VEGFR3: A New Target for Antiangiogenesis Therapy?

VEGFR-3 signaling plays an important role in developmental, physiological, and pathological angiogenesis and lymphangiogenesis. Tammela et al. in Nature show that VEGFR-3, via Notch regulation, is present on endothelial tip cells and is critical to sprouting angiogenesis

Hypertrophic cardiomyopathy: Translating cellular cross talk into therapeutics

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with serious adverse outcomes, including heart failure, arrhythmias, and sudden cardiac death. The discovery that mutations in sarcomere protein genes cause HCM has enabled the development of mouse models that recapitulate clinical manifestations of disease. Studies in these models have provided unexpected insights into the biophysical and biochemical properties of mutated contractile proteins and may help to improve clinical diagnosis and management of patients with HCM

Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia

Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 µg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001) or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia

Computational simulations of the effects of gravity on lymphatic transport

Physical forces, including mechanical stretch, fluid pressure and shear forces alter lymphatic vessel contractions and lymph flow. Gravitational forces can affect these forces, resulting in altered lymphatic transport, but the mechanisms involved have not been studied in detail. Here, we combine a lattice Boltzmann-based fluid dynamics computational model with known lymphatic mechanobiological mechanisms to investigate the movement of fluid through a lymphatic vessel under the effects of gravity that may either oppose or assist flow. Regularly spaced, mechanical bi-leaflet valves in the vessel enforce net positive flow as the vessel walls contract autonomously in response to calcium and nitric oxide (NO) levels regulated by vessel stretch and shear stress levels. We find that large gravitational forces opposing flow can stall the contractions, leading to no net flow, but transient mechanical perturbations can reestablish pumping. In the case of gravity strongly assisting flow, the contractions also cease due to high shear stress and NO production, which dilates the vessel to allow gravity-driven flow. In the intermediate range of oppositional gravity forces, the vessel actively contracts to offset nominal gravity levels or to modestly assist the favorable hydrostatic pressure gradients