Search PubMed⌕ Search

Biomedical subjects

D J Weatherall

Publications and source records attributed to D J Weatherall.

At least 37 records · Page 2Linked to original sources
PubMed2000

Red cells I: inherited anaemias.

Examination of the genetic mechanisms underlying the thalassaemias has led to a clearer understanding of the control of eukaryotic genes in general. Inherited disorders of haemoglobin synthesis are an important cause worldwide of morbidity and mortality, and place a large burden on patients, families, and ultimately communities. The haemoglobin disorders can be controlled, by counselling and prenatal diagnosis. Treatment is usually symptomatic, though bone-marrow transplantation for beta-thalassaemia may be successful in suitable patients.

Erythrocyte Membrane↗
PubMed2000

Thalassaemia in Sri Lanka: implications for the future health burden of Asian populations. Sri Lanka Thalassaemia Study Group.

BACKGROUND: 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 the future, 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.

Adult↗
PubMed2000

Rapid detection of alpha-thalassaemia deletions and alpha-globin gene triplication by multiplex polymerase chain reactions.

We describe a sensitive, reliable and reproducible method, based on three multiplex PCR assays, for the rapid detection of seven common alpha-thalassaemia deletions and one alpha-globin gene triplication. The new assay detects the alpha0 deletions - -SEA, - (alpha)20.5, - -MED, - -FIL and - -THAI in the first multiplex PCR, the second multiplex detects the -alpha3.7 deletion and alphaalphaalphaanti3.7 variant, the third multiplex detects the -alpha4.2 deletion. This simple multiplex method should greatly facilitate the genetic screening and molecular diagnosis of these determinants in populations where alpha-thalassaemias are prevalent.

Gene Deletion↗
PubMed1999

Why are hemoglobin F levels increased in HbE/beta thalassemia?

To try to further define the mechanisms that increase the levels of hemoglobin F (HbF) in the blood of patients with severe forms of beta thalassemia, we have studied two comparable populations of hemoglobin E (HbE)/beta thalassemics, one regularly transfused and one receiving only occasional blood transfusions. Regular transfusion was associated with a significant decrease in soluble transferrin receptor and erythropoietin levels. Globin chain synthesis studies also show a highly significant decrease in HbF synthesis relative to HbE in the transfused patients. This effect was confirmed by sequential data on one patient, studied before and after the commencement of regular blood transfusion; blood transfusion was followed by a marked increase in the alpha/gamma, beta(E)/gamma, and HbE/HbF ratios. These data suggest that the high HbF levels in HbE/beta thalassemia, and other beta thalassemia syndromes, result from increased erythropoietin levels leading to bone marrow expansion, and possibly increased F-cell production, combined with ineffective erythropoiesis giving a survival advantage to F cells. This study also suggests that alteration in blood transfusion regimes must be taken into account when interpreting changes in HbF levels seen in trials of HbF-promoting drugs.

Adolescent↗
PubMed1999

Multicentric origin of hemochromatosis gene (HFE) mutations.

Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends </=6 Mb, suggesting that this mutation has arisen during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending </=700 kb. Here we report the finding of the H63D and C282Y mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.

Alleles↗
PubMed1999

Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3.

Southeast Asian ovalocytosis (SAO) occurs at high frequency in malarious regions of the western Pacific and may afford a survival advantage against malaria. It is caused by a deletion of the erythrocyte membrane band 3 gene and the band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The SAO band 3 variant may prevent cerebral malaria but it exacerbates malaria anemia and may also increase acidosis, a major determinant of mortality in malaria. We undertook a case-control study of children admitted to hospital in a malarious region of Papua New Guinea. The SAO band 3, detected by the polymerase chain reaction, was present in 0 of 68 children with cerebral malaria compared with six (8.8%) of 68 matched community controls (odds ratio = 0, 95% confidence interval = 0-0.85). Median hemoglobin levels were 1.2 g/dl lower in malaria cases with SAO than in controls (P = 0.035) but acidosis was not affected. The remarkable protection that SAO band 3 affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium, and thus of the pathogenesis of cerebral malaria.

Animals↗
PubMed1999

Reduced soluble transferrin receptor concentrations in acute malaria in Vanuatu.

Soluble transferrin receptor (sTfR) concentration is a sensitive index of iron deficiency when used in conjunction with ferritin measurements in adults. One advantage of this assay is that unlike ferritin it does not appear to be affected by a range of infectious and inflammatory conditions or by pregnancy, rendering it a promising adjunct to the diagnosis of iron deficiency in tropical populations. We have measured plasma sTfR concentrations in a group of malaria patients (n = 21) and asymptomatic (18) and aparasitemic (76) controls in Vanuatu. Plasma sTfR concentration was significantly reduced in individuals with acute malaria (P = 0.003). While this observation provides evidence that erythropoeitic suppression may be an important etiologic component in malarial anemia, it also suggests that malaria may be a confounding factor when interpreting sTfR concentrations in such populations. The role of sTfR in the diagnosis of iron deficiency in tropical populations remains to be established.

Adolescent↗
PubMed1999

Genetic disorders of hemoglobin.

The inherited disorders of hemoglobin, the most common monogenic diseases, are now well understood at the molecular and cellular level, knowledge which has led to considerable Improvements in their control and management. Because of their particularly high gene frequencies in sub-Saharan Africa, the Indian subcontinent, and throughout Southeast Asia, the organization of their control and treatment provides a major challenge for the new millennium.

Family Health↗
PubMed1998

Gene therapy: repairing haemoglobin disorders with ribozymes.

A ribozyme-mediated approach has made it possible to replace the region in beta globin mRNA containing the sickle-cell-anaemia mutation with a gamma-globin-encoding sequence. This is an interesting new way of correcting monogenic disease, but there are major problems to overcome before it could be applied in the clinic.

Anemia, Sickle Cell↗
PubMed1998

Is hemoglobin instability important in the interaction between hemoglobin E and beta thalassemia?

Hemoglobin E (HbE; alpha2beta226glu-lys), globally the commonest hemoglobin variant, is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous beta thalassemia. Yet, when it is inherited together with a beta thalassemia allele, the resulting condition, HbE/beta thalassemia, is sometimes characterized by a severe, transfusion-dependent thalassemia major. The severity of this interaction has not been explained. We have explored the possibility that it may reflect the instability of HbE consequent upon globin chain imbalance imposed by the beta thalassemia allele. Time-course and pulse-chase globin chain synthesis studies at 37 degrees C on peripheral blood and bone marrow suggest that hemoglobin instability is not significant in steady-state HbE/beta thalassemia; this is confirmed by density-gradient centrifugation studies that show no decrease in HbE levels relative to HbA as HbE/beta+ thalassemia red blood cells age. Globin binding to membranes was assessed and only alpha globin chains were found, in contrast to other unstable hemoglobins in which both alpha and beta chains were present. However, in experiments performed on blood from HbE/beta thalassemics in the temperature range 39 degrees C to 41 degrees C, there was evidence of instability of HbE, a finding that was also observed in homozygous HbE. These findings suggest that the phenotype of HbE/beta thalassemia is primarily the result of the interaction of two beta thalassemia alleles; however, hemoglobin instability may be important during febrile episodes, contributing to worsening anemia.

5'-Nucleotidase↗
PubMed1998

Thalassemia in the next millennium. Keynote address.

Over the next decade it will be essential to make the thalassemia problem more visible to governments and international health agencies that are involved in health care in the emerging countries. This will require detailed population surveys to determine the gene frequencies of the important forms of thalassemia, together with a better understanding of their natural history and of the factors that modify their clinical phenotypes. In particular, more needs to be learnt about the natural history and ways of managing the intermediate forms of beta thalassemia. While research should continue towards definitive forms of treatment it is important, in the meantime, to pursue the development of cheap and safe oral chelating agents and to carry out clinical trials of drugs that may interact one with another to elevate the level of fetal hemoglobin, particularly in patients with different types of beta thalassemia intermedia. The partial control of the disease by carrier detection and prenatal diagnosis will only be feasible in emerging countries if it is possible to obtain the financial support of the major international agencies and the cooperation of their governments and communities; the remarkable success of this approach in some of the Mediterranean islands is a good example of what can be achieved.

Female↗