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Minor graduated from Yale's medical school, which at that time entailed two years' study, as a qualified surgeon. After caring for wounded soldiers in the Civil War, Minor began to suffer from what would much later be defined as paranoid schizophrenia. In 1868 Minor was admitted to a government hospital for the insane in Washington, D.C., and released from the Army in 1870. During a stay in London that was intended to rest his mind, he shot and killed an innocent passerby while in the grip of delusional paranoia. The British courts judged him not guilty by reason of insanity in April 1872; he was then placed in Broadmoor, an asylum in Berkshire, England, where he began to correspond with the editors of the nascent Oxford English Dictionary. He soon became an invaluable contributor to that effort. The chief editor did not learn until years into their collaboration that the brilliant and hardworking Minor was a mentally ill prison-hospital inmate. Minor's life was the subject of Simon Winchester's 1998 history, The Professor and the Madman.
In his declining years, Minor was considered less dangerous, and his brother arranged his transfer in 1910 to the same hospital in Washington, D.C., where he had been kept 42 years earlier. It was there that he finally received the diagnosis of dementia praecox, an early term for schizophrenia. A year before his death from pneumonia at age 85, he was transferred, still delusional, to a home for the elderly in Hartford, Conn. Minor was buried in New Haven's Evergreen Cemetery in March 1920. His obituary in the Yale press made no mention of his crime, stating instead that while in England "he was found to be mentally deranged ... and [in Broadmoor] he remained ... gradually recovering his mental balance, and devoting his time to scholarly pursuits." Though Minor did not in fact recover his mental health, the fruits of his scholarship done in the throes of schizophrenia can be found throughout the Oxford English Dictionary, a basic reference work in libraries throughout the English-speaking world.

