonium intoxication. Formation constants of EDTA and DTPA with Cu(II), Mg(II), Mn(II), Zn(II), and Cd(II) have been measured under biologic conditions of temperature and background electrolyte. The relative ability of these and other chelating agents to cause excretion of plutonium and the concomitant loss of certain essential trace metals has thus been assessed.

Chelating Agents↗

Computer simulation of Gumboro disease outbreak. III. Construction model G-4.

Following the simulation mode., G-3, of Gumboro disease outbreak, Model G-4 was constructed. The algorithm for computer simulation is shown in a flow chart. The postulates added to those for Models G-1 and G-2 are as follows: (1) The source of contamination is the virus remaining in the house and declining gradually in value with the lapse of time. (2) Any diseased bird excretes the virus during a certain period, so that the virus may be added to the source of contamination. (3) The morbid status of the diseased bird becomes worse in process of time, but the infection remains subclinical until a threshold value is reached. Beyond this value the bird becomes clinically diseased. In this model, more than 20 parameters are involved, and random numbers used for expressing the individual differences in the four variables, viz., the level of innate resistance, parentally conferred immunity, virus-intake, and threshold of clinical manifestation.

Animals↗

Membrane pores: a computer simulation of interacting pores analyzed by g1(tau) and g2(tau) correlation functions.

Ion channels in a cell membrane were modeled by a computer simulation of fluctuating pores distributed in a spatial array, a cellular automata. The sum of the currents through such a set of pores models a noise analysis experiment. These currents were analyzed by using the optical correlation functions gn(tau) = (fn(t)fn(t + tau))/(f2(t))n, where f(t) are the current deviations around the mean current and () denotes the time average. These functions can be easily used to determine if the noise is Gaussian. If the noise is not Gaussian, they provide additional information not already contained in the power spectrum. When the pores do not interact with each other, the noise is Gaussian and the power spectrum a Lorentzian. When the pores interact in a strongly cooperative way the noise was still Gaussian and the power spectrum still a Lorentzian, but the usual analysis applied to such a case would over-estimate the single channel conductance. If the kinetics of the pore opening and closing vary on the time scale of the experiment then the relationship g2(tau) = 1 + 2[g1(tau)]2 is no longer satisfied.

Cell Membrane↗

A role for computer simulation in solving the riddles of autoreceptor-mediated regulation of GABA release.

The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLA/ITHINK). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (-)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject.

Animals↗

Computer simulation training enhances patient comfort during endoscopy.

BACKGROUND & AIMS: Computer-based endoscopy simulator (CBES) training's impact on patient-based outcomes has never been examined. This study examines whether the endoscopy skills of trainees are improved and patient discomfort is reduced as a result of CBES training. METHODS: From July 2001-June 2002, 38 residents received either 1 week of patient-based training (PBT) alone in flexible sigmoidoscopy (FS) or 3 hours of simulator-based training (SBT) before a week of training in FS. Patients completed questionnaires grading the discomfort experienced during endoscopy (1, no pain; 10, worst pain of life). In addition, residents' performance was graded by the supervising staff and themselves with 8 performance parameters by using a 1-10 Likert scale (1, strongly agree; 5, neutral; 10, strongly disagree). RESULTS: Nineteen SBT and 19 PBT residents performed 150 and 175 FS, respectively. During this same period, staff completed 585 FS. The median patient discomfort score for SBT residents was significantly less than for PBT residents, 3 (25%-75% interquartile range [IQR], 2-5) vs. 4 (IQR, 2-6) (P < 0.01). Discomfort scores for both resident groups were significantly greater than those recorded by staff endoscopists, 2 (IQR, 1-4) (P < 0.01). No difference was seen in the residents' procedural skill scores. Resident self-evaluation scores were significantly greater than those received from the supervising staff. CONCLUSIONS: Increased patient comfort resulted from simulation training, demonstrating that CBES training has a direct benefit to the patient. Although no measurable impact on residents' performance skills was observed, we do demonstrate that residents perceive themselves as having acquired greater endoscopic skills in contrast to staff evaluations.

Clinical Competence↗

Time difference scanning gel chromatography: computer simulations.

The time difference profile method of gel scanning chromatography developed by Brumbaugh, Saffen and Chun (Biophysical Chemistry, 1979) has been examined by computer simulation. The method is found to produce values for centroid movements that mimic those of the system being examined but are not quantitatively correct. In all cases the time differential "centroid" is larger than that of the concentration derivative (true) centroid and move at a rate slightly faster than the true centroids. This faster rate slowly decreases towards the true rate but does not approach it within reasonable times. This distorted movement reflects the distorted emphasis given to the larger species in the time differential method. The time difference method has been shown to give an adequate measure of the axial dispersion coefficient, L, for single species systems.

Journal Article↗

Computer simulation of flagellar movement. I. Demonstration of stable bend propagation and bend initiation by the sliding filament model.

A program has been developed for digital computer simulation of the movement of a flagellar model consisting of straight segments connected by joints at which bending occurs. The program finds values for the rate of bending at each joint by solving equations which balance active, viscous, and elastic bending moments at each joint. These bending rates are then used to compute the next position of the model. Stable swimming movements, similar to real flagellar movements, can be generated routinely with a 25-segment model using 16 time steps/beat cycle. These results depend on four assumptions about internal flagellar mechanisms: (a) Bending is generated by a sliding filament process. (b) The active process is controlled locally by the curvature of the flagellum. (c) Nonlinear elastic resistances stabilize the amplitude of the movement. (d) Internal viscous resistances stabilize the wavelength of the movement and explain the relatively low sensitivity of flagellar movement to changes in external viscosity.

Computers↗

Voltage-clamp analysis and computer simulation of a novel cesium-resistant A-current in guinea pig laterodorsal tegmental neurons.

Increased firing of cholinergic neurons of the laterodorsal tegmental nucleus (LDT) plays a critical role in generating the behavioral states of arousal and rapid eye movement sleep. The majority of these neurons exhibit a prominent transient potassium current (IA) that shapes firing but the properties of which have not been examined in detail. Although IA has been reported to be blocked by intracellular cesium, the IA in LDT neurons appeared resistant to intracellular cesium. The present study compared the properties of this cesium-resistant current to those typically ascribed to IA. Whole cell recordings were obtained from LDT neurons (n = 67) in brain slices with potassium- or cesium-containing pipette solutions. A transient current was observed in cells dialyzed with each solution (KGluc-85%; CsGluc-79%). However, in cesium-dialyzed neurons, the transient current was inward at test potentials negative to about -35 mV. Extracellular 4-aminopyridine (4-AP; 2-5 mM) blocked both inward and outward current, suggesting the inward current was reversed IA rather than an unmasked transient calcium current as previously suggested. This conclusion was supported by increasing [K]o from 5 to 15 mM, which shifted the reversal potential positively for both inward and outward current (+17.89 +/- 0.41 mV; mean +/- SE). Moreover, recovery from inactivation was rapid (tau = 15.5 +/- 4 ms; n = 4), as reported for IA, and both inward and outward transient current persisted in calcium-free solution [0 calcium/4 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N', N'-tetraacetic acid; n = 4] and during cadmium-blockade of calcium currents (n = 3). Finally, the transient current was blocked by intracellular 4-AP indicating that adequate dialysis occurred during the recordings. Thus the Cs-resistant current is a subthreshold IA. We also estimated the voltage-dependence of activation (V1/2 = -45.8 +/- 2 mV, k = 5.21 +/- 0.62 mV, n = 6) and inactivation (V1/2 = -59. 0 +/- 2.38 mV, k = -5.4 +/- 0.49 mV, n = 3) of this current. Computer simulations using a morphologically accurate model cell indicated that except for the extreme case of only distal A-channels and a high intracellular resistivity, our parameter estimates were good approximations. In conclusion, guinea pig LDT neurons express subthreshold A-channels that are resistant to intracellular cesium ions. This suggests that these channels differ fundamentally in their ion permeation mechanism from those previously studied. It remains to be determined if Cs+ resistance is common among brain A-channels or if this property is conferred by known A-channel subunits.

4-Aminopyridine↗

Computer simulation studies and the scientific method.

The scientific method is the formal procedure for all acceptable scientific endeavors. With this methodology, there is a continual interaction between theory, in the form of an hypothesis, and objective, experimental analysis. There is a new step in the scientific method that involves the use of computer models and simulation studies. When computer models are incorporated into hypothesis formulation, they can be used in simulation studies to test ideas before they are tried experimentally. An iterative feedback between these tests and current ideas allows for a preliminary refinement of hypotheses and development of more intelligent research protocols. In this way, computer simulation studies can serve as an intermediate step in the scientific method, reducing the number of animals used in biomedical experimentation. In this article we also explore other ways that computer simulation studies could limit the use of animals in biomedical research and education.

Journal Article↗