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Biomedical subjects

D J Weatherall

Publications and source records attributed to D J Weatherall.

At least 55 records · Page 3Linked to original sources
PubMed1998

Elimination of transfusions through induction of fetal hemoglobin synthesis in Cooley's anemia.

Pharmacological stimulation of fetal hemoglobin production is of considerable interest as an alternative approach to therapy for Cooley's anemia. While intravenous compounds have been effective in inducing short-term increases in fetal hemoglobin in a few patients, long-term elimination of transfusion requirement has not been reported. In patients with Cooley's anemia, treatment with oral sodium phenylbutyrate alone, sodium phenylbytyrate combined with hydroxyurea, and hydroxyurea alone, has augmented fetal hemoglobin production and increased total hemoglobin concentration as much as 5 g/dl over baseline eliminating transfusion requirement in two patients. Parallel declines in circulating nucleated red cell count, and concentrations of serum transform receptor and erythropoietin, are consistent with more effective erythropoiesis. Over extended periods of treatment, no induction of other fetal proteins and no adverse effects were observed. Particular disease mutations and other genetic factors may be of prime importance in determining the response to agents that induce production of fetal hemoglobin.

Adult↗
PubMed1998

The hemoglobin E syndromes.

Heterozygotes and homozygotes for HbE (beta 26, GAG-AAG, Glu-Lys) are microcytic, minimally anemic, and asymptomatic. The microcytosis is attributed to the beta thalassemic nature of the beta E gene, whereas the in vitro instability of HbE does not contribute to the phenotype. However, the compound heterozygote state HbE/beta thalassemia results in a variable, and often severe anemia, with the phenotype ranging from transfusion dependence to a complete lack of symptoms. This has been well documented in Thailand, but the basis of the interaction and the cause of the variability remains unexplained. We have studied 50 HbE/beta thalassemics from the UK and 16 from Oakland, CA and assessed the role of HbE instability. Time-course globin chain synthesis experiments have shown that instability is not an important factor in the steady state, but that at 41 degrees C newly synthesized Hb molecules are unstable. We have identified one family in which HbE interacts with pyrimidine 5' nucleotidase deficiency to cause severe anemia with Hb instability. The UK individuals, mostly of Bengali origin, have Hb's from 4.5-11 g/dl. The beta thalassemia mutation, alpha thalassemia and the Xmn 1 G gamma polymorphism do not explain this variability, but the relative and absolute amounts of HbF correlate significantly with total Hb. The Oakland individuals, mostly from Southeast Asia, show similar variation in Hb, which again is largely unexplained.

Anemia↗
PubMed1998

Pathophysiology of thalassaemia.

Most of the major clinical manifestations of the beta-thalassaemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and red cell survival. The destruction of red cell progenitors and their progeny results from an extremely complex series of mechanisms all related to the presence of excess alpha-globin chain production. These include mechanical damage, interference with cell division and oxidative destruction of both organelles and components of the red cell membrane. The unequal distribution of gamma-globin chains between different precursors, and the intense selection of those with relatively higher levels of gamma chain production, lead to an extremely heterogeneous cell population in the peripheral blood. Iron overload, due to increased gastrointestinal absorption and blood transfusion is the major cause of tissue damage, morbidity and death.

Chemical Precipitation↗
PubMed1998

Beta-thalassaemia intermedia: is it possible consistently to predict phenotype from genotype?

Eighty-seven patients with beta thalassaemia of intermediate severity were investigated in our Unit to determine whether it is possible to consistently predict phenotypic severity from genotypic factors. The subjects were from the following ethnic backgrounds: Asian Indian (35.1%), Middle Eastern (24.3%), Mediterranean (21.6%), Northern European (14.9%) and South-East Asian/Chinese (4.1%). There was a wide spectrum of phenotypic severity; 49 had mild disease, 22 moderate and 16 severe disease. 22/87 patients had inherited only a single copy of a beta-thalassaemia allele, of whom 11 had also co-inherited triplicated alpha genes (alpha alpha alpha/alpha alpha or alpha alpha alpha/alpha alpha alpha) and seven had dominantly inherited beta thalassaemia. In four of the heterozygotes no explanation was found for the thalassaemia-intermedia phenotype. 65/87 patients were homozygous or compound heterozygous for 26 mutations (40 genotypes) which ranged from very mild beta+ to beta0 thalassaemia alleles. All patients with two mild or very mild beta+ thalassaemia alleles had mild to moderate disease. Although concurrent inheritance of extra alpha genes with heterozygous beta thalassaemia results in thalassaemia intermedia, the disease is mild. Co-inheritance of alpha thalassaemia as a modulating factor was not evident in this cohort of patients. Presence of the in-cis Xmn I-Ggamma site was a modulating factor but insufficient to explain the high fetal haemoglobin levels encountered. In conclusion, apart from the two categories of triplicated alpha genes with heterozygous beta thalassaemia and inheritance of mild beta+ thalassaemia alleles, it was not possible to consistently predict phenotype from alpha and beta genotypes alone, due to the influence of modulating factors, some implicated (such as inheritance of HPFH determinants) and others as yet unidentified.

Adolescent↗
PubMed1998

Red cell morphology and malaria anaemia in children with Southeast-Asian ovalocytosis band 3 in Papua New Guinea.

Southeast-Asian ovalocytosis (SAO) was diagnosed in children from Madang, Papua New Guinea, by detection of the SAO band 3 gene variant using the polymerase chain reaction. SAO band 3 was present in 16/241 (6.6%) children living in the community and 32/389 (8.2%) children with acute Plasmodium falciparum malaria (P=0.42). SAO band 3 was detected in 8.2% (23/281) of alpha+-thalassaemia homozygotes, 9.4% (20/214) of heterozygotes and 2.4% (2/85) of children with a normal alpha-globin genotype (P=0.12). The most consistent feature of SAO band 3 on microscopy of thin blood films was red cells with two or more linear or irregularly-shaped pale regions. In children living in the community, these were present in 15 with SAO band 3 (sensitivity 93.8%) and only two normals (specificity 99.1%). The presence of > or = 20% ovalocytosis was a poorer indicator of SAO band 3 (sensitivity 68.8% and specificity 100%). Haematological data were similar in SAO band 3 and normal children. However, in children with acute malaria, haemoglobin levels and red cell counts were significantly lower in SAO band 3 than normal children. The degree of ovalocytosis was lower in children with SAO band 3 during acute malaria, suggesting that a selective loss of ovalocytes may contribute to malaria anaemia in Southeast-Asian ovalocytosis.

Anemia↗
PubMed1998

Alpha thalassaemia is associated with increased soluble transferrin receptor levels.

Although alpha+ thalassaemia is the commonest haemoglobinopathy in the world, it is not known if it is associated with significant ineffective erythropoiesis, a fact of importance in interpreting its complex interaction with malaria. To study this problem, we have measured the concentrations of soluble transferrin receptor (sTIR) and ferritin in 181 children from Vanuatu with heterozygous (68) and homozygous (46) alpha+ thalassaemia, and normal controls (67). sTfR concentrations were significantly higher in both homozygotes (mean 3.1 mg/l, range 2.8-3.4) and heterozygotes (2.86 mg/l, 2.6-3.2) compared to the normal controls (2.48 mg/l, 2.3-2.7), suggesting that although globin chain imbalance is minimal, there is ineffective erythropoiesis in both these conditions. Age was also shown to significantly affect sTfR, with peak levels occurring in the 5-9 years age group. Ferritin concentrations showed a similar trend, being higher in the thalassaemic groups, although this did not reach statistical significance. No individuals had low ferritin concentrations, although two had significantly elevated sTfR levels. These observations suggest that the alpha+ thalassaemia phenotype includes an expansion of the erythron, and may suggest possible mechanisms for the increased susceptibility in babies with alpha thalassaemia to both P. falciparum and P. vivax malaria.

Adolescent↗
PubMed1998

The therapeutic reactivation of fetal haemoglobin.

Unusually high levels of fetal haemoglobin production can ameliorate sickle cell disease and beta thalassaemia. Although efforts directed at the pharmacological stimulation of fetal haemoglobin as an approach to managing these conditions have met with limited success, there is wide variation in individual responses. Whether this reflects the particular mutations that underlie these conditions or other genetic factors remains to be determined, as does the ideal combination of agents to achieve this end. These results are encouraging, however, in particular in view of the recent demonstration that other monogenic diseases, Duchenne muscular dystrophy, for example, might be amenable to the same therapeutic strategy.

Anemia, Sickle Cell↗
PubMed1997

alpha+-Thalassemia protects children against disease caused by other infections as well as malaria.

In the South West Pacific region, the striking geographical correlation between the frequency of alpha+-thalassemia and the endemicity of Plasmodium falciparum suggests that this hemoglobinopathy provides a selective advantage against malaria. In Vanuatu, paradoxically, alpha+-thalassemia increases the incidence of contracting mild malaria in the first 2 years of life, but severe disease was too uncommon to assess adequately. Therefore, we undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and alpha+-thalassemia affects more than 90% of the population. Compared with normal children, the risk of having severe malaria was 0.40 (95% confidence interval 0.22-0.74) in alpha+-thalassemia homozygotes and 0.66 (0.37-1.20) in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygous (0. 36; 95% confidence interval 0.22-0.60) and heterozygous (0.63; 0. 38-1.07) children. This clinical study demonstrates that a malaria resistance gene protects against disease caused by infections other than malaria. The mechanism of the remarkable protective effect of alpha+-thalassemia against severe childhood disease remains unclear but must encompass the clear interaction between this hemoglobinopathy and both malarial and nonmalarial infections.

Child↗
PubMed1997

Thalassaemia and malaria, revisited.

Haldane's attractive hypothesis that the high gene frequencies for thalassaemia in the Mediterranean population may have resulted from heterozygote advantage in regions where Plasmodium falciparum malaria was common in the past has been extremely difficult to verify at the population or experimental level. However, the molecular era has provided some powerful new tools to attack this old problem. It is now clear that the thalassaemias are the commonest monogenic diseases in man, with a broad distribution throughout the Mediterranean, Middle East, Indian sub-continent and South-east Asia. All these populations have specific types of thalassaemia mutations which, presumably, have arisen locally and been expanded by selection together with drift and founder effect. Recent work indicates that alpha thalassaemia provides protection against severe malaria. Quite unexpectedly at least some of this protection may be mediated by rendering very young children more susceptible to both P. vivax and P. falciparum malaria; such early immunization may provide some protection against the disease in later life.

Genetics, Population↗
PubMed1997

Plasmodium vivax: a cause of malnutrition in young children.

We studied the aetiology of malnutrition in a cohort of 1511 children < 10 years old in Espiritu Santo, Vanuatu. Malnutrition was categorized using standard anthropometric criteria as: underweight [weight-for-age (WA) Z score < -2], wasting [weight-for-height (WH) Z < -2], or stunting [height-for-age (HA) Z < -2]. On multiple logistic regression analysis, the only factors significantly associated with wasting were age < 5 years [OR (95% CI) 1.8 (1.2-2.9), p = 0.01] and having suffered one or more episodes of clinical P. vivax malaria in the 6 months preceding nutritional assessment [OR 2.4 (1.3-4.4), p = 0.006]. The incidence of P. vivax infection was significantly higher during the 6 months preceding assessment in underweight vs. non-underweight children [incidence rate ratio (IRR) 2.6 (1.5-4.4), p < or = 0.0001). These groups had similar incidences of clinical P. falciparum infection during the same period [IRR 1.1 (0.57-2.1) p = 0.8] and of either species during the 6 months following assessment [IRR P. vivax 1.3 (0.9-2.0) p = 0.2; IRR P. falciparum 1.3 (0.9-1.9) p = 0.2]. In these children, P. vivax malaria was a major predictor of acute malnutrition; P. falciparum was not. Wasting neither predisposed to nor protected against malaria of either species. Although P. vivax malaria is generally regarded as benign, it may produce considerable global mortality through malnutrition.

Age Factors↗
PubMed1996

High incidence of malaria in alpha-thalassaemic children.

The alpha+-thalassaemias are the commonest known human genetic disorders, affecting up to 80 per cent of some populations. Although there is good evidence from both epidemiological and clinical studies that these gene frequencies reflect selection by, and protection from, malaria, the mechanism is unknown. We have studied the epidemiology of malaria in childhood on the southwestern Pacific island of Espiritu Santo in Vanuatu and here we report that, paradoxically, both the incidence of uncomplicated malaria and the prevalence of splenomegaly, an index of malaria infection, are significantly higher in young children with alpha+-thalassaemia than in normal children. Furthermore, this effect is most marked in the youngest children and for the non-lethal parasite Plasmodium vivax. The alpha+-thalassaemias may have been selected for their ability beneficially to increase susceptibility to P. vivax, which, by acting as a natural vaccine in this community, induces limited cross-species protection against subsequent severe P. falciparum malaria.

Animals↗