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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation and microvascular dysfunction have been implicated in a variety of pathologic conditions affecting the brain. Features of the inflammatory response that are common to many of these pathological conditions and that are manifested in the neurovasculature include oxidative stress, diminished endothelial barrier function (increased vascular permeability), increased expression of endothelial cell adhesion molecules, and the recruitment of rolling and adherent leukocytes and platelets. The evidence implicating leukocyte-endothelial cell adhesion in cerebral microvessels as a rate-determining component of the pathophysiology associated with conditions such as ischemia-reperfusion, sickle cell disease, and gamma -irradiation is summarized. Mechanisms that have been proposed to explain the recruitment of adherent leukocytes and platelets in the diseased/injured cerebral microvasculature are also addressed, and a common paradigm for blood cell recruitment induced by seemingly unrelated pathological conditions is outlined. Although there are many structural and functional characteristics of the cerebral microvasculature that distinguish it from other regional vascular beds, the processes that underlie the recruitment of injury-causing inflammatory cells in the brain appear to closely resemble those described for other tissues.
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PMID:The evolving paradigm for blood cell-endothelial cell interactions in the cerebral microcirculation. 1788 93

Sickle cell disease (SCD) is an autosomal, recessive hemoglobinopathy characterized by hemolytic anemia, intermittent occlusion of small vessels leading to acute and chronic tissue ischemia, and organ dysfunction. Red blood cell transfusions are a therapeutic mainstay in SCD and repeated transfusions can result in iron overload. Endocrine dysfunction is the most common and earliest organ toxicity seen in subjects with chronic iron-induced cellular oxidative damage and can be seen in those without clinical evidence of iron overload. The predicted risks of iron overload and endocrine organ failure increase with both the duration of disease requiring transfusion therapy and the number of transfusions. Assessing the state of iron-overload in patients with SCD constitutes a diagnostic challenge because of the unreliability of serum ferritin levels and the risks associated with liver biopsy. In turn, MRI is the preferred noninvasive screening tool for iron overload. This article describes the endocrine and metabolic disorders reported in patients with SCD, discusses their management, and identifies gaps in current knowledge and opportunities for future research.
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PMID:Therapy insight: metabolic and endocrine disorders in sickle cell disease. 1821 12

Priapism, abnormally prolonged penile erection in the absence of sexual excitation, is associated with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. It is common among males with sickle cell disease (SCD), and SCD transgenic mice are an accepted model of the disorder. Current strategies to manage priapism suffer from a poor fundamental understanding of the molecular mechanisms underlying the disorder. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected priapic activity. ADA enzyme therapy successfully corrected the priapic activity both in vivo and in vitro, suggesting that it was dependent on elevated adenosine levels. Further genetic and pharmacologic evidence demonstrated that A2B adenosine receptor-mediated (A2BR-mediated) cAMP and cGMP induction was required for elevated adenosine-induced prolonged penile erection. Finally, priapic activity in SCD transgenic mice was also caused by elevated adenosine levels and A2BR activation. Thus, we have shown that excessive adenosine accumulation in the penis contributes to priapism through increased A2BR signaling in both Ada -/- and SCD transgenic mice. These findings provide insight regarding the molecular basis of priapism and suggest that strategies to either reduce adenosine or block A2BR activation may prove beneficial in the treatment of this disorder.
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PMID:Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. 1834 Mar 77

Sickle cell disease is caused by molecular abnormalities in the formation of hemoglobin, leading to pain crisis from recurrent vascular occlusion by sickled hemoglobin. Impaired flow in the microvasculature can lead to ischemia, tissue infarction and ulceration. Abdominal pain, a common complaint in sickle cell disease, can be due to an uncommon etiology, ischemic duodenal ulceration. This is due to primary mucosal infarction caused by sickling, leading to poor healing of infarcted areas. Prompt endoscopic and/or urgent surgical intervention should be considered, particularly if anticoagulation is an issue, as proton pump inhibitor use is ineffective in healing this type of ulcer.
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PMID:Ischemic duodenal ulcer, an unusual presentation of sickle cell disease. 1839 28

In the absence of a natural animal model for sickle cell disease, transgenic mouse models have been generated to better understand the complex pathophysiology of the disease and to evaluate potential specific therapies. In the early nineties, the simple addition of human globin genes induced the expression of hemoglobin S (HbS) or HbS-related human hemoglobins in mice still expressing mouse hemoglobin. To increase the proportion of human hemoglobin and the severity of the mouse sickle cell syndrome, the proportion of mouse hemoglobin could be decreased by a combination of mouse alpha- and beta-thalassemic defects, leading to complex genotypes and mild disease. Following the discovery of gene targeting in the mouse embryonic stem cells (ES cells), it was made possible to knock out all mouse adult globin genes (2alpha and 2beta) and to add the human homologous genes elsewhere in the mouse genome. In addition, the human gamma gene of fetal hemoglobin was protecting the fetus from HbS polymer formation. Accordingly, the resulting adult mouse models obtained in 1997, expressing human HbS-only, had a very severe anemia (Hb=5-6 g/dL). In order to survive, these "HbS-only mice" had to reduce the HbS concentration within the red blood cells. The phenotype could be less severe by adding modified human gamma genes, still expressed in adult mice. In 2006, a last "S-only" model was obtained by homologous knock in, replacing the mouse globin genes by human genes. This array of models contributes to better understand the role of different interacting factors in the complexity of sickle cell events, such as red cell defects, changes in blood flow and vaso-occlusion, hyperhemolysis, vascular tone dysregulation, oxidations, inflammation, activation and adhesion of cells, ischemia, reperfusion... In addition, each model has an appropriate usefulness to evaluate experimental therapies in vivo and to perform preclinical studies.
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PMID:Mouse models of sickle cell disease. 1850 77

In children, arterial ischemic stroke is more common than hemorrhage. The clinical presentation differs according to age, stroke type, and location. Seizures are more common with ischemia in children, especially in newborns. The presentation of pediatric ischemic stroke is more complex than in adults, so the clinical phenotype of ischemic stroke is modified. Risk factors for ischemic and hemorrhagic stroke include congenital heart disease, blood disorders, vasculopathies, infections (both current and preceding the stroke), and vascular malformations, but often no discernible etiology is determined. Current treatment is based on consensus rather than large, case-controlled studies. There is no strategy for primary prevention of pediatric or newborn stroke except in sickle cell disease. Most clinicians use aspirin for secondary prevention. Transfusion therapy is proven effective for secondary prevention of stroke associated with sickle cell disease. Prospective cohort studies are needed to understand the natural history of pediatric stroke and to determine which individuals are at greatest risk for incident and recurrent stroke. Effective treatment and prevention strategies can only be developed once the causes of stroke in children are understood and populations at greatest risk are identified.
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PMID:Pediatric and newborn stroke. 1899 Mar 11

Sickle cell disease (SCD) and beta-thalassemia (also referred to as beta-thalassemia) are common hereditary hemoglobinopathies with differing pathophysiologies and clinical courses. However, patients with both diseases exhibit increased platelet and coagulation activation, as well as decreased levels of natural anticoagulant proteins. In addition, they are characterized by thrombotic complications that may share a similar pathogenesis. The pathogenesis of hypercoagulability is likely multifactorial, with contributions from the abnormal red blood cell (RBC) phospholipid membrane asymmetry, ischemia-reperfusion injury, and chronic hemolysis with resultant nitric oxide depletion. More studies are needed to better define the contribution of hemostatic activation to the pathophysiology of SCD and beta-thalassemia. Furthermore, adequately controlled studies using anticoagulants and antiplatelet agents are warranted to define the role of hypercoagulability in specific complications of these diseases.
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PMID:Hypercoagulability in sickle cell disease and beta-thalassemia. 1899 50

Hyperbaric oxygen therapy (HBOT) is a primary or adjunctive therapy for a variety of medical disorders including some involving the eye. This paper is the first comprehensive review of HBOT for ocular indications. The authors recommend the following as ocular indications for HBOT: decompression sickness or arterial gas embolism with visual signs or symptoms, central retinal artery occlusion, ocular and periocular gas gangrene, cerebro-rhino-orbital mucormycosis, periocular necrotizing fasciitis, carbon monoxide poisoning with visual sequelae, radiation optic neuropathy, radiation or mitomycin C-induced scleral necrosis, and periorbital reconstructive surgery. Other ocular disorders that may benefit from HBOT include selected cases of ischemic optic neuropathy, ischemic central retinal vein occlusion, branch retinal artery occlusion with central vision loss, ischemic branch retinal vein occlusion, cystoid macular edema associated with retinal venous occlusion, post-surgical inflammation, or intrinsic inflammatory disorders, periocular brown recluse spider envenomation, ocular quinine toxicity, Purtscher's retinopathy, radiation retinopathy, anterior segment ischemia, retinal detachment in sickle cell disease, refractory actinomycotiC lacrimal canaliculitis, pyoderma gangrenosum of the orbit and refractory pseudomonas keratitis. Visual function should be monitored as clinically indicated before, during, and after therapy when HBOT is undertaken to treat vision loss. Visual acuity alone is not an adequate measure of visual function to monitor the efficacy of HBOT in this setting. Ocular examinations should also include automated perimetry to evaluate the central 30 degrees of visual field at appropriate intervals. Interpretation of the literature on the efficacy of HBOT in treating ocular disorders is complicated by several factors: frequent failure to include visual field examination as an outcome measure, failure to adequately address the interval from symptom onset to initiation of HBOT, and lack of evidence for optimal treatment regimens for essentially all ocular indications. Because some ocular disorders require rapid administration of HBOT to restore vision, patients with acute vision loss should be considered emergent when they present. Visual acuity should be checked immediately, including vision with pinhole correction. If the patient meets the criteria for emergent HBOT outlined in the paper, normobaric oxygen should be started at the highest inspired oxygen fraction possible until arrangements can be made for HBOT.
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PMID:Hyperbaric oxygen therapy and the eye. 1902 63

Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.
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PMID:Mechanisms of vasculopathy in sickle cell disease and thalassemia. 1907 78

Several diseases, such as malaria, sickle cell disease, and ischemia/reperfusion may cause excessive formation of hemin, which may in turn trigger hemolysis. A variety of drugs and diseases leading to hemolysis triggers suicidal erythrocyte death or eryptosis, i.e., cell membrane scrambling and cell shrinkage. Eryptosis is elicited by increased cytosolic Ca(2+) activity and by ceramide. The present study explored whether hemin stimulates eryptosis. Cell membrane scrambling was estimated from annexin V-binding to phosphatidylserine exposed at the cell surface, cell shrinkage from forward scatter in fluorescence-activated cell sorter analysis, cytosolic Ca(2+) activity from Fluo3 fluorescence and ceramide formation from fluorescence-labeled antibody binding. Exposure to hemin (1-10 microM) within 48 h significantly increased annexin V-binding, decreased forward scatter, increased cytosolic Ca(2+) activity, and stimulated ceramide formation. In conclusion, hemin stimulates suicidal cell death, which may in turn contribute to the clearance of circulating erythrocytes and thus to anemia.
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PMID:Hemin-induced suicidal erythrocyte death. 1918 15


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