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Biomedical subjects

D J Weatherall

Publications and source records attributed to D J Weatherall.

At least 235 records · Page 13Linked to original sources
PubMed1983

Maturity onset diabetes of the young is not linked to the insulin gene.

Maturity onset diabetes of the young is inherited as an autosomal dominant condition. Two families with the disease were studied to determine whether the inheritance of this type of diabetes was linked to the insulin gene. A cloned insulin gene probe was hybridised to DNA from the family members and the insulin gene on each chromosome identified by a different fragment length polymorphism. The results showed no linkage between the insulin gene and the inheritance of maturity onset diabetes of the young.

Adolescent↗
PubMed1983

The anaemia of Plasmodium falciparum malaria.

Anemia is an important complication of P. falciparum malaria infection. This paper describes recent studies that have attempted to define some of the pathophysiological mechanisms involved in different forms of infection and at different stages of the illness. After an acute infection there is a steady fall in the haemoglobin level with an inappropriate reticulocyte response. Current evidence indicates that this form of anaemia may result from a combination of acute sequestration of iron in the reticuloendothelial system associated with a shortened red cell survival. Recent studies indicate that there may be a dyserythropietic component as well. The mechanism for the shortened red cell survival is uncertain; although it may be due in part to sequestration of parasitized cells, the haemoglobin level continues to fall for several weeks after the acute episode and other factors must be involved. The role of immune haemolysis appears to be relatively small. It is becoming apparent that severe dyserythropoiesis with minimal haemolysis plays a major role in the anaemias of Plasmodium falciparum infection, particularly in immune individuals. This phenomenon has been studied by both light and electron microscopy and by assessing the in vitro kinetics of erythroid precursor proliferation. The results indicate a major defect in erythroid maturation with a significant degree of erythrophagocytosis. Although these studies have provided a clearer picture of the pathophysiology of anaemia at different phases of P. falciparum infection, there is still little indication of how the basic changes in red cell production and survival are mediated.

Acute Disease↗
PubMed1983

Clinical features and molecular analysis of acquired hemoglobin H disease.

The presence of hemoglobin H (beta 4), resulting from a deficiency of alpha-globin chain synthesis, was observed as an acquired characteristic in the red cells of five elderly patients with myeloproliferative disorders or preleukemia. The variability in amount of hemoglobin H and in the alpha/beta globin synthesis ratios in these patients is most likely explained by the relative proportions of normal and abnormal cell populations in the peripheral blood, since some reticulocyte fractions with balanced alpha/beta globin synthesis ratios and others with almost no detectable alpha-chain production could be obtained from these patients. In one patient, the hemoglobin H virtually disappeared despite continuing disease. The amount of cytoplasmic alpha-mRNA matched the proportion of alpha-chain synthesis and, in one patient, this was also true for nuclear RNA. However, extensive analysis of the alpha-globin gene complex by restriction endonuclease mapping revealed no detectable rearrangements of the normal gene organization in any of these patients, suggesting that transcription of each pair of alpha-globin genes on each chromosome 16 is defective. These observations have important implications for both the normal regulation of alpha-globin gene expression and the molecular basis of the underlying defect that is associated with the neoplastic transformation of these cells.

Aged↗
PubMed1983

Plasmodium yoelii: blood oxygen and brain function in the infected mouse.

The carriage of oxygen by the blood and the in vivo response of the brain were investigated in mice infected with a lethal strain of Plasmodium yoelii. All mice with parasitaemia exceeding 70% were severely anaemic (Hb 3.5 +/- 1.8 g/dl; mean +/- 1 SD), acidotic (blood pH 7.04 +/- 0.06) and hypoglycaemic (blood glucose 0.6 +/- 0.76 mumol/ml). The oxyhaemoglobin dissociation curve (ODC) of blood from heavily infected mice was shifted right as compared to controls, but the increase in p50 was less than expected from the accompanying acidosis. The reduced shift right was due to a decrease in the 2,3-DPG/Hb ratio in infected animals (0.72 +/- 0.12, n = 17 vs 1.10 +/- 0.09, n = 12 in controls). Despite the severity of terminal infection, the cerebral pH and the relative steady-state concentrations of PCr, ATP and Pi measured in vivo by nuclear magnetic resonance (31P NMR) were normal. Alterations in brain energy status and pH cannot account for cerebral signs or death in this proposed mouse model of cerebral malaria.

Adenosine Triphosphate↗
PubMed1983

The coombs direct antiglobulin test in Kenyans.

The direct antiglobulin test (DAT) was performed on 243 subjects in Kenya. A high incidence of positive DAT was found in children with malaria of whom 70% had RBCs coated with IgG, C3 and C4 either separately or together. Only 12% of paediatric patients with conditions other than malaria had a positive DAT. Most positive DATs in association with malaria occurred in children between 18 months and five years of age. There was a lower incidence of positive DAT in Kikuyu children from an area of low malarial transmission than in children from other tribal groups who reside in areas of high malaria endemicity. A high rate of positive DAT was also found in patients with visceral leishmaniasis. Interestingly there was an association of IgG and C4 but without C3 on red cells of five patients with visceral leishmaniasis and two schoolchildren from an area endemic for visceral leishmaniasis. This combination was not found on other patients.

Adolescent↗
PubMed1983

Molecular basis of length polymorphism in the human zeta-globin gene complex.

The length polymorphism between the human zeta-globin gene and its pseudogene is caused by an allele-specific variation in the copy number of a tandemly repeating 36-base-pair sequence. This sequence is related to a tandemly repeated 14-base-pair sequence in the 5' flanking region of the human insulin gene, which is known to cause length polymorphism, and to a repetitive sequence in intervening sequence (IVS) 1 of the pseudo-zeta-globin gene. Evidence is presented that the latter is also of variable length, probably because of differences in the copy number of the tandem repeat. The homology between the three length polymorphisms may be an indication of the presence of a more widespread group of related sequences in the human genome, which might be useful for generalized linkage studies.

Base Composition↗
PubMed1983

A lectin-like receptor is involved in invasion of erythrocytes by Plasmodium falciparum.

Glycophorin both in solution and inserted into liposomes blocks invasion of erythrocytes by the malaria parasite Plasmodium falciparum. Furthermore, one sugar, N-acetyl-D-glucosamine (GlcNAc), completely blocks invasion of the erythrocyte by this parasite. GlcNAc coupled to bovine serum albumin to prevent the sugar entering infected erythrocytes was at least 100,000 times more effective than GlcNAc alone. Bovine serum albumin coupled to lactose or bovine serum albumin alone had no effect on invasion. These results suggest that the binding of P. falciparum to erythrocytes is lectin-like and is determined by carbohydrates on glycophorin.

Animals↗
PubMed1983

Thalassaemia intermedia in Cyprus: the interaction of alpha and beta thalassaemia.

Restriction endonuclease analysis has been performed on the alpha and beta globin gene clusters of 57 Cypriots homozygous for beta thalassaemia, 30 with the transfusion dependent form of the condition (thalassaemia major) and 27 who are less severely affected (thalassaemia intermedia). There was a significant difference in the incidence of alpha thalassaemia between the two groups: 14/27 of the patients with thalassaemia intermedia also had deletion forms of alpha thalassaemia, while only 4/30 of the patients with thalassaemia major were similarly affected. Thus in Cypriot patients who are homozygous for beta thalassaemia the co-inheritance of alpha thalassaemia is an important factor in determining the clinical course.

Adolescent↗
PubMed1983

Iron metabolism in murine erythroleukaemic cells.

In an attempt to develop a model system for analysing iron metabolism in a relatively homogeneous population of early red cell precursors, the intracellular distribution of 59Fe was examined in Friend murine erythroleukaemic cells after induction of haemoglobin synthesis with dimethylsulphoxide. After incubation of the cells with 59Fe-labelled transferrin, 59Fe was incorporated into haemoglobin, various ferritin fractions, and into the pellet obtained by centrifugation. No intracellular transferrin or low molecular weight compounds were found. In a series of 'chase' experiments 59Fe accumulated in haem, and some of this radioactivity appeared to be derived from the ferritin fraction. Extra iron could be mobilized from ferritin during chase experiments using iron deficient incubation medium. These studies indicated that, at least under these experimental conditions, ferritin iron in early red cell precursors can be utilized for haemoglobin synthesis.

Animals↗
PubMed1983

Effect of alpha thalassaemia on the rheology of homozygous sickle cell disease.

A study of rheological determinants (plasma viscosity, whole-blood viscosity, and erythrocyte deformability) was made in 24 matched pairs of patients with homozygous sickle cell disease, with and without homozygous alpha-thalassaemia 2. Patients with coexisting alpha-thalassaemia showed a significant increase in erythrocyte deformability measured as filtration of washed erythrocytes through 5 micron diameter pores and also as viscosity of whole blood at high shear rate (230s-1) and standard haematocrit (0.45). This rheological advantage may explain the beneficial effect of alpha-thalassaemia 2 on haematological parameters and clinical events in homozygous sickle cell disease.

Adolescent↗
PubMed1983

Alpha thalassaemia and the macular vasculature in homozygous sickle cell disease.

The interaction of homozygous alpha thalassaemia 2 with homozygous sickle cell (SS) disease results in a generally milder haematological picture with less intravascular sickling, less haemolysis, and higher haemoglobin levels. Clinically, patients are generally more mildly affected, though not all vaso-occlusive complications are reduced. Thus there is a possibility that the advantages gained by inhibition of sickling have been offset by the rheological disadvantages of the higher haemoglobin level. The capillary bed in the perimacular region of the posterior pole has been used to examine the degree of vaso-occlusion in age and sex matched controls with SS disease with and without homozygous alpha thalassaemia 2. The results demonstrated significantly less capillary abnormalities in the perimacular region of patients with alpha thalassaemia, though the size of the foveal avascular zone and the grading of perimacular capillary drop-out did not differ between the 2 genotypes. These results are compatible with a mild inhibitory effect of alpha thalassaemia on vaso-occlusion of the macular vasculature in SS disease.

Adolescent↗
PubMed1983

Globin gene mapping studies in Sardinian patients homozygous for beta zero Thalassaemia.

The genetic factors responsible for the relatively mild clinical phenotypes of some cases of homozygous beta zero thalassaemia (thalassaemia intermedia) in Sardinia have been evaluated. The frequency of deletion forms of alpha thalassaemia was higher in patients with thalassaemia intermedia (6/8) than in those with thalassaemia major (6/17). The beta globin gene clusters were also studied, first to determine whether there were any rearrangements of the gamma genes, and second to see whether the restriction fragment length polymorphism patterns (haplotypes) of the two groups of patients were similar. The structure of the gamma genes was normal in all the patients with the single exception of a thalassaemia major patient with a triplicated gamma gene arrangement. The beta globin gene cluster haplotypes of the two groups of patients were not significantly different. However, the frequency of the various haplotypes in the thalassaemic as compared to the normal (beta A) chromosomes was different. This finding is of potential value in the antenatal diagnosis of homozygous beta thalassaemia in this population.

Child↗
PubMed1983

Multiple origins of the sickle mutation: evidence from beta S globin gene cluster polymorphisms.

Restriction site polymorphisms of the beta globin gene cluster of 244 Jamaican beta S chromosomes have been studied. Various patterns of restriction site polymorphisms (haplotypes) both 5' and 3' to the beta gene have been found. These two groups of haplotypes were found to be non-randomized with respect to each other. This is in contrast to normal beta A chromosomes where the 5' and 3' haplotypes are randomized. These findings together with the large number (18) of different beta S haplotypes found indicate that the beta S mutation probably has multiple origins.

Anemia, Sickle Cell↗
PubMed1983

Selective expression within the human alpha globin gene complex following chromosome-dependent transfer into diploid mouse erythroleukaemia cells.

Human chromosome 16, which contains the alpha globin gene complex, has been introduced into mouse erythroleukaemia cells by means of cell fusion and selectively retained to the exclusion of other human chromosomes. After induction of haemoglobin synthesis in hybrid clones, evidence for expression of the human alpha globin genes was sought by mRNA and globin chain synthesis analyses. It was found that both the human alpha 1 and alpha 2 genes were similarly expressed and that the synthesis of human alpha globin chains was nearly half that of mouse alpha chains on a per gene basis. The pattern of human alpha gene expression was similar with different inducers and with donor chromosomes of either erythroid or non-erythroid origin. However, the closely linked human embryonic alpha gene (zeta) did not produce detectable levels of zeta globin mRNA in any of the hybrid clones. Thus, there is selective activation of adult genes in the human alpha globin gene complex in the mouse erythroleukaemia cell.

Animals↗