Editorial retrospective. Iron loading in thalassemia--five years with the pump.
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Biomedical subjects
Publications and source records attributed to S T Callender.
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The haematological aspects of life with an ileostomy have been studies in 51 patients, of whom 39 had had ulcerative colitis and 12 had Crohn's disease. The findings in these patients have been compared with those in 39 healthy volunteers who were matched for age and sex with the 39 patient who had had ulcerative colitis. There was evidence of a mild degree of iron deficiency in the patients with an ileostomy. This was partly due to a pre-existing iron deficiency resulting from their preceding illness and operation, as the abnormality was less pronounced in the patients in whom the ileostomy had been established for more than 3 years. There was some evidence of excessive iron loss and a controlled trial of ferrous fumurate showed that the iron deficiency was largely corrected by this means. Circulating levels of vitamin B12 were normal, but it is relevant that some of the Crohn's disease group were receiving parenteral supplements. The absorption of vitamin B12 wa low in the patients with Crohn's disease who had had an ileal resection of more than 17 cm. The absorption of vitamin B12 in the patients who had had ulcerative colitis was increased and possible mechanisms are discussed. All but one of the patients had normal levels of plasma folate and in all the red cell blood folate was normal, which can be taken as an indication of a good dietary intake and adequate absorption.
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A group of 82 adult patients with acute myelogenous leukaemia had survived in continuous first remission for more than three years was studied. These long-surviving patients were being treated at 12 referral centres in Europe and the USA, and they were compared with other patients with acute myelogenous leukaemia from 10 of these centres. There was no clear difference in the amount of induction chemotherapy or the time taken to achieve remission. Immunotherapy was not found to improve chances of long-term survival. The 82 patients were also compared with a group of 115 patients who had no appreciable difference in the number of blood or marrow myeloblasts between these two groups at presentation, but the long survivors had significantly higher initial platelet counts and were slightly younger. The long survivors also tended to have a lower total white cell count at presentation and lower granulocyte counts; there was no obvious explanation for these differences. Eight of the 82 patients relapsed from three to four years after remission and two (of 69 patients) after four to five year. Thereafter relapse was rare, and it seems likely that some of the 40 patients who have survived for five years or more are cured.
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Iron absorption and rates of iron accumulation were analysed in a group of patients with beta-thalassaemia intermedia. Iron absorption was strikingly increased and there was a progressive iron loading with increasing age. Balance studies indicated that by the time many of these patients reach the third or fourth decades their total iron loads may be of a similar magnitude to those of transfusion-dependent beta-thalassaemia homozygotes. If these patients are to be protected from cardiac, hepatic, and endocrine complications of iron overload in middle life it will be necessary to reduce gastrontestinal iron absorption, starting from early childhood.
Out of 64 consecutive unselected patients with acute myeloid leukaemia studied during 1973-6, five developed clinical evidence of spread to the central nervous system (CNS). Neuroradiological examination showed cerebral deposits in three, in whom rapid symptomatic relief was obtained with radiotherapy. In two of these patients who developed solid intracranial deposits haematological remission could be reinduced or maintained; they were still alive 86 and 134 weeks later. When patients presented with spread to the CNS complicating generalised uncontrolled leukaemia they had short survivals. CNS infiltration may respond dramatically to appropriate treatment provided that it is not associated with generalised uncontrolled leukaemia, which has a poor prognosis. In view of this, routine "prophylaxis" of the CNS in adult acute myeloid leukaemia does not seem justified at present.
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Urinary iron excretion after single intramuscular (i.m.) bolus injections or 12 h subcutaneous (s.c.) infusions of desferrioxamine (D.F.) was determined in sixteen homozygous beta-thalassaemia patients whose ages ranged from 10 months to 23 years. At all ages the s.c. infusions resulted in greater iron loss than identical i.m. doses. With doses of 0.5-1 g of D.F. as s.c. infusions eight out of nine children aged less than 6 years with a total transfusion iron load of less than 10 g excreted sufficient iron to achieve iron balance. These results suggest that iron loading in transfusion-dependent thalassaemics may be preventable by the use of an appropriate chelation regimen started early in life.
1. Urinary iron excretion after desferrioxamine has been examined in nine patinets with different iron-loading anaemias. Particular attention has been paid to individual variation in response and the kinetics of iron removal in order to determine the most efficient and convenient method of administration. 2. Twelve-hour subcutaneous infusions of desferrioxamine were comparable with intravenous infusions and gave a mean value of 62% more iron excretion than similar intramuscular bolus doses (range 20--125%). 3. Increasing doses as 12 h subcutaneous infusions produced a linear increase in iron excretion, which was followed by a tendency to reach a plateau. Iron excretion varied greatly between patients, was not related solely to age or estimated iron load, and in most cases was increased by ascorbic acid saturation. 4. Maximum iron-excretion rates were achieved after 3--6 and then maintained throughout an infusion. With bolus injections excretion rates declined rapidly after the first 6 h, during which approximately 60% of the total iron excretion occurred. 5. The dose and method of administration should be 'tailor-made' for each patient. Overnight 12 h subcutaneous infusions can be both as effective as similar doses given over 24 h and a practical way of achieving substantial negative iron balance. 6. Since children receiving regular blood transfusions for congenital anaemias such as thalassaemia usually die at the end of the second decade, this approach to iron chelation offers the possibility of alleviating what have hitherto been fatal-iron loading states.
Absorption of 59Fe ferrous sulphate was measured in patients with a variety of iron-loading anaemias both before and during subcutaneous infusions of desferrioxamine. The infusions were associated with a reduction in absorption (P less than 0-025). This effect was not altered by saturation with ascorbic acid.
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The intrinsic factor (IF) output during basal and Histalog-stimulated gastric secretion has been estimated in two series of patients with chronic duodenal ulcer before and 3 months or more after treatment by either highly selective vagotomy or truncal vagotomy and pyloroplasty. The effects of the two different vagotomy operations appear to be virtually identical and each produced significant reductions in intrinsic factor secretion after Histalog stimulation. This confirms the view expressed by previous workers that it is the vagotomy as such which is responsible, excluding the drainage procedure from any possible role. Furthermore, as these results were demonstrated 3 months after operation, it is likely that the depressed IF secretion is a permanent feature and one which, it is postulated, may become progressively more severe. In both series there is a marked reduction in IFoutput during the second hour of stimulated gastric secretion, indicating an early wash-out of preformed IF. This persists after vagotomy.
Three members of an Oxfordshire family have polycythaemia. In each case their whole-blood oxygen affinity is increased. This is due to a previously undescribed haemoglobin variant which has been named haemoglobin Radcliffe (alpha2beta299(Gl)Ala). In addition to having a high oxygen affinity haemoglobin Radcliffe shows virtually no haem-haem interaction and a diminished Bohr effect. It is synthesized at the same rate and is as stable as haemoglobin A. X-ray analysis indicates that crystals of deoxyhaemoglobin Radcliffe are isomorphous with those of deoxyhaemoglobin A. Solutions of haemoglobin Radcliffe were also studied by high-resolution proton nuclear magnetic resonance spectroscopy. The structure/function relationships of haemoglobin Radcliffe are discussed in the light of these studies.
Absorption from a 5 mg dose of iron as Fe++ or haemoglobin iron was studied using a Total Body Counter in control subjects and patients with coeliac disease. In both groups the majority of subjects were iron deficient. Thirteen control subjects, 13 patients with untreated coeliac disease and 14 on treatment with gluten-free diet had both absorption tests. Absorption of Fe++ iron was reduced in untreated coeliac disease. This was particularly significant in iron deficient patients. Absorption was improved on treatment with gluten-free diet; In contrast, the absorption of haemoglobin iron was not affected in coeliac disease, indicating that absorption of iron in this form is not dependent on the integrity of the mucosa of the proximal small bowel.