Determination of saltiness from the laws of thermodynamics--estimating the gas constant from psychophysical experiments.

One can relate the saltiness of a solution of a given substance to the concentration of the solution by means of one of the well-known psychophysical laws. One can also compare the saltiness of solutions of different solutes which have the same concentration, since different substances are intrinsically more salty or less salty. We develop here an equation that relates saltiness both to the concentration of the substance (psychophysical) and to a distinguishing physical property of the salt (intrinsic). For a fixed standard molar entropy of the salt being tasted, the equation simplifies to Fechner's law. When one allows for the intrinsic 'noise' in the chemoreceptor, the equation generalizes to include Stevens's law, with corresponding decrease in the threshold for taste. This threshold reduction exemplifies the principle of stochastic resonance. The theory is validated with reference to experimental data.

The tissue distribution of tumor necrosis factor-alpha in rats: a compartmental model.

Tumor necrosis factor (TNF) is widely accepted to be the mediator of the cascade of metabolic abnormalities associated with both critical and chronic illness. TNF binding to cell surface receptors mediates its physiologic actions, although the exact mechanism of TNF action is unknown. Therefore, this study was designed to investigate the in vivo metabolism of TNF using a mathematical model to examine tissue uptake and loss of TNF over time. Two distinct patterns of TNF uptake were observed. Muscle tissues were found to accumulate TNF over the entire experimental period, whereas the visceral organs were found to have a rapid initial accumulation of TNF followed by a rapid loss of TNF back to the plasma or out into the bile or the urine. These patterns of TNF binding and retention may reflect the number of TNF receptors or their affinity for TNF, as well as the balance between cell surface and soluble TNF receptors. Furthermore, TNF binding patterns provide insight into the biologic action of TNF at these sites.

Kinetics of T cell turnover following thymectomy.

We develop a mathematical formula that provides the number of cells in an isolated population that have divided k times in n days (O< or =k< or =n). This differential cell division formula is applied to the kinetics of peripheral T cells in the diabetes-prone BB rat following thymectomy. These rats received daily intraperitoneal injections of the DNA precursor, bromodeoxyuridine (BrdUrd), over a period of 12-13 days. As the cells divided, they incorporated BrdUrd progressively into their DNA molecules, and the differential formula provides a close prediction of the fraction of BrdUrd-positive T cells present each day during this 'pulse' phase. No further BrdUrd was administered after 13 days, and the diminishing fraction of BrdUrd-positive cells was recorded for several more weeks. The differential cell division formula was capable of describing the rather complex form of the retention curve as BrdUrd-tagged DNA molecules passed to progeny cells during this 'chase' phase. We believe that this simple formula may be found generally useful in describing cell kinetic data in mitotically active cells.

Unification of psychophysical phenomena: the complete form of Fechner's law.

Many of the laws and empirical observations of fundamental psychophysics can be unified with a single equation, which has been called the complete form of Fechner's law. It can be shown that this law embraces both of the commonly used forms: Stevens's and Fechner's laws. It assumes one or the other form with appropriate values of the parameters. However, the complete equation confers an advantage beyond simply containing the classical laws. It offers greater flexibility in the representation of experimental data. It is shown that psychophysical phenomena may be represented by any number of triplets of quantities: subjective magnitude of stimulus, subjective just noticeable difference (jnd), and differential threshold. Each of the preceding quantities are functions of the physical magnitude of the stimulus. The investigator has the license to choose two of these quantities in the form he or she thinks is best; the third quantity is determined by the choice of the first two. Thus, for example, different forms of the law of sensation and different forms of the mathematical function for differential threshold may coexist with equal validity.

Noncompartmental models of whole-body clearance of tracers: a review.

Noncompartmental models are defined as models that allow for transport of material through regions of the body that are not necessarily well-mixed or of uniform concentration. The clearance of a substance of interest (metabolite or drug) from a noncompartmental system will not necessarily be governed by a sum of exponentials or even be describable by a set of ordinary differential equations. The model may involve diffusion or other random walk processes, leading to the solution in terms of the partial differential equation of diffusion or in terms of probability distributions. It may use the theory of linear systems to obviate the need for defining any precise anatomical structure. A number of the models reviewed deal with plasma clearance curves that are best described by power functions of time. Circulatory models are reviewed from their inception to the present. Recent studies on clearance as a fractal process are introduced.

Simulation of human sensory performance.

The capacity of human sensory systems for transmitting information has been approximated in the past by using statistical estimators. However, a substantial margin of error remained. The problem is that the error can be reduced to a negligible level only by increasing the number of human trials or tests to the order of about 10(4). Since a human subject can perform at peak only in the order of 10(2) trials per day, the requisite total number of trials could be obtained realistically only by pooling of data from several subjects. Following Houtsma, we have overcome this problem to a large extent by the use of computer simulation. By introducing parameters characteristic of a given subject into the simulation program, we are able to reproduce the subject's performance (say for 500 trials), and to extrapolate his or her performance using the simulation program to 30000 trials. In this way we can establish limits to the capacity of a single human being to transmit information.

Nutrition support affects the distribution and organ uptake of cachectin/tumor necrosis factor in rats.

BACKGROUND: We have previously observed a potentiation of the metabolic response to cachectin/tumor necrosis factor (TNF) by total parenteral nutrition (TPN) but not in anorexic orally fed animals. We hypothesized that nutritional status might affect TNF clearance kinetics. METHODS: We compared the clearance of a bolus of labeled TNF in TPN-fed animals given sufficient nutrients to grow called weight-gaining rats (WGR) with those given 50% of the WGR called weight-losing rats (WLR) and with orally fed rats (OFR). Data were analyzed using a two-compartment open system model and by linear systems analysis. RESULTS: The data from both types of analysis indicator that although metabolic clearance was similar, WGR had a slower fractional TNF clearance rate (FCR) as well as a larger volume of distribution than WLR or OFR. Further analysis showed that an increased proportion of the total mass of TNF resided in a plasma-associated compartment in WGR compared with WLR and OFR. In addition, WGR had reduced uptake of labeled TNF by the kidney. CONCLUSION: The data suggest that nutrition support influences either the distribution of TNF or the FCR, resulting in a greater retention in the plasma-associated compartment with intact absolute removal rates. This study has important implications concerning the type of nutrition support provided to the critically ill patient because our data suggest that clinical states with increased circulating TNF levels may be adversely affected by currently available nutritional practices.

A universal model of single-unit sensory receptor action.

We present a model governing the operation of all "isolated" sensory receptors with their primary afferent neurons. The input to the system is the intensity of a sensory signal, be it chemical, optical etc., and the output is the rate of neural impulse transmission in the afferent neuron. The model is based on the premise that information is conserved when transmitted by an efficient sensory channel. Earlier studies on this informational or entropic model of receptor function were constrained to the cases where the sensory stimulus assumed the form of an infinite step function. The theory was quite successful in treating mathematically all responses to such elementary sensory stimuli--both neural, and by extension, psychophysical. For example, the theory unified the logarithmic and power laws of sensation. However, the earlier model was incapable of predicting responses to time-varying stimuli. The generalized model, which we present here, accounts for both steady and time-varying signals. We show that more intense stimuli are remembered by sensory receptors for longer periods of time than are less intense stimuli.

Sites of infusion and sampling for measurement of rates of production in steady state.

When labeled and unlabeled (endogenously produced) substances enter an organism through different ports of entry, the anatomical location of these entry sites must be taken into account explicitly in calculating rates of appearance. All traditional formulas that are used for calculating rates of appearance are based on the assumption that labeled and unlabeled substances enter by means of the same port. These formulas are, therefore, not in general valid for metabolites such as lactate, where the entry ports differ. In such cases, specific activity will not be uniform throughout the organism even when the labeled and unlabeled substances are both in steady state. One cannot speak of the (unique) specific activity, because none exists. It is useful in these cases to define a distributed specific activity, which is the ratio of the concentration of labeled substance at one anatomical site to the concentration of unlabeled substance at another. We can then show that the rate of appearance for the double steady state (steady tracer infusion method) is given, approximately, as the ratio of the rate of infusion of the labeled substance to a particular distributed specific activity.

Noncompartmental analysis in metabolism.

A new type of model called a department is formulated to complement the compartment. While a compartment may be dominated by convective transport, a department is dominated by diffusive transport. Although exit from a compartment is limited by the rate of biophysical or biochemical removal ("kc"), exit from a department is limited by the rate of transport to the site of biophysical or biochemical removal.

Application of the entropy theory of perception to auditory intensity discrimination.

The entropy theory of perception has been developed from principles of information theory and predicts both psychophysical data and firing rates of sensory receptors or primary afferents. It has demonstrated how mathematical relationships subsist among many previously unrelated phenomena, such as adaptation processes, reaction times and subjective magnitudes and can be applied to most modalities of perception. The current study demonstrates how the theory can be applied to intensity discrimination of auditory pure tones. A psychophysical experiment of intensity discrimination was carried out under computer control in three practiced normal hearing listeners. Three different derivations for the entropic description of intensity discrimination were applied to the data and analyzed in terms of computer generated best-fitting parameters. The physiological meaning of these parameters is discussed.

On the fundamental nature of perception.

The process of recognition or isolation of one or several entities from among many possible entities is termed intellego perception. It is shown that not only are many of our everyday percepts of this type, but perception of microscopic events using the methods of quantum mechanics are also intellego in nature. Information theory seems to be a natural language in which to express perceptual activity of this type. It is argued that the biological organism quantifies its sensations using an information theoretical measure. This, in turn, sets the stage for a mathematical theory of sensory perception.

An informational approach to sensory adaptation.

Concepts from information theory can enhance our understanding of perceptual processes by providing a unified picture of the process of perception. A single equation is shown to embrace adaptation phenomena, stimulus-response relations, and differential thresholds. Sensory adaptation is regarded as representing a gain in information by the receptor. It is calculated that for constant stimuli in the form of step inputs, insects and arachnids obtain approximately the same amount of information per stimulus from their respective environments as do human beings.

Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D3 production.

To understand the relationships among 1) the dose of 25-hydroxyvitamin D [25(OH)D] in vivo, 2) the activity of 1-hydroxylase in renal mitochondria, and 3) the production of 1,25-dihydroxyvitamin D [1,25(OH)2D] in vivo, we gave rats different chronic or acute doses of 25-hydroxyvitamin D3 [25(OH)D3]. We followed the metabolism of intracardially administered [25-hydroxy-26,27-methyl-3H]cholecalciferol [25(OH)[3H]D3] for 24 h before killing by measuring extracts of serum by chromatography. Specific activity of 1-hydroxylase in kidney was measured at death. In rats given 0-2,000 pmol 25(OH)D3 chronically by mouth, there was a dose-dependent decline in the percent of serum radioactivity made up of 1,25-dihydroxy-[26,27-methyl-3H]cholecalciferol [1,25(OH)2[3H]D3] as well as a decline in mitochondrial 1-hydroxylase, and these correlated significantly (r = 0.83, P less than 0.001). Serum %1,25(OH)2[3H]D3 in this experiment ranged from 0.8 to 42%. A small part of this range could be accounted for by a faster metabolic clearance rate (MCR) of 1,25(OH)2D3 from rats supplemented with 25(OH)D3 (MCR, 2.12 +/- 0.10 ml/min) compared with rats restricted in vitamin D (MCR, 0.94 +/- 0.06 ml/min, P less than 0.001). The activity of 1-hydroxylase was by far the major factor determining serum %1,25(OH)2[3H]D3. When different acute doses of 25(OH)D3 were given to rats with identical specific activities of 1-hydroxylase, the resulting 1,25(OH)2D3 concentrations in serum correlated with the 25(OH)D3 dose (r = 0.99, P less than 0.001). We conclude that the behavior of 1-hydroxylase in vivo is analogous to the classic behavior in vitro of an enzyme functioning below its Michaelis constant (Km). The amount of 1-hydroxylase present in renal mitochondria determines the fraction (not simply the quantity) of 25(OH)D metabolized to 1,25(OH)2D3 in vivo.

Automatic speech recognition--can it improve the man-machine interface in medical expert systems?

Computer-aided medical diagnosis has existed for two decades, but has not yet attained widespread acceptance among physicians. It is proposed that automatic speech recognition may be a significant factor in the eventual acceptance of the technology by the medical profession. The current state-of-the-art of automatic speech recognition is briefly surveyed, and problems with the technology are discussed. A potential natural language interface with DIAG, an expert system for aiding in dermatologic diagnosis, is described. A system that has been developed for accepting input of body parts in freestyle format is presented as a prototype for a natural language interface with an automatic speech recognition device.

An informational approach to reaction times.

Simple reaction time is the minimum time required to respond to a signal such as a steady light or tone. Such a reaction time is taken to be the time required for transmission of a fixed quantity of information. delta H, from stimulus to subject. That is, information summation replaces energy summation. This information is calculated from consideration of the quantum nature of the stimulus. The theoretically derived equation for reaction time is fitted to experimental data. Piéron's empirical law for reaction time is obtained as an approximation from a proposed informational equation. The exponent in Piéron's law is found to be the same as the exponent in the power law of sensation. Threshold appears to be the smallest stimulus capable of transmitting the quantity of information delta H.

Calculation of metabolic fluxes with anatomically separated sources of tracer and tracee.

Traditional calculations of metabolic fluxes using isotope dilution are based on the assumption that tracer and tracee enter the distribution space through effectively identical ports. If the tracer infusion site is not identical with the site of endogenous release of the tracee, the traditional equations for calculating rate of appearance (Ra) of a metabolite may give rise to appreciable errors due to the presence of gradients in specific activity. When tracer and tracee enter by means of anatomically disparate sites, such as may be encountered in the study of metabolite (e.g., lactate, alanine, and glycerol) or free fatty acid turnover, one must employ a modification of the traditional specific activity. This modified specific activity is obtained as the ratio of tracer concentration "near" (in the same compartment as) the source of tracee to the concentration of tracee near the source of tracer infusion. This concept is employed to derive equations for calculating metabolic turnover in both steady- and non-steady-state conditions when entry sites of tracer and tracee are dissimilar.