Inhibition of interleukin-2-stimulated enhancement of human natural killer (NK) cell activity by carbaryl, an anticholinesterase insecticide.

The potency of the anticholinesterase (antiCHE) insecticides as serine hydrolase inhibitors, and evidence for serine hydrolase activity in interleukin-2 (IL2) signalling suggest that the natural killer (NK) cell may be a target for dysregulation by antiCHE insecticides. NK cells are large granular lymphocytes (LGL) that respond to IL2 by proliferating and increasing their cytolytic efficiency. In the present study, we assessed the effects of carbaryl (CA, an antiCHE insecticide) and alpha-naphthol (NA, the major metabolite of CA) on both target cell killing per se and IL2 enhancement of target cell killing by human NK cells. Human LGL, collected from the peripheral blood of normal donors, were cultured for 4 days with human recombinant IL2 (HRIL2), then assayed by a 51Chromium (51Cr) release assay for lytic activity against human K562 cells. When added at the beginning of the culture period, CA inhibited enhancement of cytolytic efficiency in a concentration-dependent manner; at concentrations (0.5 and 5.0 microM) compatible with no cholinergic toxicity. Reduction of the effector/target cell (E/T) ratio in the 51Cr release assay markedly enhanced the observed inhibition by CA. In one experiment, inhibition increased from 6% to 20%, 17% to 35%, and 53% to 73% at 0.5, 5.0, and 50 microM CA, respectively, when E/T was reduced from 10:1 to 2.5:1. This result is consistent with reduced cytolytic efficiency of individual NK cells exposed to CA. NA had no effect at 0.5 or 5.0 microM but caused some inhibition at 50 microM. Neither CA nor NA produced LGL death. When CA or NA was added directly to the 51Cr release assay, inhibition was not observed. The mechanism of inhibition of IL2-stimulated enhancement of target cell killing is not yet known, however, the results are consistent with impairment of IL2 signalling, by CA.     

Percutaneous balloon valvotomy for the treatment of isolated tricuspid stenosis

A 46-year-old woman with isolated tricuspid stenosis complained of increasing fatigue and dyspnea on exertion. Exercise Doppler echocardiography reproduced her symptoms and revealed a marked increase in trans-tricuspid gradient. Successful percutaneous balloon tricuspid valvotomy was performed, with resolution of her symptoms.     

Metabolic consequences of physical inactivity.

Physical inactivity is associated with alteration of normal physiologic processes leading to muscle atrophy, reduced exercise capacity, insulin resistance, and altered energy balance. Bed rest studies in human beings using stable isotopes of amino acids indicate that muscle unloading decreases the turnover rates of muscle and whole-body proteins, with a prevailing inhibition of protein synthesis. In the fasting state, muscle and whole-body nitrogen loss was not accelerated during bed rest. In experimental postprandial states, the amino acid-mediated stimulation of protein synthesis was impaired, whereas the ability of combined insulin and glucose infusion to decrease whole-body proteolysis was not affected by muscle inactivity. Thus, an impaired ability of protein/amino acid feeding to stimulate body protein synthesis is the major catabolic mechanism for the effect of bed rest on protein metabolism. This suggests that a protein intake level greater than normal could be required to achieve the same postprandial anabolic effect during muscle inactivity. Metabolic adaptation to muscle inactivity also involves development of resistance to the glucoregulatory action of insulin, decreased energy requirements, and increased insulin and leptin secretion. These alterations may lead to the development of the metabolic syndrome that is defined as the association of hyperinsulinemia, dyslipidemia, hypertension, hyperglycemia, and abdominal obesity. This cluster of metabolic abnormalities is a risk factor for coronary artery disease and stroke. Evidence indicates that exercise training programs may counteract all of these abnormalities both in healthy sedentary subjects and in patients affected by a variety of chronic disease states.     

Eosinophil migration in response to three molecular species of platelet activating factor

Multiple molecular species of the eosinophil chemoattractant platelet activating factor (PAF) are produced as a result of inflammatory processes. We therefore compared the ability of three naturally occurring PAF species (C160, C180, and C181), which only varied at carbon 1, to induce eosinophil chemotaxis through naked 3-m pore polycarbonate filters. Timecourse experiments indicated that all species of PAF tested induced significant and equivalent eosinophil migration at 1 h which peaked at 2 h. Overall, the rank order of chemotactic potency for the PAF species was relatively equivalent. The specific PAF antagonist WEB 2086 inhibited eosinophil migration induced by all three PAF species equally. We conclude that the degree of PAF-induced eosinophil migration is not dependent upon the molecular species of PAF.accepted by G. W. CarterThis work was supported in part by a Veterans Administration Merit Review Award.