222 research outputs found
Prevention of morbidity in Sickle Cell Disease phase II (Improvement of pain and quality of life in children with Sickle Cell Disease with auto-adjusting Continuous Positive Airways Pressure: Phase II) (POMS 2b pediatric cohort)
No full textThe investigation of resveratrol and analogs as potential inducers of fetal hemoglobin
No full textBeta-thalassemia, is a hemoglobinopathy characterized by reduced beta-globin chain synthesis, leading to imbalanced globin chain production, ineffective erythropoiesis and anemia. Increasing gamma-globin gene expression is a promising therapeutic approach as it reduces this imbalance by combining with the excess alpha globin chains and producing fetal hemoglobin (HbF). Furthermore, increased iron absorption and repeated blood transfusions lead to iron overload and tissue damage secondary to reactive oxygen species. Compounds exhibiting both antioxidant and HbF inducing activities are, therefore, highly desirable therapeutic agents. Resveratrol, a natural phytoalexin, combines these two activities but is also cytotoxic. Nine hydroxystilbenic resveratrol derivatives were synthesized in an attempt to identify compounds that retain the HbF-inducing and antioxidant activities of resveratrol but exhibit reduced cytotoxicity. Three derivatives (P1, P4 and P11) exhibited similar hemoglobin-inducing properties to resveratrol in K562 cells, however, only P11 showed reduced cytotoxicity. All three derivatives demonstrated variable HbF-inducing activity in primary erythroid progenitor cells from healthy donors. Resveratrol and P11 increased HbF induction significantly, with P11 having the highest activity. Additionally, P4 significantly increased progenitor numbers. A combinatorial treatment in K562 cells using resveratrol and decitabine resulted in a statistically significant increase in hemoglobin-inducing activity only above the level shown by resveratrol alone
Proteomic analysis of plasma from children with sickle cell anemia and silent cerebral infarction
No full textSilent cerebral infarction is the commonest neurological abnormality in children with sickle cell anemia, affecting 30-40% 14 year olds. There are no known biomarkers to identify children with silent cerebral infarcts and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma proteins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS). 19 children had silent cerebral infarcts and 32 normal MRI; the children with silent infarcts had lower HbF levels (8.6 vs. 16.1%, P=0.049) and higher systolic blood pressures (115 vs 108.6, P=0.027). Plasma proteomic analysis showed 13 proteins increased more than 1.3 fold in the SCI patients, including proteins involved in hypercoagulability (α2-antiplasmin, fibrinogen-γ chain, thrombospondin-4), inflammation (α2-macroglobulin, complement C1s and C3) and atherosclerosis (apolipoprotein B-100). Higher levels of gelsolin and retinol-binding protein 4 were also found in the population with silent infarcts, both of which have been linked to stroke. We investigated the genetic basis of these differences by studying 359 adults with sickle cell disease (199 with silent cerebral infarcts, 160 normal MRIs), who had previously undergone a genome-wide genotyping array. None of the genes coding for the differentially expressed proteins were significantly associated with silent infarction. Our study suggests that silent cerebral infarcts in sickle cell anemia may be associated with higher systolic blood pressure, lower HbF levels, hypercoagulability, inflammation and atherosclerotic lipoproteins.</p
Ethnic differences in F cell levels in Jamaica: a potential tool for identifying new genetic locicontrolling fetal haemoglobin
No full textHigh levels of fetal haemoglobin (HbF) are protective in ?-haemoglobinopathies. The proportion of erythrocytes containing HbF (F-cells, FC) was measured in healthy adults of African and Caucasian ancestry to assess the feasibility of localizing genes for the FC trait using admixture mapping. Participants were Afro-Caribbean (AC) blood donors and residents of a rural enclave with a history of recent German admixture (Afro-German, AG) recruited in Jamaica, and Caucasian Europeans recruited in Jamaica and the UK. FC levels were significantly different between groups (P < 0·001); the geometric mean FC level in the AC sample (n = 176) was 3·75% [95% confidence interval (CI) 3·36–4·18], AG sample (n = 631) was 2·77% (95% CI 2·63–2·92), and among Caucasians (n = 1099) was 3·26% (95% CI 3·13–3·39). After adjustment for age, sex, haemoglobin electrophoresis pattern, and HBG2 genotype, FC levels in the AC group remained significantly different (P < 0·001) from those in the Caucasian and the AG group but the difference between the Caucasian and AG groups became non-significant (P = 0·46) despite substantial differences in average ancestry. The data confirm ethnic differences in FC levels and indicate the potential usefulness of these populations for admixture mapping of genes for FC level
Fetal hemoglobin is associated with peripheral oxygen saturation in sickle cell disease in Tanzania
No full textFetal hemoglobin (HbF) and peripheral hemoglobin oxygen saturation (SpO2) both predict clinical severity in sickle cell disease (SCD), while reticulocytosis is associated with vasculopathy, but there are few data on mechanisms. HbF, SpO2 and routine clinical and laboratory measures were available in a Tanzanian cohort of 1175 SCD individuals aged≥5years and the association with SpO2 (as response variable transformed to a Poisson distribution) was assessed by negative binomial model with age and sex as covariates. Increase in HbF was associated with increased SpO2 (rate ratio, RR=1.19; 95% confidence intervals [CI] 1.04, 1.37 per natural log unit of HbF; p=0.0004). In univariable analysis, SpO2 was inversely associated with age, reticulocyte count, and log (total bilirubin) and directly with pulse, SBP, hemoglobin, and log(HbF). In multivariable regression log(HbF) (RR 1.191; 95%CI 1.04, 1.37; p=0.013), pulse (RR 1.01; 95%CI 1.00, 1.01; p=0.026), SBP (RR 1.008; 95%CI 1.00, 1.02; p=0.014), and hemoglobin (1.120; 95%CI 1.05, 1.19; p=0.001) were positively and independently associated with SpO2 while reticulocyte count (RR 0.985; 95%CI 0.97, 0.99; p=0.019) was independently inversely associated with SpO2. In SCD, improving SpO2, in part through cardiovascular compensation and associated with reduced reticulocytosis, may be a mechanism by which HbF reduces disease severity.</p
Haemoglobin and the Inherited Disorders of Globin Synthesis
No full textMutations in the globin gene complex might alter the switch from fetal to adult haemoglobin synthesis, resulting in persistence of γ-globin expression, and hereditary persistence of fetal haemoglobin (HPFH). The thalassaemias are the commonest single-gene disorders. The affected individuals with thalassaemia intermedia were constitutionally heterozygous for β0-thalassaemia, but subsequent investigations revealed a somatic deletion of chromosome 11p15, including the β-globin gene complex, in trans to the mutation in a subpopulation of erythroid cells. In many populations, because there is a high incidence of both β-thalassaemia and other globin gene mutations, it is quite common for an individual to inherit a β-thalassaemia allele from one parent and a gene for a structural haemoglobin variant from the other. Most of the unstable haemoglobins result from single amino acid substitutions or small deletions.</p
Genetic Factors Modifying Sickle Cell Disease Severity
No full textSickle cell disease (SCD) is a monogenic disorder caused by a single base mutation but despite its apparent genetic simplicity, the clinical phenotype is hugely variable. In addition to environmental factors, family and epidemiological studies indicate that genetic variants co-inherited with the sickle mutation have a key role in modifying the disease course. This article provides an overview of the genetic modifi ers of SCD known to date. Co-inheritance of thalassemia and persistent fetal hemoglobin (HbF) production are established major genetic modifi ers but they do not explain the full spectrum of the phenotypic variability of SCD. While characterization of some of the key variants and pathways involved in HbF regulation have provided new therapeutic targets for HbF reactivation, generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifi ers yet to be discovered. Elucidation of new genetic modifi ers may also provide an insight into other “ldruggable” targets for therapeutic intervention.</p
The molecular basis of β-thalassemia.
No full textThe β-thalassemias are characterized by a quantitative deficiency of β-globin chains underlaid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural β gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most β-thalassemias are inherited in a Mendelian recessive fashion but there is a subgroup of β-thalassemia alleles that behave as dominant negatives. Unraveling the molecular basis of β-thalassemia has provided a paradigm for understanding of much of human genetics.</p
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