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Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain.

ABSTRACT: Altered mitochondrial function occurs in sickle cell disease (SCD), due in part to low nitric oxide (NO) bioavailability. Arginine, the substrate for NO production, becomes acutely deficient in SCD patients with vaso-occlusive pain episodes (VOE). To determine if arginine improves mitochondrial function, 12 children with SCD-VOE (13.6 ± 3 years; 67% male; 75% hemoglobin-SS) were randomized to 1 of 3 arginine doses: (1) 100 mg/kg IV 3 times/day (TID); (2) loading dose (200 mg/kg) then 100 mg/kg TID; or (3) loading dose (200 mg/kg) followed by continuous infusion (300 mg/kg per day) until discharge. Platelet-rich plasma mitochondrial activity, protein expression, and protein-carbonyls were measured from emergency department (ED) presentation vs discharge. All VOE subjects at ED presentation had significantly decreased complex-V activity compared to a steady-state cohort. Notably, complex-V activity was increased at discharge in subjects from all 3 arginine-dosing schemes; greatest increase occurred with a loading dose (P < .001). Although complex-IV and citrate synthase activities were similar in VOE platelets vs steady state, enzyme activities were significantly increased in VOE subjects after arginine-loading dose treatment. Arginine also decreased protein-carbonyl levels across all treatment doses (P < .01), suggesting a decrease in oxidative stress. Arginine therapy increases mitochondrial activity and reduces oxidative stress in children with SCD/VOE. This trial was registered at www.clinicaltrials.gov as #NCT02536170.

SUBMITTER: Morris CR

PROVIDER: S-EPMC7498366 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A polygenic score for acute vaso-occlusive pain in pediatric sickle cell disease.

Project description:Individuals with monogenic disorders can experience variable phenotypes that are influenced by genetic variation. To investigate this in sickle cell disease (SCD), we performed whole-genome sequencing (WGS) of 722 individuals with hemoglobin HbSS or HbSβ0-thalassemia from Baylor College of Medicine and from the St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study. We developed pipelines to identify genetic variants that modulate sickle hemoglobin polymerization in red blood cells and combined these with pain-associated variants to build a polygenic score (PGS) for acute vaso-occlusive pain (VOP). Overall, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10-14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10-13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.

| S-EPMC8341359 | biostudies-literature

Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.

Project description:Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.

| S-EPMC5435522 | biostudies-literature

Association between baseline fetal hemoglobin levels and incidence of severe vaso-occlusive pain episodes in children with sickle cell anemia.

Project description:The ameliorating effect of high fetal hemoglobin (HbF) levels on the incidence of pain episodes in sickle cell anemia (SCA) is well-known; however, in children this relationship is less clearly established. We hypothesized that higher HbF levels in children with SCA are associated with fewer severe pain episodes. A meta-analysis of data from the Silent Infarct Transfusion Trial (n?=?456) and the Cooperative Study of Sickle Cell Disease (n?=?764), demonstrated that baseline HbF levels were associated with the incidence of severe pain, commonly defined across studies as an event requiring hospitalization (P-value?=?0.02).

| S-EPMC4387562 | biostudies-literature

Normal saline bolus use in pediatric emergency departments is associated with poorer pain control in children with sickle cell anemia and vaso-occlusive pain.

Project description:Vaso-occlusive pain events (VOE) are the leading cause of emergency department (ED) visits in sickle cell anemia (SCA). This study assessed the variability in use of intravenous fluids (IVFs), and the association of normal saline bolus (NSB), on pain and other clinical outcomes in children with SCA, presenting to pediatric emergency departments (PED) with VOE. Four-hundred charts of children age 3-21 years with SCA/VOE receiving parenteral opioids at 20 high-volume PEDs were evaluated in a retrospective study. Data on type and amount of IVFs used were collected. Patients were divided into two groups: those who received NSB and those who did not. The association of NSB use on change in pain scores and admission rates was evaluated. Among 400 children studied, 261 (65%) received a NSB. Mean age was 13.8 ± 4.9 years; 46% were male; 92% had hemoglobin-SS. The IVFs (bolus and/or maintenance) were used in 84% of patients. Eight different types of IVFs were utilized and IVF volume administered varied widely. Mean triage pain scores were similar between groups, but improvement in pain scores from presentation-to-ED-disposition was smaller in the NSB group (2.2 vs 3.0, P = .03), while admission rates were higher (71% vs 59%, P = .01). Use of NSB remained associated with poorer final pain scores and worse change in pain scores in our multivariable model. In conclusion, wide variations in practice utilizing IVFs are common. NSB is given to >50% of children with SCA/VOE, but is associated with poorer pain control; a controlled prospective trial is needed to determine causality.

| S-EPMC6510594 | biostudies-literature

Ketamine for Sickle Cell Vaso-Occlusive Crises: A Systematic Review.

Project description:IntroductionVaso-occlusive crisis (VOC) is one of the main causes of hospital admission in patients with sickle cell disease (SCD). Ketamine is often used as an adjuvant to opioids to control sickle cell crisis; however, there is a lack of evidence about its safety and efficacy for VOC in SCD patients.ObjectiveTo synthesize evidence from published reports about the efficacy and safety of ketamine in the management of acute painful VOC in both pediatric and adult SCD patients.MethodsA systematic literature search of PubMed, Scopus, Web of Science, EBSCO and Cochrane Library was conducted, up to March 2019. Studies reporting the analgesic effects and side effects of ketamine in the management of acute painful VOC in pediatric and adult SCD patients were included. The primary outcome measure was improvement in pain scale, and the secondary outcomes were reduction in opioid utilization and side effects. Studies were narratively summarized in this review.ResultsFourteen studies (with a total of 604 patients) were included in the final analysis. Several case reports and case series showed that ketamine significantly reduced pain scales and opioid utilization in both populations. The only randomized controlled trial available showed that ketamine was noninferior to morphine in reducing pain scores, but had a higher incidence of nonlife-threatening, reversible adverse effects. However, a retrospective study of 33 patients showed a higher pain score in the ketamine group with an acceptable short-term adverse effect.ConclusionKetamine has a potentially comparable efficacy with other opioids in reducing the pain during VOC in SCD patients. However, it also likely has a higher rate of transient adverse events. Owing to the lack of published randomized controlled trials, current evidence is not sufficient to confirm the safety and efficacy of ketamine. Future well-designed randomized controlled trials are strongly recommended.

| S-EPMC7839575 | biostudies-literature

Liver stiffness increases acutely during sickle cell vaso-occlusive crisis.

Project description:Acute vaso-occlusive crisis (VOC) in sickle cell disease (SCD) is an important cause of end-organ damage. It is estimated that 10-39% of VOC occurs with hepatic involvement. Current assessments of hepatic involvement during VOC are unsatisfactory. We investigated transient elastography (TE) as a marker of hepatic involvement, its relationship with histology, and biochemical markers during VOC. SCD patients were evaluated with biochemical markers and TE at steady-state and during VOC. Change in TE and biochemical markers were correlated with length of hospital stay. When available, liver biopsy and tricuspid regurgitation velocity (TRV) at steady-state were correlated with TE. Twenty-three patients were evaluated (mean age = 34.3 years, standard deviation = 7.96). In 15 patients with liver biopsies, TE correlated with fibrosis (P = 0.01) and TRV (P = 0.0063), but not hepatic iron. Hemolysis biomarkers changed during VOC (P < 0.022), but not alanine aminotransferase (ALT). Paired comparison of TE at steady-state and during VOC showed an increased from 6.2 to 12.3 kPa (P = 0.0029). Increasing TE during VOC associated with increasing ALT and alkaline phosphatase (P = 0.0088 and 0.0099, respectively). At steady-state, increasing inflammation on biopsy (P = 0.0037) and TRV (P = 0.0075) correlated with increasing TE during VOC. Increased hospital stay was associated with higher ALT (P = 0.041), lower albumin (P = 0.046), hemoglobin/hematocrit (P < 0.0021) but not TE. TE may identify patients with hepatic involvement during VOC independent of biochemical measures. Increase in TE may reflect both hepatic passive congestion and hepatic involvement during VOC. TE may serve as a physiological biomarker for hepatic features of VOC.

| S-EPMC3808506 | biostudies-literature

Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review.

Project description:Sickle-cell disease (SCD) is characterized by frequent and painful vaso-occlusive crises (VOCs). Various treatments have been evaluated over the years. However, a clear overview is lacking. The objective of this study was to systematically review all pharmacotherapeutical strategies in the prevention of VOCs beyond hydroxyurea. We performed a systematic literature search (MEDLINE, Embase, CENTRAL). Eligible studies were controlled clinical trials evaluating pharmacotherapeutical interventions targeting the reduction of VOCs in patients with SCD. Primary outcomes were the number or duration of SCD-related pain days, VOCs, or hospital admissions for VOCs. Secondary outcomes included time to first VOC or hospital admission for a VOC. A standardized data extraction sheet was used. The methodological quality of studies was assessed using Cochrane's risk-of-bias tool. A total of 36 studies were included in this review, covering 26 different prophylactic interventions. The most promising interventions for reducing the frequency of either VOCs or hospitalizations were the oral antioxidants l-glutamine and ω-3 fatty acids and the IV antiadhesive agent crizanlizumab. Twenty-three studies did not show any beneficial effect of the intervention under investigation, and 6 studies were either too small or methodologically inadequate to draw conclusions. Because of the heterogeneity of interventions, no meta-analysis was performed. In conclusion, this review identified 3 promising pharmacotherapeutical strategies in the prevention of VOCs in SCD. Importantly, this study highlights the discrepancy between the significant burden of SCD worldwide and the low number of adequate trials performed. This review was registered at PROSPERO (CRD42015025250).

| S-EPMC5728463 | biostudies-literature

Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia.

Project description:OBJECTIVE:To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of patients with sickle cell anemia (SCA) enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease. STUDY DESIGN:Clinical and laboratory characteristics of children with SCA who had ?3 severe pain crises requiring health care in the preceding year were compared with those of subjects with <3 such episodes. RESULTS:Seventy-five children (20%) reported ?3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR, 1.2; 95% CI, 1.1-1.3; P < .0001), ?-thalassemia trait (OR 3.5; 1.6-6.7; P = .002), higher median hemoglobin (OR 1.7; 95% CI: 1.2-2.4; P < .003), and lower lactate dehydrogenase concentration (OR 1.82; 95% CI: 1.07-3.11; P = .027). Children with high pain frequency also had an increased iron burden (serum ferritin, 480 vs 198 ?g/L; P = .006) and higher median tricuspid regurgitation jet velocity (2.41 vs 2.31 m/s; P = .001). Neither hydroxyurea use nor fetal hemoglobin levels were significantly different according to severe pain history. CONCLUSIONS:In our cohort of children with SCA, increasing age was associated with higher frequency of severe pain episodes as were ?-thalassemia, iron overload, higher hemoglobin and lower lactate dehydrogenase concentration, and higher tricuspid regurgitation velocity.

| S-EPMC3258348 | biostudies-literature

A biophysical indicator of vaso-occlusive risk in sickle cell disease.

Project description:The search for predictive indicators of disease has largely focused on molecular markers. However, biophysical markers, which can integrate multiple pathways, may provide a more global picture of pathophysiology. Sickle cell disease affects millions of people worldwide and has been studied intensely at the molecular, cellular, tissue, and organismal level for a century, but there are still few, if any, markers quantifying the severity of this disease. Because the complications of sickle cell disease are largely due to vaso-occlusive events, we hypothesized that a physical metric characterizing the vaso-occlusive process could serve as an indicator of disease severity. Here, we use a microfluidic device to characterize the dynamics of "jamming," or vaso-occlusion, in physiologically relevant conditions, by measuring a biophysical parameter that quantifies the rate of change of the resistance to flow after a sudden deoxygenation event. Our studies show that this single biophysical parameter could be used to distinguish patients with poor outcomes from those with good outcomes, unlike existing laboratory tests. This biophysical indicator could therefore be used to guide the timing of clinical interventions, to monitor the progression of the disease, and to measure the efficacy of drugs, transfusion, and novel small molecules in an ex vivo setting.

| S-EPMC3633235 | biostudies-literature

Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease.

Project description:Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-κB leading to the production of cytokines and adhesion molecules which promote inflammation, pain, and vaso-occlusion. In SCD, TLR4 inhibition has been shown to modulate heme-induced microvascular stasis and lung injury. We sought to delineate the role of endothelial verses hematopoietic TLR4 in SCD by developing a TLR4 null transgenic sickle mouse. We bred a global Tlr4-/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS-Tlr4-/- had similar complete blood counts and serum chemistries as SS-Tlr4 +/+ mice. However, SS-Tlr4-/- mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS-Tlr4 +/+ mice in response to challenges with heme, lipopolysaccharide (LPS), and hypoxia/reoxygenation (H/R). To define a potential mechanism for decreased microvascular stasis in SS-Tlr4-/- mice, we measured pro-inflammatory NF-κB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS-Tlr4 +/+ livers, SS-Tlr4 -/- livers had lower adhesion molecule and cytokine mRNAs, NF-κB phospho-p65, and adhesion molecule protein expression. Furthermore, lung P-selectin and von Willebrand factor immunostaining was reduced. Next, to establish if endothelial or hematopoietic cell TLR4 signaling is critical to vaso-occlusive physiology, we created chimeric mice by transplanting SS-Tlr4 -/- or SS-Tlr4 +/+ bone marrow into AA-Tlr4 -/- or AA-Tlr4 +/+ recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA-Tlr4-/- . These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.

| S-EPMC7851052 | biostudies-literature

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