Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is currently under development as an enzyme replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder caused by a deficiency of thymidine phosphorylase. The rationale for the development of EE-TP is based on the pathologically elevated metabolites (thymidine and deoxyuridine) being able to freely diffuse across the erythrocyte membrane where the encapsulated enzyme catalyses their metabolism to the normal products. The systemic toxic potential of EE-TP was assessed when administered intermittently by iv bolus injection to BALB/c mice and Beagle dogs for 4 weeks. The studies consisted of one control group receiving sham-loaded erythrocytes twice weekly and two treated groups, one dosed once every 2 weeks and the other dosed twice per week. The administration of EE-TP to BALB/c mice resulted in thrombi/emboli in the lungs and spleen enlargement. These findings were also seen in the control group, and there was no relationship to the number of doses administered. In the dog, transient clinical signs were associated with EE-TP administration, suggestive of an immune-based reaction. Specific antithymidine phosphorylase antibodies were detected in two dogs and in a greater proportion of mice treated once every 2 weeks. Nonspecific antibodies were detected in all EE-TP-treated animals. In conclusion, these studies do not reveal serious toxicities that would preclude a clinical trial of EE-TP in patients with MNGIE, but caution should be taken for infusion-related reactions that may be related to the production of nonspecific antibodies or a cell-based immune response.
This article examines how the Kennedy administration assessed the risk posed by Soviet short-range missiles in Cuba and the associated combat troops, particularly in the months after the peak of the Cuban missile crisis. The issue had a strong domestic political subtext that played out for months. Missiles in Cuba had been a topic of discussion well before the dramatic events of October 1962, and the dispute about them dragged on well past the famous “thirteen days.” Many studies assume a final resolution to the crisis that did not actually exist. The evidence from this period indicates that domestic political considerations were a fundamental factor in Kennedy's decision-making and apparently induced him to take a slightly harder line in the post-crisis negotiations with the Soviet Union than he otherwise might have. But the evidence also suggests that Kennedy was more willing than some of his advisers and many Congressional critics to accept a degree of permanent military risk in Cuba.
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