Kinetic laws, phase-phase expansions, renormalization group, and INR calibration.

We introduce systematic approaches to chemical kinetics based on the use of phase-phase (log-log) representations of the rate equations. For slow processes, we obtain a corrected form of the mass-action law, where the concentrations are replaced by kinetic activities. For fast reactions, delay expressions are derived. The phase-phase expansion is, in general, applicable to kinetic and transport processes. A mechanism is introduced for the occurrence of a generalized mass-action law as a result of self-similar recycling. We show that our self-similar recycling model applied to prothrombin assays reproduces the empirical equations for the International Normalized Ratio calibration (INR), as well as the Watala, Golanski, and Kardas relation (WGK) for the dependence of the INR on the concentrations of coagulation factors. Conversely, the experimental calibration equation for the INR, combined with the experimental WGK relation, without the use of theoretical models, leads to a generalized mass-action type kinetic law.

Canalization effect in the coagulation cascade and the interindividual variability of oral anticoagulant response. A simulation study.

BACKGROUND: Increasing the predictability and reducing the rate of side effects of oral anticoagulant treatment (OAT) requires further clarification of the cause of about 50% of the interindividual variability of OAT response that is currently unaccounted for. We explore numerically the hypothesis that the effect of the interindividual expression variability of coagulation proteins, which does not usually result in a variability of the coagulation times in untreated subjects, is unmasked by OAT. RESULTS: We developed a stochastic variant of the Hockin-Mann model of the tissue factor coagulation pathway, using literature data for the variability of coagulation protein levels in the blood of normal subjects. We simulated in vitro coagulation and estimated the Prothrombin Time and the INR across a model population. In a model of untreated subjects a "canalization effect" can be observed in that a coefficient of variation of up to 33% of each protein level results in a simulated INR of 1 with a clinically irrelevant dispersion of 0.12. When the mean and the standard deviation of vitamin-K dependent protein levels were reduced by 80%, corresponding to the usual Warfarin treatment intensity, the simulated INR was 2.98 ± 0.48, a clinically relevant dispersion, corresponding to a reduction of the canalization effect.Then we combined the Hockin-Mann stochastic model with our previously published model of population response to Warfarin, that takes into account the genetical and the phenotypical variability of Warfarin pharmacokinetics and pharmacodynamics. We used the combined model to evaluate the coagulation protein variability effect on the variability of the Warfarin dose required to reach an INR target of 2.5. The dose variance when removing the coagulation protein variability was 30% lower. The dose was mostly related to the pretreatment levels of factors VII, X, and the tissue factor pathway inhibitor (TFPI). CONCLUSIONS: It may be worth exploring in experimental studies whether the pretreatment levels of coagulation proteins, in particular VII, X and TFPI, are predictors of the individual warfarin dose, even though, maybe due to a canalization-type effect, their effect on the INR variance in untreated subjects appears low.

Clinical use of body surface potential mapping in cardiac arrhythmias.

The electrocardiology and specifically body surface potential maps (BSPM) have two main objectives in the arrhythmologic field: 1) identification of signs of susceptibility to arrhythmias, and 2) identification of site of origin of the arrhythmias. In order to detect the susceptibility to ventricular arrhythmias, maps were recorded with different lead systems by different authors and, in particular, various methods of analysis of BSPM have been used to study repolarization potentials: QRST integral maps, eigenvector analysis, principal component analysis, autocorrelation analysis. From these analyses several markers of vulnerability to arrhythmias were identified, which demonstrated a predictive accuracy of various degree in selected patient populations. As concerns the identification of site of origin of the arrhythmias, the use of 62 leads BSPMs during endocardial pace mapping technique enabled more precise identification of the site of origin of postinfarction ventricular tachycardia episodes, compared with the use of the 12-lead electrocardiography (ECG). Recently a new electrocardiographic modality (ECG-imaging) enabled to compute non-invasively and with high resolution epicardial potential distribution and epicardial activation sequences from potentials recorded on the body surface together with cardiac computed tomography images. The ECG-imaging has been successfully applied in humans using geometrical information from computed tomography of each subject, in different heart conditions: normal heart, heart with a conduction disorder, focal activation initiated by right or left ventricular pacing, focal ventricular tachycardia and atrial flutter.

Proposed principles of maximum local entropy production.

Articles have appeared that rely on the application of some form of "maximum local entropy production principle" (MEPP). This is usually an optimization principle that is supposed to compensate for the lack of structural information and measurements about complex systems, even systems as complex and as little characterized as the whole biosphere or the atmosphere of the Earth or even of less known bodies in the solar system. We select a number of claims from a few well-known papers that advocate this principle and we show that they are in error with the help of simple examples of well-known chemical and physical systems. These erroneous interpretations can be attributed to ignoring well-established and verified theoretical results such as (1) entropy does not necessarily increase in nonisolated systems, such as "local" subsystems; (2) macroscopic systems, as described by classical physics, are in general intrinsically deterministic-there are no "choices" in their evolution to be selected by using supplementary principles; (3) macroscopic deterministic systems are predictable to the extent to which their state and structure is sufficiently well-known; usually they are not sufficiently known, and probabilistic methods need to be employed for their prediction; and (4) there is no causal relationship between the thermodynamic constraints and the kinetics of reaction systems. In conclusion, any predictions based on MEPP-like principles should not be considered scientifically founded.

The effect of intrathoracic heart position on electrocardiogram autocorrelation maps.

We studied the influence of the heart position in the thorax on the autocorrelation (AC) maps consisting of correlation coefficients between each pair of instantaneous electrocardiogram potential distributions over a time interval. We used a thorax-shaped electrolytic-filled tank with an isolated and perfused dog heart placed at positions spanning 5 cm on each space direction. The correlation coefficient between QRST AC maps was in the range of 0.92 to 0.99, whereas the correlation coefficient between the corresponding QRST integral maps was in the range of 0.55 to 0.87, proving that AC maps are less influenced by the heart position than integral maps. Thus, diagnostic indexes computed from the AC maps can be expected to be more specific to phenomena taking place in the myocardium than to criteria based directly on electrocardiogram amplitudes in various leads.