Alpha(+)-thalassemia protects African children from severe malaria. (57/248)

The high frequency of alpha(+)-thalassemia in malaria-endemic regions may reflect natural selection due to protection from potentially fatal severe malaria. In Africa, bearing 90% of global malaria morbidity and mortality, this has not yet been observed. We tested this hypothesis in an unmatched case-control study among 301 Ghanaian children with severe malaria and 2107 controls (62% parasitemic). In control children, alpha(+)-thalassemia affected neither prevalence nor density of Plasmodium falciparum. However, heterozygous alpha(+)-thalassemia was observed in 32.6% of controls but in only 26.2% of cases (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.56-0.98). Protection against severe malaria was found to be pronounced comparing severe malaria patients with parasitemic controls (adjusted OR in children < 5 years of age, 0.52; 95% CI, 0.34-0.78) and to wane with age. No protective effect was discernible for homozygous children. Our findings provide evidence for natural selection of alpha(+)-thalassemia in Africa due to protection from severe malaria.  (+info)

Disposition of artesunate and dihydroartemisinin after administration of artesunate suppositories in children from Papua New Guinea with uncomplicated malaria. (58/248)

A detailed pharmacokinetic analysis was performed with 47 children from Papua New Guinea with uncomplicated falciparum or vivax malaria treated with artesunate (ARTS) suppositories (Rectocaps) given in two doses of approximately 13 mg/kg of body weight 12 h apart. Following an intensive sampling protocol, samples were assayed for ARTS and its primary active metabolite, dihydroartemisinin (DHA), by liquid chromatography-mass spectrometry. A population pharmacokinetic model was developed to describe the data. Following administration of the first dose, the mean maximal concentrations of ARTS and DHA were 1,085 nmol/liter at 0.9 h and 2,525 nmol/liter at 2.3 h, respectively. The absorption half-life for ARTS was 2.3 h, and the conversion half-life (ARTS to DHA) was 0.27 h, while the elimination half-life of DHA was 0.71 h. The mean common volumes of distribution for ARTS and DHA relative to bioavailability were 42.8 and 2.04 liters/kg, respectively, and the mean clearance values relative to bioavailability were 6 and 2.2 liters/h/kg for ARTS and DHA, respectively. Substantial interpatient variability was observed, and the bioavailability of the second dose relative to that of the first was estimated to be 0.72. The covariates age, sex, and alpha-thalassemia genotype were not influential in the pharmacokinetic model development; but the inclusion of weight as a covariate significantly improved the performance of the model. An ARTS suppositories dose of 10 of 20 mg/kg is appropriate for use in children with uncomplicated malaria.  (+info)

Simultaneous detection of alpha-thalassemia and beta-thalassemia by oligonucleotide microarray. (59/248)

In this study, we describe a reliable microarray-based assay for the simultaneous detection of alpha/beta-globin genotypes. The efficiency and specificity of this method were evaluated by blinded analysis of 1,880 samples. The assay provides unambiguous detection of complex combinations of heterozygous, compound heterozygous and homozygous alpha/beta-thalassemia genotypes.  (+info)

Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. (60/248)

Abnormalities of hemoglobin synthesis are usually inherited but may also arise as a secondary manifestation of another disease, most commonly hematologic neoplasia. Acquired hemoglobin disorders can be seen in any population and are not restricted to areas of the world with high incidences of inherited hemoglobinopathies. In fact, the acquired hemoglobinopathies may be more readily recognized where inherited hemoglobin abnormalities are rare and less likely to cause diagnostic confusion. Acquired alpha-thalassemia is the best characterized of the acquired red blood cell disorders in patients with hematologic malignancy, and it is almost always associated with a myelodysplastic syndrome (MDS). At least 2 molecular mechanisms for acquired alpha-thalassemia are now recognized: acquired deletion of the alpha-globin gene cluster limited to the neoplastic clone and, more commonly, inactivating somatic mutations of the trans-acting chromatin-associated factor ATRX, which cause dramatic down-regulation of alpha-globin gene expression. Here we review the clinical, hematologic, and molecular genetic features of alpha-thalassemia arising in a clonal myeloid disorder, and we discuss howATRX might affect gene expression in normal and abnormal hematopoiesis through epigenetic mechanisms.  (+info)

Hemoglobinopathies in newborns from Salvador, Bahia, Northeast Brazil. (61/248)

Hemoglobinopathies are hereditary disorders of the hemoglobin molecule with a high prevalence worldwide. Brazil has a prevalence of 0.1 to 0.3% of newborns with sickle cell anemia and 20.0 to 25.0% of heterozygous alpha2 thalassemia among African Brazilians. In the present study, we investigated the presence of variant hemoglobins and alpha2(3.7 Kb) and alpha2 (4.2 Kb) thalassemia in newborns from Salvador, Bahia, Brazil. Samples of umbilical cord blood from a total of 590 newborns were analyzed, of which 57 (9.8%) were FAS; 36 (6.5%) FAC; one (0.2%) SF; and five (0.9%) FSC. One hundred fourteen (22.2%) newborns had alpha2(3.7 Kb) thalassemia, of whom 101 (19.7%) were heterozygous and 13 (2.5%) homozygous, showing statistical significance for hematological data between newborns with normal alpha genes and alpha2(3.7 Kb) thalassemia carriers. The alpha2(4.2 Kb) thalassemia was not found. Frequencies found in the present study confirm that hemoglobinopathies are a public health problem in Brazil, emphasizing the need for neonatal screening and genetic counseling programs.  (+info)

Both heterozygous and homozygous alpha+ thalassemias protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya. (62/248)

Although the alpha+ thalassemias almost certainly confer protection against death from malaria, this has not been formally documented. We have conducted a study involving 655 case patients with rigorously defined severe malaria and 648 controls, frequency matched on area of residence and ethnic group. The prevalence of both heterozygous and homozygous alpha+ thalassemia was reduced in both case patients with severe malaria (adjusted odds ratios [ORs], 0.73 and 0.57; 95% confidence intervals [95% CIs], 0.57-0.94 and 0.40-0.81; P = .013 and P = .002, respectively, compared with controls) and among the subgroup of children who died after admission with severe malaria (OR, 0.60 and 0.37; 95% CI, 0.37-1.00 and 0.16-0.87; P = .05 and P = .02, respectively, compared with surviving case patients). The lowest ORs were seen for the forms of malaria associated with the highest mortality-coma and severe anemia complicated by deep, acidotic breathing. Our study supports the conclusion that both heterozygotes and homozygotes enjoy a selective advantage against death from Plasmodium falciparum malaria.  (+info)

Hematologic differences between African-Americans and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume. (63/248)

The average results of some laboratory measurements, including the hemoglobin, mean corpuscular volume (MCV), serum transferrin saturation (TS), serum ferritin, and white blood cell count of African-Americans differ from those of whites. Anonymized samples and laboratory data from 1491 African-American and 31 005 white subjects, approximately equally divided between men and women, were analyzed. The hematocrit, hemoglobin, MCV, TS, and white blood cell counts of African-Americans were lower than those of whites; serum ferritin levels were higher. When iron-deficient patients were eliminated from consideration the differences in hematocrit, hemoglobin, and MCV among women were slightly less. The -3.7-kilobase alpha-thalassemia deletion accounted for about one third of the difference in the hemoglobin levels of African-Americans and whites and neither sickle trait nor elevated creatinine levels had an effect. Among all subjects, 19.8% of African-American women would have been classified as "anemic" compared with 5.3% of whites. Among men, the figures were 17.7% and 7.6%. Without iron-deficient or thalassemic subjects, the difference had narrowed to 6.1% and 2.77% and to 4.29% and 3.6%, respectively. Physicians need to take into account that the same reference standards for hemoglobin, hematocrit, MCV, and TS and the white blood cell count do not apply to all ethnic groups.  (+info)

Nutritional iron status in children with alpha+ thalassemia and the sickle cell trait in a malaria endemic area on the coast of Kenya. (64/248)

Although hemoglobinopathies such as alpha+ thalassemia and the sickle cell trait might contribute to anemia in African children, we hypothesized that they might also enhance iron absorption under circumstances of critical availability, and that this could attenuate their hematologic effects. We found no support for this hypothesis in a cohort of children living on the coast of Kenya.  (+info)