Summary. The aim of this study was to identify signal transduction pathways activated by erythropoietin (EpO) and erythropoietin co-stimulatory factors (kit ligand), insulin-like growth factor, thrombopoietin, interleukin 3 and granulocyte-macrophage colony-stimulating factor) in normal human bone marrow CD34 1 cells and d 11 erythroid burst forming unit derived glycophorin 1 cells. The activation of these signal transduction pathways was further correlated with various biological effects such as (i) cell proliferation, (ii) inhibition of apoptosis, (iii) activation of adhesion and (iv) secretion of the matrix metalloproteinases (MMPs) MMP-9 and MMP-2, and vascular endothelial growth factor (VEGF). We found that in human CD34 1 cells and erythroblasts erythropoietic factors may activate similar but different signalling pathways, and that activation of each of the JAK-STAT, MAPK p42/44 or PI-3K-AKT axes alone is not sufficient either to stimulate cell proliferation or inhibit apoptosis, suggesting that these processes are regulated by orchestrated activation of multiple signalling cascades. Accordingly, we found that although cell proliferation was more related to simultaneous activation of JAK-STAT and MAPK p42/44, the effect on cell survival correlated with activation of PI-3K-AKT, MAPK p42/44 and JAK-STAT proteins. We also demonstrated that differentiating normal human erythroid cells lose their adhesive properties and secrete angiopoietic factors such as MMP-9, MMP-2 and VEGF, and we postulate that this secretion by early erythroid cells may play a role in their maturation and egress from the haematopoietic niches of the bone marrow.

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SUMMARYBackground: The effects of a-and b-adrenergic agents on gall-bladder motility remain undefined. Aim: To determine the effects of a-and b-antagonists on gall-bladder motility in healthy humans. Methods: In this single, blind, three-way crossover study, a slow-release formulation of propranolol 80 mg (b-antagonist), indoramin 25 mg (post-synaptic a 1 -antagonist) and placebo were administered to 10 healthy volunteers on three separate days 8 h before the assessment of gall-bladder volumes by ultrasonography. Gall-bladder volumes were assessed in the fasting state and at 5-min intervals for 50 min after a standard proprietary enteral feed (Ensure 186 mL, Abbott).

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