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S-nitrosylation, the modification by nitric oxide of free sulfhydryl groups in cysteines, has become an important regulatory mechanism in carcinogenesis and metastasis. S-nitrosylation of targets in tumor cells contributes to metastasis regulating epithelial to mesenchymal transition, migration and invasion. In the tumor environment, the role of S-nitrosylation in endothelium has not been addressed; however, the evidence points out that S-nitrosylation of endothelial proteins may regulate angiogenesis, adhesion of tumor cells to the endothelium, intra and extravasation of tumor cells and contribute to metastasis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Patients with clinically evident chronic venous insufficiency were evaluated to relate the degree of insufficiency and calf muscle pump dysfunction to venous ulceration., Methods: Sixty-nine limbs in 55 patients with chronic venous insufficiency by Society for Vascular Surgery/International Society for Cardiovascular Surgery Classification were compared in three groups: classes 1 and 2 with no history of ulceration (19 limbs); class 3 with healed ulceration (20 limbs); and class 3 with active ulcers (30 limbs). Air plethysmography measurements of outflow fraction, venous volume, venous filling time, venous filling index, ejection fraction, ejection volume, residual volume fraction, and residual volume were made. In 62 of the 69 limbs, color-flow duplex ultrasonography was used to determine the pattern of reflux., Results: The outflow fraction was normal in 84%, 75%, and 77% of nonulcerated, healed, and ulcerated limbs. The venous filling index was abnormal in most limbs (nonulcerated 95%, healed 90%, ulcerated 98%) but not significantly different among groups. Differences in calf muscle pump function were significant. Ulcerated limbs had significantly poorer ejection fractions (p = 0.0002) and greater residual volume fractions (p = 0.0006) than nonulcerated or healed limbs. By ultrasonography, deep and superficial vein incompetence was present in most limbs and was not statistically different among groups. Although venous insufficiency was not measurably different among groups, limbs with active venous ulcers had significantly poorer calf muscle pump function than those with healed ulcers or with no history of ulceration., Conclusion: Venous insufficiency is necessary but not sufficient to cause ulceration, and a deficiency of the calf muscle pump is significant to the severity of venous ulceration.

Color-flow and duplex ultrasonography were used to determine the optimal method for documenting venous valvular reflux. Popliteal veins were examined in 10 normal limbs and 11 limbs with clinical evidence of chronic venous insufficiency (CVI). Peak reflux velocity (spectral) and duration of reflux (spectral and color) were measured with the patient in supine and standing positions, with manual and pneumatic compression applied sequentially to thigh and calf. Manual and pneumatic compression produced equivalent reflux velocity and duration. In normal limbs peak reflux velocity was always less than 22 cm/sec, with a mean reverse flow duration of 0.3 sec +/- 0.03 (SEM). In limbs with CVI, reflux velocity varied widely among protocols. Reflux duration and velocity were greater in the supine position than in the standing position for both normal limbs and limbs with CVI (p < 0.04). Duration was significantly increased for thigh versus calf compression in normal limbs (p < 0.001) but decreased in limbs with CVI (p < 0.003). Methods that used thigh compression or supine position were less capable of discriminating normal limbs from limbs with CVI. Standing calf compression provided the greatest rates of sensitivity (91%), specificity (100%), and accuracy (95%). Compared with spectral Doppler scanning, color-flow ultrasonography produced a consistently shorter reflux duration (p < 0.001). In limbs with CVI with a mean spectral duration of 2.5 sec +/- 0.2 (SEM), mean color Doppler duration was 0.7 sec shorter. Our results demonstrate that popliteal vein incompetence is identified optimally by reflux duration after standing calf compression; adequate manual compression is sufficient to identify reflux; color-flow Doppler ultrasonography may underestimate reflux duration.

Increased vascular permeability is an early and sensitive indicator of ischemic muscle injury, occurring before significant histologic or radionuclide changes are evident. We investigated the effect of iloprost, a stable prostacyclin analog, on microvascular permeability in a rat striated muscle model. In six control and six experimental animals the cremaster muscle was dissected, placed in a closed-flow acrylic chamber, and suffused with a bicarbonate buffer solution. Dextran labeled with fluorescein was injected intravenously as a macromolecular tracer, and microvascular permeability was determined on the basis of clearance of the fluorescent tracer. Two hours of ischemia were followed by 2 hours of reperfusion. In the experimental group iloprost (0.5 microgram/kg/min) was given in a continuous intravenous infusion. Microvascular permeability increased significantly during reperfusion in both control and experimental animals (p less than 0.0001). Treatment with iloprost, however, significantly attenuated this response compared to the control group, 4.8 +/- 0.3 versus 7.3 +/- 0.5 microliters/gm/min, respectively (p less than 0.0001). Iloprost decreases the rise in vascular permeability after ischemia and reperfusion. Experimental clinical use of iloprost under controlled conditions in the treatment of patients with acute skeletal muscle ischemia appears justified.