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1.  Plasma glial fibrillary acidic protein levels in children with sickle cell disease 
American journal of hematology  2011;86(5):10.1002/ajh.21995.
To determine if glial fibrillary acidic protein (GFAP) is associated with brain injury in children with sickle cell disease (SCD), we measured plasma GFAP among cross-sectional groups of unselected children with SCD, subsets of children with SCD and normal brain MRI or MRI evidence of cerebral infarct, healthy pediatric controls, and adults with brain injury. Children with SCD had higher plasma GFAP than healthy pediatric controls (mean concentrations 0.14±0.37 vs. 0.07±0.08 ng/mL; P=0.003); also, 16.0% (16/100) of children with SCD and cerebral infarct had GFAP elevations above the 95th percentile of healthy pediatric controls (P=0.04). Although not statistically significant, more children with SCD and cerebral infarct had elevated GFAP levels than children with SCD and no infarct (16/100, 16.0% vs. 14/168, 8.3%; P=0.07). Children with SCD and acute brain ischemia had a higher proportion of elevated GFAP than SCD children with normal MRI (3/6, 50% vs. 8.3%; P=0.01). GFAP was associated with elevated systolic blood pressure in the preceding year and correlated positively with white blood cell count and negatively with age and performance IQ. Plasma GFAP is elevated among children with SCD and may be associated with subclinical brain injury.
doi:10.1002/ajh.21995
PMCID: PMC3870012  PMID: 21523806
sickle cell; cerebral infarct; glial fibrillary acidic protein
2.  Plasma interleukin-1β(beta) concentration is associated with stroke in sickle cell disease 
Cytokine  2009;49(1):39-44.
The pathogenesis of sickle cell disease (HbSS), which has numerous complications including stroke, involves inflammation resulting in alteration of plasma inflammatory protein concentration. We investigated HbSS children with abnormal cerebral blood flow detected by trans-cranial Doppler ultrasound (TCD) who participated in multi-center stroke prevention (STOP) study, to determine if plasma inflammatory protein concentration is associated with the outcome of stroke in the STOP study. Thirty-nine plasma samples from HbSS participants with elevated TCD who had no stroke, HbSS-NS (n=13) or had stroke, HbSS-S (n=13), HbSS steady-state controls (n=7) and controls with normal hemoglobin, HbAA (n=6), were analyzed simultaneously for 27 circulating inflammatory proteins. Logistic regression and receiver operating characteristics curve analysis of stroke on plasma inflammatory mediator concentration, adjusted for age and gender, demonstrated that interleukin-1β (IL-1β) was protective against stroke development (HbSS-NS = 19, 17–23, HbSS-S = 17, 16 – 19 pg/mL, median and 25th–75th percentile; Odds ratio = 0.59, C.I. = 0.36 – 0.96) and was a good predictor of stroke (area under curve = 0.852). This result demonstrates a strong association of systemic inflammation with stroke development in HbSS via moderately increased plasma IL-1β concentration, which is furthermore associated with a decreased likelihood of stroke in HbSS.
doi:10.1016/j.cyto.2009.10.002
PMCID: PMC2808442  PMID: 19900820
Sickle cell; Stroke; Interleukin-1β; Cytokine; Chemokine
3.  Transport proteins and acute phase reactant proteins in children with sickle cell anemia. 
Transport proteins, acute-phase reactant proteins (APRP), hematology, and anthropometry were studied in 34 sickle cell disease (SCD) children (20 boys, 14 girls) and 27 controls without growth deficits (13 boys, 14 girls) [corrected]. The age range was 1/2 to 16 1/2 years. Weight deficits (< 80%) by Waterlow's classification were observed in 41% of SCD boys and 25% of SCD girls, and height deficits (< 90%) were observed in 25% SCD boys and 25% girls. Mean white blood cell counts were significantly higher (P < .001) and hematocrit and hemoglobin (Hb) lower (P < .005) in SCD children than in controls. Although both groups had similar mean levels of albumin, transferrin, and APRP, SCD children had significantly lower mean levels of retinol-binding protein (RBP) (P < .001) and retinol-prealbumin (P < .001). Retinol-binding protein levels were abnormal in 18 (53%) SCD children and in only 23% controls (chi 2 = 14.06; P < 0.005); transferrin levels were abnormal in 20% of SCD children and in none of the controls. Children with SC and SF Hb phenotype had normal mean levels of RBP, whereas those with S beta thal and SS phenotype had levels below normal. Growth-retarded children by weight and height had reduced mean levels of RBP and prealbumin compared with growth-normal SCD children. The implication of primary protein-energy malnutrition on growth retardation in SCD children is under study.
PMCID: PMC2607658  PMID: 7512147
4.  TISSUE FACTOR-POSITIVE MONOCYTES IN CHILDREN WITH SICKLE CELL DISEASE: CORRELATION WITH BIOMARKERS OF HAEMOLYSIS 
British Journal of Haematology  2012;157(3):370-380.
SUMMARY
Tissue Factor (TF) initiates thrombin generation, and whole blood TF (WBTF) is elevated in sickle cell disease (SCD). We sought to identify the presence of TF-positive monocytes in SCD and their relationship with the other coagulation markers including WBTF, microparticle-associated TF, thrombin-antithrombin (TAT) complexes and D-dimer. Whether major SCD-related pathobiological processes, including haemolysis, inflammation and endothelial activation, contribute to the coagulation abnormalities was also studied. The cohort comprised children with SCD (18 HbSS, 12 HbSC, mean age 3.6 years). We demonstrated elevated levels of TF-positive monocytes in HbSS, which correlated with WBTF, TAT and D-Dimer (p=0.02 to p=0.0003). While TF-positive monocytes, WBTF, TAT and D-dimer correlated with several biomarkers of haemolysis, inflammation and endothelial activation in univariate analyses, in multiple regression models the haemolytic markers (reticulocytes and lactate dehydrogenase) contributed exclusively to the association with all four coagulant markers evaluated. The demonstration that haemolysis is the predominant operative pathology in the associated perturbations of coagulation in HbSS at a young age provides additional evidence for the early use of therapeutic agents, such as hydroxycarbamide to reduce the haemolytic component of this disease.
doi:10.1111/j.1365-2141.2012.09065.x
PMCID: PMC3323750  PMID: 22360627
Sickle cell disease; tissue factor-positive monocytes; coagulation abnormalities; biomarkers of haemolysis; biomarkers of inflammation
5.  Hospital Admission for Acute Painful Episode Following Methacholine Challenge in an Adolescent With Sickle Cell Disease 
Pediatric pulmonology  2009;44(7):728-730.
Summary
Asthma is associated with increases in sickle cell disease (SCD)-related morbidity and mortality. A thorough evaluation for asthma in children with SCD is important and may involve methacholine challenge (MCh). In this report, we present a 14-year-old male with SCD who was admitted for an acute painful episode following MCh. Pain events after MCh have not been previously reported in children with SCD. The risk–benefit ratio should be strongly considered prior to performance of MCh in this patient population, and all possible complications, including an acute painful episode, should be openly discussed with the parents and pediatric patient.
doi:10.1002/ppul.21049
PMCID: PMC3729266  PMID: 19504562
methacholine challenge; sickle cell disease; pain; asthma
6.  Patent Foramen Ovale in Patients with Sickle Cell Disease and Stroke: Case Presentations and Review of the Literature 
Case Reports in Hematology  2013;2013:516705.
Although individuals with sickle cell disease (SCD) are at increased risk for stroke, the underlying pathophysiology is incompletely understood. Intracardiac shunting via a patent foramen ovale (PFO) is associated with cryptogenic stroke in individuals without SCD. Recent evidence suggests that PFOs are associated with stroke in children with SCD, although the role of PFOs in adults with stroke and SCD is unknown. Here, we report 2 young adults with SCD, stroke, and PFOs. The first patient had hemoglobin SC and presented with a transient ischemic attack and a subsequent ischemic stroke. There was no evidence of cerebral vascular disease on imaging studies and the PFO was closed. The second patient had hemoglobin SS and two acute ischemic strokes. She had cerebral vascular disease with moyamoya in addition to a peripheral deep venous thrombosis (DVT). Chronic transfusion therapy was recommended, and the DVT was managed with warfarin. The PFO was not closed, and the patients' neurologic symptoms were stabilized. We review the literature on PFOs and stroke in SCD. Our cases and the literature review illustrate the dire need for further research to evaluate PFO as a potential risk factor for stroke in adults with SCD.
doi:10.1155/2013/516705
PMCID: PMC3730376  PMID: 23956892
7.  Right and left ventricular function and myocardial scarring in adult patients with sickle cell disease: a comprehensive magnetic resonance assessment of hepatic and myocardial iron overload 
Background
Patients with Sickle cell disease (SCD) who receive regular transfusions are at risk for developing cardiac toxicity from iron overload. The aim of this study was to assess right and left cardiac volumes and function, late gadolinium enhancement (LGE) and iron deposits in patients with SCD using CMR, correlating these values with transfusion burden, ferritin and hemoglobin levels.
Methods
Thirty patients with SCD older than 20 years of age were studied in a 1.5 T scanner and compared to age- and sex-matched normal controls. Patients underwent analysis of biventricular volumes and function, LGE and T2* assessment of the liver and heart.
Results
When compared to controls, patients with SCD presented higher left ventricular (LV) volumes with decreased ejection fraction (EF) with an increase in stroke volume (SV) and LV hypertrophy. The right ventricle (RV) also presented with a decreased EF and hypertrophy, with an increased end-systolic volume. Although twenty-six patients had increased liver iron concentrations (median liver iron concentration value was 11.83 ± 9.66 mg/g), only one patient demonstrated an abnormal heart T2* < 20 msec. Only four patients (13%) LGE, with only one patient with an ischemic pattern.
Conclusions
Abnormal heart iron levels and myocardial scars are not a common finding in SCD despite increased liver iron overload. The significantly different ventricular function seen in SCD compared to normal suggests the changes in RV and LV function may not be due to the anemia alone. Future studies are necessary to confirm this association.
doi:10.1186/1532-429X-15-83
PMCID: PMC3848779  PMID: 24050721
8.  Association of Variants at BCL11A and HBS1L-MYB with Hemoglobin F and Hospitalization Rates among Sickle Cell Patients in Cameroon 
PLoS ONE  2014;9(3):e92506.
Background
Genetic variation at loci influencing adult levels of HbF have been shown to modify the clinical course of sickle cell disease (SCD). Data on this important aspect of SCD have not yet been reported from West Africa. We investigated the relationship between HbF levels and the relevant genetic loci in 610 patients with SCD (98% HbSS homozygotes) from Cameroon, and compared the results to a well-characterized African-American cohort.
Methods and Findings
Socio-demographic and clinical features were collected and medical records reviewed. Only patients >5 years old, who had not received a blood transfusion or treatment with hydroxyurea were included. Hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes. SNaPshot PCR, Capillary electrophoresis and cycle sequencing were used for the genotyping of 10 selected SNPs. Genetic analysis was performed with PLINK software and statistical models in the statistical package R. Allele frequencies of relevant variants at BCL11A were similar to those detected in African Americans; although the relationships with Hb F were significant (p <.001), they explained substantially less of the variance in HbF than was observed among African Americans (∼ 2% vs 10%). SNPs in HBS1L-MYB region (HMIP) likewise had a significant impact on HbF, however, we did not find an association between HbF and the variations in HBB cluster and OR51B5/6 locus on chromosome 11p, due in part to the virtual absence of the Senegal and Indian Arab haplotypes. We also found evidence that selected SNPs in HBS1L-MYB region (HMIP) and BCL11A affect both other hematological indices and rates of hospitalization.
Conclusions
This study has confirmed the associations of SNPs in BCL11A and HBS1L-MYB and fetal haemoglobin in Cameroonian SCA patients; hematological indices and hospitalization rates were also associated with specific allelic variants.
doi:10.1371/journal.pone.0092506
PMCID: PMC3965431  PMID: 24667352
9.  Transcranial Doppler Screening and Prophylactic Transfusion Program Is Effective in Preventing Overt Stroke in Children With Sickle Cell Disease 
The Journal of pediatrics  2010;157(3):479-484.
Objective
To assess the impact of our transcranial doppler ultrasonography (TCD) program on the incidence of first stroke and the rate of transfusion for stroke prevention in children with sickle cell disease.
Study design
In this single-institution, retrospective study, we compared the incidence of stroke and of transfusion for stroke prevention in 475 patients followed in the 8-year period prior to instituting TCD screening to the rate in 530 children in the 8-year period afterwards.
Results
The incidence of overt stroke in the pre-TCD period was 0.67 per 100 patient-years, compared with 0.06 per 100 patient-years in the post-TCD period (p<0.0001). Of the two strokes in the post-TCD period, one occurred in a child too young for the screening protocol and one in a child with high velocities solely in the anterior cerebral arteries. The rate of transfusion therapy for stroke prevention increased from 0.67 per 100 patient-years to 1.12 per 100 patient-years since instituting our program (p=0.008).
Conclusions
Our program has been successful in reducing the rate of first overt stroke, but with increased use of transfusion. Additional modifications to screening might further reduce the risk of first stroke, and studies of alternative treatments may be beneficial.
doi:10.1016/j.jpeds.2010.03.007
PMCID: PMC2931594  PMID: 20434165
Sickle cell disease; stroke; Transcranial Doppler ultrasonography; blood transfusion; pediatric hematology
10.  The Excess Burden of Stroke in Hospitalized Adults with Sickle Cell Disease 
American journal of hematology  2009;84(9):548-552.
Objective
To compare the relative rates and risk factors associated with stroke in adults vs. children with sickle cell disease (SCD) in the U.S. over the last decade.
Methods
We identified incident strokes in patients with SCD using ICD-9 codes for acute stroke and SCD and the California Patient Discharge Databases. We estimated SCD prevalence by using the incidence of SCD at birth with adjustment for early mortality from SCD.
Results
We identified 255 acute strokes (70 primary hemorrhagic and 185 ischemic) among 69,586 hospitalizations for SCD-related complications from 1998–2007. The rate of stroke in children [<18 years old (310/100,000 person-years)] was similar to young adults [18 to 34 years old (360/100,000 person-years)], but much higher in middle-aged [35 to 64 years old (1160/100,000 person-years)] and elderly adults [≥65 years old (4700/100,000 person-years)]. Stroke was associated with hypertension in children and hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and renal disease in adults. Most acute strokes (75%) and in-hospital deaths from stroke (91%) occurred in adults.
Interpretation
Our results suggest that the rate of stroke in SCD peaks in older adults and is 3-fold higher than rates previously reported in African-Americans of similar age (35 to 64 years) without SCD. Stroke in SCD is associated with several known adult risk factors for ischemic and hemorrhagic stroke. Studies for the primary and secondary prevention of stroke in adults with SCD are urgently needed.
doi:10.1002/ajh.21476
PMCID: PMC2737603  PMID: 19623672
Stroke; sickle cell disease; epidemiology; transfusion
11.  CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions 
The Journal of Clinical Investigation  2011;121(4):1397-1401.
Hemolytic transfusion reactions (HTRs) can produce serious and potentially life-threatening complications in sickle cell disease (SCD) patients; however, the mechanisms underlying these complications remain undetermined. We established a model of alloimmune, IgG-mediated HTRs in a well-characterized humanized murine model of SCD. HTRs induced acute vaso-occlusive crisis (VOC), resulting in shortened survival of SCD mice. Acute VOC was associated with elevated circulating inflammatory chemokine levels, including striking elevation of the levels of the neutrophil chemoattractant CXCL1. Recombinant CXCL1 administration was sufficient to induce acute VOC in SCD mice, characterized by leukocyte recruitment in venules, capture of circulating red blood cells, reduction of venular flow, and shortened survival. In contrast, blockade of the CXCL1 receptor, CXCR2, prevented HTR-elicited acute VOC and prolonged survival in SCD mice. These results indicate that CXCL1 is a key inflammatory mediator of acute VOC in SCD mice. Targeted inhibition of CXCL1 and/or CXCR2 may therefore represent a new therapeutic approach for acute VOC in SCD patients.
doi:10.1172/JCI45336
PMCID: PMC3069787  PMID: 21383500
12.  Refining the Value of Secretory Phospholipase A2 as a Predictor of Acute Chest Syndrome in Sickle Cell Disease: Results of a Feasibility Study (PROACTIVE) 
British Journal of Haematology  2012;157(5):627-636.
Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts; and those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.
doi:10.1111/j.1365-2141.2012.09105.x
PMCID: PMC3349768  PMID: 22463614
Acute chest syndrome; sPLA2; transfusion; vaso-occlusive episode; pulmonary fat embolism
13.  Sickle Cell Disease in Children 
Drugs  2012;72(7):895-906.
Early identification of infants with sickle cell disease (SCD) by newborn screening, now universal in all 50 states in the US, has improved survival, mainly by preventing overwhelming sepsis with the early use of prophylactic penicillin. Routine transcranial Doppler screening with the institution of chronic transfusion decreases the risk of stroke from 10% to 1% in paediatric SCD patients. Hydroxyurea decreases the number and frequency of painful crises, acute chest syndromes and number of blood transfusions in children with SCD. Genetic research continues to be driven toward the prevention and ultimate cure of SCD before adulthood. This review focuses on clinical manifestations and therapeutic strategies for paediatric SCD as well as the evolving topic of gene-focused prevention and therapy.
doi:10.2165/11632890-000000000-00000
PMCID: PMC3899685  PMID: 22519940
14.  Tricuspid regurgitant velocity elevation in a three-year old child with sickle cell anemia and recurrent acute chest syndromes reversed not by hydroxyurea but by bone marrow transplantation 
Hematology Reports  2011;3(2):e12.
Elevated Tricuspid Regurgitant Velocity (TRV) has been related to higher mortality in adults and to hemolysis, lower oxygen saturation during 6-minute walk test and acute chest syndrome (ACS) in children with sickle cell disease (SCD). Hydroxyurea (HU) has reduced TRV value in children and adults. We describe a three year old HbSS child with recurrent ACS, hypoperfusion of the left lung, mild hemolysis and persistent TRV elevation. TRV did not normalize after HU, despite improvement in clinical conditions and in baseline laboratory parameters related to hemolysis and blood viscosity, but normalized after bone marrow transplantation (BMT). Our experience suggests that in young patients, TRV reduction can be a positive concomitant effect of BMT.
doi:10.4081/hr.2011.e12
PMCID: PMC3238484  PMID: 22184533
sickle-cell disease; pulmonary hypertension; tricuspid regurgitant jet velocity; hydroxyurea, bone marrow transplantation.
15.  LIPID LEVELS IN SICKLE-CELL DISEASE ASSOCIATED WITH HEMOLYTIC SEVERITY, VASCULAR DYSFUNCTION AND PULMONARY HYPERTENSION 
British journal of haematology  2010;149(3):436-445.
Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single-institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular hemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) in SCD vs. ethnically-matched healthy controls. Several cholesterol parameters correlate significantly with markers of anemia, but not endothelial activation or PH. More importantly, serum triglyceride levels are significantly elevated in SCD compared to controls. Elevated triglyceride levels correlate significantly with markers of hemolysis (lactate dehydrogenase and arginase; both p<0.0005), endothelial activation (soluble E-selectin, p<0.0001; soluble P-selectin, p=0.02; soluble vascular cell adhesion molecule-1, p=0.01), inflammation (leukocyte count, p=0.0004; erythrocyte sedimentation rate, p=0.02) and PH (amino-terminal brain natriuretic peptide, p=0.002; prevalence of elevated tricuspid regurgitant velocity (TRV), p<0.001). In a multivariate analysis, triglyceride levels correlate independently with elevated TRV (p=0.002). Finally, forearm blood flow studies in adult patients with SCD demonstrate a significant association between increased triglyceride/HDL-C ratio and endothelial dysfunction (p<0.05). These results characterize elevated plasma triglyceride levels as a potential risk factor for PH in SCD.
doi:10.1111/j.1365-2141.2010.08109.x
PMCID: PMC3212812  PMID: 20230401
16.  HLA Alloimmunization Is Associated With RBC Antibodies in Multiply Transfused Patients With Sickle Cell Disease 
Pediatric blood & cancer  2010;54(4):552-558.
Background
Alloimmunization to minor red blood cell (RBC) antigens occurs commonly in sickle cell disease (SCD). Patients with alloimmunization demonstrate increased risk for new alloantibody formation with subsequent transfusion. Alloimmunization to human leukocyte antigens (HLA) can occur with RBC transfusion and may result in graft rejection during stem cell or organ transplantation. The prevalence and risk factors for HLA alloimmunization in multiply transfused pediatric SCD patients are unknown.
Procedure
A cross-sectional study of HLA alloimmunization in SCD patients aged 3–21 years with a history of ≥3 RBC transfusions was performed to test the hypothesis that HLA alloimmunization is associated with RBC alloimmunization. Antibodies to class I and class II HLA were measured by Flow Panel Reactive Antibody (FlowPRA®).
Results
Seventy-three SCD patients (30 with RBC antibodies) were tested. HLA antibodies were detected in 25/73 (34%) patients; class I HLA antibodies occurred in 24/73 (33%) and class II HLA antibodies occurred in 3 (4%). Among patients with RBC antibodies, 16/30 (53%) had HLA antibodies, while 9/43 (21%) patients without RBC antibodies had HLA antibodies (OR 4.32 [1.6–12.1]). In a multivariate analysis, antibodies to RBC antigens were an independent predictor of HLA alloimmunization (P =0.041). The association of RBC and HLA immunization was strongest among patients with no history of chronic transfusion therapy.
Conclusions
This analysis is the first description of HLA alloimmunization in pediatric SCD patients who receive primarily leukoreduced RBC transfusions and demonstrates that HLA alloimmunization tendency is associated with antibodies to RBC antigens.
doi:10.1002/pbc.22327
PMCID: PMC3722881  PMID: 19890898
alloimmunization; human leukocyte antigen (HLA); sickle cell disease; transfusion
17.  Oxidative stress and inflammation in iron-overloaded patients with β-thalassaemia or sickle cell disease 
British journal of haematology  2006;135(2):254-263.
Summary
Blood transfusion therapy is life-saving for patients with β-thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1.8-fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0.001) and specific diagnosis (P = 0.019). A significant 2-fold elevation of non-transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2.2-fold elevation of the inflammatory marker interleukin (IL)-6 relative to controls, and a 3.6- and 1.7-fold increase in IL-5 and IL-10 relative to thalassaemia. Although α-tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, γ-tocopherol, a nitric oxide-selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and γ-tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.
doi:10.1111/j.1365-2141.2006.06277.x
PMCID: PMC2185791  PMID: 17010049
iron overload; thalassaemia; sickle cell disease; oxidative stress; inflammation; cytokines; non-transferrin bound iron; malondialdehyde; lipid peroxidation; vitamin E
18.  Reversible posterior leukoencephalopathy syndrome in sickle cell anemia 
Pediatric neurology  2009;40(4):298-301.
This report describes a 10 year old African American woman with sickle cell anemia (HbSS) who developed headaches and seizures associated with hypertension during hospitalization for a pulmonary abscess. Hypertension developed following multiple transfusions associated with a relatively abnormally high hematocrit and headache. Magnetic resonance imaging (MRI) was consistent with posterior leukoencephalopathy. Neurological symptoms, hypertension and high hematocrit resolved following erythrocytapheresis. An MRI one month after the episode was normal. Since reversible posterior leukoencephalopathy syndrome (RPLS) has only been reported in HbSS during severe acute chest syndrome, this report documents that milder illness can be associated with RPLS in HbSS. This report highlights the subtle symptoms that may herald serious neurological events in high-risk patients. Examination of the pathophysiology of RPLS in the context of HbSS suggests that patient with HbSS and subtle neurological symptoms should be treated with high vigilance.
doi:10.1016/j.pediatrneurol.2008.10.024
PMCID: PMC2903963  PMID: 19302944
Reversible posterior leukoencephalopathy syndrome; Seizure; Headache; Sickle Cell Anemia; Hypertension
19.  Feasibility of Web-based Technology to Assess Adherence to Clinic Appointments in Youth with Sickle Cell Disease 
Web-based tools to improve clinic attendance have been effectively used in pediatric conditions but have not been tested in pediatric sickle cell disease (SCD). The goal of this pilot study was to assess barriers to clinic attendance and the feasibility of a web-based assessment tool to promote problem-solving around clinic appointments. Study participants included 30 youth with SCD (M=11.7±3.5 years; 57% male; 60% HbSS; 20% HbSC; 17% HB+Thal) and their primary caregivers. Medical chart review indicated that 61% of participants attended at least two SCD clinic appointments in the past year. The primary barrier to clinic attendance was inability to take off from work/school (33%). Regarding feasibility and acceptability, the computerized program was well-received by patients and caregivers, with youth and caregivers reporting a high degree of usefulness and preference for computerized assessment. Results suggest that this innovative approach shows promise and should be tested on a larger sample of youth with SCD.
doi:10.1097/MPH.0b013e318240d531
PMCID: PMC3311776  PMID: 22278205
innovation; compliance; disease management; technology; pediatric
20.  Higher Rates of Hemolysis Are Not Associated with Albuminuria in Jamaicans with Sickle Cell Disease 
PLoS ONE  2011;6(4):e18863.
Background
Albuminuria is a marker of glomerular damage in Sickle Cell Disease (SCD). In this study, we sought to determine the possible predictors of albuminuria in the two more prevalent genotypes of SCD among the Jamaica Sickle Cell Cohort Study participants.
Methods
An age-matched cohort of 122 patients with HbSS or HbSC genotypes had measurements of their morning urine albumin concentration, blood pressure, body mass index, haematology and certain biochemistry parameters done. Associations of albuminuria with possible predictors including hematological parameters, reticulocyte counts, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels were examined using multiple regression models.
Results
A total of 122 participants were recruited (mean age 28.6 years ±2.5 years; 85 HbSS, 37 HbSC). 25.9% with HbSS and 10.8% with HbSC disease had microalbuminuria (urine albumin/creatinine ratio  =  30–300 mg/g of creatinine) whereas 16.5% of HbSS and 2.7% of HbSC disease had macroalbuminuria (urine albumin/creatinine ratio>300 mg/g of creatinine). Mean arterial pressure, hemoglobin levels, serum creatinine, reticulocyte counts and white blood cell counts were statistically significant predictors of albuminuria in HbSS, whereas white blood cell counts and serum creatinine predicted albuminuria in HbSC disease. Both markers of chronic hemolysis, i.e. AST and LDH levels, showed no associations with albuminuria in either genotype.
Conclusions
Renal disease, as evidenced by excretion of increased amounts of albumin in urine due to a glomerulopathy, is a common end-organ complication in SCD. It is shown to be more severe in those with HbSS disease than in HbSC disease. Rising blood pressure, lower hemoglobin levels and higher white blood cell counts are hints to the clinician of impending renal disease, whereas higher rates of hemolysis do not appear to play a role in this complication of SCD.
doi:10.1371/journal.pone.0018863
PMCID: PMC3077410  PMID: 21533141
21.  Self-Care Recommendations of Middle-Aged and Older Adults with Sickle Cell Disease 
Nursing Research and Practice  2011;2011:270594.
Self-care management is an important part of living with a chronic illness. Sickle cell disease (SCD) is a chronic disease with acute, painful exacerbations that often results in a shortened life expectancy. Some middle-aged and older adults with SCD lived with the disease prior to having a diagnosis and without modern advances. The purpose of this study is to share the self-care recommendations of middle-aged and older adults with SCD. Using descriptive qualitative methods, data were gathered through semistructured interviews from 11 individuals living with SCD, including 6 women and 5 men. Self-care recommendations themes included physiological, psychological, and provider-related. The self-care recommendations may be seen as an additional resource or “words of wisdom” for younger adults with SCD who can use the recommendations to better manage their own disease. Additionally, providers may be able to use these recommendations to inform their practice.
doi:10.1155/2011/270594
PMCID: PMC3168929  PMID: 21994819
22.  Elevation of IgE in children with sickle cell disease is associated with doctor diagnosis of asthma and increased morbidity 
Background
A doctor diagnosis of asthma is associated with increased morbidity (pain and acute chest syndrome, ACS) among children with sickle cell disease (SCD). An association between IgE levels and asthma and morbidity has not been investigated in children with SCD.
Objective
We tested the hypothesis that elevated total and allergen-specific IgE levels are associated with asthma and SCD morbidity in children with SCD.
Methods
A cross-sectional study of children with SCD who participated in the Silent Cerebral Infarct Trial was conducted. Logistic regression and negative binomial regression were used to investigate potential associations of total and allergen-specific IgE levels with asthma diagnosis and SCD morbidity, both confirmed by medical record review. Elevation of total IgE was defined as age- and sex-adjusted IgE exceeding 90th percentile compared to a non-atopic reference population. IgE antibody positivity to Altermaria alternata (mold), Blatella germanica (cockroach), and Dermatophagoides pteronyssinus (dust mite) was assessed by ImmunoCAP analysis.
Results
Children with SCD (140 asthmatics, 381 non-asthmatics) were evaluated. Elevations in total IgE (p = 0.04) and IgE antibody specific for Altermaria alternata (p = 0.0003), Blatella germanica (p = 0.008), and Dermatophagoides pteronyssinus (p = 0.01) were associated with asthma. ACS (p = 0.048) but not pain (p = 0.20) was associated with total IgE, but neither were associated with specific IgE levels.
Conclusions
Significantly increased levels of total and allergen-specific IgE levels are associated with asthma in SCD. High IgE levels are a risk factor for ACS and not pain rates.
doi:10.1016/j.jaci.2010.12.1114
PMCID: PMC3105194  PMID: 21388662
Total IgE; allergen-specific IgE; asthma risk indicator; acute chest syndrome; pain; sickle cell disease; hemoglobinopathies
23.  Does blood transfusion affect pituitary gonadal axis and sperm parameters in young males with sickle cell disease? 
Objective:
We evaluated the effect of packed red cell transfusion (PCTx) on serum concentrations of gonadotropins luteinizing hormone and follicle-stimulating hormone (LH and FSH) and testosterone (T) levels and measured sperm parameters in young adults with sickle cell disease (SCD) on top-up transfusion (TTx) and those on exchange transfusion (ETx) regimen.
Materials and Methods:
Basal serum concentrations of FSH, LH, and T and semen parameters were evaluated before and 7 days after PCTx in 18 young adults with transfusion-dependent SCD, aged 20.7 ± 2.88 years. They had full pubertal development (Tanner's stage 5), and capacity to ejaculate. They were regularly transfused since early childhood. Chelation therapy was started early during the first 2 years of life using desferrioxamine and was replaced by deferasirox for the last 4-5 years. Ten patients were on TTx and eight were on ETx regimen.
Results:
PCTx significantly increased hemoglobin (Hb) from 8.5 ± 1.17 g/dl to 10.5 ± 0.4 g/dl, T from 12.3 ± 1.24 nmol/L to 14.23 ± 1.22 nmol/L and gonadotropins’ concentrations. Sperm parameters improved significantly after PCTx including: total sperm count from 87.4 ± 24.6 million/ml to 146.2 ± 51.25 million/ml, total progressive sperm motility (TPM) from 40.8 ± 11.1 million/ml to 93.4 ± 38.3 million/ml, rapid progressive sperm motility (RPM) progressive motility from 29.26 ± 8.75 million/ml to 67.4 ± 29 million/ml. After PCTx the total sperm count, TPM and RPM were significantly better in the ETx group versus the TTx group. Before and after PCTx, T concentrations were correlated significantly with sperm total count, volume, TPM and RPM (r = 0.53, 0.55, 0.42, and 0.38, respectively, P < 0.01). Hb concentrations were correlated significantly with sperm count, TPM, RPM, and % of sperms with normal morphology (r = 0.60, 0.69, 0.66, and 0.86, respectively, P < 0.001).
Conclusion:
Our study suggests that in males with SCD blood transfusion is associated with significant acute enhancement of sperm parameters and with increased concentrations of serum T, LH, and FSH. Improvement of sperm parameters were significantly better in the ETx group verses the TTx group. These “acute” effects on spermiogenesis are reached with an unknown mechanism/s and suggest a number of pathways that need further human and/or experimental studies.
doi:10.4103/2230-8210.122599
PMCID: PMC3872712  PMID: 24381868
Desferrioxamine; gonadotropins; sickle cell disease; spermatogenesis; testosterone
24.  PATTERN OF PULMONARY MANIFESTATIONS IN PATIENTS WITH SICKLE CELL DISEASE AND FEVER 
Objectives:
The objective of this study was to determine the frequency and pattern of pulmonary manifestations in febrile patients with sickle-cell disease (SCD), a condition prevalent in the Eastern Province of Saudi Arabia.
Design:
The main pulmonary complications in febrile adult SCD patients were studied between January 1986 and December 1990.
Material and Methods:
The medical records, chest X-rays and microbiological data of all febrile (temperature >38°C) SCD patients >12 years of age admitted to KFHU during the study period were retrospectively reviewed.
Results:
Of the 164 patient-episodes in 49 male and 19 female SCD patients, chest X-rays were abnormal in 33 (20.1%) episodes. Of these 33, there was consolidation in 17 (52%), pleural effusion in 6 (18%), pleural effusion and consolidation in 4 (12%), consolidation with collapse in 3 (9%), pleural thickening in 2 (6%) and bronchogenic carcinoma in one.
Conclusion:
Pneumonia was the most common complication in Saudi SCD patients with abnormal chest X-rays. Chest X-rays are most useful in SCD patients with symptoms of chest infection, abnormal chest signs, or those with persistent fever during vaso-occlusive crisis.
PMCID: PMC3410080  PMID: 23012060
Chest X-ray; sickle cell disease; pulmonary manifestations
25.  Defects in Postabsorptive Plasma Homeostasis of Fatty Acids in Sickle Cell Disease 
Background
The chronic hemolytic anemia experienced by sickle cell disease (SCD) patients leads to adverse effects on oxygen transport by the blood and to a decrease in oxygen availability for peripheral tissues. Limited tissue oxygen availability has the potential to modify events of intracellular metabolism and, thus, alter lipid homeostasis.
Methods
The impact of SCD on plasma fatty acid homeostasis was determined in 8 African American SCD patients and in 6 healthy African American control subjects under postabsorptive conditions and during a 3-hour IV infusion of a nutrient solution containing lipid, glucose, and amino acids.
Results
SCD patients had higher fasting levels of plasma nonesterified fatty acids (NEFA), triglycerides, and phospholipids than healthy controls. Similarly, SCD patients had higher fasting levels of fatty acids in plasma triglycerides and phospholipids than healthy controls. Infusion of nutrients resulted in equivalent plasma NEFA profiles, total NEFA, and triglycerides in SCD patients and controls. However, the plasma phospholipid concentrations and fatty acid composition of plasma triglycerides and phospholipids were significantly higher in SCD patients; in particular, plasma pools of oleic acid were consistently increased in SCD. Plasma free oleic acid levels were elevated basally, leading to increased oleic acid content in triglycerides and phospholipids both postabsorptively and during nutrient infusion.
Conclusions
There is an underlying defect in lipid metabolism associated with SCD best manifested during the fasting state. This abnormality in lipid homeostasis has the potential to alter red blood cell (RBC) membrane fluidity and function in SCD patients.
PMCID: PMC2916689  PMID: 17595432

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