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The authors discuss the use of computers in medicine. A patient presenting with a condition requiring surgery is represented by a data file in a computer program. The user obtains data from the file by selecting items from a menu. Data are presented on the screen in pop-up windows. By examining the data and making judgments, the user may determine the pathology and make first a provisional and then a definitive diagnosis.
The optimal amplitude and slew rate of intracardiac electrograms for pacemaker sensing were examined on a theoretical basis by computer simulation. The simulation was based on the concept that it is the voltage at the position of the pacing electrode in an electrical field of a moving electrical dipole. By changing the distance between the electrode and the myocardium and the moving velocity of the electrical dipole, simulated ECGs with arbitrary amplitudes and slew rates were generated by the computer and fed to a bandpass filter. This filter was equivalent to those assembled in some models of permanent pacemakers and had a center pass-band frequency of 50 Hz and a Q of 1.0. The outputs of the filter were measured. The results showed that, for pacemakers sensing, simulated intracardiac electrograms with high amplitude should have high slew rates and those with low amplitudes should have low slew rates, although the absolute values depend on the characteristics of the bandpass filter and the sensing threshold of the pacemaker.
Previously physiological experiments carried out on mice have proved that copper and zinc can interfere with the pharmacological effects of histamine that lead to anaphylactic shock. A quantitative study of the interactions between essential metal ions and histamine in plasma was thus undertaken. The progressive approach towards a reliable computer-simulated distribution of the histamine-containing plasma species necessitated a large series of physicochemical determinations of the formation constants of the binary and ternary metal complexes involved. The present paper deals with the determination of the formation constants in the zinc-serine, zinc-histamine-serine, zinc-histamine-lysine, copper-serine, copper-histamine-serine, and copper-histamine-valine systems, which were still necessary to reach the reliable simulation required. The subsequent final distribution of histamine in plasma has thus been computed, and interpreted in terms of a possible role for zinc in assisting the histamine catabolism process. Further computer calculations simulating the increase of the zinc concentration in human blood plasma support this interpretation. The antagonizing role of copper against that of zinc has also been examined.
Tumor growth is considered to depend on tumor cell proliferation and on tumor cell motility. The present study investigates in which way these two cellular properties influence the evolving morphological pattern. Computer simulations were performed, where cells were either dividing or moving for a variable distance at a present probability. The simulation parameters (probability of motility, maximum moving distance) were set interactively. The resulting patterns were evaluated by binary morphological criteria, 13 of 17 binary criteria showed a significant relationship with the simulation parameters (median test: p = less than 0.05). Discriminant analysis of two sets of simulations with different simulation parameters provided a correct classification with an efficiency of 100% (k-nearest-neighbour method; jack-knife-procedure). The results indicate that cell proliferation and motility affect morphological patterns in a reproducible way and that the patterns in turn provide morphological clues for the quantitative estimation of motility and proliferation.
There is a variable delay between a reduction in alveolar PO2 and the decrease in arterial oxygen saturation recorded on a pulse oximeter. The decrease in arterial oxygen saturation in response to disconnexion of a paralysed patient from the breathing system, oxygen supply failure with continued mechanical ventilation and disconnexion of the fresh gas supply to Mapleson D and circle absorption breathing systems were studied by simulations on the MacPuf computer model of the cardiorespiratory system. The simulations revealed that there were marked differences between the rate of arterial desaturation which resulted from each of the three types of oxygen supply failure and that arterial oxygen saturation may reach dangerous levels before a pulse oximeter alarm is activated.
The properties of the slow inward current, isi, in the sino-atrial (s.a.) node of the rabbit have been investigated using two microelectrodes to apply voltage clamp to small, spontaneously beating, preparations. Many of the experimental results can be closely simulated using the computer model of s.a. node electrical activity (Noble & Noble 1984) which has been developed from models of Purkinje fibre activity (Noble 1962; DiFrancesco & Noble 1984). Comparison of the computed reconstructions with experimental results provides a test of the validity of the modelling. Experiments using paired depolarizing clamp pulses show that inactivation of isi is calcium-entry dependent although, unlike the inactivation of Ca2+ currents in some other systems, it also shows some voltage-dependence. Re-availability (recovery from inactivation) of isi in s.a. node is much slower than inactivation at the same potential, showing that isi is not controlled by a single first order process. This very slow recovery from inactivation of isi in the s.a. node and the slow time course of its activation and inactivation at voltages near threshold (-40 to -50 mV) can be closely modelled by assuming that there are two components of 'total isi': a fast inward current, iCa,f' representing the 'gated' fraction and a second, slower, inward current component, iNaCa which, we propose, is caused by the sodium-calcium exchange that ensues when the initial Ca2+ -entry triggers the release of stored intracellular Ca2+. When repetitive trains of clamp pulses are given, a 'staircase' of isi magnitude is seen which can be increasing ('positive') or decreasing ('negative') according to the potential level and frequency of the pulse train given. When computer reconstructions of such staircases are made, it is found that the positive staircases (which, in contrast to negative staircases, imply that more complex processes than simple inactivation are present) can be closely simulated by a model which incorporates slower processes (suggested Na-Ca exchange current) in the total isi in addition to the gated current component.(ABSTRACT TRUNCATED AT 400 WORDS)
The usefulness of measuring respiratory flow in the airway and at the chest wall and of measuring respiratory input impedance (Z) to monitor high frequency ventilation was investigated by computer simulation using a monoalveolar 10-coefficient model. The latter included a central airway with its resistance (Rc) and inertance (lc), a resistive peripheral airway (Rp), a lumped bronchial compliance (Cb), alveolar gas compliance (Cgas), lung tissue with its resistance (RL) and compliance (CL), and chest wall resistance (RW), inertance (lw) and compliance (Cw). Gas flow in the peripheral airway (Vp), shunt flow through Cb (Vb), gas compression flow (Vgas) and rate of volume change of the lung (VL) and of the chest (VW) were computed and expressed as a function of gas flow in the central airway (Vc). For normal values of the coefficients, Vp/Vc was found to decrease moderately with increasing frequency and was still 0.75 at 20 Hz. Peripheral airway obstruction (Rp x 5) considerably decreased Vp/Vc, particularly at high frequency. It did not change the relationship between the two measurable flows, Vc and Vw, but increased the effective resistance at low frequency and shifted the reactance curve to the right. A reduced lung or chest wall compliance produced little change in Vp/Vc and Z except at very low frequencies; however, it decreased the phase lag between Vw and Vc. Finally, an increased airway wall compliance decreased Vp/Vc, but had little effect on Z and Vw/Vc. It is concluded that measuring respiratory impedance may help in detecting some, but not all of the conditions in which peripheral flow convection is decreased during high frequency oscillations.
A description is given of a computer simulation technique which predicts the specific absorption rate (SAR) distribution within the human body resulting from the application of radiofrequency electromagnetic energy. The method uses an extension to the principle of over-relaxation of electric potentials and the basis of the simulation is a realistic three-dimensional model derived from both dielectric and anatomical data. Two of the principal means of applying radiofrequency hyperthermia, namely the use of capacitive electrodes and inductive coils, have been provided for. The accuracy of the simulation has been favourably tested using an agar split-phantom and an infrared thermograph camera. The simulations can be used to assist the design and clinical use of radiofrequency applicators, and examples are given of the application of both an inductive coil and switched capacitive electrodes to heat the thorax.
A mathematical model of insulin sensitive glucose transporter regulation is developed. Model structure is based on experimental evidence from adipocytes and myocytes. Model parameters correspond with known cellular processes. As an example, computer simulation results are compared with data from rat adipocytes. Cellular processes explicitly represented in the model include state-dependent glucose transporter synthesis and degradation rates, insulin sensitive glucose transporter translocation rates, and a glucose transporter endocytosis rate. Most of these processes are represented as first-order events. Using more complex representations of the model structure (e.g. higher order rate constants or saturable pathways) or alternative structures did not result in qualitatively better results. The model is able to accurately simulate the insulin sensitive, insulin concentration dependent, reversible translocation of glucose transporters observed in normal adipocytes. The model is also able to accurately simulate the changes in regulation of glucose transporter translocation observed with increases in cell surface area. Finally, the model can simulate pathogenic states which induce impairment of glucose transporter regulation (e.g. altered glucose transporter regulation in adipocytes from rats on high fat diets, rats with streptozotocin induced diabetes, and fasted rats). Since the structure of our model is sufficient to explain glucose transporter regulation in both normal and pathological states, it may aid in understanding the post-receptor components of insulin resistance (decreased sensitivity or responsiveness to insulin) seen in pathological states such as obesity and diabetes mellitus.
Research has shown that smoking reduces mood fluctuation in smokers and deprivation of smoking leads to mood change. The purpose of this study was to assess the effects of three hours of deprivation and subsequent smoking on mood in smokers while operating a computer simulation of an air traffic controller's job in a 2 x 2 (Deprived vs. Nondeprived x Nicotine vs. Nicotine Free Cigarettes) factorial design. Subjects operated the simulation for two 20 minute periods, and after each period subjects smoked a nicotine or nicotine-free cigarette. Mood was assessed prior to operating the simulation and before and after each cigarette was smoked. Contrary to predictions, mood generally changed as a function of the procedure and not deprivation status or type of cigarette smoked.
A minimal mechanism is proposed which describes the transcriptional and translational processes for four phage proteins (RNA polymerase, DNase, primase and DNA polymerase) involved in T3/T7 DNA replication. Phage DNA replication is also included. It is shown how lag times may be incorporated into a kinetic mechanism. The distinct three-stage transport of phage DNA into the bacterial host (E. coli) is considered. DNA transport is assumed to be rate-determining for the transcription of class I and II proteins. Transcriptional and translational lag times have been calculated on the basis of available gene mapping of T7 phages. The kinetic behavior of T7 and T3 phage infection is practically identical. The hydrolysis of bacterial DNA by phage DNase (endonculease and exonuclease) as well as the subsequent phosphorylation to the deoxymononucleoside triphosphates are assumed to be rate-determining in phage DNA replication. Good agreement with experiment is obtained in our computer simulations.
A new interpretation of existing data permits us to define a model capable of accounting for agonist-induced Ca2+ oscillations in the cytosol of electrically non-excitable cells. The model only requires one Ca2+ store, which contains Ca2+ channels controlled by inositol 1,4,5-trisphosphate and Ca2+. Computer simulations may generate different experimentally observed patterns of Ca2+ oscillations.
A series of computer simulations of gel patterns assuming non-cooperative binding of a protein to two targets on the same DNA fragment was performed and applied to interprete gel mobility shift experiments of Tet repressor-tet operator binding. While a high binding affinity leads to the expected distribution of free DNA, DNA bound by one repressor dimer and DNA bound by two repressor dimers, a lower affinity or an increased electrophoresis time results in the loss of the band corresponding to the singly occupied complex. The doubly occupied complex remains stable under these conditions. This phenomenon is typical for protein binding to DNA fragments with two identical sites. It results from statistical disproportionation of the singly occupied complex in the gel. The lack of the singly occupied complex is commonly taken to indicate cooperative binding, however, our analysis shows clearly, that cooperativity is not needed to interprete these results. Tet repressor proteins and small DNA fragments with two tet operator sites have been prepared from four classes of tetracycline resistance determinants. The results of gel mobility shift analyses of various complexes of these compounds confirm the predictions. Furthermore, calculated gel patterns assuming different gel mobilities of the two singly occupied complexes show discrete bands only if the electrophoresis time is shorter than the inverse of the microscopic dissociation rate constant. Simulations assuming increasing dissociation rates predict that the two bands first merge into one, which then disappears. This behavior was verified by gel mobility analyses of Tet repressor-tet operator titrations at increased salt concentrations as well as by direct footprinting of the complexes in the gel. It is concluded that comparison of the intensities of the single and the double occupation bands allow a rough estimation of the dissociation rate constant. On this basis the sixteen possible Tet repressor-tet operator combinations can be ordered with decreasing binding affinities by a simple gel shift experiment. The implications of these results for gel mobility analyses of other protein-DNA complexes are discussed.
Computer simulation models have been developed to investigate the effect of intravenous infusions of nutritive amino acid solutions metal equilibria in plasma. The distribution of Ca(II), Mg(II), Zn(II), Cu(II), and Mn(II) among the ligands in the nutritive fluid is calculated and used to estimate the amounts of each metal that should be included in future preparations.
Intermediary metabolism in rat hearts perfused with 11 mM glucose plus 1 mM palmitate was simulated by a computer model. Several enzyme submodels in a previous version of the isolated rat heart computer model were improved, and a new fatty acid oxidation pathway model was added. Compartmentation of metabolites in a pseudo-stationary state was calculated, and its implications are discussed, e.g., citrate level may not regulate glycolysis because it is mostly mitochondrial. Citrate synthetase, controlled largely by its inhibitors, is of key importance in regulating fatty acid metabolism. The response of aconitase to the mitochondrial Mg2+ level is of major importance in setting both the mitochondrial citrate and isocitrate levels. Pyruvate dehydrogenase is about 96% in the inactive phosphorylated form, and the active form is also 15% inhibited by products, severely limiting pyruvate oxidation and causing preferential utilization of palmitate as the metabolic fuel. The simulation is consistent with a creatine phosphate shuttle which delivers high energy phosphate to the site of its utilization for mechanical work.
According to a classical, antigen-driven view of the immune system, autoimmunity is due to the presence of self-reactive lymphocyte clones which have not been eliminated. However, computer simulations of the immune network show that the greater the degree of connectivity of a clone, the greater its degree of tolerance to chronic antigenic stimulation. This tolerance does not correspond to an absence of response on the part of the system as a whole. On the contrary, stimulation by a 'tolerogenic antigen' results in widespread modification and overall activation of the whole network. This suggests that on an autopoietic network view of the immune system, autoimmunity arises not because of the presence of self-reactive clones, which is completely normal, but because such clones are inadequately connected to the network. This amounts to a complete reversal in perspective, whose significance for the clinical treatment of autoimmunity and the future of immunology is discussed.
Parallel investigations were done using the reticular formation of the lower brainstem of dogs and computer simulated neuronal networks with properties of reticular neurones. By the aid of the simulations, understanding of the functional organisation of the common brainstem system, reticular formation and the experiments performed were optimized. The fact that discharge sequences of model neurones are very similar to those of reticular neurones was proved by interval histograms and covariance histograms. Discharges of neighbouring reticular neurones tend to be strongly coupled. In the model the discharges of the neurones could be coupled by common afferent inflows. Physiologically, neighbouring reticular neurones receive common afferents from peripheral somato-sensory systems. Neighbouring neurones with strongly coupled discharging are organized in subpopulations. The configurations of the subpopulations are determined by number and type of afferents actively influencing neurones and by the level of intrinsic activity of the network. Signal processing and transfer by neuronal subpopulations depend on the level of activity and on the degree of coupled discharging, i.e. the local organisation of the neurones.
We show that the use of a computer simulation method introduced to calculate the equilibrium thermodynamic properties of a model of a two-component lipid bilayer membrane [Freire, E., & Snyder, B. (1980) Biochemistry 19, 88-94] is incorrect. This is done by comparing the method to that of Metropolis, which has been proven to generate equilibrium distribution of that model, and by showing that back-processes have been omitted in the implicit master equation of Freire and Snyder. We have illustrated this explicitly by first generating distributions according to the method of Freire and Snyder and then allowing the system to relax via the Kawasaki method, which uses the technique of Metropolis. We show that relaxation to a different distribution occurs. We also remark that the cluster distributions generated by the Freire-Snyder method are substantially different from those occurring in equilibrium distributions. Thus, conclusions about equilibrium thermodynamic properties such as specific heats and transition enthalpies or about transport properties or cluster properties at equilibrium cannot be drawn from the results obtained by using this method. Finally, we point out that the method of Freire and Snyder is appropriate to so-called aggregation models, which have been used to study irreversible growth; and we suggest biological systems that might be simulated by their method.