Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line.

Growth of a human leukemic T-cell line (CEM C7) in 10(-6) M dexamethasone results in inhibition of growth and rapid loss of cell viability after a delay of approximately 18 to 24 hours. Analysis of dexamethasone-treated cells by flow-microfluorometry showed that they were arrested in the G1 phase of the cell cycle. Loss of cell viability began at the same time as G1 accumulation was first detectable, and 20% of all cells were found to be blocked in G1 at this time suggesting that loss of viability and G1 arrest were coincident events. Half-maximal and maximal effects on both viability and G1 arrest after 48 hours in steroid were nearly identical with respect to steroid concentration and corresponded to half-maximal and full occupancy of glucocorticoid specific receptor by hormone, consistent with a glucocorticoid receptor mediated mechanism for both phenomena. Most non-viable cells were arrested in G1, and accumulation of cells in G1 was irreversible; removal of steroid in the presence of colcemid did not result in a decreased fraction of G1 cells. Furthermore, dexamethasone treatment did not protect cells against the effects of 33258 Hoechst-amplified killing of bromodeoxyuridine substituted cells exposed to light. These results show that dexamethasone arrests these leukemic cells in G1 and strongly suggest that dexamethasone-treated cells are killed upon entry into G1.     

Enzymes of cyclic nucleotide degradation in eye tissues during experimental ocular herpes

Activity of phosphodiesterases disintegrating cAMP and cGMP in the cornea, sclera and ciliary body was investigated in health and in different stages of experimental herpetic keratitis. The problems concerning the role of the cyclase system in the pathogenesis of herpetic keratitis and the possibility of applying some of the drugs to the disease treatment are discussed.     

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.