The earliest direct reference is found in the writings of Dr. Nott, of Mobile, Ala., who in 1848 suggested that the dissemination of the yellow fever poison was evidently by means of some insect "that remained very close to the ground." But the first who positively pointed to the mosquito as the spreader of yellow fever, who showed that absence of mosquitoes precluded the existence of the disease and who prescribed the ready means to stamp it out, by fumigation and by preventing the bites of the insects, was Dr. Louis D. Beauperthuy, a French physician, then located in Venezuela. The writer has an original copy of his paper, published in 1853, where he fastens the guilt upon the domestic mosquitoes, believing, in accord with the prevailing teachings of medical science, that the mosquitoes infected themselves by contact or feeding upon the organic matter found in the stagnant waters where they are hatched, afterwards inoculating the victims by their sting. He recognized the fact that yellow fever is not contagious and therefore could not think of the possibility of man-to-man infection, as we know it to-day. The keenest observer was this man Beauperthuy, and, even at that benighted time in the history of tropical medicine, made most interesting studies of the blood and tissues, employing the microscope and the chemical reactions in his research. No one believed him, and a commission appointed to report upon his views said that they were inadmissible and all but declared him insane. This field of investigation remained dormant for a comparatively long period of time. Meanwhile another medical writer, Dr. Greenville Dowell, mentions in 1876, that "if we compare the effect of heat and cold on gnats and mosquitoes with yellow fever, it will be difficult to believe it is of the same nature, as it is controlled by the same natural laws." Soon after this, in 1879, the first conclusive proof of the direct transmission of a disease from man-to-man was presented by the father of tropical medicine, Sir Patrick Manson, with regard to filaria, a blood infection that often causes the repulsive condition known as elephantiasis and which the mosquito takes from man and after a short time gives over to another subject. This discovery attracted world-wide attention and many looked again towards the innumerable species of biting insects that dwell in the Tropic Zone, as possible carriers of the obscure diseases which also prevail in those regions.