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Biomedical subjects

D J Weatherall

Publications and source records attributed to D J Weatherall.

At least 289 records · Page 16Linked to original sources
PubMed1981

Haemoglobin synthesis by fetal erythroid cells in an adult environment.

Although the developmental switch from fetal to adult haemoglobin production has been well characterized in terms of protein synthesis, very little is known about its control at the cellular level. In order to determine whether the switch is controlled by environmental factors or programmed into the haemopoietic cell population, we have studied the effects of transplantation of fetal and adult haemopoietic cells into lethally irradiated lambs on haemoglobin synthesis by the transplanted cells. In two lambs which were irradiated but not transplanted, two lambs which were grafted with autologous marrow, and one lamb which was grafted from an allogenic twin, haemoglobin synthesis showed an adult pattern following transplantation, with gamma-chain synthesis never exceeding 7% of non-alpha chain production. Of 11 lambs transplanted with fetal haemopoietic cells, only two showed evidence of engraftment. During the 24-26 d that these animals survived, haemoglobin synthesis showed a predominantly fetal pattern, though there was a gradual increase in beta-chain production of donor origin. This increase occurred earlier than would be expected from the gestational age of the transplanted cells, but more slowly than might be expected if environmental factors were entirely responsible for expression of adult or fetal haemoglobin synthesis.

Aging↗
PubMed1981

Ultrastructure of red cells containing haemoglobin H inclusions induced by redox dyes.

Electron microscope studies have been performed to investigate the ultrastructural basis of the characteristic golf-ball-like light microscope appearance which develops when the erythrocytes of patients with HbH disease are stained supravitally with brilliant cresyl blue or new methylene blue. The data indicate that the golf-ball appearance resulted from the formation of many spherical or biconvex masses of electron-dense material which were attached to and which bulged the cell membrane. These masses presumably consisted of denatured HbH. A variable proportion of the red cells of the four patients investigated failed to form such membrane-associated inclusions even after treatment with redox dyes for 24 h. Studies of subpopulations of red cells which were separated according to cell age suggested that there was a considerable variation in the HbH content of young red cells and indicated that with increasing cell age there is an increase in the proportion of red cells which do not contain appreciable quantities of HbH.

Coloring Agents↗
PubMed1981

Continuous long-term culture of human bone marrow.

Human bone marrow was cultured with alpha medium, 10(-6)M hydrocortisone and a mixture of horse and fetal calf serum in a long-term liquid culture system. An adherent layer was formed with contained fat cells, macrophages, fibroblast-like and epithelioid cells. The layer harboured myeloid cells and their presumptive precursors whilst the nonadherent cells were composed of immature myeloid elements plus mature macrophages and granulocytes whose numbers were maintained for periods of up to 12 weeks. Experiments showed that the use of serum mixtures was superior to horse or fetal calf serum alone and successful culture was accompanied by early growth of the hydrocortisone-dependent fat cells in the adherent layer.

Bone Marrow Cells↗
PubMed1981

Haemoglobin synthesis in human erythroid bursts during ontogeny: reproducibility and sensitivity to culture conditions.

Patterns of haemoglobin (Hb) synthesis were analysed in erythroid bursts grown in vitro from human fetal, umbilical cord and adult blood to determine the reproducibility of the system and its sensitivity to various alterations in culture conditions. The proportion of Hb F synthesis in duplicate plates from the same sample showed little variation but when an individual was studied under the same conditions but at different times, far more variability was observed. We have confirmed that the synthesis of Hb F and Hb A in the cultures is asynchronous, relatively more Hb F being synthesized earlier in the maturation of the colony. Hence factors affecting colony maturation are likely to change the apparent pattern of Hb synthesis. Removal of adherent cells prior to plating resulted in the presence of more mature colonies and lower levels of Hb F synthesis at any fixed time in culture. Furthermore, the overall ratio of gamma:beta chain synthesis measured in the whole plate was dependent on the proportion of large, immature multicluster bursts present. The significance of measurements of Hb synthesis in erythroid bursts can be assessed only if all of these factors are recognized and taken into account.

Adult↗
PubMed1980

A new genetic basis for hemoglobin-H disease.

We studied 11 families with alpha-thalassemia from the Qatif population of eastern Saudi Arabia to determine the genetic and molecular basis of hemoglobin-H disease, which is being encountered in this area with increasing frequency. The results show that there are two common alpha-thalassemia haplotypes, a deletion (-alpha/) determinant and a nondeletion (alpha alpha T/) determinant, which interact to produce a series of overlapping phenotypes. The most severe, hemoglobin-H disease, results from the homozygous state for the nondeletion determinant--a pattern of inheritance not previously recognized for this condition. Its molecular and genetic properties are thus different from those that produce the condition in Oriental or Mediterranean populations.

Child↗
PubMed1980

Defective synthesis of HbE is due to reduced levels of beta E mRNA.

Haemoglobin E (alpha 2 beta 2(26)Glu leads to Lys) is one of the commonest haemoglobin variants. There are an estimated 30 million carriers of the beta E gene in South-East Asia, where they comprise more than 50% of the population in some areas; however, the reasons for this high frequency have never been adequately explained. Homozygotes for HbE may be midly anaemic, but they do not have any clinical disability. However, individuals heterozygous for both beta E and beta thalassaemia (HbE/beta thalassaemia) have a severe clinical disorder which in some cases may approach that seen in homozygous beta thalassaemia and which is by far the commonest form of symptomatic thalassaemia in the Indian subcontinent and South-East Asia. Haemoglobin E is the only common structural variant which interacts with beta thalassaemia to produce a severe disorder and the underlying mechanism of the interaction is not known. We have studied several homozygotes and heterozygotes for HbE and show here that the beta E chain is inefficiently synthesized and produces the phenotype of a mild form of beta thalassaemia; hence, when inherited together with beta thalassaemia it causes a marked beta-chain deficit. Furthermore, the mechanism for the defective production of beta E chains seems to be a reduction of beta E mRNA, a most unexpected finding in a disorder caused by a single amino acid substitution and presumably by a single nucleotide change in the DNA of the beta globin gene.

Globins↗
PubMed1980

Characterisation of a new alpha thalassemia 1 defect due to a partial deletion of the alpha globin gene complex.

A new deletion causing alpha thalassemia has been characterised in a Greek family. Detailed mapping of the alpha gene complex shows that the deletion extends for 5.2 kb and removes the whole of the alpha 2 gene and the 5' end of the alpha 1 gene. The affected chromosome, therefore produces no normal alpha chains and results in a phenotype of alpha thalassemia 1.

Chromosome Deletion↗
PubMed1980

Haemoglobin Bart's hydrops syndrome in Greece.

A case of haemoglobin Bart's hydrops syndrome was characterised in a Greek family with a history of three other fetuses with hydrops. Family studies showed that both the mother and father carried alpha-thalassaemia genes, and globin-chain synthesis analysis of the present fetus showed a total absence of alpha-chain production. The haemoglobin composition of the fetus was similar to that seen in cases in south-east Asia, and analysis of DNA from the Greek case confirmed the total deletion of the alpha-chain genes. The extent of the deletion, however, differed from that seen in south-east Asian cases and included the loss of one of the embryonic zeta-chain genes. Thus the severe form of alpha-thalassaemia occurs in Greece but has arisen independently from the similar condition in south-east Asia. The condition must be considered in any woman of this racial background who gives a history of unexplained stillbirths.

Adult↗
PubMed1980

A novel alpha-globin gene arrangement in man.

The human genome has two linked alpha-globin genes on chromosome 16. Deletion of one or more of them, as occurs in alpha-thalassaemia, leads to a reduced output of alpha-globin mRNA in proportion to the number of alpha-globin genes lost. In some racial groups deletion of one of the pair of alpha-globin genes may result from unequal crossing over between the genes on homologous chromosomes by a mechanism resembling that postulated for the formation of the delta beta fusion genes of the Lepore haemoglobins. By analogy, the opposite chromosome in this cross-over should have three alpha-globin genes just as the 'anti-Lepore chromosome has three non-alpha chain genes. We describe here a Welsh family in which three members have five alpha-globn increased alpha mRNA output and it may therefore produce the phenotype of mild beta-thalassaemia.

DNA Restriction Enzymes↗
PubMed1980

Gene deletions in alpha thalassemia prove that the 5' zeta locus is functional.

The deletions in the zeta-alpha globin gene cluster in two infants with the hemoglobin Bart's hydrops fetalis syndrome (homozygous alpha thalassemia 1) have been mapped by restriction endonuclease analysis using a zeta-specific probe. DNA from a Thai infant lacked the psi alpha 1 gene and both alpha genes, but the zeta genes were present. A Greek infant's DNA had also lost the 3' zeta 1 gene. Because zeta globin was synthesized in the infant's cord blood, this indicates that the 5' zeta 2 gene recently identified by Lauer et al. [Lauer, J., Shen, C. J. & Maniatis, T. (1980) Cell, in press] must be functional.

Chromosome Deletion↗
PubMed1980

Detection of alpha thalassaemia in Negro infants.

A prospective study of 2191 Negro infants in Jamaica showed that approximately 7% of them had detectable levels of Hb Bart's (gamma 4) in the neonatal period. The red cell indices, globin chain biosynthesis and restriction endonuclease mapping of DNA from these infants were used to determine the significance of Hb Bart's at birth. The results indicate that the genotypes alpha alpha/alpha alpha, -- alpha/alpha alpha and -- alpha/ -- alpha are associated with 0%, 0.1-2%, and greater than 2% Hb Bart's respectively. Although trace amounts of Hb Bart's may be associated with the genotype -- alpha/alpha alpha this is not always the case and therefore haemoglobin analysis in the neonatal period cannot be used to diagnose this genotype with any certainty.

Black People↗
PubMed1980

The anaemia of P. falciparum malaria.

The haematological changes in a group of young Gambian children with P. falciparum malaria have been analysed. In children with acute infection anaemia was most marked during the period after treatment. Although many of these patients developed a positive direct Coombs test during this period of the illness it is not clear whether the anaemia which occurs after treatment has an immune basis. A second group of children showed quite different haematological findings. They appear to have a more chronic form of P. falciparum malaria infection, were profoundly anaemic at presentation, showed gross dyserythropoietic changes in their bone marrows, and had a full reticulocyte response and rise in haemoglobin after treatment. A third group of children were encountered whose haematological abnormalities were intermediate to those of the acute and chronic groups. These findings indicate that the patho-physiological mechanisms responsible for the anaemia of P. falciparum malaria are different at different stages of the illness.

Anemia↗
PubMed1980

The genetic basis of Hb Q-H disease.

A Chinese family has been studied in which two siblings have haemoglobin Q-H disease. Using a combination of haematological and haemoglobin analysis, globin chain synthesis, analysis of alpha/beta globin messenger RNA ratios and restriction endonuclease mapping, it has been shown that each of these siblings has received one chromosome on which both alpha chain genes have been deleted and another on which there is only a single alpha chain locus which carries the alpha Q mutation. Their genotype is thus --/-alpha Q. Despite the fact that the haemoglobin Q mutation in this family is carried on a chromosome with a single alpha chain locus, heterozygous carriers for the variant have only 25% or less haemoglobin Q. Our observations indicate that the molecular basis for haemoglobin Q-alpha thalassaemia is similar to that for the common form of haemoglobin H disease in Orientals. Furthermore, they provide clear evidence that the level of an alpha chain variant in heterozygous carriers is not a reliable reflection of the number of alpha globin genes.

Aged↗
PubMed1980

The increased susceptibility of young red cells to invasion by the malarial parasite Plasmodium falciparum.

The relationship between red cell age and susceptibility to invasion by the malarial parasite Plasmodium falciparum has been examined by several different methods including short-term cultures of parasitized human blood. The results indicate that reticulocytes and young red cells are more susceptible to invasion by this parasite as compared with metabolically older cell populations. This is contrary to the current belief that red cells of all ages are invaded indiscriminately by P. falciparum. This observation has important theoretical, clinical and practical implications; its mechanism remains as yet unclear.

Age Factors↗