Summary. The susceptibility of human red cells to autoxidation was measured (i) in various groups of normal subjects, (ii) in haemolytic states, and (iii) in non‐haemolytic disease. Many types of haemolytic disease—notably thalassaemia major and autoimmune haemlytic anaemia—were associated with a greatly and persistently increased susceptibility of the red cell lipids to autoxidation. In two patients with haemolytic disease this was the only biochemical abnormality found. Susceptibility to autoxidation is about three times higher in the newborn period than it is in adult life; and there is a comparatively wide scatter in old age.

At University College Hospital and the Whittington Hospital in London we have 31 children with thalassemia major, most of them under 16 years of age. They are mostly the offspring of parents who have emigrated from Cyprus in the last 20 years. The 24 who require transfusion are maintained on a moderateley high scheme; i.e., the hemoglobin is raised from 9 up to 14 g % by six or eight weekly transfusions. Since there can no longer be any doubt that thalassemic patients with transfusional siderosis develop symptoms attributable to iron overload, usually starting around puberty, we have felt that the only hope of a reasonable long-term prognosis lies in the use of iron-chelating agents. Thalassemic patients on maintenance transfusion do not usually excrete significant quantities of iron in the urine in response to desferrioxamine until they are about three years old, because they must have an abnormal iron load to respond to the drug at all. This in itself is the central problem of chelation therapy. Once they have passed their third birthday, all our patients receive desferrioxamine, 500 mg intramuscularly six days a week, and 2 g/pint in the blood at transfusion. We have had twelve patients on long-term chelation, ten for three years and two for five years; the remaining patients are either too young or have only recently come into our care. The injections have been well tolerated, and there have been no complications of any kind from the use of desferrioxamine. We have measured the amount of iron excreted in the urine, and clinical observations have included liver biopsy and endocrinological studies in some patients. Measurements of liver-iron concentration have been done by Dr. Michael Barry.It is still too early to assess the clinical value of the chelation scheme we are using, but nevertheless some useful observations can be made at this stage. These clinical observations will be presented under the three headings of our expectations, our findings, and improvements in our chelation scheme in the light of these findings.Our expectations are outlined in FIGURE 1, which shows the factors affecting iron balance in a thalassemic patient on chelation therapy. First on the input side is excessive gastrointestinal iron absorption, which can reach 10 mg/day in an anemic patient. We know little about this except that it is reduced by transfusion,l and that it can be a substantial item in our patients. The major factor on the input side is iron received as blood, which averages 5-15 mg/day in our patients, according to age and transfusion status. On the output side, there are spontaneous losses of iron in the urine and stool. Our patients over four years old, when not chelated, lose on average 1.5 mg/24 hr (range 0.1-2.2

The iron chelating ability and potential toxicity of subcutaneous infusions of the calcium and zinc salts of diethylene triamine penta‐acetic acid (DTPA) have been assessed in metabolic balance studies in 2 iron‐loaded thalassaemic patients. Infusions of calcium DTPA were locally well tolerated and the drug was as effective as desferrioxamine in mobilising iron. However, daily infusions in the 1st patient also produced symptomatic zinc depletion which could not be controlled by simultaneous oral zinc supplements. Zinc DTPA proved ineffective as an iron chelator, but zinc balance could be maintained in the 2nd patient by combining intermittent (every 4 d) use of calcium DTPA with oral zinc supplements. Combined studies with desferrioxamine and calcium DTPA showed the drugs to have additive effects, probably as a result of the chelation of iron from different body sites.

Summary. The incorporation of radioactive amino acids into the polypeptide chains of haemoglobin has been studied in reticulocyte preparations from five patients with β‐thalassaemia and four control patients. In both groups of patients an intracellular pool of free α‐chains has been found, but the pool is much larger in patients with β‐thalassaeniia major. The α‐chains exist in two forms: α‐dimers and α‐monomers, but the results suggest that they are released as dimers from the ribosomes and that the α‐chains for Hb‐A and Hb‐F synthesis are derived from the α‐dimer pool. The α‐dimers are also gradually converted to the monomers, and this may be the first stage in the denaturation of this protein. The results also show that the α‐dimer can exchange with the α‐chains of Hb‐A and that this exchange is more rapid in the presence of in vivo aged Hb‐A. In one patient with thalassaemia it was shown that there was no pool of unreleased β‐chains on the ribosomes. There is also no evidence for the release of incompleted β‐chains in our patients.