Regulation of lymphatic capillary regeneration by interstitial flow in skin

Decreased interstitial flow (IF) in secondary lymphedema is coincident with poor physiological lymphatic regeneration. However, both the existence and direction of causality between IF and lymphangiogenesis remain unclear. This is primarily because the role of IF and its importance relative to the action of the prolymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C (which signals primarily through its receptor VEGFR-3) are poorly understood. To clarify this, we explored the cooperative roles of VEGFR-3 and IF in a mouse model of lymphangiogenesis in regenerating skin. Specifically, a region of lymphangiogenesis was created by substituting a portion of mouse tail skin with a collagen gel within which lymphatic capillaries completely regenerate over a period of 60 days. The relative importance of IF and VEGF-C signaling were evaluated by either inhibiting VEGFR-3 signaling with antagonistic antibodies or by reducing IF. In some cases, VEGF-C signaling was then increased with exogenous protein. To clarify the role of IF, the distribution of endogenous matrix metalloproteinases (MMPs) and VEGF-C within the regenerating region was determined. It was found that inhibition of either VEGFR-3 or IF suppressed endogenous lymphangiogenesis. Reduction of IF was found to decrease lymphatic migration and transport of endogenous MMP and VEGF-C through the regenerating region. Therapeutic VEGF-C administration restored lymphangiogenesis following inhibition of VEGFR-3 but did not increase lymphangiogenesis following inhibition of IF. These results identify IF as an important regulator of the pro-lymphangiogenic action of VEGF-C

Ventricular Dysrhythmias Associated with Poisoning and Drug Overdose: A 10-Year Review of Statewide Poison Control Center Data from California

Background: Ventricular dysrhythmias are a serious consequence associated with drug overdose and chemical poisoning. The risk factors for the type of ventricular dysrhythmia and the outcomes by drug class are not well documented. Objective: The aim of this study was to determine the most common drugs and chemicals associated with ventricular dysrhythmias and their outcomes. Methods: We reviewed all human exposures reported to a statewide poison control system between 2002 and 2011 that had a documented ventricular dysrhythmia. Cases were differentiated into two groups by type of arrhythmia: (1) ventricular fibrillation and/or tachycardia (VT/VF); and (2) torsade de pointes (TdP). Results: Among the 300 potential cases identified, 148 cases met the inclusion criteria. Of these, 132 cases (89 %) experienced an episode of VT or VF, while the remaining 16 cases (11 %) had an episode of TdP. The most commonly involved therapeutic classes of drugs associated with VT/VF were antidepressants (33/132, 25 %), stimulants (33/132, 25 %), and diphenhydramine (16/132, 12.1 %). Those associated with TdP were antidepressants (4/16, 25 %), methadone (4/16, 25 %), and antiarrhythmics (3/16, 18.75 %). Drug exposures with the greatest risk of death in association with VT/VF were antidepressant exposure [odds ratio (OR) 1.71; 95 % confidence interval (CI) 0.705–4.181] and antiarrhythmic exposure (OR 1.75; 95 % CI 0.304–10.05), but neither association was statistically significant. Drug exposures with a statistically significant risk for TdP included methadone and antiarrhythmic drugs. Conclusions: Antidepressants and stimulants were the most common drugs associated with ventricular dysrhythmias. Patients with suspected poisonings by medications with a high risk of ventricular dysrhythmia warrant prompt ECG monitoring