Decision analysis and clinical judgment.
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Biomedical subjects
Publications and source records attributed to A Essig.
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Sodium transport and oxygen consumption were studied simultaneously in the short-circuited frog skin. Sodium transport was evaluated from I(o)/F, where I(o) is the short-circuit current measured with standard Ringer's solution bathing each surface and F is the Faraday constant. Oxygen tension was measured polarographically. Under a variety of circumstances the rate of oxygen consumption from the outer solution exceeded that from the inner solution, the ratio being constant (0.57 +/- 0.09 SD). Both I(o) and the associated rate of oxygen consumption J(ro) declined nonlinearly with time, but the relationship between them was linear, suggesting that the basal oxygen consumption was constant. For each skin numerous experimental points were fitted by the best straight line. The intercept (J(ro))(Io=0) then gave the basal oxygen consumption, and the slope dNa/dO(2) gave an apparent stoichiometric ratio for a given skin. The basal oxygen consumption was about one-half the total oxygen consumption in a representative untreated short-circuited skin. Values of dNa/dO(2) in 10 skins varied significantly, ranging from 7.1 to 30.9 (as compared with Zerahn's and Leaf and Renshaw's values of about 18). KCN abolished both I(o) and J(ro). 2,4-dinitrophenol (DNP) depressed I(o) while increasing J(ro) four- to fivefold. Anti-diuretic hormone stimulated and ouabain depressed both I(o) and J(ro); in both cases apparent stoichiometric ratios were preserved.
Studies were made of the dependence of the rate of oxygen consumption, J(r), on the electrical potential difference, Deltapsi, across the frog skin. After the abolition of sodium transport by ouabain the basal oxygen consumption was independent of Deltapsi. In fresh skins J(r) was a linear function of Deltapsi over a range of at least +/-70 mv. Treatment with aldosterone stimulated the short-circuit current, I(o), and the associated rate of oxygen consumption, J(ro), and increased their stability; linearity was then demonstrable over a range of +/-160 mv. Brief perturbations of Deltapsi (+/-30-200 mv) did not alter subsequent values of I(o). Perturbations for 10 min or more produced a "memory" effect both with and without aldosterone: accelerating sodium transport by negative clamping lowered the subsequent value of I(o); positive clamping induced the opposite effect. Changes in J(ro) were more readily detectable in the presence of aldosterone; these were in the same direction as the changes in I(o). The linearity of J(r) in Deltapsi indicates the validity of analysis in terms of linear nonequilibrium thermodynamics-brief perturbations of Deltapsi appear to produce no significant effect on either the phenomenological coefficients or the free energy of the metabolic driving reaction. Hence it is possible to evaluate this free energy.
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Oxidative phosphorylation is analyzed by means of nonequilibrium thermodynamics. It is shown that a mitochondrial system may be characterized in terms of the externally fixed affinities (negative free energies) for oxidation and phosphorylation A(o) (ex) and A(p) (ex), without knowledge of internal activities. If the electrochemical potential difference of H(+) is also fixed, a decision can be made between the chemiosmotic and chemical hypotheses. The chemiosmotic hypothesis is shown to be a limiting case of the chemical hypothesis. In general the P/O ratio cannot be expected to be constant, but will vary with A(p) (ex)/A(o) (ex); for certain ranges the variation may be marked.
Steady-state concentration gradients across cell membranes have often been attributed to the associated leakage of solute down its electrochemical potential gradient, and active transport at an equal rate in the opposite direction. Several workers have evaluated the minimal energetic requirements of such a "pump-leak" model for sodium in muscle tissue, presuming that influx occurs only via the leak pathway and to no extent by way of the active transport pathway. The high energy requirements so predicted have led to the suggestions that either (a) sodium is not actively transported, being at equilibrium distribution across the cell surface, or (b) substantial sodium movement must be by means of exchange diffusion. The present treatment, based on the consideration that the active transport mechanism is bidirectional, demonstrates that the rates of influx and efflux associated with a given rate of active transport are explicit functions of two parameters: (1) the ratio of the exchange resistance of the active pathway to that of the leak pathway, and (2) the electrochemical potential difference across the cell surface. Lacking precise values for these parameters, the demonstration of a high rate of isotope flux is not compelling evidence either against active transport or for a discrete exchange diffusion mechanism. Various concepts and criteria of exchange diffusion are discussed.
Discussions of active transport usually assume stoichiometry between the rate of transport J(+) and the metabolic rate J(r). However, the observation of a linear relationship between J(+) and J(r) does not imply a stoichiometric relationship, i.e., complete coupling. Since coupling may possibly be incomplete, we examine systems of an arbitrary degree of coupling q, regarding stoichiometry as a limiting case. We consider a sodium pump, with J(+) and J(r) linear functions of the electrochemical potential difference, -X(+), and the chemical affinity of the metabolic driving reaction, A. The affinity is well defined even for various complex reaction pathways. Incorporation of a series barrier and a parallel leak does not affect the linearity of the composite observable system. The affinity of some region of the metabolic chain may be maintained constant, either by large pools of reactants or by regulation. If so, this affinity can be evaluated by two independent methods. Sodium transport is conveniently characterized by the open-circuit potential (Deltapsi)(I=0) and the natural limits, level flow (J(+))(X+=0), and static head X(0) (+) = (X(+))(J+=0). With high degrees of coupling -X(0) (+)/F approaches the electromotive force E(Na) (Ussing); -X(0) (+)/F cannot be identified with ((RT/F) ln f)(X+=0), where f is the flux ratio. The efficiency eta = -J(+)X(+)/J(r)A is of significance only when appreciable energy is being converted from one form to another. When either J(+) or -X(+) is small eta is low; the significant parameters are then the efficacies epsilon(J+) = J(+)/J(r)A and epsilon(X+) = -X(+)/J(r)A, respectively maximal at level flow and static head. Leak increases both J(+) and epsilon(J+) for isotonic saline reabsorption, but diminishes -X(0) (+) and epsilon(Xfemale symbol). Electrical resistance reflects both passive parameters and metabolism. Various fundamental relations are preserved despite coupling of passive ion and water flows.
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Precise evaluation of permeability of biological tissues is often prevented by imprecise knowledge of operative forces. This problem has been approached by analysis of fluxes of isotopic species applied to opposite surfaces of a membrane. A simple and rather general flux ratio equation has been derived which may permit evaluation of membrane permeability, even without knowledge of forces, or of the nature of active transport processes. Permeability as thus defined should be insensitive to coupled flows, either of other species or of metabolism. In appropriate circumstances application of the equation may permit evaluation of the contributions of the various processes to the transport of the examined species. Composite series membranes would be expected to obey the unmodified general equation. Heterogeneous parallel pathways would alter the relation in a predictable manner. The effect of isotope interaction is specifically incorporated. The formulation is applied to consideration of energetics of active transport.
Asplenia may predispose to fulminant invasive infections caused by encapsulated bacteria. We observed a 13 months old child with (so far unknown) congenital familiar asplenia, who died from pneumococcal sepsis. General vaccination of all infants with pneumococcal conjugate vaccine may prevent this disease, which is associated with a high rate of mortality in infants with asplenia.