Assuntos
Elementos Facilitadores Genéticos , Hemoglobina H/genética , alfa-Globinas/genética , Talassemia alfa/genética , Adulto , Alelos , Cromatina/genética , Cromatina/ultraestrutura , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/ultraestrutura , Eritroblastos/patologia , Eritropoese , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Genótipo , Hemoglobina E/genética , Hemoglobina H/análise , Humanos , Masculino , Linhagem , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Deleção de Sequência , Suriname/etnologia , alfa-Globinas/biossíntese , Talassemia alfa/sangue , Globinas beta/genéticaRESUMO
Members of the GATA family of transcription factors play key roles in the differentiation of specific cell lineages by regulating the expression of target genes. Three GATA factors play distinct roles in hematopoietic differentiation. In order to better understand how these GATA factors function to regulate genes throughout the genome, we are studying the epigenomic and transcriptional landscapes of hematopoietic cells in a model-driven, integrative fashion. We have formed the collaborative multi-lab VISION project to conduct ValIdated Systematic IntegratiON of epigenomic data in mouse and human hematopoiesis. The epigenomic data included nuclease accessibility in chromatin, CTCF occupancy, and histone H3 modifications for 20 cell types covering hematopoietic stem cells, multilineage progenitor cells, and mature cells across the blood cell lineages of mouse. The analysis used the Integrative and Discriminative Epigenome Annotation System (IDEAS), which learns all common combinations of features (epigenetic states) simultaneously in two dimensions-along chromosomes and across cell types. The result is a segmentation that effectively paints the regulatory landscape in readily interpretable views, revealing constitutively active or silent loci as well as the loci specifically induced or repressed in each stage and lineage. Nuclease accessible DNA segments in active chromatin states were designated candidate cis-regulatory elements in each cell type, providing one of the most comprehensive registries of candidate hematopoietic regulatory elements to date. Applications of VISION resources are illustrated for the regulation of genes encoding GATA1, GATA2, GATA3, and Ikaros. VISION resources are freely available from our website http://usevision.org.
Assuntos
Cromatina/metabolismo , Epigenoma , Fatores de Transcrição GATA/metabolismo , Regulação da Expressão Gênica , Hematopoese , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Animais , Diferenciação Celular , Cromatina/genética , Fatores de Transcrição GATA/genética , HumanosRESUMO
Clinical and hematological features are presented for 261 patients with identified ß-thalassemia (ß-thal) mutations. Mutations causing Hb S [ß6(A3)GluâVal]-ß(0)-thal were IVS-II-849 (A>G) in 44%, frameshift codon (FSC) 6 (-A) in 14%, Hb Monroe [ß30(B12)ArgâThr] in 14%, and IVS-II-1 (G>A) in 10%. Mutations causing Hb S-ß(+)-thal with 14-25% Hb A (type III) were -29 (A>G) mutation in 60%, -88 (C>T) in 22% and the polyadenylation signal site (polyA) (T>C) mutation in 14%, and in Hb S-ß(+)-thal with 1-7% Hb A (type I), all had the IVS-I-5 (G>C) mutation. Hematologically, only minor differences occurred between the four Hb S-ß(0)-thal mutations, but among the three mutations causing Hb S-ß(+)-thal type III, levels of Hb A(2), Hb F, hemoglobin (Hb), MCV and MCH were highest in the -88 and lowest in the polyA mutations. Clinically, Hb S-ß(0)-thal and Hb S-ß(+)-thal type I were generally severe, and Hb S-ß(+)-thal type III disease with the -88 mutation was milder than that caused by the polyA mutation.
Assuntos
Talassemia beta/genética , Adulto , Anemia Falciforme/genética , Anemia Falciforme/mortalidade , Anemia Falciforme/fisiopatologia , Criança , Códon , Hemoglobina Fetal/genética , Estudos de Associação Genética , Testes Hematológicos , Hemoglobina A2/genética , Hemoglobinas Anormais/genética , Humanos , Recém-Nascido , Mutação , Triagem Neonatal , Análise de Sequência de DNA , Taxa de Sobrevida , Talassemia beta/mortalidade , Talassemia beta/fisiopatologiaRESUMO
Oxygen saturation was determined by pulse oximetry in a representative sample of Jamaican patients with steady state sickle cell disease in a cohort study from birth. There were 220 with homozygous sickle cell (SS) disease and 142 with sickle cell-haemoglobin C (SC) disease aged 9-18 years, and 122 with a normal haemoglobin (AA) genotype aged 15-18 years. Pulse oximetry (SpO2) values were lower in SS disease (mean [95 percent confidence interval]), 92.5 [92.0-93.3]. Inhalation of 100 percent oxygen in SS patients with 02 saturations below 90 percent consistency increased saturation to 99-100 percent. In SS disease, Sp02 correlated positively with haemoglobin and fetal haemoglobin and negatively with reticulocyte counts but not MCHC, MCV or bilirubin level. Mean Sp02 in SS subjects with a normal alpha globin gene complement (mean[SD], 91.7 [3.9]percent) was lower than in heterozygotes (93.4 [4.0] percent) or homozygotes (96.1 [3.0] percent) for alpha+thalassaemia, the effects of alpha-thalassaemia not being explained by differences in haemoglobin or MCHC. In SS disease, Sp02 levels were not associated with age (within this age range), sex, number of sick clinic visits or number of hospital admissions. Higher Sp02 levels were associated with greater heights and weights, more frequent painful crises and less frequent acute chest syndrome, but these associations were not significant after adjustment for haemoglobin level. Desaturation is common in steady-state SS disease and knowledge of the individual's steady-state value may be important in the interpreting low value during acute complications.(AU)
Assuntos
Criança , Feminino , Humanos , Masculino , Adolescente , Anemia Falciforme/sangue , Anemia Falciforme/metabolismo , Oximetria , Fatores Etários , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/metabolismo , Dor no Peito/sangue , Dor no Peito/metabolismo , Estudos de Coortes , Genótipo , Crescimento/fisiologia , Testes de Inteligência , Oximetria/normas , Oximetria/estatística & dados numéricos , Oxigênio/administração & dosagem , Oxigênio/sangue , Valores de Referência , Índice de Gravidade de Doença , Fatores Sexuais , JamaicaRESUMO
AIMS: (1) To estimate the proportion of subjects with homozygous sickle cell disease who have a benign clinical course, and (2) to assess factors that may be predictive of benign disease. MATERIAL: Subjects (n = 280) were participants in a longitudinal cohort study of sickle cell disease. They were classified as benign or control based on clinical history from birth to age 13 years old. Associations with growth, hematology, and an index of social status were investigated. RESULTS: Benign disease occurred in 43 (15 percent) patients. Neither growth nor social status were related to benign disease. There were only two statistically independent association: alpha thalassemia status and average steady state fetal hemoglobin (HbF). Patients with a normal complement of alpha globin genes were 2.2 (1.0, 4.9) times more likely to have frequent painful crises, dactylitis, and bone necrosis. The odds of having benign disease were 1.09 (1.02, 1.17) times higher for each unit increase in HbF, and 44 percent of subjects with HbF in the top decile (HbF > 13.8 percent) of the distribution had benign disease. There was no evidence for a threshold effect of high HbF on benign disease. CONCLUSION: A benign clinical course of sickle cell disease may occur in Jamaica and is associated with a normal alpha globin gene complement, and high levels of HbF. Ability to predict benign disease at birth is limited.(AU)
Assuntos
Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Traço Falciforme/epidemiologia , Traço Falciforme/genética , Deleção de Genes , Estudos de Coortes , Hemoglobina Fetal/análise , Globinas/análise , Homozigoto , Jamaica/epidemiologia , Prognóstico , Classe SocialRESUMO
Oxygen saturation was determined by pulse oximetry in a representative sample of Jamaican patients with steady-state sickle cell disease in a cohort study from birth. There were 220 with homozygous sickle cell (SS) disease and 142 with sickle cell- haemoglobin C (SC) disease aged 9-18 years, and 122 with a normal haemoglobin (AA) genotype aged 15-18 years. Pulse oximetry (SpO2) values were lower in SS disease (mean [95 percent confidence interval], 92.5 [92.0-93.0]) than in SC disease (96.7 [96.9-96.9]) or AA controls (97.1 [96.8-97.3]). Inhalation of 100 percent oxygen in SS patients with O2 saturations below 90 percent consistently increased saturation to 99-100 percent. In SS disease, SpO2 correlated positively with haemoglobin and fetal haemoglobin and negatively with reticulocyte counts but not with MCHC, MCV or bilrubin level. Mean SpO2 in SS subjects with a normal alpha globin gene complement (mean [SD], 91.7 [3.9] percent) was lower than in heterozygotes (93.4 [4.0] percent) or homozygotes (96.1 [3.0] percent) for O+ thalassaemia, the effects of O-thalassaemia not being explained by differences in haemoglobin or MCHC. In SS disease, SpO2 levels were not associated with age (within this age range), sex, number of sick clinic visits or number of hospital admissions. Higher SpO2 levels were associated with greater height and weight, more frequent painful crises and less frequent acute chest syndrome, but these associations were not significant after adjustment for haemoglobin level. Desaturation is common in steady-state SS disease and knowledge of the individual's steady-state value may be important in the interpreting low values during acute complications.(AU)
Assuntos
Adolescente , Criança , Feminino , Humanos , Masculino , Anemia Falciforme/sangue , Anemia Falciforme/metabolismo , Oximetria , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/metabolismo , Dor no Peito/sangue , Dor no Peito/metabolismo , Genótipo , Crescimento/fisiologia , Testes de Inteligência , Oxigênio/administração & dosagem , Oxigênio/sangue , Valores de Referência , Índice de Gravidade de Doença , Oximetria/normas , Oximetria/estatística & dados numéricos , Fatores Sexuais , Fatores Etários , Estudos de CoortesRESUMO
OBJECTIVE: To investigate the role of hematological indices, socioeconomic status, and morbidity in prepubertal growth in homozygous sickle cell (SS) disease from birth to 9 years at the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica. RESULTS: Height increment between 3 and 9 years correlated positively with total haemoglobin at age 7 years in boys but not girls. Attained height and weight at 7 years correlated positively with haemoglobin and fetal haemoglobin in boys but not girls. Only the correlation between haemoglobin and weight showed a significant gender difference. Partial correlation analysis suggested that the effect of haemoglobin was accounted for by the effect of fetal haemoglobin and further analysis indicated that height correlated with F reticulocyte count (a measure of fetal haemoglobin production) in both sexes but not with the ratio of F cells to F reticulocytes (a measure of F cell enrichment). Growth was not significantly related to mean red cell volume, proportional reticulocyte count, alpha thalassaemia, socioeconomic status, or morbidity. CONCLUSION: A high concentration of fetal haemoglobin in boys with SS disease is associated with greater linear growth. It is postulated that in boys, low concentrations of fetal haemoglobin increase haemolysis and hence metabolic requirements for erythropoiesis, putting them at greater risk of poor growth. Differences in the relationship to haemotoloy and growth between boys and girls with SS disease dictate that future analyses of growth take gender into account (AU).x
Assuntos
Humanos , Recém-Nascido , Feminino , Masculino , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Crescimento/fisiologia , Hemoglobinas/análise , Estatura/fisiologia , Peso Corporal/fisiologia , Estudos de Coortes , Hemoglobina Fetal/análise , Homozigoto , Fatores Sexuais , Classe SocialRESUMO
Homozygous alpha+ thalassaemia (alpha-/alpha-) ameliorates some of the clinical manifestations of homozygous sickle cell (SS) disease but its effect on retinal complications remains unknown. This has been assessed by visual examination and flourescein angiography in 39 subjects with SS disease and homozygous alpha+ thalassaemia and in 39 age/sex matched controls with SS disease but with a normal alpha genotype (alpha alpha/alpha alpha). The results indicate that homozygous alpha+ thalassaemia reduces the extent of peripheral retinal vessel closure but has no apparent effect on the frequency of proliferative sickle retinopathy (AU)
Assuntos
Humanos , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Feminino , Anemia Falciforme/complicações , Talassemia/complicações , Doenças Retinianas/etiologia , Fatores Etários , Anemia Falciforme/genética , Angiofluoresceinografia , Homozigoto , Fatores SexuaisRESUMO
The purpose of the study was to investigate age- and sex-related variations in the haematology of older patients with SS disease, in order to determine haematological characteristics possibly favouring survival. Steady state haematology was available in 181 patients aged 40-73 years. There appeared to be no consistent sex differences in any of the indices examined. Longitudinal analyses were performed for the 133 patients with at least two observations, using analysis of covariance (ANCOVA) methods. Highly significant declines in total haemoglobin (Hb), platelet counts and absolute reticulocyte count were displayed in both sexes. Overall, Hb levels decreased by approximately 0.076 gm/dl/year in females and 0.113 gm/dl/year in males. Significant increases occurred in HbA, HbF and MCV in females only. The total nucleated count (NBC) fell with age, although the decline was only significant in females. These observations are consistent with a progressive bone marrow failure which is not explained by the commonly occurring renal impairment in older SS patients since the changes persisted in analyses confined to the 84 patients with normal creatinine levels (C=120 æmol/l). The mechanism for this bone marrow failure is currently unknown. The prevalence of homozygous alpha thalassaemia in the study group (4.4 percent) was similar to that in the overall SS population, providing no evidence that this may lead to improved survival, as has been suggested (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Anemia Falciforme/sangue , Fatores Etários , Fatores SexuaisRESUMO
The red cell distribution width (RDW) has been studied during the clinical steady state in 1121 patients with homozygous sickle cell (SS) disease, 344 with sickle cell-haemoglobin C (SC) disease, 68 with sickle cell-beta+ thalassaemia, 49 with cell beta§ thalassaemia and in 130 control subjects with a normal (AA) genotype. The mean RDW was moderately increased in Sbeta+ thalassaemia and SC disease and markedly increased in Sbeta§ thalassaemia and SS disease. In SS, SC and Sbeta§ thalassaemia genotypes, lower RDW values occurred in females and with alpha thalassaemia. The RDW correlated negatively with total haemoglobin, mean cell haemoglobin concentration, mean cell volume and fetal haemoglobin (HbF) and positively with reticulocyte count in SS disease. A low RDW was associated with higher weight and less frequent dactylitis, painful crisis, acute chest syndrome, acute splenic sequestration and hospital admissions. A low RDW in SS disease is consistent with a high total haemoglobin, high HbF, low reticulocyte count, alpha thalassaemia and a more mild clinical course. (AU)