Elevated levels of haemoglobin F (Hb F) have been foudn in a wide range of haematological malignancies, but very high levels were found only in juvenile chronic myeloid leukaemia (JCML), and erythroleukaemia occurring in infancy. In both these disorders a reversion to a fetal form of erythropoiesis may occur, as judged by both the structure of the Hb F and by the disappearance of Hb A2 and the carbnoic-anhydrase isozymes during the course of the illness. The clinical picture of JCML is not always associated with a reversion to fetal erythropoiesis; there appears to be a heterogeneity of conditions with this clinical label. Thus the reversion to a completely fetal pattern of erythropoiesis seems to occur in a variety of leukaemias which start in early life. This change is associated with a uniformly bad prognosis. Of a group of 17 patients with acute myeloid leukaemia 15 developed an increase in the level of Hb F about 60 days after the commencement of treatment; significantly greater increases were observed in those achieving a clinical remission. The level of Hb F usually declined during remission but high levels persisted in a few cases. Increased levels of Hb F were found also in patients with other haematological malignancies who had undergone periods of marrow aplasia during treatment. In all cases the Hb F was heterogeneously distributed throughout the red cells. Analysis of gamma15 or gammaCB3 peptides of Hb F from a variety of leukaemias gave glycine compositions ranging from 0.20 to 0.85 residues with many values in the fetal range; all cases with a reversion to fetal erythropoiesis had values in the fetal range. Attempts to confirm the 'fetal' origin of the cells containing Hb F by means of other markers was possible only in the cases of JCML and in one child with erythroleukaemia. These studies indicate that in some forms of leukaemia there may be a genuine reversion to fetal erythropoiesis while in others the emergence of cells containing Hb F appears to be part of a rapid regeneration process occurring after a period of marrow aplasia. The diagnostic and prognostic value of these observations is discussed.
Summary. The in vitro synthesis of the α and β peptide chains of globin have been measured in 11 patients suffering from sideroblastic anaemia (four congenital and seven idiopathic acquired). In the I0 patients who were anaemic the findings were similar. The synthesis of the globin chains was found to be defective in two respects; firstly, synthesis was asynchronous with an apparent deficiency of the synthesis of α chains, and, secondly, a large proportion of both α and β chains synthesized were not associated with haem but were free in the cell in the form of αβ dimers. Addition of haem to the incubation mixture greatly stimulated the synthesis of both chains, removed the free dimer pool and appeared to stimulate a chain synthesis. The finding that a large proportion of the α and β chains synthesized are not associated with haem but are free within the cell as a dimer pool, is very strong evidence that the underlying defect in sideroblastic anaemia is haem deficiency. The defective synthesis of a chains relative to β chains is as yet unexplained but may account for the low haemoglobin A2 associated with this condition.
Summary. The effect of pyridoxal‐5‐phosphate, δ‐aminolaevulinic acid and haematin hydrochloride on the in‐vitro synthesis of globin by reticulocytes has been examined in sideroblastic anaemia. In each of the seven patients studied, haematin consistently stimulated globin synthesis. In two siblings suffering from congenital sideroblastic anaemia δ‐ALA also stimulated globin synthesis. It was, however, ineffective in another patient with the same disorder with different clinical and haematological features. This evidence strongly supports our earlier conclusions that sideroblastic anaemia is brought about by a deficiency of haem. It also demonstrates biochemical heterogenity in the congenital type of sideroblastic anaemia.
Quantitative experiments to study the binding of acetylsalicylic acid (ASA) and salicylic acid (SA) by human serum albumin (HSA) were carried out using 14C-labeled ASA or SA and gel filtration to separate the free from the bound forms. Two binding procedures were employed: the ASA or SA was incubated with the HSA, or the mixture was placed in an equilibrium dialysis cell. By withdrawing samples at intervals, the extent of binding or the attainment of equilibrium could be assessed. Evidence that filtration by the gel caused unbinding of the bound SA was obtained, with resultant lower percentage binding of SA by HSA than that obtained by equilibrium dialysis without gel filtration. In either case, binding equilibrium was reached in 4-8 hr. The binding of ASA by HSA was markedly different from that of SA. The experiments both with or without gel filtration demonstrated a progressive increase in binding of ASA in the 20- to 53-hr periods studied. In addition, ASA apparently displaces SA from its binding sites on albumin, an observation that may have therapeutic implications.
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