Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Age-related changes in adaptation to severe anemia in childhood in developing countries(National Academy of Sciences, 2007) O Donnell, A.; Premawardhena, A.; Arambepola, M.; Allen, S.J.; Peto, T.E.; Fisher, C.A.; Rees, D.C.; Olivieri, N.F.; Weatherall, D.J.Severe forms of anemia in children in the developing countries may be characterized by different clinical manifestations at particular stages of development. Whether this reflects developmental changes in adaptation to anemia or other mechanisms is not clear. The pattern of adaptation to anemia has been assessed in 110 individuals with hemoglobin (Hb) E beta-thalassemia, one of the commonest forms of inherited anemia in Asia. It has been found that age and Hb levels are independent variables with respect to erythropoietin response and that there is a decline in the latter at a similar degree of anemia during development. To determine whether this finding is applicable to anemia due to other causes, a similar study has been carried out on 279 children with severe anemia due to Plasmodium falciparum malaria; the results were similar to those in the patients with thalassemia. These observations may have important implications both for the better understanding of the pathophysiology of profound anemia in early life and for its more logical and cost-effective management.Item A Novel molecular basis for beta thalassemia intermedia poses new questions about its pathophysiology(American Society of Hematology, 2005) Premawardhena, A.; Fisher, C.A.; Olivieri, N.F.; de Silva, S.; Sloane-Stanley, J.; Wood, W.G.; Weatherall, D.J.During a study of the molecular basis for severe forms of beta thalassemia in Sri Lanka, 2 patients were found to be heterozygous for beta thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated alpha globin genes in combination with heterozygous beta thalassemia. The other is homozygous for a triplicated alpha globin gene arrangement and heterozygous for beta thalassemia. Their differences in clinical phenotype are explainable by the interaction of other genetic factors and, in particular, their early management. The clinical course of the 2 propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with beta thalassemia intermedia associated with extended alpha globin gene arrangements. The hemoglobin (Hb) F levels in these patients with severe beta thalassemia intermedia, compared with other forms of this condition in the Sri Lankan population and elsewhere, are unusually low, a consistent finding in extended alpha globin gene interactions and in dominant beta thalassemia, raising the possibility that increased levels of HbF production in beta thalassemia may require mutations at both beta globin gene lociItem Haemoglobin E beta thalassaemia in Sri Lanka(Lancet Publishing Group, 2005) Premawardhena, A.; Fisher, C.A.; Olivieri, N.F.; de Silva, S.; Arambepola, M.; Perera, W.; O Donnell, A.; Peto, T.E.; Viprakasit, V.; Merson, L.; Muraca, G.; Weatherall, D.J.Haemoglobin E beta thalassaemia is the commonest form of severe thalassaemia in many Asian countries, but little is known about its natural history, the reasons for clinical diversity, or its management. We studied 109 Sri Lankan patients with the disorder over 5 years. 25 patients were not receiving transfusion; transfusion was stopped with no deleterious effect in a further 37. We identified several genetic and environmental factors that might contribute to the phenotypic diversity of the disorder, including modifiers of haemoglobin F production, malaria, and age-related changes in adaptive function. Our findings suggest that haemoglobin E beta thalassaemia can be managed without transfusion in many patients, even with low haemoglobin levels. Age-related changes in the pattern of adaptation to anaemia suggest that different and more cost-effective approaches to management should be explored.Item Iron overload and iron-chelating therapy in haemoglobin E/beta thalassaemia(Lippincott Williams and Wilkins, 2000) Olivieri, N.F.; de Silva, S.; Premawardhena, A.P.; Sharma S.; Viens, A.M.; Taylor, C.M.; Brittenham, G.M.; Weatherall, D.J.Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both non-transfused and transfused patients will be necessary to permit firm conclusions.Item Thalassaemia in Sri Lanka: implications for the future health burden of asian populations(Lancet Publishing Group, 2000) de Silva, S.; Fisher, C.A.; Premawardhena, A.P.; Lamabadusuriya, S.P.; Peto, T.E.; Perera, G.; Old, J.M.; Clegg, J.B.; Olivieri, N.F.; Weatherall, D.J.; Sri Lanka Thalassaemia Study GroupBACKGROUND: Thalassaemias pose an increasing problem for the Indian subcontinent and many Asian countries. We analysed the different types of thalassaemia in the Sri Lankan population, surveyed gene frequencies in schoolchildren, and estimated the burden of disease and requirements for its control. METHODS: We analysed blood samples from patients attending clinics in nine hospitals and defined the different types of beta thalassaemia by high-performance liquid chromatography (HPLC) and DNA analysis. The range of mutations was obtained by analysis of beta-globin genes. Capillary blood was obtained from schoolchildren from different parts of the island and analysed by HPLC to provide an approximate assessment of the carrier frequency of beta thalassaemia and haemoglobin E (HbE). To estimate the frequency of alpha thalassaemia the alpha-globin genotypes were also analysed when it was possible. FINDINGS: Blood samples were obtained from 703 patients with beta thalassaemia and from 1600 schoolchildren. The thalassaemia mutations were unevenly spread. Although 23 different beta-thalassaemia mutations were found, three accounted for the thalassaemia phenotype in about 70% of the patients, most whom are homozygotes or compound heterozygotes for IVS1-5 (G-->C) or IVS1-1 (G-->A). The third common mutation, codon 26 (G-->A), which produces HbE, interacts with one or other of these mutations to produce HbE/beta thalassaemia; this comprises 13.0-30.9% of cases in the main centres. Samples from 472 patients were analysed to determine the alpha-globin genotype. Overall, 15.5% patients were carriers for deletion forms of alpha+ thalassaemia. Average gene frequencies showed that there will be more than 2000 patients requiring treatment at any one time, in thefuture, of whom those with HbE/beta thalassaemia will account for about 40%. INTERPRETATION: In Sri Lanka, interactions of the two common beta-thalassaemia alleles will nearly always result in a transfusion-dependent disorder. However, about 40% of patients will have HbE/beta thalassaemia, which has a variable course. The management of these disorders could require about 5% of the total health budget. We need to learn more about the natural history and appropriate management of HbE/beta thalassaemia if resources are to be used effectively.