In vivo effects of interleukin-11 and stem cell factor in combination with erythropoietin in the regulation of erythropoiesis

Summary. In this study we evaluated the in vivo effects of interleukin-11 (IL-11) and stem cell factor (SCF), in combination with erythropoietin (EPO) on murine erythropoiesis. Mice were treated for 7d with IL-11, SCF and EPO, each at three dose levels. In total, 27 different dose combinations were tested. IL-11 as well as SCF could only marginally stimulate erythroid progenitor cell numbers, but IL-11 in combination with SCF was able to increase BFU-E and CFU-E numbers 4-fold, in the absence of exogenous EPO. This resulted in an increased reticulocyte count. In contrast with the stimulatory effect on immature erythroid cell stages, IL-11 treatment induced a mild anaemia, which probably resulted from a plasma volume expansion. The additional treatment with EPO resulted in strong synergistic effects on CFU-E numbers. The combination of high-dose IL-11 and high-dose SCF was able to increase the overall efficiency of EPO-induced erythroid amplification, which was reflected by a left-shift of the in vivo EPO dose-response curve. The stimulating effects of IL-11 and SCF were further demonstrated when the effects on the reticulocyte count of a single high-dose EPO injection were assessed in normal and SCF + IL-11 treated mice. Whereas a single EPO dose increased the reticulocyte count by a factor of 3, IL-11 + SCF pretreatment increased this to a factor of 7. This study shows that in vivo SCF and IL-11 are important modulators of red blood cell production. First, these factors probably increase the input from the stem cell compartment into the erythroid lineage, where subsequently EPO is required for further amplification. Additionally, however, IL-11 and SCF increase the overall efficiency of EPO-induced amplification, probably due to a stimulatory effect on late-stage erythroid cells and to a redistribution of cells from marrow to spleen.     

Risk of Ventricular Arrhythmias in Survivors of Myocardial Infarction

The most recent studies have made it clear that the prognosis of asymptomatic post-MI patients has significantly improved in the last two decades. Holter monitoring as well as a low LyEF still is an important method for the risk stratification in the thrombolytic era of patients with post-MI. Patients with normal noninvasive tests do have a good prognosis. The electrophysiological stimulation seems to be the clinically most valuable single method to predict arrhythmic events. However, as an invasive procedure it is not suitable as a screening test for a large cohort. The stepwise risk stratification technique using first noninvasive followed by invasive procedures seem to be most suitable and effective for identifying asymptomatic infarct survivors which incidence of arrhythmic events is as high as the recurrence rate of patients who had been resuscitated from ventricular fibrillation. Consequently, prophylactic implantation of a defibrillator in asymptomatic MI patients, whose positive predictive value is around 30% becomes more and more interesting.