Leukokinetic Studies. VII. Morphology of the Bone Marrow and Blood of Dogs Given Vinblastine Sulfate

The effect of a single injection of vinblastine sulfate was studied in 50mongrel dogs. Nine of 34 dogs given 0.2 mg./Kg. of VLB died with gastrointestinal toxicity and the mortality rate increased as the dosage of VLB wasincreased. The morphologic pattern of leukocyte suppression and recovery inthe bone marrow and blood was studied in detail in surviving animals.

The cells of the bone marrow were markedly affected by VLB. Within 4hours there was an increase in the number of cells in metaphase and, by day1, virtually all proliferating leukocytes and erythrocytes had disappeared. Anorderly repopulation of the bone marrow followed.

The neutrophils, eosinophils, lymphocytes and monocytes of the blood wereall markedly altered in concentration after VLB. Each type of cell first decreased to abnormally small numbers and then increased to abnormally largenumbers in the blood. The curve of disappearance from and reappearance inthe blood differed for each cell type.

The changes in blood neutrophil number and morphology were correlatedwith changes in the blood neutrophil precursor cells of the marrow. The following conclusions were reached concerning the neutrophils and the assumptions implicit to these conclusions were detailed.

1. In the dog, the marrow contains enough post-mitotic granulocytes toreplace those lost from the blood for at least 3 to 4 days.

2. The release of mature neutrophils from the bone marrow is a functionof the rate at which blood neutrophils are lost and proceeds normally evenwhen the marrow granulocyte reserve is partially depleted.

Submitted on March 27, 1963 Accepted on August 20, 1963     

ATP1A3 mutations in infants: a new rapid‐onset dystonia–Parkinsonism phenotype characterized by motor delay and ataxia

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid‐onset dystonia–Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre‐existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.     

HUNTERS SYNDROME AND COOLEY'S ANAEMIA IN THE SAME PATIENT Effect of Multiple Transfusions

It has been reported that plasma and leukocyte infusions have a beneficial effect on patients with Hurler's and Hunter's syndromes. A 5-year-old boy with Hunter's syndrome and Coo-ley's anaemia is presented. This boy received a total of 38 transfusions over a 4-year period. The usual clinical manifestations of the Hunter's syndrome were fully developed, and were not, in any obvious way, ameliorated by the transfusions.     

BOVINE PROTHROMBIN FRAGMENT 1, SEGMENT 1–10

The N-terminal decapeptide methyl ester, H-Ala-Asn-Lys-Gly-Phe-Leu-Gla-Gla-Val-Arg-OCH₃ (16) of bovine prothrombin fragment 1 has been prepared by standard solution techniques, via a fragment coupling strategy. Hexapeptide Boc-Ala-Asn-Lys^e(Boc)-Gly-Phe-Leu-OBzl (9) was obtained by coupling Boc-Ala-Asn-Lys^e (Boc)Gly-OH (6) to the trifluoroacetate salt of H-Phe-Leu-OBzl (8). Hydrogenolysis of (9) followed by coupling to HCl-H-Gla^γ (O^tBu)₂-Gla^γ (O^tBu)₂-Val-Arg(HCl)-OCH₃ (14) gave the fully protected decapeptide (15). Treatment of 15 with 90% trifluoroacetic acid followed by ion exchange chromatography yielded the methyl ester (16). The decapeptide 16 labeled with¹²⁵I using the Bolton-Hunter reagent, did not bind to antibodies specific for the calcium ion-induced conformation of bovine fragment 1.