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1.
J Pediatr Hematol Oncol ; 36(3): 185-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24309610

RESUMO

Obstructive and restrictive pulmonary changes develop in children with sickle cell disease, but reports conflict as to the type of change that predominates. We prospectively performed spirometry, plethysmography, and lung diffusing capacity in 146 children aged 7 to 20 years with hemoglobin SS or Sß(0)-thalassemia. Nineteen percent of the patients had obstructive physiology as defined according to guidelines of the American Thoracic Society. In addition, 9% had restrictive physiology and 11% had abnormal but not categorized physiology. Increasing age, patient-reported or family-reported history of asthma or wheezing, and higher lactate dehydrogenase concentration were independent predictors of obstruction as reflected in lower forced expiratory volume in the first second/forced vital capacity. In conclusion, abnormal pulmonary function, most often obstructive, is common in children with hemoglobin SS and Sß(0)-thalassemia. Full pulmonary function testing should be performed in children with hemoglobin SS or Sß(0)-thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers.


Assuntos
Obstrução das Vias Respiratórias/etiologia , Anemia Falciforme/complicações , Asma/etiologia , Pulmão/fisiopatologia , Adolescente , Adulto , Obstrução das Vias Respiratórias/patologia , Anemia Falciforme/patologia , Asma/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Testes de Função Respiratória , Fenômenos Fisiológicos Respiratórios , Fatores de Risco , Adulto Jovem
2.
JAMA ; 305(9): 893-902, 2011 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-21364138

RESUMO

CONTEXT: Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). OBJECTIVE: To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo. MAIN OUTCOME MEASURES: The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home. RESULTS: There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. CONCLUSION: Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00094887.


Assuntos
Anemia Falciforme/complicações , Fatores Relaxantes Dependentes do Endotélio/administração & dosagem , Óxido Nítrico/administração & dosagem , Dor/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Medição da Dor , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
3.
Blood Cells Mol Dis ; 42(1): 16-24, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18829352

RESUMO

Five major beta-globin locus haplotypes have been established in individuals with sickle cell disease (SCD) from the Benin, Bantu, Senegal, Cameroon, and Arab-Indian populations. Historically, beta-haplotypes were established using restriction fragment length polymorphism (RFLP) analysis across the beta-locus, which consists of five functional beta-like globin genes located on chromosome 11. Previous attempts to correlate these haplotypes as robust predictors of clinical phenotypes observed in SCD have not been successful. We speculate that the coverage and distribution of the RFLP sites located proximal to or within the globin genes are not sufficiently dense to accurately reflect the complexity of this region. To test our hypothesis, we performed RFLP analysis and high-density single nucleotide polymorphism (SNP) genotyping across the beta-locus using DNA samples from healthy African Americans with either normal hemoglobin A (HbAA) or individuals with homozygous SS (HbSS) disease. Using the genotyping data from 88 SNPs and Haploview analysis, we generated a greater number of haplotypes than that observed with RFLP analysis alone. Furthermore, a unique pattern of long-range linkage disequilibrium between the locus control region and the beta-like globin genes was observed in the HbSS group. Interestingly, we observed multiple SNPs within the HindIII restriction site located in the Ggamma-globin intervening sequence II which produced the same RFLP pattern. These findings illustrated the inability of RFLP analysis to decipher the complexity of sequence variations that impacts genomic structure in this region. Our data suggest that high-density SNP mapping may be required to accurately define beta-haplotypes that correlate with the different clinical phenotypes observed in SCD.


Assuntos
Anemia Falciforme/genética , Análise Mutacional de DNA , Haplótipos , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Globinas beta/genética , Negro ou Afro-Americano/genética , Frequência do Gene , Genótipo , Hemoglobina A/genética , Hemoglobina Falciforme/genética , Humanos , Polimorfismo de Fragmento de Restrição
4.
Pediatr Hematol Oncol ; 24(3): 159-70, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17454785

RESUMO

Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.


Assuntos
Anemia Falciforme/complicações , Hipertensão Pulmonar/etiologia , Anemia Falciforme/fisiopatologia , Criança , Humanos , Hipertensão Pulmonar/fisiopatologia
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