Mechanism of action of angiostatic steroids: Suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis

Recently, a novel class of angiostatic steroids which block angiogenesis in several systems has been described. Since the elaboration of proteases is believed to be an important component of angiogenesis, we tested whether these steroids blocked the fibrinolytic response of endothelial cells to the angiogenic protein, basic fibroblast growth factor [bFGF]). Cultured bovine aortic endothelial (BAE) cells were incubated with bFGF and/or medroxyprogesterone acetate (MPA), an angio-static steroid which has been shown to inhibit vascularization, collagenolysis, and tumor growth. When bFGF (3 ng/ml) was added to confluent monolayers of BAE cells, plasminogen activator (PA) activity in the medium was increased threefold. In contrast, MPA at 10^?6 M, 10^?7 M, 10^?8 M, and 10^?9 M decreased PA levels in the medium by 83%, 83%, 75%, and 39%, respectively. The stimulation of PA levels in BAE cells by bFGF (3 ng/ml) was abrogated by the presence of 10^?6 M MPA. This decrease in PA activity was found to be mediated by a significant increase in plasminogen activator inhibitor type-1 (PAI-1) production. MPA, therefore, negated one of the important enzymatic activities associated with the angiogenic process. In contrast to the decreased levels of secreted PA in cultures exposed simultaneously to MPA and bFGF, cell-associated PA levels remained high, consistent with earlier observations indicating that PAI-1 does not inhibit cell-associated PA. Thus, angiostatic steroids may exert their inhibitory effects on angiogenesis by increasing the synthesis of PAI-1. This, in turn, inhibits PA activity and, therefore, plasmin generation, which is essential for the invasive aspect of angiogenesis. © 1993 Wiley-Liss, Inc.     

Distributions of Potential in Cylindrical Coordinates and Time Constants for a Membrane Cylinder

A mathematical problem relating to membrane cylinders is stated and solved; its implications are illustrated and discussed. The problem concerns the volume distribution, in cylindrical coordinates, of the electric potential inside and outside a membrane cylinder of finite length (with sealed ends), during passive decay of an initially nonuniform membrane potential. The time constants for equalization with respect to the angle, theta, are shown to be typically about ten thousand times smaller than the time constant, tau(m) = R(m)C(m), for uniform passive membrane potential decay. The time constants for equalization with respect to length are shown to agree with those from one-dimensional cable theory; typically, they are smaller than tau(m) by a factor between 2 and 10. The relation of the membrane current density, I(m)(theta, x, t), to the values (at the outer membrane surface) of the extracellular potential phi(e)(r, theta, x, t) and of partial differential(2)phi(e)/ partial differentialx(2), is examined and it is shown that these quantities are not proportional to each other, in general; however, under certain specified conditions, all three of these quantities are proportional with each other and with phi(i)(r, theta, x, t) and partial differential(2)phi(i)/ partial differentialx(2) (at the inner membrane surface). The relation of these results to those of one-dimensional cable theory is discussed.     

Prognosis in Early Adult Life of Coeliac Children Treated with a Gluten-free Diet

Long-term follow up of 57 young adults with coeliac disease diagnosed in childhood showed that 13 had relapsed clinically and had resumed a gluten-free diet Of the remainder, who were taking a normal diet and were apparently normal, 19 had low serum folate levels and 11 low serum iron levels. Pregnancy was found particularly likely to provoke an overt relapse.Only six patients were found to be stunted in height, while the menarche had occurred within the average range. The study also confirmed the very low present-daymortality rate of coeliac disease in childhood, which at the Hospital for Sick Children in London has been 0·4% between 1951 and 1968. In view of the finding that childhood coeliac disease usually persists, even though not causing symptoms, it is suggested that the use of a gluten-free diet should be lifelong.