In the coming year we propose serial studies of endogenous CO production in patients with sickle cell disease both in the steady state and during mild painful crises. Further work will be done to establish the technic with particular reference to the effect of the dyspoesis of megaloblastic anemia on CO production and any acute changes brought on by therapy. To examine the possibility that there is excessive mortality for subjects with sickle cell trait, we have re-instituted screening for abnormal hemoglobins by electrophoresis, all black individuals autopsied by the Medical Examiner of D.C. Thus far, 1427 have been studied. We expect to continue this study until we reach 1000,1500 deaths from "natural causes". Beyond this point, we will continue to examine certain kinds of cases if the possiblity is strong that there is a relationship between sickle cell trait and the cause of death. Alcohol is often mentioned as a precipitating factor in painful sickling crisis. Although direct evidence for this is lacking, we have been impressed and intrigued by the occurrence of two serious vaso-occlusive crises in an 18 year old man, with essentially asymptomatic sickle cell disease all his life, which followed several hours after a bout of alcoholic intoxication. It is proposed that alcohol may precipitate sickling by producing a hyperosmolar environment leading to intracellar dehydration of the red cells and rise in MCHC. We plan to test this hypothesis in an in vitro filtration system to determine the effect of varying concentrations of alcohol on the deformability of normal and sicklable red cells. We will continue to study unusualy abnormal Hb syndromes when they are found such as the E-like Hb discovered in an Irish family in Washington.