BackgroundRecent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis. Design and MethodsTwenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions. ResultsResults showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age. ConclusionsResults from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year. Haematologica 2011;96(11):1589-1594. doi:10.3324/haematol.2011 This is an open-access paper. Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

The rules of engagement between zinc finger transcription factors and DNA have been partly defined by in vitro DNA-binding and structural studies, but less is known about how these rules apply in vivo. Here, we demonstrate how a missense mutation in the second zinc finger of Krüppel-like factor-1 (KLF1) leads to degenerate DNA-binding specificity in vivo, resulting in ectopic transcription and anemia in the Nan mouse model. We employed ChIP-seq and 4sU-RNA-seq to identify aberrant DNA-binding events genome wide and ectopic transcriptional consequences of this binding. We confirmed novel sequence specificity of the mutant recombinant zinc finger domain by performing biophysical measurements of in vitro DNA-binding affinity. Together, these results shed new light on the mechanisms by which missense mutations in DNA-binding domains of transcription factors can lead to autosomal dominant diseases.

Design and Methods SubjectsThe study included 62 consecutive SCA children followed either at the Sickle Cell Disease Reference Centres of the University Hospital of Pointe-à-Pitre, Guadeloupe (n=41) and of the Robert Debré Mother and Child University Hospital in Paris (n=21), France. Overall, 27 boys and 35 girls between 2 months and 16 years of age were included. All children were at steadysate, i.e. free of any acute events for one month prior to blood sampling and transfusion-free for at least three months prior to blood sampling. Among the 62 children, 49 had never received HC and 13 had been treated with HC for at least six months at the time of the study, with an average dose of 21.8±3.2 mg/kg per day. This latter group was compared to a control group composed of 26 SCA children matched for sex and age, selected from the 49 SCA children untreated by HC. All the children's parents provided their written consent before inclusion in the study which had been approved by the ethical committees from Guadeloupe and Paris.

High plasma level of microparticles (MPs) deriving mainly from erythrocytes and platelets has been detected in sickle cell anemia (SCA) patients. Flow cytometry was used to determine the concentration of MPs in two groups of SCA patients exhibiting marked differences in painful vaso-occlusive crisis rates [a non-severe group (n = 17) and a severe group (n = 12)], and in a control group composed of healthy subjects (n = 20). A 3- to 4-fold increase of total MP plasma concentration was detected in SCA patients. Higher platelet-derived MPs concentration was detected in the severe SCA group while erythrocyte-derived MPs concentration was increased in the non-severe SCA patient group only. Our results suggest that plasma concentration of MPs shed by platelets is a biomarker of the vaso-occlusive phenotype-related severity.