Nutritional vitamin B12 deficiency in an infant.
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Biomedical subjects
Publications and source records attributed to B C Lampkin.
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The in vivo therapeutic effect of vincristine, cytosine arabinoside, and corticosteroids on leukemic blast cells in the bone marrow was evaluated. 24 studies were done in 21 children with acute leukemia. 19 children had acute lymphoblastic leukemia, and two children had acute myeloblastic leukemia. Direct cytotoxicity or lysis of blast cells after drug administration was looked for by serial measurements of the volume of marrow buffy coat. Changes in proliferative capacity were evaluated by serial measurements of number of cells in mitosis and the per cent of cells in deoxyribonucleic acid (DNA) synthesis, as indicated by tritiated thymidine incorporation. Corticosteroid administration caused lysis of leukemic blast cells. Each drug affected the proliferative capacity of the leukemic cells by an action at a different part of the mitotic cycle. Corticosteroids suppressed the entry of cells into DNA synthesis. Vincristine arrested cells in mitosis. Cytosine arabinoside inhibited DNA synthesis. After the inhibitory effect of cytosine arabinoside, an increased number of cells began to synthesize DNA, a phenomenon indicating that partial synchronization of the mitotic cycle had been achieved in the leukemic cell population. The action of these drugs at different parts of the mitotic cycle might be important in designing treatment regimens where in two or more of these drugs are used.
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In 31 children with acute leukemia, the proliferative activity of the leukemic marrow cell population as measured by mitotic and labeling indexes varied widely from patient to patient and from one disease stage to another. Leukemic marrow had a small but statistically significant diurnal variation of proliferative activity. Changes in labeling indexes were directly related to changes in the proportion of large dividing blasts in the marrow. Generation times of dividing leukemic blast cells in 3 patients were similar at diagnosis and in relapse. Changes in proliferative activity of leukemic marrow can be explained by progressive accumulation of nondividing leukemic cells.
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Evidence that recessive cellular alleles at specific chromosomal loci are involved in tumorigenesis has been recently shown by work on tissues from patients with retinoblastoma, a neoplasm of embryonic retina whose predisposition is inherited as an autosomal dominant trait. A comparison of germ-line and tumour genotypes at loci on human chromosome 13, defined by restriction fragment length polymorphisms, showed that loss of the chromosome bearing the wild-type allele at the Rb-1 locus occurred frequently in the development of retinoblastoma. We report here results of similar studies of another embryonal neoplasm, Wilms' tumour of the kidney. Examination of germ-line and tumour genotypes from seven patients showed that five cases were consistent with the presence on human chromosome 11 of a locus in which recessive mutational events are expressed after abnormal chromosomal segregation events during mitosis.
Children with the Beckwith-Wiedemann syndrome have a greatly increased potential for the specific development of the embryonal tumours hepatoblastoma, rhabdomyosarcoma and Wilms' tumour. Data obtained with molecular probes suggest that the association between these disparate, rare tumour types reflects a common pathogenetic mechanism that entails the somatic development of homozygosity for a mutant allele at a locus on human chromosome 11.
A genetic description of the human genome requires maps of three types. The first shows the frequency of chromosomal interchange during meiosis, relying on many equally spaced markers, and is limited to interchanges that do not unmask defects lethal to the conceptus, whose every cell will contain such abnormalities. The second is the physical description of genomic regions defined by karyotypic rearrangements, DNA segments, genes, or their products. A third description of somatic chromosomal interchanges at mitosis is also required. Because mitotic exchanges occur in a single postembryonic somatic progenitor cell, lethal effects on the organism are reduced. These events have been important in genetic mapping in Drosophila melanogaster and fungi, but they have rarely been detected in mammals. Here we report a significant frequency of mitotic recombination in human tumours and the first application of this information in localizing their predisposing locus.
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Five patients with acute myeloid leukemia (AML) received a one hour infusion of iododeoxyuridine (IUdR) 100 mg/M2 to label S-phase cells in vivo. The aspirate was labeled in vitro either with tritiated thymidine (3HTdr) or bromodeoxyuridine (BrdU) to measure the duration of S-phase (Ts). The mean Ts using 3HTdr (Ts1) was 15.9h (13.1-19.8h) and using BrdU (Ts2) was 17.1h (14.5-20.6h). Total cell cycle time (Tc) ranged between 44.7h to 158.8h using Ts1 and 54.0h to 170.5h using Ts2. Based on this close approximation between the results, we confirm the reliability of the newly developed method that relies purely on immunohistochemical reaction.
The feasibility of a fluorescence in situ hybridization (FISH) technique for the detection of leukemic clones with masked chromosomal aberration in interphase nuclei was tested in childhood acute lymphoblastic leukemia (ALL). Twenty-one cases of ALL previously studied by classical metaphase cytogenetics were retrospectively analysed using a centromere-specific chromosome 7 probe. Five cases with karyotypic abnormalities of chromosome 7 (2 with trisomy 7, 2 with monosomy 7 and 1 with trisomy & tetrasomy 7) showed a correlation with FISH results, whereas in five other cases monosomy 7 was found in 12-43% of cells only by FISH. The unexpected detection of monosomy 7 in these latter ALL patients suggests that either these clones are quiescent or unable to enter mitosis in vitro. This suggests that FISH and metaphase cytogenetics must be combined whenever possible to obtain comprehensive karyotypic information.