Exercise rapidly increases eukaryotic elongation factor 2 phosphorylation in skeletal muscle of men

Protein synthesis in skeletal muscle is known to decrease during contractions but the underlying regulatory mechanisms are unknown. Here, the effect of exercise on skeletal muscle eukaryotic elongation factor 2 (eEF2) phosphorylation, a key component in protein translation machinery, was examined. Eight healthy men exercised on a cycle ergometer at a workload eliciting ∼67% peak pulmonary oxygen consumption     with skeletal muscle biopsies taken from the vastus lateralis muscle at rest as well as after 1, 10, 30, 60 and 90 min of exercise. In response to exercise, there was a rapid (i.e. < 1 min) 5- to 7-fold increase in eEF2 phosphorylation at Thr56 that was sustained for 90 min of continuous exercise. The in vitro activity of skeletal muscle eEF2 kinase was not altered by exercise indicating that the increased activity of eEF2 kinase to eEF2 is not mediated by covalent mechanisms. In support of this, the increase in AMPK activity was temporally unrelated to eEF2 phosphorylation. However, skeletal muscle eEF2 kinase was potently activated by Ca²⁺–calmodulin in vitro , suggesting that the higher eEF2 phosphorylation in working skeletal muscle is mediated by allosteric activation of eEF2 kinase by Ca²⁺ signalling via calmodulin. Given that eEF2 phosphorylation inhibits eEF2 activity and mRNA translation, these findings suggest that the inhibition of protein synthesis in contracting skeletal muscle is due to the Ca²⁺-induced stimulation of eEF2 kinase.     

Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees

Several psychophysiological abnormalities associated with schizophrenia have been proposed as genetic trait markers of vulnerability to the disorder. Smooth pursuit eye tracking dysfunction and abnormal long latency event-related potentials are the most promising candidates. Both are independent of the effects of psychotropic medication or mental state at the time of testing, and twin studies demonstrate that each has a high level of heritability. Having recorded smooth pursuit eye tracking and event-related potentials in 20 high-density schizophrenic families, we find abnormalities in one or both measures in most of the families studied. The abnormalities, when present, occur in the family members with schizophrenia and other forms of functional psychosis, and they have a bimodal distribution with approximately half the nonschizophrenic relatives also showing eye tracking dysfunction and/or abnormal event-related potentials. Some of these relatives had psychiatric symptoms; others were normal. Our results suggest that psychophysiological examination can help to clarify the boundaries of schizophrenia spectrum disorder. By helping to decide the phenotypic status of nonschizophrenic family members, this should increase the power of DNA linkage studies.     

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography

Objective: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. Methods: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined␣with positron emission tomography (PET) with [¹¹C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. Results: PET showed a high degree of binding of [¹¹C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. Conclusion: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals. Received: 21 August 1996 / Accepted in revised form: 22 November 1996     

Dual mechanisms of regulation of type I iodothyronine 5''-deiodinase in the rat kidney, liver, and thyroid gland. Implications for the treatment of hyperthyroidism with radiographic contrast agents.

Alterations in thyroid hormone status and the administration of radiographic contrast agents can markedly influence iodothyronine metabolism and, in particular, the activity of type I 5'-deiodinase (5'DI). In the present studies, the mechanisms responsible for these effects have been reassessed. As previously reported, the addition of iopanoic acid (IOP) to broken cell preparations resulted in a competitive pattern of 5'DI inhibition. However, the in vivo administration to rats of IOP or 3,3',5'-triiodothyronine (rT3) resulted in a noncompetitive pattern of inhibition of 5'DI in the liver, kidney, and thyroid gland, whereby marked decreases in maximal enzyme velocity (V max) were noted, with no change in the value of the Michaelis-Menten constant. In rats rendered hyperthyroid by the injection of 3,5,3'-triiodothyronine (T3), 5'DI activity was significantly increased in the liver and the kidney. The administration of IOP to these thyrotoxic animals resulted in a rapid loss of enzyme activity characterized by an approximate 80% decrease in 5'DI V max values in both tissues. Furthermore, this inhibitory effect persisted for longer than 60 h after a single IOP injection. IOP administration also decreased 5'DI V max levels in the thyroid gland by 52%. In other experiments, treatment of intact Reuber FAO hepatoma cells with IOP or rT3 induced a rapid decrease in 5'DI V max levels. In cells treated with cycloheximide, these agents enhanced the rate of disappearance of enzyme activity by greater than 12-fold, indicating a predominant effect on accelerating the rate of enzyme inactivation and/or degradation. These studies demonstrate that iodothyronines and other iodinated compounds have complex regulatory effects on 5'DI that entail alterations in the rates of both enzyme activation and inactivation. The previously accepted concept that rT3 and IOP impair thyroxine (T4) to T3 conversion in vivo by acting as competitive inhibitors is an oversimplification. Rather, the clinically beneficial effects of administering these agents to patients with hyperthyroidism may result primarily from the rapid and prolonged inactivation of 5'DI which occurs in the thyroid gland and peripheral tissues.     

Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability. Received: 29 November 1996 Received after revision: 10 April 1997 Accepted: 15 May 1997     

Das Zytokinnetzwerk

Cytokines are extracellular mediators which co-ordinate the immune system and which are essential for several differentiation processes e.g.hematopoiesis.Cytokines bind to specific receptors on the surface of target cells thereby initiating an intracellular signalling cascade leading to cytokine- and cell-specific reactions.The cytokine network is characterised by diverse regulation mechanisms and by the close interaction of different cytokine systems.Interaction and regulation takes place at the level of cytokines, its receptors and at the level of intracellular signal transduction molecules.The resulting network allows the co-ordinated response of different cell types and tissues to environmental changes.A detailed knowledge of this “language of the immunsystem” may reveal many new therapeutical strategies for the treatment of inflammation, autoimmune disease or neoplasia.     

A cohort study of tobacco use,diet, occupation,and lung cancer mortality

In 1966, a cohort of White males aged 35 or over, who were policy-holders with the Lutheran Brotherhood Insurance Society (United States), completed a mail questionnaire on tobacco use, diet, and demographic characteristics. During the 20 years of follow-up, 219 lung cancer deaths occurred. Besides the strong relationship with cigarette smoking, we observed an effect on lung cancer risk among current users of cigars or pipes who were nonsmokers of cigarettes (relative risk [RR]=3.5, 95 percent confidence interval[CI]=1.0–12.6) or who were past/occasional users of cigarettes (RR=2.7, CI=1.4–5.3). In addition, elevated risks (from 1.5 to 2.6) of lung cancer were found among craftsmen and laborers, with the highest risks among subjects who worked in the mining or manufacturing industry. No association between current (as of 1966) use of beer or hard liquor and lung cancer was observed, although past users were at elevated risk. An inverse association between lung cancer and intake of fruits was observed, and risks of lung cancer were lower among persons in the highest dietary intake quintiles of vitamins A and C. Except for oranges, however, none of the inverse associations with fruits or dietary nutrients had statistically significant trends. The findings from this cohort study add to the evidence of an adverse effect of cigar/pipe smoking and possibly protective effect of dietary factors on lung cancer risk.