Role of plasminogen activator inhibitor-1 in promoting fibrin deposition in rabbits infused with ancrod or thrombin

The role of defective fibrinolysis caused by elevated activity of plasminogen activator inhibitor-1 (PAI-1) in promoting fibrin deposition in vivo has not been well established. The present study compared the efficacy of thrombin or ancrod, a venom-derived enzyme that clots fibrinogen, to induce fibrin formation in rabbits with elevated PAI-1 levels. One set of male New Zealand rabbits received intravenous endotoxin to increase endogenous PAI-1 activity followed by a 1-hour infusion of ancrod or thrombin; another set of normal rabbits received intravenous human recombinant PAI-1 (rPAI-1) during an infusion of ancrod or thrombin. Thirty minutes after the end of the infusion, renal fibrin deposition was assessed by histopathology. Animals receiving endotoxin, rPAI-1, ancrod, or thrombin alone did not develop renal thrombi. All endotoxin-treated rabbits developed fibrin deposition when infused with ancrod (n = 4) or thrombin (n = 6). Fibrin deposition occurred in 7 of 7 rabbits receiving both rPAI-1 and ancrod and in only 1 of 6 receiving rPAI-1 and thrombin (P < .01). In vitro, thrombin but not ancrod was inactivated by normal rabbit plasma and by purified antithrombin III or thrombomodulin. The data indicate that elevated levels of PAI-1 promote fibrin deposition in rabbits infused with ancrod but not with thrombin. In endotoxin-treated rabbits, fibrin deposition that occurs with thrombin infusion may be caused by decreased inhibition of procoagulant activity and not increased PAI-1 activity.     

Identification of T lymphocytes in human mixed hemopoietic colonies

The addition of a T-cell growth-promoting medium (PHA-TCM) to culture conditions that support growth of multi-lineage hemopoietic colonies enhances the proliferation of cells with lymphoid morphology within these colonies. These cells were identified as T lymphocytes by their ability to form rosettes with SRBC and their reaction with monoclonal antibodies (OKT3, OKT4) directed against T-cell-specific surface components. They continue to proliferate extensively under the influence of PHA-TCM after transfer of mixed colonies into liquid suspension culture. Supportive evidence for a common progenitor of myeloid and lymphoid cells within single mixed colonies is provided by Y-chromatin body analysis of E-rosette positive and negative cells in colonies grown in cocultures of male and female bone marrow cells.     

Reversal of granulocyte adherence to nylon fibers using local anesthetic agents: possible application to filtration leukapheresis

The effects of the cationic anesthetic agents tetracaine and lidocaine on granulocyte function, morphology, and adherence to nylon fibers were studied in an attempt to improve current methods of granulocyte collection by filtration leukapheresis (FL). When dissolved in acid- citrate-dextrose (ACD) plasma, these drugs significantly increased granulocyte elution from the fibers in a dose-related fashion. Granulocytes exposed to tetracaine and lidocaine remained more than 95% viable, retained normal bactericidal capacity after the drugs were washed from the cells, and had preserved membrane integrity, as evidenced by the normal ultrastructural appearance of tetracaine- exposed cells and an absence of leakage of lysozyme or lactic dehydrogenase. Granulocytes eluted with the anesthetic agents were rounded in shape with a reduction in the number of filopodial cytoplasmic projections and a relative absence of cytoplasmic vacuolization when compared to granulocytes eluted with ACD plasma alone. Dose-related inhibition of phagocytosis and adherence, which was largely reversible after washing the granulocytes, was noted. Greater than 95% of the lidocaine could be removed from the eluate with a single centrifugation and resuspension, indicating that granulocytes prepared by FL with anesthetic-enhanced elution could be potentially transfusable.     

Acute hemodynamic and electrophysiologic effects and safety of high-dose intravenous diltiazem in patients receiving metoprolol.

The anti-ischemic efficacy of diltiazem may improve with increments in dosage and with additional beta-blocking therapy. However, the combined administration could lead to adverse effects through amplification of negative inotropic and chronotropic properties. To evaluate hemodynamic tolerability and safety of high-dose intravenous diltiazem in patients with coronary artery disease receiving long-term metoprolol treatment, 9 such patients were studied for 30 minutes after onset of intravenous diltiazem administration (0.5 mg/kg for 5 minutes, followed by 15 mg/hour). Diltiazem plasma levels peaked at 5 minutes (641 +/- 74 micrograms/liter), decreasing to 177 micrograms/liter at 30 minutes. Average metoprolol levels (43 +/- 12 micrograms/liter) did not change. Diltiazem immediately decreased systemic vascular resistance, left ventricular systolic and mean aortic pressures (29, 21 and 20%, respectively, at 5 minutes), and they remained significantly reduced at 30 minutes. Heart rate initially increased by 11% during the bolus infusion (p < 0.05). Concomitantly, contractility indexes Vmax and Vce40, measured at fixed heart rates, also increased significantly by 11%. Both heart rate and contractility indexes returned to baseline levels thereafter. Cardiac output increased by 10% (p = not significant), stroke index remained unchanged, but stroke work decreased significantly by 20%. Also, the tension-time index was significantly reduced (23%). Diltiazem induced moderate negative lusitropic effects, the first derivative of negative left ventricular pressure decline decreased by 12% and Tau 2 lengthened by 13%. Concomitantly, left ventricular filling pressure increased from 19 +/- 2 to 23 +/- 3 mm Hg, but only at 5 and 15 minutes. PQ, QRS and QTc intervals were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low vitamin B6 status in patients with acute myocardial infarction

The vitamin B6 status of 84 patients with acute myocardial infarction was compared with that of 84 control subjects. Pyridoxal and pyridoxal 5'-phosphate (PLP) in plasma and erythrocytes, as well as the basal and total potential activity of the PLP-dependent enzyme aspartate aminotransferase in erythrocytes, were measured for a comprehensive assessment of vitamin B6 status. The mean levels of all vitamin B6 indexes (except pyridoxal) were lower in the patients than in the control subjects. The differences were statistically significant, except for erythrocyte PLP and total potential enzyme activity. The adjusted relative odds of a myocardial infarction for subjects in the lowest quartile of plasma PLP was about 5 times higher when compared with those in the highest quartile (relative odds = 5.2, 95% confidence interval = 1.4 to 18.9). Similar findings were found with the other vitamin B6 indexes. No significant association between infarct size, as estimated by creatine kinase level, and the vitamin B6 indexes was observed.     

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.     

Storage of platelet concentrates using ion exchange resin charged with dibasic phosphate.

Platelet concentrates were prepared at twice the normal concentration and stored at room temperature for 7 days in either standard bags (controls) or bags to which 1 or 2 g of Amberlite resin beads charged with dibasic phosphate had been added. The resin beads served as a buffer system by providing a "slow release" form of phosphate ions as well as by binding CO2 produced during platelet metabolism. Control platelets demonstrated rapid falls in pH, ATP content, morphology score, and thrombin-induced nucleotide release after 24 hr of storage with a fall in pH to less than 6.0 by day 3. Profound ultrastructural changes and a rise in pO2, suggesting loss of platelet viability, accompanied these changes. In contrast, the resin-stored platelets remained near normal after 24 hr of storage, with preservation of discoid morphology, 95% of ATP levels, excellent ultrastructural appearance, and evidence of continued oxygen consumption after 3 days of storage. Even after 7 days of storage, ATP levels remained greater than 50% of baseline and ultrastructurally intact platelets were seen. In the 1-g resin bags the pH remained at baseline levels (6.9-7.0), while there was a rise in pH in the 2-g resin bags. These results demonstrate the beneficial effects of maintaining a higher pH during platelet storage and provide a new approach to studying the metabolic changes that occur during longer term storage.