Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis

Plasminogen activator-inhibitor C-1 (PAI-1) plays a critical role in the regulation of fibrinolysis, serving as the primary inhibitor of tissue-type plasminogen activator. Elevated levels of PAI-1 are a risk factor for recurrent myocardial infarction, and locally increased PAI-1 expression has been described in atherosclerotic human arteries. Recent studies have shown that the administration of angiotensin converting enzyme inhibitors reduces the risk of recurrent myocardial infarction in selected patients. Since angiotensin II (Ang II) has been reported to induce PAI-1 production in cultured astrocytes, we have hypothesized that one mechanism that may contribute to the beneficial effect of angiotensin converting enzyme inhibitors is an effect on fibrinolytic balance. In the present study, we examined the interaction of Ang II with cultured bovine aortic endothelial cells (BAECs) and the effects of this peptide on the production of PAI-1. 125I-Ang II was found to bind to BAECs in a saturable and specific manner, with an apparent Kd of 1.4 nM and Bmax of 74 fmol per mg of protein. Exposure of BAECs to Ang II induced dose-dependent increases in PAI-1 antigen in the media and in PAI-1 mRNA levels. Induction of PAI-1 mRNA expression by Ang II was not inhibited by pretreating BAECs with either Dup 753 or [Sar1, Ile8]-Ang II, agents that are known to compete effectively for binding to the two major angiotensin receptor subtypes. These data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.     

Subarachnoid haemorrhage induced proliferation of leptomeningeal cells and deposition of extracellular matrices in the arachnoid granulations and subarachnoid space. Immunhistochemical study

Subarachnoid haemorrhage (SAH) often leads to subarachnoid fibrosis and resultant normal pressure hydrocephalus; however, how subarachnoid fibrosis occurs is unknown. We examined the changes within arachnoid granulations (AGs) and the subarachnoid space (SAS) chronologically at the parasagittal region obtained from patients with SAH at autopsy and made comparison with controls by immunostaining for cytokeratin, specific marker for leptomeningeal cells and by the elastica Masson-Goldner methods. Within a week some AGs were torn, and many inflammatory cells filled the AGs and SAS. Cytokeratin positive cells were scarce. During the next two weeks cytokeratin positive cells increased. After three weeks, AGs and SAS were filled by dense deposits of extracellular matrices surrounded by multiple layers of leptomeningeal cells.     

Enhancement mode InP MISFET's with sulfide passivation andphoto-CVD grown P3N5 gate insulators

High performance enhancement mode InP MISFET's have been successfully fabricated by using the sulfide passivation for lower interface states and with photo-CVD grown P₃N₅ film used as gate insulator. The MISFET's thus fabricated exhibited exhibited pinch-off behavior with essentially no hysteresis. Furthermore the device showed a superior stability of drain current. Specifically under the gate bias of 2 V for 10⁴ seconds the room temperature drain current was shown to reduce from the initial value merely by 2.9% at the drain voltage of 4 V. The effective electron mobility and extrinsic transconductance are found to be about 2300 cm ²/V·s and 2.7 mS/mm, respectively. The capacitance-voltage characteristics of the sulfide passivated InP MIS diodes show little hysteresis and the minimum density of interface trap states as low as 2.6×10¹⁴/cm² eV has been attained     

Hemocompatibility in hemodialysis and erythropoietin therapy

Two studies designed to investigate the effect of recombinant human erythropoietin (rHuEPO) treatment of anemia in chronic dialysis patients on hemocompatibility were conducted. Study 1, whose main aim was to establish whether treatment with rHuEPO enhances coagulation activation during dialysis, included 15 patients before rHuEPO therapy at a mean hematocrit (HCT) of 22.3% and then during therapy at a HCT of 29.3%. The plasma concentrations of the thrombin-antithrombin III complex were not higher during rHuEPO therapy than before it when performing hemodialysis with a Cuprophan membrane. No significant difference was demonstrated either in the values of activated clotting times (Hemochron), thrombocyte or white blood cell counts (Coulter S+II), or in plasma C5a concentrations (ELISA) established during dialysis sessions before and during rHuEPO therapy. In Study 2, which focused primarily on the question of whether or not rHuEPO therapy increases thrombocyte activation during hemodialysis, 8 patients on chronic dialysis were examined both before therapy at a mean HCT value of 22.1% and during rHuEPO therapy at a HCT of 31.5%, invariably during dialysis with either a Cuprophan or polyacrylonitrile (AN69HF) membrane. The plasma concentrations of beta-thromboglobulin (ELISA) did not differ between the examinations made during rHuEPO and before rHuEPO therapy; however, statistically significant differences were found between dialysis sessions involving Cuprophan and AN69HF membranes. No significant difference between examination before and during rHuEPO was demonstrated in activated clotting time nor thrombocyte and white blood cell counts in this study either. The authors conclude that rHuEPO therapy does not enhance coagulation activation during hemodialysis, does not have an effect on thrombocyte activation, and does not influence complement activation and changes in white blood cell counts.     

Percutaneous lumbar nucleotomy

The nature of the events whereby the reactive intermediates resulting from the bioactivation of bromobenzene and furosemide induce hepatotoxicity is unknown. To examine a role for disturbances in intracellular calcium homeostasis, secondary to a depletion in cellular reduced glutathione (GSH) and reduced protein thiols (PSHs), isolated mouse hepatocytes were exposed to cytotoxic concentrations of bromobenzene or furosemide. Cytosolic calcium concentration, as well as thiol status, was determined. The incubation of hepatocytes with 3.0 mM bromobenzene, and subsequent additions (1.2 mM) of the agent every hour, resulted in significant GSH depletion. The loss of plasma membrane integrity at 1.5 h preceded both a rise in the cytosolic Ca2+ concentration and depletion of total PSH content. Furosemide (1.0 mM) produced a 70% depletion in cellular GSH content in isolated hepatocytes. The initiation of cell damage occurred concurrently with both a rise in the cytosolic Ca2+ concentration and a depletion of total PSH content 4 h following furosemide addition. Since the increase in cytosolic Ca2+ did not precede cytotoxicity, these results do not support an initiating role for Ca2+ deregulation in bromobenzene and furosemide hepatotoxicities. In addition, depletion of PSH content did not correlate with bromobenzene- or furosemide-induced cytotoxicity.