Sickle cell trait (SCT) is a very prevalent disorder in the United States, especially among African Americans or people of African descent. However, even with the prevalence of the disorder, there are no standardized guidelines for providing patients with information about SCT and the implications of the disorder at physicals and well-check visits. The purpose of this evidence-based project was to increase awareness for African American patients 18-44 years old in the practice setting about SCT and to provide options for testing and genetic counseling. Kotter's contemporary change theory was used as a guide to implement the new practice approach. A quasi-experimental, single-group, pretest-posttest-only design was used to explore the relationship between providing consistent SCT education and the impact on the rate of SCT screening and genetic counseling. A total of 71 patients participated in the program. The analysis showed a significant (p < 0.001) mean difference of 18.16 points from the preintervention SCT and genetics test mean, which indicated that the intervention was successful in raising SCT and genetics knowledge scores among the target population. The results demonstrated that the implementation of SCT education in the practice setting can enhance social implications related to SCT awareness and opportunities for SCT testing and genetic counseling. The implementation of SCT clinical guidelines can help to increase awareness about SCT and improve the overall population health and reduce the financial burden affiliated with care of those with sickle cell disease and SCT complications.

Sickle cell disease is a hereditary blood disorder caused by a point mutation in the gene encoding hemoglobin. This mutation causes hemoglobin molecules to polymerize during de-oxygenation of erythrocytes producing rod-shaped polymers that bend and distort the red blood cell membrane, making it more rigid and “sickled”. This sickling causes red blood cells to lose their flexibility and ability to navigate small capillaries and also enhances the production of pro-inflammatory membrane-derived microparticles, leading to chronic inflammation and many complications such as peripheral artery disease, stroke, myocardial infarction, vasculitis and even death. Sphingolipids are a class of lipids containing a backbone of sphingoid bases and are integral components of erythrocyte and microparticle membranes. Many of these lipids are known to mediate biological processes, but their expression, distribution and orientation in erythrocytes during sickle cell disease has never been explored. Sphingomyelin, the most abundant sphingolipid in the red blood cell membrane is hydrolyzed by sphingomyelinase to produce ceramide, which has been shown to alter membrane dynamics and enhance microvessel formation. Additionally, ceramide can be further metabolized to form sphingosine and sphingosine 1-phosphate, which is a bioactive ligand for 5 known G-protein coupled receptors present on most blood and vascular cells that modulates cell motility, proliferation, migration and phenotype. Prior to this work, it was not understood how sphingolipid metabolism contributes to vascular inflammation in sickle cell disease. Together, this body of work has elucidated key enzymatic and lipidomic alterations in sphingolipid metabolism (i.e. the activation of acid sphingomyelinase on red blood cells) that result in the production of sphingolipid-rich erythrocyte-derived microparticles, which enhance inflammatory cell activation. Our work has elucidated novel pharmacological targets to reduce microparticle generation and subsequent vascular inflammation in sickle cell disease.

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All over Africa, traditional healers use medicinal plants to prepare medicines to treat a wide range of illnesses. One of these illnesses is sickle cell anaemia or drepanocytosis or sicklemia. This disease is particularly common among sub-Saharan Africans with a clear predominance in equatorial Africa. However, it also exists in North Africa, Greece, Turkey, Saudi Arabia and India. An estimated 50 million people are affected worldwide. A literature review on sickle cell anaemia revealed that a number of plants have anti-drepanocytosic activity. The availability and frequency of ethnobotanic use of plants were taken into account when selecting the plants investigated in this study. Cajanus cajan, Callistemon viminalis, Melaleuca bracteata var. Revolution Gold and Syzygium guineense (from DRC and South Africa) were selected for study. The selected plants were subjected to modern phytochemical analysis. A total of 8 compounds were isolated from the plants’ extracts and their structures determined by modern spectroscopic techniques (1D and 2D NMR, FT-IR and MS). S. guineense from DRC (Democratic Republic of Congo) yielded flavanonoid glycoside (A) as its major chemical constituent. The South African S. guineense afforded 4 compounds namely betulinic acid (B), sitosterol (C), friedelan-3-one (D) and a betulinic acid derivative (E). Cajanus cajan showed the presence of fatty acids, one of them was characterized as an unsaturated fatty acid (I). Callistemon viminalis afforded one compound, betulic acid (F) and Melaleuca bracteata afforded two compounds which were characterized as betulinic acid acetate (G) and ursolic acid acetate (H). CH3-(CH2)n-CH2-CH=CH-CH2-CH=CH-(CH2)n-CH2-CH2-COOH The investigation of the anti-drepanocytosis activities of the extractives and their crude extracts showed in vitro antisickling activity. Ethyl acetate crude extracts of Callistemon viminalis and Melaleuca bracteata; hexane, dichloromethane and ethyl acetate crude extracts of Syzygium guineense of DRC, betulinic acid, betulinic acid acetate and maslinic acid showed a high antisickling activity, more than 70% of normalization. The compound BF4, a fatty acid, from Melaleuca bracteata was found to have a medium activity, between 50 and 70% of normalization and oleanolic acid showed the weakest activity, between 10 and 50 % of normalization. Maslinic acid and oleanolic acid which were used for anti-sickling bioassay were isolated and characterized from Syzygium cordatum by my supervisor, Professor Shode. Others crude extracts and pure isolated compounds were found to be non-active antisickling agents. These included crude hexane and methanol extracts of Cajanus cajan; crude dichloromethane extract of Callistemon viminalis; crude dichloromethane, methanol and 80% aqueous methanol extracts of Melaleuca bracteata; crude hexane, dichloromethane, ethyl acetate, and methanol extracts of Syzygium guineense (South Africa); ursolic acid from Melaleuca bracteata and flavanone glycoside from Syzygium guineense of DRC. This is the first report of the in vitro anti-sickling activity of betunilic acid, betulinic acid acetate, oleanolic acid, and maslinic acid. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2010.

Sickle cell anemia is caused by a single mutation in the β-hemoglobin gene, HBB. The disease originated in Africa and affects millions of people worldwide. Sickle hemoglobin tetramers polymerize upon deoxygenation and lead to hemolysis and vaso-occlusion. Patients with high fetal hemoglobin (HbF) can have milder disease. The only FDA-approved drug is hydroxyurea that increases HbF. HbF modulates the disease by preventing the polymerization of sickle hemoglobin and reduces the pain episodes, anemia, and organ damage associated with the disease. There are five common haplotypes associated with the HbS gene and that are very loosely associated with disease severity and HbF. Understanding the genetic bases of HbF regulation is a key factor to identify potential drug targets to induce HbF for therapeutic purposes. To fully understand the mechanism behind HbF regulation, developing a fast and accurate computational method for sickle cell haplotype classification is useful for examining the variability of HbF among sickle cell patients. Moreover, investigating the cis and trans-acting regulators of HbF gene expression to pinpoint the mechanism through which they regulate HbF is essential to develop a successful treatment. The availability of high-throughput genetic data provides an excellent opportunity to study HbF regulation in sickle cell patients and normal people comprehensively. The work reported in this thesis describes a fast and accurate method for sickle cell HBB haplotype classification. I also examine the differential effect of cis and trans-acting HbF hemoglobin regulators on -globin gene expression using the GTEx database and identify BCL2L1 as a new potential trans-regulator of HbF.

According to the national survey of genetic blood disorders, the prevalence of haemoglobinopathies in Oman is 9.5% with Sickle Cell Disease (SCD) and Sickle Cell Trait (SCT) representing two major public health concerns and having great impact on individuals’ lives as well as on society (Al-Riyami et al., 2001). Complications related to SCD arise owing to ischemic tissue injury and may result in organ dysfunction and premature death. Patients with SCD often experience painful crises (vaso-occlusion), renal disease, acute chest syndrome (ACS) and other lifethreatening conditions. Physical education teachers tend to exclude children with SCD from PE classes due to their health status. It is currently unknown whether exercise might have beneficial, adverse or no effect in children and adults with SCD. Consequently, the recommendation of exercise for children and adults with SCD is rare. accordingly, there were three objectives to the work within this thesis: First, to investigate physical fitness markers in SCD and SCT and compare them to normal healthy children. With no reference data available, the aim of the first study was to provide a general idea of this population’s physical fitness parameters. The results suggest that children with SCT had similar anthropometric measurements, physical fitness and exercise responses to normal healthy children. In contrast, SCD children who were shorter and had lower body mass, higher fat mass and lower physical fitness than SCT and normal healthy children. In addition, children with SCD exhibited higher heart 3 rate and blood lactate responses in response to exercise than SCT children and normal healthy children. The second study was designed to determine cardiovascular responses to exercise in children with SCD and SCT and to compare them with those of normal healthy children from the same age ranges. Normal healthy children had a significantly higher estimated maximal oxygen uptake (VO2max) than SCT and SCD children (P < 0.05), with SCD children achieving the lowest VO2max. The mean heart rate in SCD and SCT was significantly higher during sub-maximal exercise than in normal healthy children (P < 0.05). White blood cell (WBC) count was also higher (P < 0.05) in the SCD group than in the other two groups, which is suggestive of a chronic inflammatory state. The third study aimed to determine whether a single bout of exercise elicits changes in interleukin- 6 (IL-6) concentrations in children with SCD. Children with SCD exhibited higher baseline IL-6 concentrations than the normal healthy children (P < 0.05), suggesting a persistent inflammatory state. However, the exercise bout did not elicit a significant change in IL-6 concentrations in either normal healthy or SCD children. The final study investigated the effect of an acute bout of exercise on postprandial changes in triacylglycerides (TAG), glucose, insulin and total cholesterol. Postprandial TAG concentrations were reduced in the exercise trial (P < 0.05). The postprandial glucose and insulin responses were also reduced in the exercise trial (P < 0.05). In conclusion, the work in this thesis suggests that Omani children with SCD have lower physical fitness than normal healthy children, and that exercise might have beneficial effects on this population. The lower physical fitness of SCD children is associated with altered body composition and lower oxygen-carrying capacity of the blood, as these children had shorter stature, lower body mass, higher fat mass and exhibited lower VO2max. The potential benefit of exercise for this population is demonstrated by the alterations of postprandial lipaemia after an acute bout of exercise. Higher TAG has been associated with increased incidence of vaso-occlusive events in subjects with SCD, and exercise lowered postprandial TAG concentrations in children with SCD.

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Thesis (M.S.)--Florida State University, 2004. / Advisor: Dr. Dean Falk, Florida State University, College of Arts and Sciences, Dept. of Anthropology. Title and description from dissertation home page (viewed June 21, 2004). Includes bibliographical references.

Sickle cell disease (SCD) is a disorder in which defective hemoglobin causes sickling of red blood cells, inducing painful vaso-occlusive crises when blood flow is blocked at sites of red blood cell (RBC) clotting that can ultimately result in organ failure or death. This work demonstrates that sphingolipid metabolism is dysregulated in SCD and that this pathway can be targeted pharmacologically to prevent vaso-occlusion. We suggest a pathway in which the sickling of RBCs in SCD activates acid sphingomyelinase, altering the distribution and concentration of sphingolipids in the RBC membrane and resulting in the production of sphingolipid-rich microparticles that are secreted and can interact with cells in circulation. Sphingosine-1-phosphate (S1P) is believed to be a key modulator of SCD because it is stored at high concentrations in RBCs. Sphingolipid metabolism was confirmed to be dysregulated in SCD; most notably, S1P was significantly elevated in RBCs, and plasma, and microparticles, and the activity of acid sphingomyelinase and concentration of its byproduct, microparticles, were significantly elevated in SCD RBCs. Treatment of monocytes with S1P and SCD RBCs increased their adhesion over four-fold to endothelial cells, indicating that altered sphingolipid distribution in RBCs may contribute to vaso-occlusion through increasing myeloid cell adhesion. A cytokine profile of macrophages treated with SCD microparticles suggest that microparticles play a role in this process by increasing the secretion of inflammatory cytokines associated with SCD crises, including MIP-1α, IL-6, and TNF-α. Pilot in vitro studies in RBCs and in vivo studies in mice implicate that drugs targeting the sphingolipid metabolic pathway may be more effective treatment options than blood transfusions in managing SCD and preventing vaso-occlusive crises.