1,721,082 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
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
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
Super-elevated LDH and thrombocytopenia are markers of a severe subtype of vaso-occlusive crisis in sickle cell disease
No full textHow I treat the older adult with sickle cell disease
No full textWith increasing survival, cumulative complications of sickle cell disease (SCD), which develop insidiously over time, are becoming more apparent and common in older patients, particularly those in their fifth decade and beyond. The older patient is also more likely to develop other age-related nonsickle conditions that interact and add to the disease morbidity. A common misconception is that any symptom in a SCD patient is attributable to their SCD and this may lead to delays in diagnosis and appropriate intervention. We recommend regular comprehensive reviews and monitoring for early signs of organ damage and a low threshold for the use of hydroxyurea and blood transfusions as preventative measures for end-organ disease. Treatable comorbidities and acute deterioration should be managed aggressively. Although the primary goal in management of the older adult with SCD is improving anemia and minimizing organ damage, the time has come for us to be more proactive in considering curative therapies previously offered to the younger patient. Curative or experimental interventions should be discussed early, before complications render the patients ineligible for these treatments.</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
Prevention of morbidity in sickle cell disease (POMS 2): a pilot study of nocturnal respiratory support shows that auto-adjusting positive airways pressure is safe and Is preferred to oxygen therapy
No full textGenetic architecture of hemoglobin F control
No full textPurpose of review Much effort has been spent on understanding the regulation of fetal hemoglobin (HbF, alpha(2)gamma(2)) production and its reactivation in adults, as elevated HbF levels are correlated with reduced morbidity and mortality in sickle cell anemia and beta thalassemia, diseases that represent a major public health problem. Interindividual HbF variation is largely genetically controlled, but the inheritance patterns are not clear. Recent findings HbF persistence, measured either as percentage HbF or as percentage F cells, is increasingly understood as a quantitative genetic trait; multiple genes together with an environmental component determine the measured value in any given individual. Recent genome-wide studies have shown that common genetic polymorphisms account for a large proportion of the common variation in HbF levels, not only in healthy adults but also in patients with these beta hemoglobinopathies. Genetic variation at only three major loci (Xmn1-HBG2, HBS1L-MYB intergenic region on chromosome 6q23 and BCL11A on chromosome 2p16) account for a relatively large proportion (20-50%) of the phenotypic variation in HbF levels. Two of the major quantitative trait loci include oncogenes emphasizing the importance of cell proliferation and differentiation as an important contribution to the HbF phenotype. Summary The review traces our progress in the understanding of HbF persistence in adults as a quantitative trait and the changing genetic methodology that has helped in the dissection of the genetic architecture underlying HbF variability. We also speculate on the plausible mechanisms underlying the increased HbF production
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