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Pamaquine (6-methoxy-8-amino [N-diethylaminoisopentyl] quinoline) is recognized to be a potentially dangerous drug. However, a definitive appraisal of its hazard had not been achieved at a time when the further exploration of the antimalarial activity of the 8-aminoquinolines was considered advisable. Pamaquine toxicity can involve the gastro-intestinal tract, the central nervous system, and the circulating blood. Symptoms referable to the gastro-intestinal tract and the central nervous system may be annoying, but there is no evidence that they constitute a hazard to life or persist beyond the termination of therapy. Effects on the blood do constitute a serious hazard and are considered in this paper. MATERIALS AND METHODSMost of the patients utilized as subjects either were having malaria at the time of the observations or had had the disease from one to six weeks previously. None of the patients had malaria long enough to be considered likely subjects for the development of blackwater fever. Most subjects were suffering from asymptomatic neurosyphilis and many had received prior antiluetic therapy. (e) Fragility of erythrocytes to hypotonic saline. A 2 per cent suspension of erythrocytes in sterile physiological saline was prepared from blood containing one drop of saturated potassium oxalate per 5 ml. of blood. 0.5 ml. of the cell suspension was added as soon as possible to 2 ml. each of 0.9 per cent sodium chloride (control), to distilled water (total hemoglobin), and to a series of sodium chloride dilutions usually ranging from 0.48 per 121

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We studied Joseph disease clinically and pathologically in two patients of Portuguese ancestry, but from different families. We found involvement of spinocerebellar tracts, Clarke's column, anterior horn cells, motor cranial nerve nuclei, and substantia nigra. One patient also had pallidosubthalamic and pontocerebellar degeneration with normal inferior olives. The second patient, a Joseph family member, had nerve cell loss in the subthalamic nucleus. The neostriatum appeared normal in both cases. The pigmented nuclei contained a few Lewy bodies. The almost identical pathology in two families support the hypothesis that Joseph disease is a genetic entity.