The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis

BACKGROUND AND OBJECTIVES: Intermittent pneumatic compression (IPC) is an effective form of deep vein thrombosis prophylaxis for general surgery patients. The antithrombotic effect of IPC is thought to be the result of increased venous velocity and stimulation of endogenous fibrinolysis. However, the mechanism of enhanced fibrinolytic activity and the relative effects on normal and postthrombotic veins have not been defined. The purposes of this study are 1) to quantify changes in fibrinolytic activity with IPC; 2) to study the mechanism of fibrinolytic enhancement with IPC; and 3) to evaluate whether postthrombotic patients have the same capacity for fibrinolytic enhancement with IPC as do normal subjects. METHODS: Twelve volunteers (6 normal and 6 postthrombotic) had 5 IPC devices applied for 120 minutes in random fashion, 1 per week x 5 weeks. The devices included single-chamber, sequential, foot, calf, and long-leg compression. Subjects had an indwelling antecubital venous cannula placed for blood drawn at baseline, 60, 120, and 180 minutes after IPC devices were applied. Global fibrinolytic activity (euglobulin fraction, fibrin plate assay), tissue plasminogen activator (tPA) antigen (Ag) and activity (Act), plasminogen activator inhibitor-1 (PAI-1) Ag and Act, alpha-2-antiplasmin-plasmin complexes, and von Willebrand factor (vWF) antigen were assayed. RESULTS: A striking elevation in fibrinolytic activity was noted at 180 minutes with all devices in normal subjects and postthrombotic patients (p = 0.01-0.0001); however, baseline and stimulated fibrinolytic activity was attenuated in postthrombotic patients (<0.03). The tPA-Act increased only in normal subjects (3.8 +/- 1.9%) (p = 0.057), despite a decrease in plasma tPA-Ag, which was observed in both normal subjects (-12.4 +/- 3.8%) (p = 0.009) and patients (-17.2 +/- 3.1%) (p = 0.001). PAI-1-Ag decreased in both normal subjects (-13.4 +/- 3.8%) (p = 0.007) and patients (-12.0 +/- 3.1%) (p = 0.013) with a marked reduction in PAI-1-Act in both normal subjects (p = 0.003) and patients (p = 0.004). There were no changes in vWF, and alpha-2-antiplasmin-plasmin complexes increased only in postthrombotic patients (p = 0.021). CONCLUSIONS: Stimulation of endogenous fibrinolytic activity occurs after IPC, both in normal subjects and postthrombotic patients; however, baseline and overall fibrinolytic response in postthrombotic patients is reduced. The mechanism of increased fibrinolytic activity is likely because of a reduction in PAI-1, with a resulting increase of tPA activity.     

Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B tested against Candida albicans

Time-kill curves were determined for three isolates of Candida albicans tested against fluconazole and amphotericin B at multiples of the MIC. Fluconazole produced fungistatic activity, with concentration-related growth effects observed over a narrow range of concentrations. Amphotericin B exhibited fungicidal activity, with enhancement of activity over a broader range of concentrations.     

Diabetic cystopathy presenting as primary acute urinary retention in a previously undiagnosed young male diabetic patient

Lower genito-urinary problems are part of the polyneuropathy of diabetes. Cystopathy affects 40%-85% of diabetic patients, although less than half are symptomatic. We report on a 42-year-old patient who was not known to be diabetic, and who presented to the urologists with primary acute urinary retention. His underlaying disease was detected by a test for random blood glucose. More common causes were excluded with careful clinical and radiological examinations. He was managed with insulin and self-catheterization. Diabetes should be considered as a differential diagnosis in relatively young men who present with unexplained acute urinary retention.     

The effect of salmeterol on human eosinophils is both stimulus- and response-dependent

Salmeterol, a long-acting beta 2-adrenoceptor agonist, also possesses some anti-inflammatory properties, but whether eosinophils are the target of such action has been equivocal. To clarify the direct effect of salmeterol on eosinophil functions, we have studied the effect of the drug on the various responses of purified human eosinophils. Superoxide anions (O2-) release and adherence to fibronectin-coated plastic plates induced by platelet-activating factor (PAF), interleukin-5 (IL-5), leukotriene B4 (LTB4) and phorbol myristate acetate (PMA), as well as degranulation induced by C5a and formyl methionyl leucyl phenylalanine (FMLP), in the presence of cytochalasin B (CB) were studied. In the concentration range 10(-8)-10(-5) M, the drug inhibited PAF- and IL-5-induced O2- release, with an IC50 values of 3.2 +/- 1.2 x 10(-7) M and 2.2 +/- 0.4 x 10(-6) M, respectively, Superoxide anion release by LTB4 was only modestly inhibited while that due to PMA was completely unaffected. On the other hand, eosinophil adherence induced by all the 4 stimuli were significantly inhibited within the same concentration range. On eosinophil degranulation, the drug failed to significantly inhibit the release of eosinophil peroxidase (EPO) induced by either C5a or FMLP. In contrast, beta-hexoseaminidase (beta-HA) release by the same agents was significantly inhibited, the inhibition being more pronounced for FMLP-induced, than C5a-induced release. None of the effects of the drug was reversed by the selective beta 2-adrenoceptor antagonist ICI 118551 at a concentration of 10(-7) M. These results show that salmeterol may have some direct inhibitory effects on human eosinophil functions but that these effects are both stimulus- and response-dependent, and are unlikely to be mediated via beta 2 adrenoceptors.     

Chimeric influenza viruses incorporating epitopes of outer membrane protein F as a vaccine against pulmonary infection with Pseudomonas aeruginosa

Peptide 10 (NATAEGRAINRRVE, residues 305-318 of mature protein F) is one of two linear B-cell epitopes within outer membrane protein F of Pseudomonas aeruginosa both of which have been shown to elicit whole cell-reactive antibodies and to afford protection in animal models against P. aeruginosa infection. Influenza A virus was chosen as a vector to present this epitope in a human-compatible vaccine. Various lengths of the peptide 10 epitope ranging from a 5-mer (GRAIN), 7-mer (AINRRVE), 8-mer (TAEGRAIN), 9-mer (GRAINRRVE), 11-mer (AEGRAINRRVE) to a 12-mer (TAEGRAINRRVE) were attempted to be presented into the antigenic B-site of the hemagglutinin (HA) of live recombinant influenza virus. Using PCR, DNA sequences encoding these various peptide 10 lengths were inserted into the HA gene of influenza A/WSN/33 virus. By using a reverse-genetics transfection system, RNA transcribed in vitro from these chimeric HA genes was reassorted into infectious virus. To date chimeric viruses have been rescued and purified containing the peptide 10 5-mer, 7-mer, 8-mer, and 11-mer. RT-PCR and sequencing have confirmed the presence of P. aeruginosa sequences in the HA RNA segment of each chimeric virus. Each of the four chimeric viruses produced to date was used to immunize mice to determine the ability of each chimeric virus to elicit antibodies reactive with whole cells of P. aeruginosa. The immunization protocol consisted of a series of three intranasal inoculations, followed by two intramuscular injections of the chimeric virus. The chimeric virus incorporating the 11-mer elicited IgG antibodies that reacted with various immunotype strains of P. aeruginosa in a whole cell ELISA at titers of 80 to 2,560, whereas the chimeric virus incorporating the 8-mer elicited whole cell-reactive IgG antibodies at titers of 320 to 2,560. These data suggest that these two chimeric viruses may have vaccine efficacy against P. aeruginosa infection. These studies may result in the development of a chimeric influenza virus-protein F vaccine which would prove to be suitable for use in children with cystic fibrosis for the prevention of pulmonary colonization of these children with P. aeruginosa.