ABSTRACT
Professor Oliver Smithies is the Weatherspoon Eminent Distinguished Professor of Pathology and Laboratory Medicine at the University of North Carolina, Chapel Hill. Along with Mario Capecchi and Martin Evans, Oliver was awarded the Nobel Prize in Medicine in Physiology or Medicine in 2007 for his contributions to the development of gene targeting using homologous recombination in embryonic stem cells. This technique has had an immense impact on biomedical research over the past two decades. Professor Smithies has had a long and distinguished career as a researcher and mentor. Here, he provides an entertaining and enlightening discussion of his life in science.
Subject(s)
Gene Targeting/history , Molecular Biology/history , Nobel Prize , Biomedical Research , Embryonic Stem Cells , History, 20th Century , History, 21st Century , Humans , Recombination, Genetic/geneticsABSTRACT
Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms in response to a chronic blood pressure increase. Vasoactive peptides, such as endothelin, participate in hypertension-associated vascular fibrosis by stimulating collagen I formation and increasing contractility of arterial wall. In the present study, we tested the hypothesis that activation of the epidermal growth factor (EGF) receptor pathway mediates these events. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Endothelin induced a rapid phosphorylation of the mitogen-activated protein kinase (MAPK)/ERK and increased collagen I gene activity in freshly isolated aortas. This effect of endothelin was totally inhibited by an endothelin receptor antagonist, an EGF receptor phosphorylation inhibitor, and a blocker of the MAPK/ERK cascade. In parallel experiments, inhibition of EGF receptor phosphorylation decreased the endothelin-induced pressor effect in isolated aortic rings and in anesthetized animals in vivo. In addition, the endothelin-induced increase of blood pressure was blunted in the waved-2 mice, a strain expressing functionally impaired EGF receptors. Our results provide the first evidence that the EGF receptor mediates at least two of the major actions of endothelin in the vascular tissue: contractility and fibrogenesis.
Subject(s)
Aorta/drug effects , Endothelin-1/pharmacology , ErbB Receptors/physiology , Vasoconstriction/drug effects , Animals , Aorta/pathology , Aorta/physiopathology , Blood Pressure/drug effects , Collagen Type I/genetics , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Fibrosis , Flavonoids/pharmacology , In Vitro Techniques , Luciferases/genetics , Luciferases/metabolism , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/metabolism , Promoter Regions, Genetic/genetics , Quinazolines/pharmacology , Tyrphostins/pharmacologyABSTRACT
PURPOSE: To characterize the visual sensations reported after bilateral implantation of the Array multifocal intraocular lens (IOL) (Allergan Surgical) and evaluate the means to mitigate unwanted visual sensations. SETTING: Surgery centers in Kansas City, Missouri, and Lake Worth, Florida, USA. METHODS: A retrospective parallel-group assessment of subjective nighttime visual sensations was conducted in 22 patients who had bilateral implantation of the Array multifocal IOL. Thirteen patients were recruited from a small subset of patients who were dissatisfied with the Array because of unwanted visual sensations (UVS group). The parallel group included 9 patients who were satisfied with the Array and not bothered by visual sensations (satisfied group). The primary endpoint was the patient's characterization of visual phenomena under simulated nighttime conditions. The secondary endpoint was the effect of adding trial lenses of -0.50 diopter (D) and -1.00 D to the patient's distance spectacle correction. RESULTS: Most patients reported that the simulation produced visual sensations similar to their real-life experiences. Patients in the UVS group reported the visual sensations as large starbursts and somewhat spoke-like starbursts with fine lines. Patients in the satisfied group reported them as blurred large or small starbursts. A few reported a color variance and finer quality to the starburst in real life. Visual phenomena were generally mitigated by the addition of a -0.50 D or -1.00 D lens. CONCLUSIONS: Both study groups reported similar visual phenomena. The difference between those who were bothered by the visual sensations and those who were not appears to be a function of individual tolerance. The visual sensations may be mitigated with minus-lens overcorrection.
