In point of area its period of greatest extent was during the first half of the nineteenth century. Since the middle of the nineteenth century its area has been decreasing rapidly, until at the present time this disease is confined to a half dozen centers in South America. Within the epidemic area the loss of human life from this disease has been very great, the United States and Spain, being the most populous countries affected. South America lies generally well east of North America, and its northern coast is about opposite the southern part of North America, so that the neck of land which connects the two runs east and west and is known as the Isthmus of Panama. Most of this isthmus is embraced in the present Republic of Panama. Columbus was the first white man to visit Panama. On his third expedition he entered the Bay of Bocas del Toro, and spent some time there. On this same expedition he also visited Limon Bay, into which the northern end of the Panama Canal at present empties. He also visited Porto Bello, which afterwards became rich, famous, and populous, and which is located on the northern extremity of the royal paved highway running north from the old city of Panama. He left more than one hundred men under his brother, Diego, at Belen, some fifty miles west of the present town of Colon. After several years of sickness, hardships and deprivations, this colony was finally destroyed by the Indians. Spain afterwards ennobled Columbus’ grandson, Luis, under the title of Duke of Veragua, and granted to him a large tract of land in the neighborhood of this old colony, to which was given the name “Dukedom of Veragua.” One of the provinces of the Republic of Panama which covers about the same area as did the tract referred to, is known as the Province of Veragua. The old royal highway just referred to, running between Panama and Porto Bello, lies from five to fifteen miles east of the Canal. Columbus’ third voyage was made in 1498. A few years later, Balboa, with a party of Spanish adventurers, under the authority of the Captain-General from Santo Domingo, arrived in the eastern part of Panama and made permanent settlements, at first on the north coast, and discovered the Pacific.