Sickle cell disease (SCD) is a genetic hemoglobinopathy leading to 2 major clinical manifestations: severe chronic hemolytic anemia and iterative vaso-occlusive crises. SCD is also accompanied by ...profound muscle microvascular remodeling. The beneficial effects of endurance training on microvasculature are widely known. The aim of this study was to evaluate the effects of an endurance training program on microvasculature of skeletal muscle in SCD patients. A biopsy of the vastus lateralis muscle and submaximal incremental exercise was performed before and after the training period. Of the 40 randomized SCD patients, complete data sets from 32 patients were obtained. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the nontraining (n = 17) group maintained a normal lifestyle. Training consisted of three 40-minute cycle ergometer exercise sessions per week for 8 weeks. Histological analysis highlighted microvascular benefits in the training SCD patients compared with nontraining patients, including increases in capillary density (P = .003), number of capillaries around a fiber (P = .015), and functional exchange surface (P < .0001). Conversely, no significant between-group difference was found in the morphology of capillaries. Indexes of physical ability also improved in the training patients. The moderate-intensity endurance exercise training program improved the muscle capillary network and partly reversed the microvascular defects commonly observed in skeletal muscle of SCD patients. This trial was registered at www.clinicaltrials.gov as #NCT02571088.
•A moderate-intensity endurance exercise training program in SCD patients increases the capillary network without changing its morphology.•This type of training also partly reverses the microvascular deficits commonly observed in SCD patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Osteonecrosis of the femoral head is a frequent complication in adult patients with sickle cell disease. However, little is known about the natural history of asymptomatic lesions.
One hundred and ...twenty-one patients (121 hips) with sickle cell disease and asymptomatic osteonecrosis of the femoral head that was contralateral to a hip with symptomatic osteonecrosis were identified with magnetic resonance imaging between 1985 and 1995. The lesions were graded with use of the Steinberg classification system. The patients were followed with annual plain radiographs. The mean duration of follow-up was fourteen years.
At the time of the initial evaluation, fifty-six hips were classified as Steinberg stage 0, forty-two hips were classified as Steinberg stage I, and twenty-three hips were classified as Steinberg stage II. At the time of the most recent follow-up, pain had developed in 110 previously asymptomatic hips (91%) and collapse had occurred in ninety-three hips (77%). Symptoms always preceded collapse. Of the fifty-six hips that were classified as Steinberg stage 0 at the time of the initial evaluation, forty-seven (84%) had symptomatic osteonecrosis and thirty-four (61%) had collapse at the time of the most recent follow-up. Of the forty-two asymptomatic stage-I hips, forty (95%) became symptomatic within three years and thirty-six (86%) had collapse of the femoral head. Of the twenty-three asymptomatic stage-II hips, all became symptomatic within two years and all collapsed; the mean interval between the onset of pain and collapse was eleven months. At the time of the final follow-up, ninety-one hips (75%) had intractable pain and required surgery.
Untreated asymptomatic osteonecrosis of the femoral head in patients with sickle cell disease has a high likelihood of progression to pain and collapse. Because of the high prevalence of complications after total hip arthroplasty in patients with this disease, consideration should be given to early surgical intervention with other procedures in an attempt to retard progression of the disease.
Sickle cell disease is an autosomal genetic condition which represents the most frequent genetic disease in Île-de-France and Caribbean islands. The main clinical manifestations can be divided into ...infectious disease, hemolytic anemia and vaso-occlusive events. Pulmonary complications represent 20 to 30% of mortality due to sickle cell and can be divided into acute and chronic events. Acute chest syndrome (ACS) is an acute lung injury often preceded by a vaso-occlusive crisis and triggered by different factors including: hypoventilation, pulmonary infectious disease and vascular occlusions. These occlusions can be secondary to fat embolism, thrombosis or sickling. Treatment is mainly supportive combining oxygen supplementation adequate hydration analgesia and sedation. Exchange transfusion may be indicated in severe forms of ACS, characterized by a right ventricular dysfunction and acute respiratory failure. Pulmonary hypertension is the most serious chronic complication. Its frequency is estimated at 6% in adult patients and is more often described in patients with venous ulcers and higher levels of chronic hemolysis. Prognosis is poor with 12.5% of patients dying in the first two years following diagnosis irrespective of the actual pulmonary artery pressure level. There are currently limited data on the effects of any treatment modality. Other respiratory complications such as sleep disorders and nocturnal hypoxemia, infiltrative lung disease and exertional dyspnea are described and should be considered.
Lutheran (Lu) blood group and Basal Cell Adhesion Molecule (BCAM) antigens are both carried by two glycoprotein (gp) isoforms of the immunoglobulin superfamily representing receptors for laminin α
5 ...chain. They are expressed in red blood cells, in endothelial cells of vascular capillaries and in epithelial cells of several tissues. Lu/BCAM gps are overexpressed in sickle red blood cells (SS RBCs). Stimulation of SS RBCs by epinephrine activates the PKA depending signaling pathway and induces reinforced Lu/BCAM-mediated adhesion to laminin10/11. We have analyzed the phosphorylation state of Lu/BCAM long isoform cytoplasmic tail and showed that it is phosphorylated by CKII, GSK3b and PKA. Phosphorylation of this isoform in transfected K562 cells is stimulated by effectors of the PKA pathway and induces cell adhesion to laminin10/11. Lu/BCAM gps are highly expressed in endothelial cells and exhibit potential integrin binding motifs. We showed that they interact with integrin α
4β
1, the unique integrin expressed on the surface of young reticulocytes. Adhesion assays under flow conditions showed that SS RBCs adhere to primary human endothelial cells (HUVEC) after selective activation of intergin α
4β
1 and that this adhesion is mediated by endothelial Lu/BCAM gps. Our studies show that Lu/BCAM gps expressed either on erythroid or on endothelial cells are involved in SS RBC-endothelium interactions and could play a role in the abnormal adhesion of SS RBCs to vascular endothelium contributing to the vaso-occlusive crises reported for sickle cell disease patients.
Les glycoprotéines (gps) Lu/BCAM sont des molécules d’adhérence, récepteurs de la laminine 10/11, portant les antigènes de groupe sanguin Luthéran (Lu) et l’antigène tumoral
basal cell adhesion molecule (BCAM). Elles sont exprimées dans les globules rouges (GR), les cellules endothéliales des vaisseaux capillaires et dans les cellules épithéliales de nombreux tissus. La stimulation des GR drépanocytaires (SS) par l’adrénaline induit une activation de la voie PKA et une adhérence renforcée à la laminine 10/11 médiée par le récepteur Lu/BCAM. Nous avons déterminé les états de phosphorylation de l’isoforme longue des gps Lu/BCAM in vitro et
ex vivo. Cette isoforme est phosphorylée par les kinases CKII, GSK3β et PKA dans des cellules érythroleucémiques K562 et épithéliales MDCK transfectées. La phosphorylation de la gp Lu/BCAM est stimulée par des activateurs de la voie PKA et induit l’adhérence des cellules K562 à la laminine10/11. Les protéines Lu/BCAM sont fortement exprimées dans les cellules endothéliales et présentent un motif potentiel de liaison à l’intégrine α4β1. Nous avons montré qu’elles interagissent avec l’intégrine α4β1, unique intégrine exprimée à la surface des GR drépanocytaires jeunes. Des expériences d’adhérence en flux ont montré que les GR SS adhèrent aux cellules endothéliales primaires après activation sélective de l’intégrine α4β1 et que cette adhérence dépend en partie des protéines Lu/BCAM endothéliales. L’ensemble de nos travaux montrent que les protéines Lu/BCAM érythroïdes et endothéliales pourraient être impliquées dans l’adhérence anormale des GR SS à l’endothélium et contribueraient ainsi aux crises vaso-occlusives in vivo.
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