Interactions: Dose effect relationships and isoeffect curves

Summary Interaction from several agents, i.e., a greater or smaller effects than expected from the sum of the individual effects can be of essentially two types: a) The agents could act in paralell on the same target, and a term depending on the doses of the agents involved would have to be added to the individual dose effect relationships (parergic interaction). b) The agents could act at different points in the chain of events leading to the observed effect, and the action of the second agent, the promotor, would be, at least in part, contingent on the action of the first inducer agent so that the dose effect relationships are linked in a multiplicative manner (metergic interaction). The dose effect surfaces for interaction depend on the type of dose effect relationship of the individual agents. Formulas are given for the general cases and are exemplified in graphs. Typical isobolic diagrams are also illustrated. These formulas may be adapted to experimental data by means of non-linear regression or maximum-likelihood analysis.     

Effect of heparin on the activation of the anticoagulation system by alpha-thrombin

Heparin-regulated alpha-thrombin ability to activate the response of the anticoagulation system has been studied by the perfusion of sinocarotid area of rabbits with DIP-alpha-thrombin-heparin complex. In a series of experiments the area was perfused with 1.8 micron DIP-alpha-thrombin and significant changes in anticoagulation parameters have been registered in systemic circulation. During perfusion of sinocarotid area by DIP-alpha-thrombin-heparin complex (2 microns) no activation of anticoagulation system was noted. DIP-alpha-thrombin-heparin perfusates contained no endogenic heparin, unlike DIP-alpha-thrombin perfusates. This confirms the absence of anticoagulation system response to DIP-alpha-thrombin. Control perfusion by heparin alone in equimolar concentrations revealed no changes in anticoagulation system. It is assumed that heparin, blocking cation subcentre of the recognition centre for high molecular compounds in the enzyme molecule, prevents the response of anticoagulation system, disturbing the enzyme ability to bind to specific receptors of the vascular walls.     

An alkaline shift induces the heat shock response in Escherichia coli.

Activation of heat shock response was observed after an alkaline shift of extracellular pH: it peaked at 5 to 10 min, as was previously reported for the heat-induced response, and was dependent on a functional rpoH gene, which is the positive regulator of the heat shock response. An induction of over sixfold was observed for dnaK and groE. The response was induced by the alkalization of extracellular pH but not by the alkalization of intracellular pH. An acidic shift of extracellular pH failed to activate the heat shock response, showing that the response is specific to the alkaline shift.     

Investigation of the lipid dependence of pyrophosphatase activity from rat liver microsomes and hepatoma by phospholipase C

The lipid dependence of pyrophosphatase activity was studied by treatment of liver and hepatoma microsomes with phospholipase C from Cl. perfringens and B. cereus and a subsequent incorporation of various classes of phospholipids into the delipidated microsomes. Phospholipase C hydrolysis sharply lowers the pyrophosphatase activity of liver and hepatoma microsomes. The enzyme activity is restored after introduction of phospholipids into delipidated liver microsomes, the maximal effect being achieved on incorporation of phosphatidylcholine. All the phospholipids tested exerted the same reactivation effects on the delipidated microsomes of hepatoma. However, a more complete delipidation of hepatoma microsomes by phospholipase C hydrolysis and a subsequent organic solvent extraction revealed a specific dependence of the enzyme activity on phosphatidylserine.     

Effect of dietary cis and trans fatty acids on serum lipoprotein[a] levels in humans.

Serum lipoprotein[a] (Lp[a]) is a strong risk factor for coronary heart disease. We therefore examined the effect of dietary fatty acid composition on serum Lp[a] levels in three strictly controlled experiments with healthy normocholesterolemic men and women. In Expt. I, 58 subjects consumed a control diet high in saturated fatty acids for 17 days. For the next 36 days, 6.5% of total energy intake from saturated fatty acids was replaced by monounsaturates plus polyunsaturates (monounsaturated fatty acid diet; n = 29) or by polyunsaturates alone (polyunsaturated fatty acid diet; n = 29). Both diets caused a slight, nonsignificant, increase in median Lp[a] levels, with no difference between diets. In Expt. II, 10% of energy from the cholesterol-raising saturated fatty acids (lauric, myristic, and palmitic acid) was replaced by oleic acid or by trans-monounsaturated fatty acids. Each of the 59 participants received each diet for 3 weeks in random order. The median level of Lp[a] was 26 mg/l on the saturated fatty acid diet; it increased to 32 mg/l (P less than 0.020) on the oleic acid diet and to 45 mg/l (P less than 0.001) on the trans-fatty acid diet. The difference in Lp[a] between the trans-fatty acid and the oleic acid diets was also highly significant (P less than 0.001). Expt. III involved 56 subjects; all received 8% of energy from stearic acid, from linoleic acid, or from trans-monounsaturates, for 3 weeks each. All other nutrients were equal.(ABSTRACT TRUNCATED AT 250 WORDS)     

An unsupervised neural network model for the development of reflex co-ordination

In this paper, we present a model for the development of connections between muscle afferents and motoneurones in the human spinal cord. The model consists of a limb with six muscles, one motoneurone pool, one pooled (Ia-like) afferent for each muscle and a central programme generator. The weights of the connections between the afferents and the motoneurone pools are adapted during centrally induced movements of the limb. The connections between the afferents and the motoneurone pools adapt in a hebbian way, using only local information present at the synapses. This neural network is tested in two examples of a limb with two degrees of freedom and six muscles. Despite the simplifications, the model predicts the pattern of autogenic and heterogenic monosynaptic reflexes quite realistically.     

Phospholipid oxidation catalyzed by cytochrome c in liposomes

Oxidation of liposome phospholipids has been studied in the presence of cytochrome c. Sonicated vesicles of soya bean or egg-yolk lipids, or purified phospholipid preparations, were treated with oxidized cytochrome c at a 10:4 lipid/protein ratio (w/w). Lipid peroxidation was examined by oxygen polarography, gas-liquid chromatography (GLC) and the thiobarbituric acid test. Oxidized, but not reduced, cytochrome effectively catalyzes lipid oxidation under these conditions. Oxygen consumption and disappearance of unsaturated fatty acids follow closely similar patterns, the O2 consumption rate showing a maximum (1.53 mol O2/min per mol heme) shortly before fatty acid loss reaches its peak. GLC and O2 consumption data suggest that monohydroperoxides are the most abundant oxidized species in the system. The thiobarbituric acid reaction, however, appears only to be of qualitative value in peroxidation studies. In order to test the mechanism through which oxidation occurs in our system, the effect of liposome composition and the presence of antioxidants was tested, both on cytochrome c binding to bilayers and on O2 consumption. Oxidized and reduced cytochrome c bind the lipid bilayers with similar affinity, but only the oxidized form is active in autoxidation. Antioxidants do not modify either cytochrome c binding to sonicated liposomes. Lipid composition does influence considerably cytochrome binding, and O2 consumption is correspondingly altered. Studies with various antioxidants and inhibitors suggest that both free radicals and singlet oxygen may be involved in the process under study.