Isochromosome of a deleted 20q: a rare but recurrent chromosome abnormality in myelodysplastic syndromes.

Interstitial deletion of the long arm of chromosome 20, as the sole abnormality, is commonly observed in myeloid malignancies, including myeloproliferative disorder, myelodysplastic syndrome, and acute myeloid leukemia. The breakpoints of the deletion are typically located in the region 20q11.2 approximately q13.3, although smaller deletions within this region have also been reported. We present here 4 patients with myelodysplastic syndrome with an isochromosome of the deleted long arm of chromosome 20: ider(20)(q10)del(20)(q11q13). Fluorescence in situ hybridization studies were performed on the bone marrow samples from these patients to prove the identity of this unusual chromosome abnormality.

Iron state and hepatic disease in patients with thalassaemia major, treated with long term subcutaneous desferrioxamine.

Liver biopsies were performed on 51 regularly transfused patients with beta thalassaemia, age range 5-36 (mean 18.6) years, who had received regular subcutaneous desferrioxamine (DFX) treatment for periods between one and eight years (40 for eight years). The biopsy specimens were examined by light microscopy and immunofluorescence for hepatitis B virus surface and core antigens (HBsAg and HBcAg), and the iron content was determined chemically. The results were compared with serum ferritin concentration and aspartate transaminase (AST) activity and with hepatitis B virus serology. Biopsy specimens, in which chemical liver iron had been determined in 12, were also available from 17 patients. Mean serum ferritin (+/- SD) had fallen from 5885 (3245) micrograms/l to 1638 (976) micrograms/l in 36 patients after eight years' chelation, while mean (+/- SD) liver iron concentration had fallen from 2945 (900) micrograms/100 mg dry weight to 857 (435) micrograms/100 mg dry weight in 12 of them. All biopsy specimens examined were negative for HBs and HBc antigens. The presence of histological features of hepatitis was associated with increased liver iron content, increased fibrosis, and with progression of fibrosis between the two biopsies. Procollagen III peptide was assayed in 28 patients but did not correlate with the degree of hepatitis, fibrosis, or with chemical liver iron content. We conclude that with regular subcutaneous DFX, mean concentrations of serum ferritin and liver iron are maintained in these patients at about five and 10 times the normal value, respectively, and that progression of liver damage is more likely to be due to viral hepatitis, presumably related to the parenterally transmitted non-A, non-B agents than to iron overload.

Deletion of chromosome arm 15q and hitherto unreported duplication of del(15q) in myeloid disorders.

Deletion of the long arm of chromosome 15 has been described as a recurrent chromosomal abnormality in myeloid malignancies. We present here some additional case reports of deletion 15 including two cases with an extra copy of the deleted chromosome, a finding that has not previously been described. We compare our cases to those previously reported. Our findings show that, contrary to previous reports, this abnormality may not always be associated with an unfavorable prognosis. They also indicate that deletion 15q most frequently appears to be associated with myelomonocytic disease. Potential candidate genes on 15q that may be involved in the tumorigenesis of these cases are discussed.

Racial differences in the energy cost of standardised activities.

The assumption is currently made by international organisations that individuals of the same size living in the same environment and having the same mode of living will have the same energy requirements whatever their race. Reports of very low energy intakes are frequently doubted. To investigate possible racial differences the energy cost of standardised activities was measured in European, Asian, and African males under the same experimental conditions. Subjects were closely matched for height, weight and Quetelet index. The energy cost of each activity, lying, sitting and standing, was significantly higher, by 10-17%, in Europeans as compared to Asians and Africans, between whom no differences were found. Whether these differences are morphological or metabolic is discussed. It is concluded that differences in energy requirements do exist over and above those due to body size and activity.

Intradermal hepatitis B vaccine in thalassaemia and sickle cell disease.

Thirty two patients with beta thalassaemia and sickle cell disease who were having regular blood transfusions were selected to test the efficacy and immunogenicity of low dose (2 micrograms or 0.1 ml) intradermal hepatitis B vaccine compared with the standard (20 micrograms or 1 ml) intramuscular dose. There was no significant difference in the rates of seroconversion, seroconversion had occurred in all patients by seven months. There were no significant differences in antibody titres between the intramuscular and intradermal groups at 1, 2, and 6 months. Although the titres were significantly higher in the intramuscular group at seven months and at 12-18 months, the antibody titre in the intradermal group did not fall below 10 IU/l. The results of this study suggest that low dose intradermal hepatitis B vaccination is an effective and economical way of stimulating an immune response in patients with beta thalassaemia and sickle cell disease.

1,2-Dimethyl-3-hydroxypyrid-4-one, an orally active chelator for treatment of iron overload.

Subcutaneous desferrioxamine, though effective in preventing or reducing iron overload in transfusion-dependent refractory anaemia, is expensive and inconvenient. One potentially cheaper and orally active alternative is 1,2-dimethyl-3-hydroxypyrid-4-one (L1). This drug has been tested in three multiply transfused patients with myelodysplasia. Gelatin capsules were taken at doses ranging from 0.5 g to 3.0 g. Urinary iron excretion increased substantially in all three patients and in the one tested was equal to that achieved with comparable doses of subcutaneous desferrioxamine. The amounts of iron excreted were related to the dose of L1 administered and the iron load of the patients. The urinary excretion of zinc, magnesium, and calcium did not increase, and the drug was well tolerated.

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.

Reversal of desferrioxamine induced auditory neurotoxicity during treatment with Ca-DTPA.

Auditory neurotoxicity occurred in 13 (26%) of 50 evaluable patients receiving long term desferrioxamine chelation. In five of these patients, all of whom were receiving high doses of desferrioxamine, the toxicity caused deafness. These five patients were treated with subcutaneous calcium diethylene triamine pentacetic acid (Ca-DTPA) with zinc supplements instead of desferrioxamine, and their hearing improved during periods of seven to 19 months. Their serum ion concentrations remained unchanged. We suggest that all patients receiving long term desferrioxamine should have audiometric assessments at 6-12 monthly intervals. Ca-DTPA with oral zinc supplements should be considered as alternative to desferrioxamine as an iron chelating treatment in patients with auditory neurotoxicity.

High incidence of cardiomyopathy in beta-thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation.

Cardiac scintigraphy has been performed in 60 beta-thalassaemia major patients aged 8-35 years who received regular blood transfusions and subcutaneous desferrioxamine (DFX) chelation. Fifty-seven showed no clinical, radiological or electrocardiographic evidence of heart disease and 3 had clinically apparent cardiac failure. Twenty-two patients (37%) showed severe cardiac functional impairment defined by a resting left ventricular ejection fraction (LVEF) less than 45% and/or a drop of greater than 12% on stress, while 19 were normal and 19 had a mild abnormality. There was no significant correlation between abnormality of LVEF and age, serum ferritin, number of units transfused, dose and duration of subcutaneous DFX therapy, liver disease or sexual maturation. Non-compliant patients (defined as the use of subcutaneous DFX less than 4 times weekly) generally showed worse cardiac function. Repeat study on 17 patients after 6-28 months of better compliance with subcutaneous or intravenous DFX (using an indwelling catheter) showed a significant overall improvement in LVEF associated with a significant drop in serum ferritin. We conclude that cardiac scintigraphy uncovers a high incidence of cardiac functional abnormality in asymptomatic, well-transfused thalassaemia patients, particularly those poorly compliant with chelation. Those with poor LVEF results should be offered intensive chelation therapy to improve cardiac function.