Coronary artery anomalies were found in 1,686 patients (1.3% incidence) undergoing coronary arteriography at the Cleveland Clinic Foundation from 1960 to 1988. Of the 1,686 patients, 1,461 (87%) had anomalies of origin and distribution, and 225 (13%) had coronary artery fistulae. Most coronary anomalies did not result in signs, symptoms, or complications, and usually were discovered as incidental findings at the time of catheterization. Eighty-one percent were "benign" anomalies: 1) separate origin of the left anerior descending and circumflex from the left sinus of Valsalva; 2) ectopic origin of the circumflex from the right sinus of Valsalva; 3) ectopic coronary origin from the posterior sinus of Valsalva; 4) anomalous coronary origin from the ascending aorta; 5) absent circumflex; 6) intercoronary communications; and 7) small coronary artery fistulae. Other anomalies may be associated with potentially serious sequelae such as angina pectoris, myocardial infarction, syncope, cardiac arrhythmias, congestive heart failure, or sudden death. Potentially serious anomalies include: 1) ectopic coronary origin from the pulmonary artery; 2) ectopic coronary origin from the opposite aortic sinus; 3) single coronary artery; and 4) large coronary fistulae. Coronary artery anomalies require accurate recognition, and at times, surgical correction.

Damage to the cornea from chemical burns is a serious clinical problem that often leads to permanent visual impairment. Because transforming growth factor (TGF)-␤ has been implicated in the response to corneal injury, we evaluated the effects of altered TGF-␤ signaling in a corneal alkali burn model using mice treated topically with an adenovirus (Ad) expressing inhibitory Smad7 and mice with a targeted deletion of the TGF-␤/activin signaling mediator Smad3. Expression of exogenous Smad7 in burned corneal tissue resulted in reduced activation of Smad signaling and nuclear factor-B signaling via RelA/ p65. Resurfacing of the burned cornea by conjunctival epithelium and its differentiation to cornea-like epithelium were both accelerated in Smad7-Adtreated corneas with suppressed stromal ulceration, opacification, and neovascularization 20 days after injury. Introduction of the Smad7 gene suppressed invasion of monocytes/macrophages and expression of monocyte/macrophage chemotactic protein-1, TGF-␤1, TGF-␤2, vascular endothelial growth factor, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-2 and abolished the generation of myofibroblasts. Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7. Together these data suggest that overex-

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Conjunctival and subconjunctival fibrogenesis and inflammation are sight compromising side effects that can occur subsequent to glaucoma filtration surgery. Despite initial declines in intraocular pressure resulting from increasing aqueous outflow, one of the activated responses includes marshalling of proinflammatory and pro-fibrogenic cytokine mediator entrance into the aqueous through a sclerostomy window and their release by local cells, as well as infiltrating activated immune cells. These changes induce dysregulated inflammation, edema and extracellular matrix remodeling, which occlude outflow facility. A number of therapeutic approaches are being taken to offset declines in outflow facility since the current procedure of inhibiting fibrosis with either mitomycin C (MMC) or 5-fluorouracil (5-FU) injection is nonselective. One of them entails developing a new strategy for reducing fibrosis induced by wound healing responses including myofibroblast transdifferentiation and extracellular matrix remodeling in tissue surrounding surgically created shunts. The success of this endeavor is predicated on having a good understanding of conjunctival wound healing pathobiology. In this review, we discuss the roles of inappropriately activated growth factor and cytokine receptor linked signaling cascades inducing conjunctival fibrosis/scarring during post-glaucoma surgery wound healing. Such insight may identify drug targets for blocking fibrogenic signaling and excessive fibrosis which reduces rises in outflow facility resulting from glaucoma filtration surgery.

Retinal pigment epithelial (RPE) cells dedifferentiate and undergo epithelial-mesenchymal transition (EMT) following retinal detachment, playing a central role in formation of fibrous tissue on the detached retina and vitreous retraction (proliferative vitreoretinopathy (PVR)). We have developed a mouse model of subretinal fibrosis with implications for PVR in which retinal detachment is induced without direct damage to the RPE cells. Transforming growth factor-b (TGF-b) has long been implicated both in EMT of RPEs and the development of PVR. Using mice null for Smad3, a key signaling intermediate downstream of TGF-b and activin receptors, we show that Smad3 is essential for EMT of RPE cells induced by retinal detachment. De novo accumulation of fibrous tissue derived from multilayered RPE cells was seen following experimental retinal detachment in eyes of wild type, but not Smad3-null mice. Expression of a-smooth muscle actin, a hallmark of EMT in this cell type, and extracellular matrix components, lumican and collagen VI, were also not observed in eyes of Smad3-null mice. Our data show that induction of PDGF-BB by Smad3-dependent TGF-b signaling is likely an important secondary proliferative component of the disease process. The results suggest that blocking the Smad3 pathway might be beneficial in prevention/treatment of PVR.