General practice and the new science emerging from the theories of 'chaos' and complexity.
This paper outlines the general practice world view and introduces the main features of the theories of 'chaos' and complexity. From this, analogies are drawn between general practice and the theories, which suggest a different way of understanding general practice and point to future developments in general practice research. A conceptual and practical link between qualitative and quantitative methods of research is suggested. Methods of combining data about social context with data about individuals and about biomedical factors are discussed. The paper emphasizes the importance of data collected over time and of considering the multiplicative interactions between variables. Finally, the paper suggests that to develop this type of research, general practice many need to reassess systems of categorizing and recording appropriate data. (+info)
Inhibitory contributions to spatiotemporal receptive-field structure and direction selectivity in simple cells of cat area 17.
Intracortical inhibition contributes to direction selectivity in primary visual cortex, but how it acts has been unclear. We investigated this problem in simple cells of cat area 17 by taking advantage of the link between spatiotemporal (S-T) receptive-field structure and direction selectivity. Most cells in layer 4 have S-T-oriented receptive fields in which gradients of response timing across the field confer a preferred direction of motion. Linear summation of responses across the receptive field, followed by a static nonlinear amplification, has been shown previously to account for directional tuning in layer 4. We tested the hypotheses that inhibition acts by altering S-T structure or the static nonlinearity or both. Drifting and counterphasing sine wave gratings were used to measure direction selectivity and S-T structure, respectively, in 17 layer 4 simple cells before and during iontophoresis of bicuculline methiodide (BMI), a GABAA antagonist. S-T orientation was quantified from fits to response temporal phase versus stimulus spatial phase data. Bicuculline reduced direction selectivity and S-T orientation in nearly all cells, and reductions in the two measures were well correlated (r = 0.81) and reversible. Using conventional linear predictions based on response phase and amplitude, we found that BMI-induced changes in S-T structure also accounted well for absolute changes in the amplitude and phase of responses to gratings drifting in the preferred and nonpreferred direction. For each cell we also calculated an exponent used to estimate the static nonlinearity. Bicuculline reduced the exponent in most cells, but the changes were not correlated with reductions in direction selectivity. We conclude that GABAA-mediated inhibition influences directional tuning in layer 4 primarily by sculpting S-T receptive-field structure. The source of the inhibition is likely to be other simple cells with certain spatiotemporal relationships to their target. Despite reductions in the two measures, most receptive fields maintained some directional tuning and S-T orientation during BMI. This suggests that their excitatory inputs, arising from the lateral geniculate nucleus and within area 17, are sufficient to create some S-T orientation and that inhibition accentuates it. Finally, BMI also reduced direction selectivity in 8 of 10 simple cells tested in layer 6, but the reductions were not accompanied by systematic changes in S-T structure. This reflects the fact that S-T orientation, as revealed by our first-order measures of the receptive field, is weak there normally. Inhibition likely affects layer 6 cells via more complex, nonlinear interactions. (+info)
Estimation of Ki in a competitive enzyme-inhibition model: comparisons among three methods of data analysis.
There are a variety of methods available to calculate the inhibition constant (Ki) that characterizes substrate inhibition by a competitive inhibitor. Linearized versions of the Michaelis-Menten equation (e.g., Lineweaver-Burk, Dixon, etc.) are frequently used, but they often produce substantial errors in parameter estimation. This study was conducted to compare three methods of analysis for the estimation of Ki: simultaneous nonlinear regression (SNLR); nonsimultaneous, nonlinear regression, "KM,app" method; and the Dixon method. Metabolite formation rates were simulated for a competitive inhibition model with random error (corresponding to 10% coefficient of variation). These rates were generated for a control (i.e., no inhibitor) and five inhibitor concentrations with six substrate concentrations per inhibitor and control. The KM/Ki ratios ranged from less than 0.1 to greater than 600. A total of 3 data sets for each of three KM/Ki ratios were generated (i.e., 108 rates/data set per KM/Ki ratio). The mean inhibition and control data were fit simultaneously (SNLR method) using the full competitive enzyme-inhibition equation. In the KM,app method, the mean inhibition and control data were fit separately to the Michaelis-Menten equation. The SNLR approach was the most robust, fastest, and easiest to implement. The KM,app method gave good estimates of Ki but was more time consuming. Both methods gave good recoveries of KM and VMAX values. The Dixon method gave widely ranging and inaccurate estimates of Ki. For reliable estimation of Ki values, the SNLR method is preferred. (+info)
Chaos and the transition to ventricular fibrillation: a new approach to antiarrhythmic drug evaluation.
Sudden cardiac death resulting from ventricular fibrillation can be separated into 2 components: initiation of tachycardia and degeneration of tachycardia to fibrillation. Clinical drug studies such as CAST and SWORD demonstrated that focusing exclusively on the first component is inadequate as a therapeutic modality. The hope for developing effective pharmacological therapy rests on a comprehensive understanding of the second component, the transition from tachycardia to fibrillation. We summarize evidence that the transition from tachycardia to fibrillation is a transition to spatiotemporal chaos, with similarities to the quasiperiodic transition to chaos seen in fluid turbulence. In this scenario, chaos results from the interaction of multiple causally independent oscillatory motions. Simulations in 2-dimensional cardiac tissue suggest that the destabilizing oscillatory motions during spiral-wave reentry arise from restitution properties of action potential duration and conduction velocity. The process of spiral-wave breakup in simulated cardiac tissue predicts remarkably well the sequence by which tachycardia degenerates to fibrillation in real cardiac tissue. Modifying action potential duration and conduction velocity restitution characteristics can prevent spiral-wave breakup in simulated cardiac tissue, suggesting that drugs with similar effects in real cardiac tissue may have antifibrillatory efficacy (the Restitution Hypothesis). If valid for the real heart, the Restitution Hypothesis will support a new paradigm for antiarrhythmic drug classification, incorporating an antifibrillatory profile based on effects on cardiac restitution and the traditional antitachycardia profile (classes 1 through 4). (+info)
In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand.
Reported are the in vitro susceptibilities of Plasmodium falciparum to artesunate, mefloquine, quinine and chloroquine of 86 isolates and to dihydroartemisinin of 45 isolates collected from areas of high resistance to mefloquine within Thailand near the borders with Myanmar and Cambodia, and from southern Thailand where P. falciparum is generally still sensitive to mefloquine. All the isolates were highly sensitive to artesunate, but the geometric mean IC50S were higher in isolates from the Thai-Myanmar and Thai-Cambodian borders than in those from southern Thailand. The IC50S for mefloquine and artesunate were strongly correlated (Pearson r = 0.605; n = 86; P < 0.00001). As expected, the in vitro sensitivities to dihydroartemisinin and artesunate were similar and strongly correlated (at IC50, Pearson r = 0.695; n = 45; P < 0.00002). The correlation between the activity of mefloquine and artesunate requires further investigation in order to determine the potential for development of cross-resistance in nature. Our results suggest that combination with mefloquine is not the ideal way of protecting the usefulness of artemisinin and its derivatives. A search for more suitable partner drugs to these compounds and careful regulation of their use are necessary in the interest of ensuring their long therapeutic life span. (+info)
The relation between body size and normalized small solute clearances in continuous ambulatory peritoneal dialysis.
The normalized peritoneal clearances of small solutes depend on the ratio of their concentration in dialysate and plasma (D/P) and the drain volume (Dv) corrected for some measure of body size such as body water (V) or body surface area (BSA). The clearance formulas (D/P) x (Dv/V) and (D/ P) x (Dv/BSA) can be used to examine why large individuals tend to be underdialyzed. Large people have low normalized drain volumes (Dv/V, Dv/BSA). It is not known whether size affects the D/P ratios. The purpose of this study was to examine the relationship between normalized peritoneal clearances (Kt/Vurea, CCr per 1.73 m2 BSA) and four size indicators (weight, height, V, BSA) in 301 patients on continuous ambulatory peritoneal dialysis (four daily exchanges with 2-L exchange volume) who underwent 613 clearance studies. Highly significant (P < 0.001) nonlinear relationships were found between Kt/Vurea and weight (r2 = 0.371), height (r2 = 0.289), BSA (r2 = 0.436), and V (r2 = 0.527); and between CCr and weight (r2 = 0.178), height (r2 = 0.115), BSA (r2 = 0.199), and V (r2 = 0.151). There were also significant negative correlations between the normalized drain volumes (Dv/V and Dv/BSA) and all four indicators of body size. Raw (not normalized) peritoneal clearances and drain volumes correlated positively with size. However, D/P(urea) or D/P(creatinine) did not vary with any size indicator except for a weak association between D/P(creatinine) and V (r = 0.089, P = 0.028). This association was not confirmed when V was used to stratify subjects into quartiles, and group differences for D/P(creatinine were tested by one-way ANOVA. This study shows that the exclusive cause of the low normalized peritoneal clearances in large subjects on continuous ambulatory peritoneal dialysis is a low normalized drain volume. No evidence was found to indicate that body size influences the D/P ratio of small solutes. The portion of the variance in normalized clearance explained by size varies by size indicator and solute (urea versus creatinine). (+info)
Even slight movements disturb analysis of cardiovascular dynamics.
We hypothesized that spontaneous movements (postural adjustments and ideomotion) disturb analysis of heart rate and blood pressure variability and could explain the discrepancy between studies. We measured R-R intervals and systolic blood pressure in nine healthy sitting subjects during three protocols: 1) no movement allowed, 2) movements allowed but not standing, 3) movements and standing allowed. Heart rate and blood pressure were not altered by movements. Movements with or without standing produced a twofold or greater increase of the overall variability of R-R intervals and of the low-frequency components of spectral analysis of heart rate variability. The spectral exponent beta of heart rate variability (1. 123 at rest) was changed by movements (1.364), and the percentage of fractal noise (79% at rest) was increased by standing (91%, coarse-graining spectral analysis). Spontaneous movements could induce a plateau in the correlation dimensions of heart rate variability, but they changed its nonlinear predictability. We suggest that future studies on short-term cardiovascular variability should control spontaneous movements. (+info)
Nonlinear, fractal, and spectral analysis of the EEG of lizard, Gallotia galloti.
Electroencephalogram (EEG) from dorsal cortex of lizard Gallotia galloti was analyzed at different temperatures to test the presence of fractal or nonlinear structure during open (OE) and closed eyes (CE), with the aim of comparing these results with those reported for human slow-wave sleep (SWS). Two nonlinear parameters characterizing EEG complexity [correlation dimension (D2)] and predictability [largest Lyapunov exponent (lambda(1))] were calculated, and EEG spectrum and fractal exponent beta were determined via coarse graining spectral analysis. At 25 degrees C, evidence of nonlinear structure was obtained by the surrogate data test, with EEG phase space structure suggesting the presence of deterministic chaos (D2 approximately 6, lambda(1) approximately 1. 5). Both nonlinear parameters were greater in OE than in CE and for the right hemisphere in both situations. At 35 degrees C the evidence of nonlinearity was not conclusive and differences between states disappeared, whereas interhemispheric differences remained for lambda(1). Harmonic power always increased with temperature within the band 8-30 Hz, but only with OE within the band 0.3-7.5 Hz. Qualitative similarities found between lizard and human SWS EEG support the hypothesis that reptilian waking could evolve into mammalian SWS. (+info)