BACKGROUND
An improved understanding of the regulation of the fetal hemoglobin genes holds promise for the development of targeted therapeutic approaches for fetal hemoglobin induction in the β-hemoglobinopathies. Although recent studies have uncovered trans-acting factors necessary for this regulation, limited insight has been gained into the cis-regulatory elements involved.
METHODS
We identified three families with unusual patterns of hemoglobin expression, suggestive of deletions in the locus of the β-globin gene (β-globin locus). We performed array comparative genomic hybridization to map these deletions and confirmed breakpoints by means of polymerase-chain-reaction assays and DNA sequencing. We compared these deletions, along with previously mapped deletions, and studied the trans-acting factors binding to these sites in the β-globin locus by using chromatin immunoprecipitation.
RESULTS
We found a new (δβ)0-thalassemia deletion and a rare hereditary persistence of fetal hemoglobin deletion with identical downstream breakpoints. Comparison of the two deletions resulted in the identification of a small intergenic region required for γ-globin (fetal hemoglobin) gene silencing. We mapped a Kurdish β0-thalassemia deletion, which retains the required intergenic region, deletes other surrounding sequences, and maintains fetal hemoglobin silencing. By comparing these deletions and other previously mapped deletions, we elucidated a 3.5-kb intergenic region near the 5′ end of the δ-globin gene that is necessary for γ-globin silencing. We found that a critical fetal hemoglobin silencing factor, BCL11A, and its partners bind within this region in the chromatin of adult erythroid cells.
CONCLUSIONS
By studying three families with unusual deletions in the β-globin locus, we identified an intergenic region near the δ-globin gene that is necessary for fetal hemoglobin silencing. (Funded by the National Institutes of Health and others.)
Objective To assess the efficacy and safety of low dose adrenaline injected subcutaneously to prevent acute adverse reactions to polyspecific antivenom serum in patients admitted to hospital after snake bite. Design Prospective, double blind, randomised, placebo controlled trial. Setting District general hospital in Sri Lanka. Subjects 105 patients with signs of envenomation after snake bite, randomised to receive either adrenaline (cases) or placebo (controls) immediately before infusion of antivenom serum. Interventions Adrenaline 0.25 ml (1:1000). Main outcome measures Development of acute adverse reactions to serum and side effects attributable to adrenaline. Results 56 patients (cases) received adrenaline and 49 (controls) received placebo as pretreatment. Six (11%) adrenaline patients and 21 (43%) control patients developed acute adverse reactions to antivenom serum (P = 0.0002). Significant reductions in acute adverse reactions to serum were also seen in the adrenaline patients for each category of mild, moderate, and severe reactions. There were no significant adverse effects attributable to adrenaline. Conclusions Use of 0.25 ml of 1:1000 adrenaline given subcutaneously immediately before administration of antivenom serum to patients with envenomation after snake bite reduces the incidence of acute adverse reactions to serum.
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