Asymmetric Dimethylarginine Levels and Its Correlation to Cerebral Blood Flow in Children with Sickle Cell Anemia.
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SUBMITTER: El-Shanshory M
PROVIDER: S-EPMC6825090 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
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Asymmetric Dimethylarginine Levels and Its Correlation to Cerebral Blood Flow in Children with Sickle Cell Anemia.
El-Shanshory Mohamed M Hablas Nahed N Nagy Hala H Fathy Naglaa N
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion 20190313 4
Asymmetric dimethylarginine (ADMA) level may play a role in the pathogenesis of cerebrovascular stroke in Children with Sickle Cell Anemia (SCA). To assess the plasma level of ADMA in children with SCA and its correlation to cerebral blood flow. This is a cross sectional study was carried out on 30 children with homozygous SCA under follow up in the Out Patients Clinic, Pediatric Department at Tanta University Hospital and 30 healthy children as a control group. Both groups had undergone the fol ...[more]
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Project description:BACKGROUND:Blood transfusions are administered to children and adults with sickle cell anemia (SCA) for secondary stroke prevention, or as treatment for recurrent pain crises or acute anemia, but transfusion effects on cerebral hemodynamics and metabolism are not well-characterized. PURPOSE:To compare blood transfusion-induced changes in hemometabolic parameters, including oxygen extraction fraction (OEF) and cerebral blood flow (CBF), within and between adults and children with SCA. STUDY TYPE:Prospective, longitudinal study. SUBJECTS:Adults with SCA (n?=?16) receiving simple (n?=?7) or exchange (n?=?9) transfusions and children with SCA (n?=?11) receiving exchange transfusions were scanned once when hematocrit was near nadir and again within 7 days of transfusion. Adult controls without SCA or sickle trait (n?=?7) were scanned twice on separate days. FIELD STRENGTH/SEQUENCE:3.0T T1 -weighted, T2 -weighted, and T2 -relaxation-under-spin-tagging (TRUST) imaging, and phase contrast angiography. ASSESSMENT:Global OEF was computed as the relative difference between venous oxygenation (from TRUST) and arterial oxygenation (from pulse oximetry). Global CBF was computed as total blood flow to the brain normalized by intracranial tissue volume. STATISTICAL TESTS:Hemometabolic variables were compared using two-sided Wilcoxon signed-rank tests; associations were analyzed using two-sided Spearman's correlation testing. RESULTS:In adults with SCA, posttransfusion OEF?=?0.38?±?0.05 was lower (P?=?0.001) than pretransfusion OEF?=?0.45?±?0.09. A change in OEF was correlated with increases in hematocrit (P?=?0.02; rho?=?-0.62) and with pretransfusion hematocrit (P?=?0.02; rho?=?0.65). OEF changes after transfusion were greater (P?=?0.002) in adults receiving simple versus exchange transfusions. Posttransfusion CBF?=?77.7?±?26.4?ml/100g/min was not different (P?=?0.27) from pretransfusion CBF?=?82.3?±?30.2?ml/100g/min. In children with SCA, both posttransfusion OEF?=?0.28?±?0.04 and CBF?=?76.4?±?26.4 were lower than pretransfusion OEF?=?0.36?±?0.06 (P?=?0.004) and CBF?=?96.4?±?16.5 (P?=?0.004). DATA CONCLUSION:Cerebral OEF reduces following transfusions in adults and children with SCA. CBF reduces following transfusions more often in children compared to adults, indicating that vascular reserve capacity may remain near exhaustion posttransfusion in many adults. LEVEL OF EVIDENCE:2 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;49:466-477.
| S-EPMC6330124 | biostudies-literature
Project description:Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA (P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.
| S-EPMC5833262 | biostudies-literature
Project description:To investigate serum asymmetric dimethylarginine (ADMA) levels in children with isolated growth hormone deficiency (GHD) and to determine the effect of GH replacement therapy on these levels.31 patients diagnosed with isolated GHD and 29 age-and sex-matched healthy children were enrolled in the study. Height, weight and waist circumference were measured in all subjects. Fasting serum insulin-like growth factor-1 (IGF-1), IGF binding protein-3, glucose, insulin and lipid levels were evaluated. Serum ADMA levels were assessed using the enzyme-linked immunosorbent assay technique. The same evaluations were repeated on the 3rd and 6th months of treatment in 28 of the GHD cases.There were no significant differences in ADMA levels between the patient and control groups [0.513±0.130 (0.291-0.820) µmol/L vs. 0.573±0.199 (0.241-1.049) µmol/L]. There was a positive correlation between serum ADMA and HbA1c levels in the control group. In the GHD cases, ADMA levels negatively correlated with high-density lipoprotein levels and positively correlated with low-density lipoprotein levels. There was also a significant increase in ADMA levels in patients receiving GH therapy compared to pre-treatment levels [serum ADMA level, 1.075±0.133 (0.796-1.303) µmol/L at the 3rd month and 0.923±0.121 (0.695-1.159) µmol/L at the 6th month of treatment]. There was a negative correlation between ADMA levels and homeostasis model assessment of insulin resistance values at the 6th month evaluation. There were no relationships between ADMA levels and age, sex, or pubertal state either before or during the treatment.Serum ADMA levels were found to be similar in patients with GHD and in healthy children. However, serum ADMA levels showed a significant increase in GHD patients following GH replacement therapy.
| S-EPMC3986735 | biostudies-other
Project description:BackgroundIrregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.ObjectiveTo test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.DesignCross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.SettingClinical trial setting in tertiary care centers.PatientsAsymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.Main outcome measureIncidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).ResultsAcute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7-87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.ConclusionsChildren with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
| S-EPMC3677221 | biostudies-literature
Project description:Whole transcriptome RNA-sequencing was performed to quantify RNA expression changes in whole blood samples collected from steady state sickle cell anemia (SCA) and control subjects. Pediatric SCA and control subjects were recruited from Atlanta (GA)-based hospital(s) systems and consented for RNA sequencing. RNA sequencing was performed on an Ion Torrent S5 sequencer, using the Ion Total RNA-seq v2 protocol. Data were aligned to the hg19 reference genome and analyzed in the Partek Genomics studio package (v7.0). 223 genes were differentially expressed between SCA and controls (± 1.5 fold change FDR p < 0.001) and 441 genes show differential transcript expression (± 1.5 fold FDR p < 0.001). Differentially expressed RNA are enriched for hemoglobin associated genes and ubiquitin-proteasome pathway genes. Further analysis shows higher gamma globin gene expression in SCA (33-fold HBG1 and 49-fold HBG2, both FDR p < 0.05), which did not correlate with hemoglobin F protein levels. eQTL analysis identified SNPs in novel non-coding RNA RYR2 gene as having a potential regulatory role in HBG1 and HBG2 expression levels. Gene expression correlation identified JHDM1D-AS1(KDM7A-DT), a non-coding RNA associated with angiogenesis, enhanced GATA1 and decreased JAK-STAT signaling to correlate with HBG1 and HBG2 mRNA levels. These data suggest novel regulatory mechanisms for fetal hemoglobin regulation, which may offer innovative therapeutic approaches for SCA.
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Project description:Patients with sickle cell anemia (SCA) show higher levels of circulating pro-inflammatory cytokines and endothelial activation markers compared to healthy peers and altered blood transcriptome profiles. However, the characterization of the whole-blood transcriptome profile in response to exercise has not been evaluated in children with SCA. Twenty-three children/adolescents with SCA (10-19 years old) and 17 healthy controls (10-22 years old) performed eight 2-min bouts of cycle ergometry interspersed with 1-min rest intervals (50% or 70% of the peak workload achieved during the cardiopulmonary exercise test). Whole-blood transcriptome profile (RNA-seq) was performed before and after the exercise protocol. Following exercise, gene pathways associated with innate immunity were altered in both children with SCA and controls. Our results shed light on the common and different immune responses to acute exercise at the molecular level in children with SCA and healthy controls.
2024-05-24 | GSE244401 | GEO
Project description:Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression.
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Project description:Silent cerebral infarction is the most common neurological abnormality in children with sickle cell anemia, affecting 30-40% of 14 year olds. There are no known biomarkers to identify children with silent cerebral infarcts, and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma proteins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS). A total of 19 children had silent cerebral infarcts and 32 normal MRI; the children with silent infarcts had lower HbF levels (8.6 vs 16.1%, P=0.049) and higher systolic blood pressures (115 vs 108.6, P=0.027). Plasma proteomic analysis showed 13 proteins increased more than 1.3 fold in the SCI patients, including proteins involved in hypercoagulability (?2-antiplasmin, fibrinogen-? chain, thrombospondin-4), inflammation (?2-macroglobulin, complement C1s and C3), and atherosclerosis (apolipoprotein B-100). Higher levels of gelsolin and retinol-binding protein 4 were also found in the population with silent infarcts, both of which have been linked to stroke. We investigated the genetic basis of these differences by studying 359 adults with sickle cell disease (199 with silent cerebral infarcts, 160 normal MRIs), who had previously undergone a genome-wide genotyping array. None of the genes coding for the differentially expressed proteins were significantly associated with silent infarction. Our study suggests that silent cerebral infarcts in sickle cell anemia may be associated with higher systolic blood pressure, lower HbF levels, hypercoagulability, inflammation and atherosclerotic lipoproteins.
| S-EPMC6029528 | biostudies-literature
Project description:Background and purposeChildren with sickle cell disease have low hematocrit and elevated CBF, the latter of which can be assessed with arterial spin-labeling MR imaging. Quantitative CBF values are obtained by using an estimation of the longitudinal relaxation time of blood (T1blood). Because T1blood depends on hematocrit in healthy individuals, we investigated the importance of measuring T1blood in vivo with MR imaging versus calculating it from hematocrit or assuming an adult fixed value recommended by the literature, hypothesizing that measured T1blood would be the most suited for CBF quantification in children with sickle cell disease.Materials and methodsFour approaches for T1blood estimation were investigated in 39 patients with sickle cell disease and subsequently used in the CBF quantification from arterial spin-labeling MR imaging. First, we used 1650 ms as recommended by the literature (T1blood-fixed); second, T1blood calculated from hematocrit measured in patients (T1blood-hematocrit); third, T1blood measured in vivo with a Look-Locker MR imaging sequence (T1blood-measured); and finally, a mean value from T1blood measured in this study in children with sickle cell disease (T1blood-sickle cell disease). Quantitative flow measurements acquired with phase-contrast MR imaging served as reference values for CBF.ResultsT1blood-measured (1818 ± 107 ms) was higher than the literature recommended value of 1650 ms, was significantly lower than T1blood-hematocrit (2058 ± 123 ms, P < .001), and, most interesting, did not correlate with hematocrit measurements. Use of either T1blood-measured or T1blood-sickle cell disease provided the best agreement on CBF between arterial-spin labeling and phase-contrast MR imaging reference values.ConclusionsThis work advocates the use of patient-specific measured T1blood or a standardized value (1818 ms) in the quantification of CBF from arterial spin-labeling in children with SCD.
| S-EPMC7984682 | biostudies-literature
Project description:Hemodialysis patients exhibit anemia-related cerebral hyperperfusion and iron deposition (ID). However, the mechanisms underlying the pathology of cerebral ID are not clear. We investigated the role of cerebral blood flow (CBF) in the pathophysiology of cerebral ID in hemodialysis patients with anemia. This study recruited 33 hemodialysis patients with anemia and thirty-three healthy controls (HCs). All the subjects underwent quantitative susceptibility mapping (QSM) and arterial spin labeling (ASL) to measure ID and CBF in the cerebral nuclei. Furthermore, we evaluated lacunar infarction (LI), cerebral microbleeds, and total white matter hyperintensity volume (TWMHV). Hemodialysis patients with anemia showed significantly higher ID and CBF in some nuclei compared to the HCs after adjusting for age, sex, and total intracranial volume (TIV) [P < 0.05, false discovery rate (FDR) corrected]. CBF showed a positive correlation with ID in both patients and HCs after adjustments for age, gender, and TIV (P < 0.05, FDR corrected). Serum phosphorus, calcium, TWMHV, hypertension, and dialysis duration were independently associated with ID (P < 0.05). Hemoglobin, serum phosphorus, and LI were independently associated with CBF (P < 0.05). Mediation analysis demonstrated that CBF mediated the effects between hemoglobin and ID. Our study demonstrated that CBF mediated aberrant cerebral ID in hemodialysis patients with anemia.
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