Prokinetic effect of indoramin, an alpha-adrenergic antagonist, on human gall-bladder.

BACKGROUND: The effects of alpha- and beta-adrenergic agents on gall-bladder motility remain undefined. AIM: To determine the effects of alpha- and beta-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 (beta-antagonist), indoramin 25 mg (post-synaptic alpha1-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). RESULTS: The fasting gall-bladder volumes of subjects who received placebo or indoramin were significantly different (mean +/- S.E.M.: 16.50 +/- 2.78 mL and 13.47 +/- 2.24 mL, respectively; P < 0.001, two-way analysis of variance). The fasting gall-bladder volume after the administration of propranolol was 17.49 +/- 2.37 mL and was not significantly different from placebo (16.50 +/- 2.78 mL). When the mean post-prandial gall-bladder volumes were compared, indoramin significantly enhanced post-prandial gall-bladder emptying compared to placebo (P < 0.001). There was no significant post-prandial volume difference between placebo and propranolol. CONCLUSIONS: Indoramin, an alpha-adrenergic antagonist, acts as a prokinetic agent, enhancing post-prandial gall-bladder emptying in healthy individuals.

Biological significance of MAPK, AKT and JAK-STAT protein activation by various erythropoietic factors in normal human early erythroid cells.

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(+) cells and d 11 erythroid burst forming unit derived glycophorin+ 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(+) 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.

Biomarkers of carcinogenesis in humans exposed to polycyclic aromatic hydrocarbons.

The frequencies of micronuclei (MN) in cytokinesis-blocked lymphocytes of 91 steel foundry workers were analysed. On the basis of ambient PAH levels at the work stands and 1-hydroxypyrene concentrations in the urine, the coke-oven workers were the most exposed as compared to the rollers reference group. The difference in results for the two groups studied was not statistically significant, although MN were slightly higher for coke-oven workers. The frequency of MN did not increase with exposure: after some increase in 1-10 years, a decreasing tendency was observed.