Effect of acute \u3b2-blocker withholding on ventilatory efficiency in patients with advanced chronic heart failure

BACKGROUND: This is the first study to examine the effect of acute (24-hour) beta-blocker withholding on ventilatory efficiency in patients with advanced chronic heart failure (CHF) during maximal incremental treadmill cardiopulmonary exercise test. METHODS AND RESULTS: Seventeen CHF patients were studied either 3 hours after administration of beta-blocker (BB(ON)) or 27 hours after the last beta-blocker ingestion (BB(OFF)). The ventilatory efficiency was measured via the slope of the linear relationship between ventilation (V'(E)) and carbon dioxide production (V'CO2) (ie, V'(E)/V'CO2 slope). Measurements were also made at rest, anaerobic threshold (AT), maximal end-tidal pressure for carbon dioxide (P(ET)CO2max), respiratory compensation point (RC), and peak exercise. Compared with BB(ON), the V'(E)/V'CO2 slope was significantly increased during BB(OFF) (30.8 +/- 7.4 vs. 29.1 +/- 5.4, P = .04). At peak exercise, oxygen uptake (V'O2, 16.0 +/- 2.7 vs. 15.6 +/- 2.8 mL x kg x min) and V'CO2 (1458 +/- 459 vs. 1414 +/- 429 mL/min) were not different between the 2 conditions, whereas V'(E) was higher during BB(OFF) (49.5 +/- 10.7 vs. 46.1 +/- 9.6 L/min, P = .04). No differences were noted at AT and RC in V'O2, V'CO2, V'(E), V'(E)/V'O2, and V'(E)/V'CO2 ratios during the 2 conditions. At P(ET)CO2max, used to noninvasively estimate the CO2 set point, V'(E) was higher (33.9 +/- 7.6 vs. 31.7 +/- 7.3 L/min, P = .002) and P(ET)CO2 was lower (37.4 +/- 4.8 vs. 38.5 +/- 4.0 mm Hg, P = .03), whereas V'CO2 was unchanged (1079 +/- 340 vs. 1050 +/- 322 mL/min) during BB(OFF). CONCLUSION: Acute beta-blocker withholding resulted in decreased ventilatory efficiency mostly from an increase of V'CO2-independent regulation of V'(E) and less likely from a change in ventilation/perfusion mismatchin

Absence of Host Plasminogen Activator Inhibitor 1 Prevents Cancer Invasion and Vascularization

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

NAMI-A is a ruthenium-based compound with selective anti-metastasis activity in experimental models of solid tumours. We studied whether this activity was dependent on anti-angiogenic ability of NAMI-A. We thus investigated its in vitro effects on endothelial cell functions necessary for angiogenesis to develop, as well as its in vivo effects in the chick embryo chorioallantoic membrane model. Endothelial cell proliferation, chemotaxis, and secretion of the matrix-degrading enzyme metalloproteinase-2 were inhibited by NAMI-A in a dose-dependent manner, and without morphologic signs of cell apoptosis or necrosis. Lastly, NAMI-A displayed a dose-dependent in vivo anti-angiogenic activity in the chorioallantoic membrane model. These data suggest that the anti-angiogenic activity of NAMI-A can contribute to its anti-metastatic efficacy in mice bearing malignant solid tumours

Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

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