The action of vitamin B12.
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Biomedical subjects
Publications and source records attributed to T E Parry.
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A panel of five haematologists has examined, without consultation or prior knowledge of the diagnosis, blood films and bone marrow smears from 456 patients with a diagnosis of leukaemia. A diagnostic classification which recognized various subtypes of acute myelogenous leukaemia was used but no attempt was made to subdivide acute lymphoblastic leukaemia. Complete agreement with the initial diagnosis was low (56.4%) and was particularly poor (45.7%) when the patient had one of the forms of acute leukaemia. However, disagreements which would have involved the patient in a change of treatment were unusual (2.0%). We conclude that a high degree of diagnostic agreement for patients with leukaemia is unlikely from morphological classifications alone.
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The bone marrow cells of a patient with congenital dyserythropoietic anaemia, type II, were incubated with 3H-thymidine, 3H-uridine or 3H-leucine for 1 h and studied using the technique of electron microscope autoradiography. Several of the erythroblasts which either displayed the characteristic subsurface double membranes or showed various non-specific abnormalities of the nuclear membrane were found to be actively engaged in DNA, RNA and protein synthesis. Both members of some pairs of erythroblasts which were joined together by a spindle bridge were found to be engaged in DNA synthesis, indicating that some spindle bridges persist for a period longer than the duration of the G1 phase. A small proportion of mononucleate and binucleate late (non-dividing) erythroblasts showed a marked depression or arrest of protein synthesis and some or all of such cells were presumably destined to be phagocytosed by the bone marrow macrophages.
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The serum "uracil+uridine" level, expressed as uracil, has been measured in 21 cases of vitamin B12 deficiency, in which the serum folate was normal, and compared with the level in 97 normal subjects. The level in the vitamin B12 deficient group (11.9 mumol/1). was significantly lower than in the controls (15.7 mumol/1., P less than 0.005). Nine of the former were complicated by stystemic illness but the clinical and haematological features in the remaining 12 were consistent with the diagnosis of pernicious anaemia in relapse. The serum uracil level in this group was even lower (10.21 mumol/1., P less than 0.01). This finding is unexpected in view of the generally accepted indirect role of vitamine B12 in the methylation of deoxyuridine monophosphate to deoxythymidine monophosphate. Reasons are given for not accepting these results as reflecting the main biochemical lesion in vitamin B12 deficiency. Although they do not give direct support to an impairment in the methylation of deoxyuridine monophosphate, they do not exclude it as they test only one possible metabolic pathway and moreover they could represent the result of more than one action of vitamin B12 on uracil metabolism. They do show, however, that some aspect of uracil metabolism other than methylation is affected in vitamin B12 deficiency in man.
The serum "uracil+uridine" levels, expressed as uracil, have been measured in 10 cases of pernicious anaemia both before and after treatment, and compared with the levels in 97 normal subjects. The mean pre-treamtent value (8.82 mumol/1., range 6.0-12.0 mumol/1.) differed significantly from that of the normal controls (15.7 mumol/1., range 5.7-40.5 mumol/1., t = 8.8, P less than 0.001). This confirms the low serum uracil level previously reported in pernicious anaemia relapse. The level rose progressively after treatment, reaching a maximum on the fourth day (mean 17.85 mumol/1., range 9.3-23.4 mumol/1.). This was not significantly different from the mean of the normal control group. The difference between the pre- and post-treatment levels was significant on days 3,4 and 5 (P less than 0.005, P less than 0.001 and P less than 0.005 respectively) and the rise preceded the reticulocyte response by 24 h. A further case was treated with pysiological doses of vitamin B12 (2 mug daily for 6 d) and a similar rise in the serum uracil level noted. These results are not explained by any of the known functions of vitamin B12. They are, however, similar to the changes in the serum methionine levels previously reported in pernicious anaemia. The latter were readily explained by the known action of vitamin B12 on "de novo" methionine synthesis and it is suggested that the synthesis of uracil, like that of methionine, might be influenced by vitamin B12 in man.
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