I nominated the paper [Chinese Medical Journal, 92: 471, 1979] which showed that selenium markedly reduced the incidence of Keshan disease in certain regions of China as a landmark paper on clinical studies with selenium. This work clearly demonstrated that selenium is a required element for humans which was suspected to be essential for people because of voluminous data showing that it was required for animals [1]. These results were the stimuli for a number of subsequent studies on selenium metabolism in humans by investigators in many parts of the world. Keshan disease is a cardiomyopathy that occurred in certain regions of China. It was named for Keshan County in Heilongjiang Province, where it was prominent in 1935 [2]. Since that time the disease was recognized in many other locations of that country. It is now known that a region extending across China from the northeast to the southwest is deficient in selenium and this is where the highest incidence of Keshan disease occurred. Approximately 76 million people live in the Keshan disease endemic area of China. The first clue that this disorder may be related to selenium was that this is where the highest incidence of White Muscle Disease, a selenium deficiency disorder in grazing livestock, also occurred. An inscription on a stone pillar in Huanglong County of Shaanxi Province suggested that Keshan disease occurred there in 1812 [3], indicating that this disorder had been a problem for many decades and thus not a recent one.
In some areas of China, Keshan disease was extremely rampant. For example, in Dechang County (Sichuan Province) from 1970 to 1973 the incidence was very high, averaging about 0.2% of the population [4]. In the northeast, deaths from Keshan disease numbered almost 2,000 in Heilongjiang province in 1970. In one village alone near Qiqihar in 1964, there were 70 deaths due to this disorder in a population of 840 people. Conclusive evidence that selenium supplementation could prevent Keshan disease was obtained by a large placebo-controlled study in Mianning County of Sichuan Province conducted from 1974 to 1976, as reported in this nominated paper. Over 12,000 subjects were used in that study, making it the largest number of patients in a clinical trial ever conducted anywhere in the world to date. Following this study, selenite supplementation of salt was instituted in the high incidence areas and Keshan disease has steadily declined since that time. For example, in 1989 only 58 cases were reported in all of China and only 45 in 1990 [5]. Only one case of Keshan disease was reported in 1998 in all of China (Xia, personal communication, Academy of Preventive Medicine, Beijing, China). This very significant decline in the incidence of the