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Pain is a common complication of sickle cell disease. Sickle cell pain can often be effectively managed by pediatricians in outpatient and hospital settings. Acute pain management should be initiated quickly. Patients need to be evaluated for sickle cell complications and other causes of pain. Nonsteroidal anti-inflammatory drugs and opioids are the mainstay of pain treatment, but additional therapies include hydration, local pain control, muscle relaxants, and nonpharmacologic approaches. Healthy lifestyle habits and good behavioral and mental health are important for preventing and coping with sickle cell disease pain. Disease-modifying therapies, such as hydroxyurea, can help prevent sickle hemoglobin polymerization and acute pain episodes. Because sickle cell disease largely affects people who are racialized minorities in the United States, health-care providers need to be aware of how their own personal biases may affect care of these patients.
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Dor Aguda , Anemia Falciforme , Humanos , Estados Unidos , Dor Aguda/terapia , Dor Aguda/complicações , Anemia Falciforme/complicações , Anemia Falciforme/terapia , Hidroxiureia/uso terapêutico , Manejo da Dor , Analgésicos Opioides/uso terapêuticoRESUMO
OBJECTIVES: Individuals with sickle cell disease (SCD) are at severely heightened risk for cerebrovascular injury and acute cerebrovascular events, including ischemic and hemorrhagic stroke, potentially leading to impaired development and life-long physical and cognitive disabilities. Cerebrovascular injury specific to SCD includes inflammation caused by underlying conditions of chronic hemolysis and reduced cerebrovascular perfusion. The objectives of this study were to investigate whether expression of neuregulin-1ß (NRG-1), an endogenous neuroprotective polypeptide, is increased in SCD or experimental conditions mimicking the hemolysis and ischemic conditions of SCD, and to determine if treatment with exogenous NRG-1 reduces markers of cerebrovascular inflammation. MATERIALS AND METHODS: Plasma and brain-specific NRG-1 levels were measured in transgenic SCD mice. Endogenous NRG-1 levels and response to experimental conditions of excess heme and ischemia were measured in cultured human brain microvascular cells and astrocytes. Pre-treatment with NRG-1 was used to determine NRG-1's ability to ameliorate resultant cerebrovascular inflammation. RESULTS: Plasma and brain-specific NRG-1 were elevated in transgenic SCD mice compared to healthy controls. Neuregulin-1 expression was significantly increased in cultured human microvascular cells and astrocytes exposed to excess heme and ischemia. Pre-treatment with NRG-1 reduced inflammatory chemokine (CXCL-1 and CXCL-10) and adhesion molecule (ICAM-1 and VCAM-1) expression and increased pro-angiogenic factors (VEGF-A) in microvascular cells and astrocytes exposed to excess heme and ischemia. CONCLUSIONS: Elevated NRG-1 in SCD is likely a protective endogenous response to ongoing cerebrovascular insults caused by chronic hemolysis and reduced cerebrovascular perfusion. Administration of NRG-1 to reduce cerebrovascular inflammation may be therapeutically beneficial in SCD and warrants continued investigation.
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Anemia Falciforme , Hemólise , Neuregulina-1 , Animais , Humanos , Camundongos , Anemia Falciforme/complicações , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Heme , Hemólise/genética , Inflamação , Isquemia , Camundongos Transgênicos , Neuregulina-1/metabolismoRESUMO
Health education for children with chronic illnesses (i.e., sickle cell disease [SCD]) has focused on educating adult caregivers with minimal consideration to educating the pediatric patients. We introduce a pediatric-focused educational paradigm, health-related knowledge (HRK), teaching pediatric patients developmentally appropriate general health literacy, and disease-specific knowledge. Using science, technology, engineering, and mathematics (STEM) education concepts, pediatric-specific HRK interactive activities address educational gaps: (a) general STEM education; and (b) general health and disease-specific knowledge to improve clinical outcomes. Total 144 pediatric SCD patients completed HRK activities, revealing overwhelmingly positive feedback (87%). Seventy-five percent of participants in 6th grade and above demonstrated thorough understanding of the STEM/HRK topics taught.
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Anemia Falciforme , Letramento em Saúde , Adulto , Anemia Falciforme/terapia , Cuidadores/educação , Criança , Educação em Saúde , Conhecimentos, Atitudes e Prática em Saúde , HumanosRESUMO
OBJECTIVES: To determine the acceptability, feasibility and safety of yoga for chronic pain in sickle cell disease. DESIGN AND SETTING: In Part A of this two-part study, adolescents with SCD and chronic pain (Group 1) and their parent (Group 2) completed a survey designed to capture pain characteristics, attitudes and practices related to yoga, and potential acceptability of a yoga program. In Part B, the study assessed the feasibility and safety of an instructor-led group yoga program. The study was registered on clinicaltrials.gov (NCT03694548). INTERVENTION: Eight instructor-led group yoga sessions. MAIN OUTCOME MEASURES: Feasibility and safety outcomes were chosen a priori, as follows: 1) Proportion of adolescent patients with SCD and chronic pain approached that consent to participate in Part A, 2) Proportion of adolescent participants enrolled in Part A that consent to participate in Part B, 3) Proportion of participants enrolled in Part B that attend at least 6 of 8 yoga sessions, 4) Proportion of participants enrolled in Part B with an ED visit or a hospitalization for pain within 24 h of completion of each yoga session, 5) Proportion of participants in Part B who complete all study assessments before, and at the end of the yoga program, 6) Adherence to submission of pain diary. RESULTS: The median age of 15 patient participants in Part A was 16 (IQR 14-17), and 14 parents was 43.5 (IQR 42-51). Most participants were female. Most participant responses indicated a positive opinion of yoga. Nine adolescents (60 %) from Part A participated in Part B of the study. The median age of 9 participants in Part B was 17 (IQR 15-18), and 5 of the 9 participants were female (53.3 %). Only one participant was able to attend 3 of the 8 yoga sessions offered, and did not experience any ED visits or hospitalizations following the yoga sessions. None of the other feasibility endpoints were met in this study. CONCLUSIONS: Patients with SCD and chronic pain overall have a positive opinion of yoga, but there are challenges with recruitment and retention of participants in a clinical trial of yoga, and barriers to feasibility of an in-person group yoga intervention.
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Anemia Falciforme , Dor Crônica , Yoga , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/terapia , Dor Crônica/terapia , Estudos de Viabilidade , Feminino , Humanos , Projetos PilotoRESUMO
Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. Design, Setting, and Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Main Outcomes and Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). Results: A total of 23â¯197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10â¯714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). Conclusions and Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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Negro ou Afro-Americano/estatística & dados numéricos , Doença das Coronárias , Traço Falciforme , Idoso , Estudos de Coortes , Doença das Coronárias/complicações , Doença das Coronárias/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Traço Falciforme/complicações , Traço Falciforme/epidemiologiaRESUMO
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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Stroke, or cerebral infarction, is one of the most serious complications of sickle cell anemia (SCA) in childhood, potentially leading to impaired development and life-long physical and cognitive disabilities. About one in ten children with SCA are at risk for developing overt stroke and an additional 25% may develop silent cerebral infarcts. This is largely due to underlying cerebral injury caused by chronic cerebral ischemia and vascular insult associated with SCA. We previously identified two elevated markers of cerebral injury, plasma brain-derived neurotropic factor (BDNF) and platelet-derived growth factor (PDGF)-AA, in children with SCA and high stroke risk. The objective of this study was to investigate whether neuregulin-1ß (NRG-1), an endogenous neuroprotective polypeptide may also be elevated in children with SCA. Neuregulin-1ß is involved in the preservation of blood brain barrier integrity and brain microvascular cell viability and is cytoprotective in conditions of heme-induced injury and ischemia. Since elevated plasma heme and ischemia are signature characteristics of SCA, we hypothesized that NRG-1 would be elevated in children with SCA, and that NRG-1 levels would also correlate with our biomarkers of cerebral injury. Plasma NRG-1, BDNF and PDGF-AA levels were measured in children with SCA and healthy Controls. Plasma NRG-1 was found to be nearly five-fold higher in those children with SCA compared to Controls. Neuregulin-1ß was also positively correlated with both BDNF and PDGF-AA concentrations, but was not associated with degree of anemia, suggesting that NRG-1 production may be an endogenous response to subclinical cerebral ischemia in SCA warranting further exploration.
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Importance: African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear. Objective: To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans. Design, Setting, and Participants: This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women's Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017. Interventions or Exposures: Participants' SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation. Main Outcomes and Measures: Incident ischemic stroke. Results: This meta-analysis included 19â¯464 African American individuals (1520 with SCT, 17â¯944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47-1.35; P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar. Conclusions and Relevance: Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke.
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Negro ou Afro-Americano/estatística & dados numéricos , Isquemia Encefálica/epidemiologia , Traço Falciforme/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Idoso , Feminino , Hemoglobinas/genética , Heterozigoto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação , Traço Falciforme/genética , Estados Unidos/epidemiologiaRESUMO
Hypercoagulability in sickle cell disease (SCD) is associated with multiple SCD phenotypes, association with stroke risk has not been well described. We hypothesized that serum levels of biomarkers of coagulation activation correlate with high transcranial Doppler ultrasound velocity and decreases with blood transfusion therapy in SCD patients. Stored serum samples from subjects in the Stroke Prevention in Sickle Cell Anemia (STOP) trial were analyzed using ELISA and protein multiplexing techniques. 40 subjects from each treatment arm (Standard Care [SC] and Transfusion [Tx]) at three time points--baseline, study exit and one year post-trial and 10 each of age matched children with SCD but normal TCD (SNTCD) and with normal hemoglobin (HbAA) were analyzed. At baseline, median vWF, TAT and D-dimer levels were significantly higher among STOP subjects than either HbAA or SNTCD. At study exit, median hemoglobin level was significantly higher while median TCD velocity was significantly lower in Tx compared to SC subjects. Median vWF (409.6 vs. 542.9 µg/ml), TAT (24.8 vs. 40.0 ng/ml) and D-dimer (9.2 vs. 19.1 µg/ml) levels were also significantly lower in the Tx compared to the SC group at study exit. Blood levels of biomarkers coagulation activation/thrombin generation correlated positively with TCD velocity and negatively with number of blood transfusions. Biomarkers of coagulation activation/thrombin generation were significantly elevated in children with SCD, at high risk for stroke. Reduction in levels of these biomarkers correlated with reduction in stroke risk (lower TCD velocity), indicating a possible role for hypercoagulation in SCD associated stroke.
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Anemia Falciforme/sangue , Anemia Falciforme/complicações , Biomarcadores/sangue , Coagulação Sanguínea , Transfusão de Sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Trombina/metabolismo , Anemia Falciforme/diagnóstico por imagem , Antitrombina III/metabolismo , Criança , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Peptídeo Hidrolases/metabolismo , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Ultrassonografia Doppler Transcraniana , Fator de von Willebrand/metabolismoRESUMO
Stroke is one of the most disabling complications of sickle cell anemia (SCA). The molecular mechanisms leading to stroke in SCA or by which packed red blood cell (PRBC) transfusion prevents strokes are not understood. We investigated the effects of PRBC transfusion on serum biomarkers in children with SCA who were at high-risk for stroke. Serum samples from 80 subjects were analyzed, including baseline, study exit time point and 1 year after study exit. Forty of the 80 samples were from subjects randomized to standard care and 40 from transfusion arm. Samples were assayed for levels of BDNF, sVCAM-1, sICAM-1, MPO, Cathepsin-D, PDGF-AA, PDGF-AB/BB, RANTES (CCL5), tPAI-1, and NCAM-1 using antibody immobilized bead assay. Significantly lower mean serum levels of sVCAM-1 (2.2 × 10(6) ± 0.8 × 10(6) pg/mL vs. 3.1 × 10(6) ± 0.9 × 10(6) pg/mL, P < 0.0001), Cathepsin-D (0.5 × 10(6) ± 0.1 × 10(6) pg/mL vs. 0.7 × 10(6) ± 0.2 × 10(6) pg/mL, P < 0.0001), PDGF-AA (10556 ± 4033 pg/mL vs. 14173 ± 4631 pg/mL, P = 0.0008), RANTES (0.1 × 10(6) ± 0.07 × 10(6) pg/mL vs. 0.2 × 10(6) ± 0.06 × 10(6) pg/mL, P < 0.006), and NCAM-1 (0.7 × 10(6) ± 0.2 × 10(6) pg/mL vs. 0.8 × 10(6) ± 0.1 × 10(6) pg/mL, P < 0.0006) were observed among participants who received PRBC transfusion, compared to those who received standard care. Twenty or more PRBC transfusion over 4 years was associated with lower serum levels of sVCAM-1 (P < 0.001), PDGF-AA (P = 0.025), and RANTES (P = 0.048). Low baseline level of BDNF (P = 0.025), sVCAM-1 (P = 0.025), PDGF-AA (P = 0.01), t-PAI-1 (P = 0.025) and sICAM-1 (P = 0.022) was associated with higher probability of stroke free survival. Beyond improving hemoglobin levels, our results suggest that the protective effects of PRBC transfusion on reducing stroke in SCD may result from reduced thrombogenesis and vascular remodeling.
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Anemia Falciforme/complicações , Anemia Falciforme/terapia , Endotélio Vascular/metabolismo , Transfusão de Eritrócitos , Trombose/etiologia , Trombose/prevenção & controle , Adolescente , Anemia Falciforme/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Humanos , Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Trombose/sangue , Trombose/mortalidade , Resultado do TratamentoRESUMO
Current therapy for sickle cell disease (SCD) is limited to supportive treatment of complications, red blood cell transfusions, hydroxyurea, and stem cell transplantation. Difficulty in the translation of mechanistically based therapies may be the result of a reductionist approach focused on individual pathways, without having demonstrated their relative contribution to SCD complications. Many pathophysiologic processes in SCD are likely to interact simultaneously to contribute to acute vaso-occlusion or chronic vasculopathy. Applying concepts of systems biology and network medicine, models were developed to show relationships between the primary defect of sickle hemoglobin (Hb S) polymerization and the outcomes of acute pain and chronic vasculopathy. Pathophysiologic processes such as inflammation and oxidative stress are downstream by-products of Hb S polymerization, transduced through secondary pathways of hemolysis and vaso-occlusion. Pain, a common clinical trials endpoint, is also complex and may be influenced by factors outside of sickle cell polymerization and vascular occlusion. Future sickle cell research needs to better address the biologic complexity of both sickle cell disease and pain. The relevance of individual pathways to important sickle cell outcomes needs to be demonstrated in vivo before investing in expensive and labor-intensive clinical trials.
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Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Hemoglobina Falciforme/metabolismo , Animais , Humanos , Modelos BiológicosRESUMO
We studied the number and function of angiogenic progenitor cells and growth factors in children aged 5-18 years without acute illness, 43 with Hemoglobin SS and 68 with normal hemoglobin. Hemoglobin SS subjects had at least twice as many mononuclear cell colonies and more circulating progenitor cell than Control subjects. Plasma concentrations of erythropoietin, angiopoietin-2, and stromal-derived growth factor (SDF)-1α were significantly higher in children with Hemoglobin SS compared to Control subjects. In a multivariate analysis model, SDF-1α concentration was found to be associated with both CPC number and total white blood cell count in the Hemoglobin SS group, suggesting that SDF-1α produced by ischemic tissues plays a role in mobilizing these cells in children with Hemoglobin SS. Despite having a higher number of angiogenic progenitor cells, children with Hemoglobin SS had slower migration of cultured mononuclear cells.
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Sickle cell anemia (SCA) associated cerebrovascular disease includes vascular remodeling, abnormal cerebral blood flow (CBF) and infarction. We studied the relationships between plasma brain derived neurotropic factor (BDNF), platelet derived growth factors (PDGF-AA and -AB/BB) and high trans-cranial Doppler (TCD) velocity, an indication of CBF velocity. Baseline plasma samples from 39 children (19 SCA with abnormal/high TCD [SATCD], 13 SCA with normal TCD [SNTCD] and 7 healthy non-SCA), were assayed for BDNF, PDGF-AA and -AB/BB plus 11 other cytokines. The sensitivity, specificity and usefulness of these biomarkers for stroke prediction was investigated. All subject groups were of similar age and gender distribution. Mean BDNF was significantly higher among SATCD than SNTCD (p=0.004) as was mean PDGF-AA (p=0.001). Similarly, mean PDGF-AA was higher among SCA subjects who developed stroke than those who did not (p=0.012). Elevated BDNF and PDGF-AA were good predictors of the presence of abnormally high CBF velocity and were both associated with severity of anemia. Elevated PDGF-AA predicted risk for stroke development. Stroke incidence and high TCD velocity were associated with elevated BDNF and PDGF-AA. These findings suggest a role for BDNF and PDGF-AA in the patho-physiological mechanism of cerebrovascular disease in SCA.
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Anemia Falciforme/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator de Crescimento Derivado de Plaquetas/metabolismo , Acidente Vascular Cerebral/sangue , Ultrassonografia Doppler Transcraniana/métodos , Análise de Variância , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico por imagem , Becaplermina , Biomarcadores/sangue , Velocidade do Fluxo Sanguíneo , Circulação Cerebrovascular , Criança , Pré-Escolar , Estudos Transversais , Citocinas/sangue , Feminino , Humanos , Masculino , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-sis/metabolismo , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologiaRESUMO
Progenitor cells (PCs) are key components of vasculogenic remodeling and hematopoietic development. Decreases in the number and function of angiogenic progenitors have been observed in coronary artery disease, hypertension, and diabetic vasculopathy. Several recent studies have also demonstrated a close relationship between increased visceral fat and cardiovascular disease, implying an association between obesity and vascular dysfunction. However, very little is known about the role of PCs in obesity. We generated whole genome expression profiles of cultured PCs from 18 obese and 6 lean African-American women on Agilent microarrays and analyzed the data through bioinformatic pathway analysis using multiple databases and analytic tools. False-discovery rates (FDR) were calculated to assess statistical significance while controlling for multiple testing. We identified 1,145 upregulated and 2,257 downregulated genes associated with obesity (1.5-fold or greater absolute fold-change). Pathway analysis further identified a statistically significant downregulation of immune-response pathways in the obese subjects, including T-cell receptor signaling, natural killer cell signaling, and chemokine-signaling pathways (FDR <5%). Chemokine gene-expression patterns were consistent with an angiogenic-angiostatic imbalance and a downregulation of CXCR3 receptor-mediated signaling in the PCs from obese subjects. Overall, these findings reveal a novel transcriptional signature in cultured PCs from obese African-American women and further suggest that obesity-associated immune-compromise may originate much earlier in cellular development than currently appreciated. Clinically, this may translate into a lengthier period of immune dysregulation in obese subjects exposing them to greater risks of infection and other morbidities.
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Negro ou Afro-Americano/genética , Gordura Intra-Abdominal/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Obesidade/genética , Transdução de Sinais/genética , Transcriptoma/genética , Adolescente , Adulto , Células Cultivadas , Feminino , Humanos , Células Matadoras Naturais/imunologia , Pessoa de Meia-Idade , Obesidade/imunologia , Obesidade/metabolismo , Receptores CXCR3/genética , Adulto JovemRESUMO
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 the multi-center stroke prevention (STOP) study, to determine if plasma inflammatory protein concentration is associated with the outcome of stroke. 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-1beta (IL-1beta) 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-1beta concentration, which is furthermore associated with a decreased likelihood of stroke in HbSS.
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Anemia Falciforme , Interleucina-1beta/sangue , Acidente Vascular Cerebral , Adolescente , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Anemia Falciforme/imunologia , Velocidade do Fluxo Sanguíneo , Circulação Cerebrovascular , Criança , Pré-Escolar , Feminino , Humanos , Interleucina-1beta/imunologia , Modelos Logísticos , Masculino , Curva ROC , Fluxo Sanguíneo Regional , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/imunologia , Ultrassonografia Doppler Transcraniana , Adulto JovemRESUMO
OBJECTIVES: We hypothesized that an elevated hemoglobin synthesis rate (SynHb) and myocardial oxygen consumption (MVO2) contribute to the excess protein and energy metabolism reported in children with sickle cell anemia. PATIENTS AND METHODS: Twelve children (6-12 years old) with asymptomatic sickle cell and 9 healthy children matched for age and sex were studied. Measurements were whole-body protein turnover by [1-C]leucine, SynHb by [N]glycine, resting energy expenditure by indirect calorimetry and the systolic blood pressure-heart rate product used as an index of MVO2. Protein energy cost was calculated from protein turnover. Statistical analysis included Spearman correlations and partial correlation analyses. RESULTS: Although body mass index was significantly lower for sickle cell versus controls (P < 0.02), children with asymptomatic sickle cell had 52% higher protein turnover (P < 0.0005). Proportional reticulocyte count, SynHb, MVO2 and resting energy expenditure were also significantly higher in children with sickle cell (P < 0.01). Protein turnover correlated significantly with both SynHb (r = 0.63, P < 0.01) and reticulocyte percentage (r = 0.83, P < 0.0001). Partial correlation of these 3 variables showed reticulocyte percentage as the only variable to be significantly associated with protein turnover, even after adjusting for sickle cell anemia (P = 0.03). Partial correlation of log resting energy expenditure on MVO2 was significant, controlling for protein energy cost, sex and age (P = 0.03). CONCLUSION: These results indicate that metabolic demands of increased erythropoiesis and cardiac energy consumption account for much of the excess protein and energy metabolism in children with sickle cell anemia.
Assuntos
Anemia Falciforme/metabolismo , Metabolismo Energético , Eritropoese , Miocárdio/metabolismo , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Metabolismo Basal , Pressão Sanguínea , Calorimetria Indireta , Criança , Estudos Transversais , Feminino , Frequência Cardíaca , Hemoglobinas/biossíntese , Humanos , Masculino , Consumo de Oxigênio , Contagem de ReticulócitosRESUMO
Sickle cell anemia (HbSS) includes chronic inflammation, but the origin is unclear. We hypothesized that in stable HbSS patients the inflammation was associated with hypermetabolism. We compared selected hypermetabolic and key immunomodulator indicators in HbSS versus control children and examined associations between measures of hypermetabolism and inflammation. Twelve fasting asymptomatic HbSS children 6-12 years and 9 controls matched for age, gender and fat mass (FM) were studied. Proportional reticulocyte count (retic%) and resting energy expenditure (REE) represented hypermetabolism, and C-reactive protein (CRP) indicated inflammation. Proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), chemokine monocyte chemoattractant protein-1 (MCP-1), and energy balance cytokine leptin were measured. Methods were indirect calorimetry, enzyme-linked immunosorbent assay, and radioimmunoassay. Statistical analysis included simple correlation and regression analysis. REE (51 +/- 6 vs. 43 +/- 12 kcal/kg per fat-free mass (FFM), mean +/- SD), retic% (12 +/- 4 vs. 0.7 +/- 0.3%), CRP (5 +/- 3 vs. 0.3 +/- 0.4 mg/liter), and IL-6 (71 +/- 40 vs. 20 +/- 7 pg/ml) were significantly higher for HbSS than controls (P < 0.05). Conversely, leptin (0.1 +/- 0.1 vs. 2 +/- 1 microg/liter per kgFM) and MCP-1 (34 +/- 5 vs. 41 +/- 4 pg/ml) were significantly lower for the HbSS subjects (P < 0.01). TNF-alpha was not significantly different. There were no significant associations between REE or retic% and any cytokine measured. However, CRP was significantly associated with REE in HbSS (r = 0.8, P = 0.003) and an important predictor of REE/FFM. We provide new evidence for low circulating levels of inflammatory chemokine MCP-1 in stable HbSS children, confirm mostly low cytokine levels, inflammation, and hypermetabolism and demonstrate association of hypermetabolism with inflammation via CRP but not via cytokines.
Assuntos
Anemia Falciforme/sangue , Citocinas/sangue , Mediadores da Inflamação/sangue , Composição Corporal , Proteína C-Reativa/metabolismo , Criança , Feminino , Humanos , MasculinoRESUMO
OBJECTIVES: Although hydroxyurea is effective in treating adults with sickle-cell anemia (SCA), there is concern that it may adversely affect growth in children. We report the growth characteristics of patients in the Phase I-II pediatric hydroxyurea trial (HUG-KIDS) before and during treatment at the maximum tolerated dose for one year. STUDY DESIGN: Children and adolescents with SCA (n = 68), aged 5 to 16 years at baseline, reached the maximum tolerated dose and had serial height, weight, and Tanner stage measurements. Data from the Cooperative Study of Sickle Cell Disease (CSSCD) were used for comparison. Mixed-effects models were used to compare serial measurements as a function of age and group. RESULTS: In girls, there were no significant differences in height or weight among the pretreatment, on-treatment, and CSSCD groups. Compared with the CSSCD group, HUG-KIDS boys were heavier starting at age 9 years, and pretreatment HUG-KIDS boys were taller starting at age 7 years. The Tanner stage transitions took place at appropriate ages. CONCLUSIONS: Hydroxyurea treatment had no adverse effect on height or weight gain or pubertal development in school-aged children with SCA.