RESUMO
Sickle cell disease (SCD) is a monogenic disease characterized by multisystem morbidity and highly variable clinical course. Inter-individual variability in hemoglobin F (HbF) levels is one of the main modifiers that account for the clinical heterogeneity in SCD. HbF levels are affected by, among other factors, single nucleotide polymorphisms (SNPs) at the BCL11A gene and the HBS1L-MYB intergenic region and Xmn1 gene. Our aim was to investigate HbF-enhancer haplotypes at these loci to obtain a first overview of the genetic situation of SCD patients in Egypt and its impact on the severity of the disease. The study included 100 SCD patients and 100 matched controls. Genotyping of BCL11A (rs1886868 C/T), HBS1L-MYB (rs9389268 A/G) and Xmn1 γG158 (rs7842144 C/T) SNPs showed no statistically significant difference between SCD patients and controls except for the hetero-mutant genotypes of BCL11A which was significantly higher in SCD patients compared with controls. Baseline HbF levels were significantly higher in those with co-inheritance of polymorphic genotypes of BCL11A + HSB1L-MYB and BCL11A + Xmn1. Steady-state HbF levels, used as an indicator of disease severity, were significantly higher in SCD-Sß patients having the polymorphic genotypes of HSB1L-MYB. Fold change of HbF in both patient groups did not differ between those harboring the wild and the polymorphic genotypes of the studied SNPs. In conclusion, BCL11A, HSB1L, and Xmn1 genetic polymorphisms had no positive impact on baseline HbF levels solely but had if coexisted. Discovery of the molecular mechanisms controlling HbF production could provide a more effective strategy for HbF induction.
Assuntos
Anemia Falciforme/genética , DNA Intergênico/genética , Hemoglobina Fetal/análise , Proteínas de Ligação ao GTP/genética , Genes myb , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Proteínas Repressoras/genética , gama-Globinas/genética , Adolescente , Alelos , Anemia Falciforme/sangue , Anemia Falciforme/etnologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Desoxirribonucleases de Sítio Específico do Tipo II , Egito , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Fragmento de Restrição , Adulto JovemRESUMO
Transcranial Doppler (TCD) screening is an established tool to identify children with sickle cell disease at high risk of stroke. Our objective was to study TCD velocities among sickle cell disease patients while in a steady state. This cross-sectional study included 78 steady state sickle cell disease patients [31 Hb SS (ßS/ßS) (sickle cell anemia), 47 Hb S/ß-thalassemia (HBB: c.20A>T/ß-thal)], attending the Pediatric Hematology Clinic at Cairo University Children's Hospital, Cairo, Egypt. All patients underwent TCD velocity assessment as per the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol. In our cohort, TCD velocities were comparable among Hb S/ß-thal vs. SS patients. Hemolysis indicators correlated significantly to TCD velocities in Hb S/ß-thal patients; positive correlation was found between total bilirubin level and right middle cerebral artery (MCA) and right distal internal carotid artery (dICA) TCD velocities (r = 0.428, p = 0.00, r = 0.360, p = 0.01), respectively as well as between reticulocyte count and right MCA, right dICA and right anterior cerebral artery (ACA) TCD velocities (r = 0.424, p = 0.01), (r = 0.40, p = 0.00), (r = 0.303, p = 0.04), respectively. On the other hand, statistically significant negative correlations were found between hemoglobin (Hb) level and right ACA, right dICA TCD velocities (r = -0.290, p = 0.05), (r = -0.324, p = 0.03). Although Hb F is considered an ameliorating factor for disease severity; hemolysis stands as an indicator of risk for TCD velocity elevation, and in turn, risk for stroke among sickle cell disease patients.
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Anemia Falciforme/diagnóstico , Ultrassonografia Doppler Transcraniana , Adolescente , Alelos , Anemia Falciforme/sangue , Anemia Falciforme/etiologia , Anemia Falciforme/terapia , Biomarcadores , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Egito , Índices de Eritrócitos , Feminino , Genótipo , Hemoglobina Falciforme/genética , Humanos , Masculino , Programas de Rastreamento , Mutação , Ultrassonografia Doppler Transcraniana/métodosRESUMO
Thalassemia is a common inherited monogenic disease. It is characterized by chronic hemolysis, ineffective erythropoiesis (IE) and iron overload. Despite advances in transfusion practices and chelation therapy, still many limitations in delivering these standard therapies exist. Challenges of currently available standard care and advances in understanding the underlying pathophysiological mechanisms in thalassemia stimulated research towards development of novel therapeutic targets. Agents reducing IE as Jak 2 inhibitors and Activin II receptor traps are promising and are currently in clinical trials. Other approaches targeting iron dysregulation as mini-hepcidins, exogenous transferrin and erythroferrone inhibitors are in preclinical studies. Gene therapy, a rapidly evolving field, has exhibited remarkable progress in recent years. Studies have focused on ß or γ-globin addition, over expression of endogenous γ-globin-activating transcription factors, silencing of γ-globin repressors and genome editing of ß-globin mutations or γ-globin repressors. In this article we provide an overview of emerging recent trends in treatment of thalassemia targeting IE, iron dysregulation and novel curative treatments as gene therapy and gene editing.
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Talassemia/terapia , Terapêutica/tendências , Eritropoese , Edição de Genes , Terapia Genética , Humanos , Sobrecarga de Ferro , Talassemia/complicações , Terapêutica/métodosRESUMO
Sickle cell disease (SCD) is a relatively common inherited hemolytic anemia among individuals of African descent. Genetic factors might clarify clinical diversity of the disease and variations in treatment response. Some researchers investigated heme oxygenase-1 (HMOX1) or chemokine receptor 5 (CCR5Δ32) genotypes among SCD patients and their correlation with fetal hemoglobin (HbF) and disease severity. However, there are no such records among Arab nations. We aimed to estimate the prevalence of the HMOX1-413 A>T (rs2071746) and CCR5Δ32 (rs333) polymorphisms, and to assess their effect on SCD phenotype and HbF level among Egyptian patients. Polymerase chain reaction assay was used to determine these polymorphisms among 100 SCD patients and 100 healthy controls. Though not statistically significant, the frequency of individual carrying HMOX-1 polymorphic AT and TT genotypes in both patient and control groups was 92% and 85% respectively. Regarding CCR5Δ32 polymorphisms, all SCD patients harbored the wild genotype (100%), while the heteromutant genotype was encountered in 2% of our controls. Patients harboring mutant HMOX-1 had a less frequent vaso-occlusive crisis (VOC)/lifetime, less VOC in the last year, less incidence of stroke, less frequency of hospitalization, and responded more frequently to hydroxyurea with statistically significant differences (p = 0.028, 0.007, 0.046, 0.007, and 0.011 respectively). No significant associations with HbF level or other hematologic parameters were encountered among our cohort. Our study results suggest a protective effect of mutant HMOX-1 genotypes in ameliorating the phenotypic severity of the disease. HMOX1-413 A>T (rs2071746) polymorphisms might prove to be a prognostic marker among Egyptian SCD, but not CCR5Δ32 (rs333) polymorphisms.
Assuntos
Anemia Falciforme/genética , Heme Oxigenase-1/genética , Polimorfismo Genético , Receptores CCR5/genética , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/etnologia , Anemia Falciforme/patologia , Antidrepanocíticos/uso terapêutico , Árabes , Estudos de Casos e Controles , Criança , Pré-Escolar , Egito , Feminino , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Expressão Gênica , Genótipo , Heme Oxigenase-1/metabolismo , Hospitalização/estatística & dados numéricos , Humanos , Hidroxiureia/uso terapêutico , Masculino , Fenótipo , Receptores CCR5/metabolismo , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Sickle cell disease (SCD) is a monogenic disease associated with multisystem morbidity. Vasculopathy caused by delicate imbalance between coagulation and endothelial systems plays a pivotal role in disease course. As Protein Z and Endothelin-1 genetic polymorphisms may increase the thrombotic risk, the aim of the current work was to verify the possible impact of Protein Z (PROZ G79A) and Endothelin-1 (EDN1 G5665T) polymorphisms on the clinic-laboratory features of the SCD in a cohort of Egyptian pediatric patients. METHODS: Genotyping of Protein Z G79A and Endothelin-1 G5665T was carried out by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) assay for 100 SCD patients and 100 controls. RESULTS: Protein -Z G79A polymorphism was not associated with vascular complications in the studied SCD patients. Endothelin-1 G5665T polymorphism was associated with pulmonary dysfunction (pulmonary artery hypertension and acute chest syndrome) and severe vaso-occlusive crises (VOC). CONCLUSION: Endothelin-1 G5665T polymorphism could be considered as a molecular predictor for pulmonary dysfunction and severe VOC in SCD. Further researches with larger cohorts are recommended to understand the pathophysiology of SCD and to explain the inter-patients' variability of disease severity.
Assuntos
Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Proteínas Sanguíneas/genética , Endotelina-1/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Criança , Pré-Escolar , Egito/epidemiologia , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , MasculinoRESUMO
Hydroxycarbamide (hydroxyurea or HU) has been shown to increase fetal hemoglobin (HbF) in patients with ß-thalassemia intermedia (TI). The reported effects of HU in increasing the total hemoglobin (Hb) have been inconsistent. Studies of long-term therapy with HU in pediatric TI are rather uncommon. A retrospective observational study was carried out to evaluate the clinical responses to HU in Egyptian patients with ß-TI. One hundred patients; children (n = 82, mean age 9.9 ± 4.1 years) and adults (n = 18) were studied for the mean Hb, HbF%, median serum ferritin, transfusion history, and splenic size before and after HU therapy (mean dose 20.0 ± 4.2 mg/kg/day, range 10-29 mg/kg/day) over a follow-up period 4 to 96 months (mean 35.4 ± 19.2 months). Molecular studies were also done for group of patients (n = 42). The overall response rate to HU was 79 %; 46 % were minor responders (with a reduction in transfusion rate by 50 % or more and/or an increase in their total hemoglobin level by 1-2 g/dl) and 33 % major responders (becoming transfusion-free and/or having an increase in total hemoglobin level by >2 g/dl). Mean hemoglobin increased among responders from 6.9 ± 0.9 g/dl to 8.3 ± 1.4 g/dl (p < 0.001). A significant rise in mean HbF (27.0 vs. 42.5 %; p < 0.011) and a decrease in median serum ferritin (800 vs. 644 ng/ml; p < 0.001) were also observed among responders (n = 45). Transfusions stopped in 44 % of pretreatment frequently transfused responders (n = 11/25). Splenic size decreased in 37 % of patients (n = 30/81). The predominant ß-thalassemia mutation was 1-6 (T > C) in 32/42 (76 %) of studied patients; 28/32 were responders. Bivariate analysis showed no predictors of response as regards sex, pediatric and adult age, splenic status, or genotype. Hydroxycarbamide is a good therapeutic modality in the management of pediatric as in adult TI patients. It can minimize the need for blood transfusion, concomitant iron overload, and blood-born viral transmission especially in developing countries like Egypt.
Assuntos
Hemoglobina Fetal/análise , Hidroxiureia/uso terapêutico , Talassemia beta/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Terapia Combinada , Avaliação de Medicamentos , Egito , Ferritinas/sangue , Humanos , Hidroxiureia/efeitos adversos , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/prevenção & controle , Neutropenia/induzido quimicamente , Estudos Retrospectivos , Esplenectomia , Esplenomegalia/etiologia , Esplenomegalia/cirurgia , Reação Transfusional , Resultado do Tratamento , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/complicações , Talassemia beta/terapiaRESUMO
Elevation of echocardiography-determined tricuspid regurgitant jet velocity (TRV) predicts high systolic pulmonary artery pressure. The present study tested the hypotheses that elevated tricuspid regurgitant jet velocity is associated with both hemolysis and hypoxia and abnormal 6-min walk test (6MWT) results. This study aims to correlate elevated TRV with different clinical laboratory findings and 6MWT and to find the independent predictors of increased TRV. A prospective study of 80 patients aged 5-25 years old with sickle cell disease (SCD) under basal conditions and 40 matched controls was conducted. Hemolytic analysis was assessed by the levels of lactate dehydrogenase, serum bilirubin, and reticulocyte count. Oxygen saturation determination using pulse oximeter and 6MWT were done. The overall prevalence of elevated TRV (≥2.5 m/s) was 28.75 %. Associated risk factors were older age (r = 0.28, p = 0.01), longer duration of disease (r = 0.25, p = 0.025), higher reticulocytic count (r = 0.344, p = 0.002), lower O2 saturation (r = -0.574, p = 0.0001), and shorter walked distance in 6MWT (r = -0.75, p = 0.0001). By multivariate logistic analysis, only the distance walked during 6MWT was the independent correlate of elevated TRV (odds ratio = 0.85; 95 % CI = 0.74 to 0.98 p = 0.033). The study provides evidence for independent association of TRV with abnormal 6MWT results. The 6-min walk test can be used as noninvasive adjuvant tool for functional capacity assessment of SCD patients with elevated TRV.
Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/fisiopatologia , Teste de Esforço/métodos , Insuficiência da Valva Tricúspide/diagnóstico , Insuficiência da Valva Tricúspide/fisiopatologia , Adolescente , Adulto , Anemia Falciforme/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Consumo de Oxigênio/fisiologia , Insuficiência da Valva Tricúspide/epidemiologia , Adulto JovemRESUMO
Myocardial siderosis in thalassemia major remains the leading cause of death in developing countries. Once heart failure develops, the outlook is usually poor with precipitous deterioration and death. Cardiovascular magnetic resonance (CMR) can measure cardiac iron deposition directly using the magnetic relaxation time T2*. This allows earlier diagnosis and treatment and helps to reduce mortality from this cardiac affection. This study aims to determine the prevalence of cardiac siderosis in Egyptian patients who are heavily iron loaded and its relation to liver iron concentration, serum ferritin, and left ventricular ejection fraction. Eighty-nine ß-thalassemia patients receiving chelation therapy (mean age of 20.8 ± 6.4 years) were recruited in this study. Tissue iron levels were determined by CMR with cardiac T2* and liver R2*. The mean ± standard deviation (range) of cardiac T2* was 28.5 ± 11.7 ms (4.3 to 53.8 ms), the left ventricular ejection fraction (LVEF) was 67.7 ± 4.7 % (55 to 78 %), and the liver iron concentration (LIC) was 26.1 ± 13.4 mg Fe/g dry weight (dw) (1.5 to 56 mg Fe/g dw). The mean serum ferritin was 4,510 ± 2,847 ng/ml (533 to 22,360 ng/ml), and in 83.2 %, the serum ferritin was >2,500 ng/ml. The prevalence of myocardial siderosis (T2* of <20 ms) was 24.7 % (mean age 20.9 ± 7.5 years), with mean T2* of 12.7 ± 4.4 ms, mean LVEF of 68.6 ±5.8 %, mean LIC of 30.9 ± 13 mg Fe/g dw, and median serum ferritin of 4,996 ng/ml. There was no correlation between T2* and age, LVEF, LIC, and serum ferritin (P = 0.65, P = 0.085, P = 0.99, and P = 0.63, respectively). Severe cardiac siderosis (T2* of <10 ms) was present in 7.9 %, with a mean age of 18.4 ± 4.4 years. Although these patients had a mean T2* of 7.8 ± 1.7 ms, the LVEF was 65.1 ± 6.2 %, and only one patient had heart failure (T2* of 4.3 ms and LVEF of 55 %). LIC and serum ferritin results were 29.8 ± 17.0 mg/g and 7,200 ± 6,950 ng/ml, respectively. In this group of severe cardiac siderosis, T2* was also not correlated to age (P = 0.5), LVEF (P = 0.14), LIC (P = 0.97), or serum ferritin (P = 0.82). There was a low prevalence of myocardial siderosis in the Egyptian thalassemia patients in spite of very high serum ferritin and high LIC. T2* is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy. The possibility of a genetic component for the resistance to cardiac iron loading in our population should be considered.
Assuntos
Cardiomiopatias/etiologia , Terapia por Quelação , Hemossiderose/etiologia , Reação Transfusional , Talassemia beta/terapia , Adolescente , Adulto , Cardiomiopatias/epidemiologia , Cardiomiopatias/prevenção & controle , Criança , Estudos de Coortes , Egito/epidemiologia , Ferritinas/sangue , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/química , Ventrículos do Coração/fisiopatologia , Hemossiderose/epidemiologia , Hemossiderose/prevenção & controle , Hospitais Pediátricos , Humanos , Ferro/análise , Fígado/química , Imageamento por Ressonância Magnética , Prevalência , Volume Sistólico , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/fisiopatologiaRESUMO
Non-transfusion dependent thalassemia (NTDT) refers to a group of thalassemic disorders who do not need regular transfusions for survival, however it may be needed in certain conditions. Metformin was reported as a potential fetal hemoglobin (HbF) inducing agent in vitro but its efficacy and safety in vivo was not fully studied. This is a prospective interventional study aimed at studying the effect of metformin on HbF change in NTDT. METHODS: Patients with established diagnosis of NTDT were enrolled. They were receiving a stable fixed dose of Hydroxyurea over the last 3 months. Patients were divided into two groups: a group that received Metformin for 6 months (Metformin group) and a control group. Complete blood picture, reticulocytic count, hemoglobin electrophoresis, liver enzymes, bilirubin, kidney functions, LDH and random blood sugar were performed at onset, 3 and 6 months of the study. All adverse events were recorded. RESULTS: Forty two patients aged 12-23 years were enrolled. Metformin intake over 6 months did not show any statistically significant difference in clinical or the laboratory variables of efficacy when compared to the control group apart from reticulocytic count which was higher in Metformin group throughout the study. CONCLUSION: Metformin intake, in addition to hydroxyurea, did not yield any extra benefit among patients with NTDT.
RESUMO
BACKGROUND: Primary immune thrombocytopenia (ITP) is a common autoimmune disorder. Secretion of TNF-α, TNF-ß and IFN-γ plays a major role in the pathogenesis of ITP. OBJECTIVE: This cross-sectional study aimed to detect TNF-α (-308 G/A) and TNF-ß (+ 252 A/G) gene polymorphism in a cohort of Egyptian children with chronic ITP (cITP) to clarify their possible association with progression to chronic disease. METHODS: The study included 80 Egyptian cITP patients and 100 unrelated age- and sex-matched controls. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Patients with TNF-α homozygous (A/A) genotype had significantly higher mean age, longer disease duration and lower platelet counts (p values 0.005, 0.024 and 0.008, respectively). TNF-α wild (G/G) genotype was significantly more frequent among responders (p = 0.049). Complete response was more frequent among wild (A/A) TNF-ß genotype patients (p = 0.011), and platelet count was significantly lower among homozygous (G/G) genotype (p = 0.018) patients. Combined polymorphisms were strongly associated with susceptibility to chronic ITP. CONCLUSION: Homozygosity in either gene might contribute to a worse course of disease, increased severity and poor response to therapy. Patients expressing combined polymorphisms are more prone to progression to chronic disease, severe thrombocytopenia and longer disease duration.
Assuntos
Linfotoxina-alfa , Púrpura Trombocitopênica Idiopática , Fator de Necrose Tumoral alfa , Criança , Humanos , Estudos de Casos e Controles , Estudos Transversais , Egito , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Linfotoxina-alfa/genética , Polimorfismo de Nucleotídeo Único , Púrpura Trombocitopênica Idiopática/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
Patients with thalassemia and sickle cell disease (SCD) require blood transfusions as part of their supportive care. However, one of the most serious side effects of this treatment is the risk of red cell alloimmunization. The goal of this study was to assess the prevalence and Specificity of red cell alloimmunization in Egyptian thalassemia and sickle cell anaemia patients. This study included 200 multi transfused Egyptian patients, one hundred and forty patients with transfusion dependent thalassaemia and sixty patients with sickle cell anaemia, who were attending the Paediatric Children Hospital-Cairo University at the period from March 2019 to October 2019. Alloantibody identification was made by Diamed- ID microtyping system. In the studied groups both thalassemia and sickle patients, the prevalence of alloimmunization was 22/200 (11%) patients. The two most often alloantibodies were, antibodies against Kell antigen (37%) and against E antigen (30%). The prevalence of alloimmunization was more in females in comparison to males, but it did not reach statistical significance and patients with thalassemia major had higher alloimmunization rates than other studied groups but was not statistically significant. In the D negative patients in the research group, alloimmunization demonstrated a statistically significant difference (p = 0.01). Age, gender, age of transfusion onset and splenectomy were not contributing factors to the antibody presence in the group of patients being investigated. Before receiving blood transfusions, extended red blood cell phenotyping should be thought of as a crucial procedure for hemoglobinopathies patients who would likely have several transfusions. It is advised that haemoglobinopathies patients in Egypt be checked through phenotyping of RBC units for Kell and all Rh antigens to be phenotyped before starting transfusion in these patients which is also standard of care for these patients presently.
RESUMO
BACKGROUND: ß-Thalassemias represent a group of genetic disorders caused by human hemoglobin beta (HBB) gene mutations. The radical curative approach is to correct the mutations causing the disease. CRISPR-CAS9 is a novel gene-editing technology that can be used auspiciously for the treatment of these disorders. The study aimed to investigate the utility of CRISPR-CAS9 for gene modification of hematopoietic stem cells in ß-thalassemia with IVS-1-110 mutation. METHODS AND RESULTS: We successfully isolated CD34+ cells from peripheral blood of ß-thalassemia patients with IVS-1-110 mutation. The cells were transfected with Cas9 endonuclease together with guide RNA to create double-strand breaks and knock out the mutation. The mutation-corrected CD34+ cells were subjected to erythroid differentiation by culturing in complete media containing erythropoietin. CONCLUSION: CRISPR/Cas-9 is an effective tool for gene therapy that will broaden the spectrum of therapy and potentially improve the outcomes of ß-thalassemia.
Assuntos
Células-Tronco Pluripotentes Induzidas , Talassemia beta , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação , Globinas beta/genética , Globinas beta/metabolismo , Talassemia beta/genética , Talassemia beta/terapiaRESUMO
Thalassemia patients with persistently high levels of fetal globin typically have less severe anemia, have milder clinical syndromes, and are often transfusion independent. Therefore, the search for molecules exhibiting the property of inducing gamma-globin gene expression and fetal hemoglobin (HbF) production is of great interest. Different pharmacological agents have been studied, namely erythropoietin, short chain fatty acids and cytotoxic agents, azacytidine, and hydroxycarbamide. Hemoglobin F inducers from natural plants, such as angelicin and resveratrol, are powerful inducers of erythroid differentiation and increase HbF in erythroid progenitors of thalassemia patients. Induction of HbF in beta-thalassemia patients is expected to be crucial for developing countries unable to sustain the high cost of clinical management of beta-thalassemia patients.
Assuntos
Hemoglobina Fetal/biossíntese , Talassemia beta/tratamento farmacológico , gama-Globinas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , gama-Globinas/genéticaRESUMO
Poor physical fitness is a common problem among thalassemic patients. L-Carnitine plays an essential role in fatty acid beta-oxidation, a process especially important in the organs that preferentially use fatty acid as a source of energy such as the myocardium and the skeletal muscles. The main objective of this study is to assess the effect of the administration of oral L-carnitine on exercise tolerance and physical fitness in patients with thalassemia major. Thirty patients followed up at the New Cairo University Children Hospital were included in this study. Clinical, laboratory, and cardiopulmonary exercise testing were performed before and after 6 months of oral L-carnitine therapy (50 mg/kg/day). The oxygen consumption, cardiac output, and oxygen pulse at maximal exercise significantly increased after L-carnitine therapy (p<0.001, p=0.002 and p<0.001, respectively). However, there was no significant change in minute ventilation and ventilatory equivalent of carbon dioxide (p=0.07 and p=0.06, respectively). A weak but positive correlation between the age of the patients and the degree of improvement in exercise parameters was noted. There was also significant increase in the blood transfusion intervals after L-carnitine administration (p=0.008). However, there was no significant change in hemoglobin concentration (p=0.4). L-Carnitine seems to be a safe and effective adjunctive therapeutic approach in thalassemic patients. It improves their cardiac performance and physical fitness. The younger the patients are, the higher is the degree of improvement in their exercise parameters.
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Carnitina/administração & dosagem , Carnitina/farmacologia , Tolerância ao Exercício/efeitos dos fármacos , Aptidão Física , Talassemia beta/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Transfusão de Sangue , Criança , Terapia Combinada , Feminino , Humanos , Masculino , Consumo de Oxigênio/efeitos dos fármacosRESUMO
Primary immune thrombocytopenia is an acquired autoimmune disorder caused by the production of antiplatelet antibodies. These autoantibodies opsonize platelets for splenic clearance, resulting in low levels of circulating platelets. The current case-control study aimed at detecting the frequency of interleukin-23 receptor rs1884444 single nucleotide polymorphism in Egyptian children with primary immune thrombocytopenia and its possible role as a genetic marker for disease risk. Interleukin-23 receptor rs1884444 single nucleotide polymorphism was studied in 50 patients with primary immune thrombocytopenia and 100 healthy age and sex-matched controls by polymerase chain reaction amplification of the target gene followed by allele-specific restriction enzyme digestion. Regarding the distribution of the genotypes of the interleukin-23 receptor rs1884444 polymorphism, no statistically significant difference was found between cases and control groups. The variant genotypes (GT/TT) frequency was 10% in primary immune thrombocytopenia cases versus 7% in the control groups [P valueâ=â0.755, odds ratio (OR): 0.326, 95% confidence interval (CI): 0.099-1.076]. Similarly, no difference was found between acute and chronic cases. The variant genotypes GT/TT frequency was 10.7% in acute versus 9.1% in chronic primary immune thrombocytopenia (P valueâ=â0.849). The variant genotypes GT/TT were not found to be a risk factor for acute primary (P valueâ=â0.807, OR: 0.641, 95% CI: 0.16-2.563) or chronic primary immune thrombocytopenia (P valueâ=â0.914, OR: 0.762, 95% CI: 0.153-3.797). Our study suggests the possibility that interleukin-23 receptor gene polymorphism may not contribute to the susceptibility of development of primary immune thrombocytopenia in Egyptian children.
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Polimorfismo de Nucleotídeo Único , Púrpura Trombocitopênica Idiopática/genética , Receptores de Interleucina/genética , Doença Aguda , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença Crônica , Egito , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Masculino , Razão de Chances , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/imunologia , Receptores de Interleucina/imunologia , Fatores de RiscoRESUMO
OBJECTIVES: Sickle cell disease (SCD) is associated with a pro-inflammatory state, characterized by an elevated baseline leukocyte count and inflammatory cytokines. Inflammation, white blood cell (WBC) adhesion to vascular endothelium with subsequent endothelial injury, and repeated ischemia-reperfusion injury contribute to disease pathogenesis. Identification of genetic polymorphisms that may modulate disease severity in SCD is becoming a field of interest. The Duffy blood group antigen has been identified as a receptor for various chemokines involved in neutrophil activation and trafficking. This study aimed at investigating the effect of RBCs' Duffy antigen expression and its genetic polymorphisms on modulating disease severity and its complications among Egyptian sickle cell patients. Methods We analyzed the association of Duffy genotypes and phenotypes with clinical expression of SCD in 100 Egyptian patients. The Duffy phenotype expression was detected by indirect anti-globulin test while Duffy genotyping was conducted with polymerase chain reaction-restriction fragment length polymorphism-based assay. Results Total WBC count was strongly associated with Duffy genotype. WBCs were significantly higher in Duffy-positive patients (P = 0.002). No statistical significance was evident between individual measures of disease severity (pulmonary dysfunction, avascular necrosis, central nervous system dysfunction, kidney dysfunction, and leg ulcers) and Duffy genotype. Conclusion Our study suggests that RBC Duffy expression increases levels of WBCs in SCD patients and that Duffy genotype may not be a potential biomarker for end-organ damage in SCD.
Assuntos
Anemia Falciforme/sangue , Sistema do Grupo Sanguíneo Duffy/genética , Sistema do Grupo Sanguíneo Duffy/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Polimorfismo Genético , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) is a major health problem in Egypt with its prevalence estimated to be 14.7% among the general population in 2008. Patients receiving frequent blood transfusions like those with sickle cell disease (SCD) are more exposed to the risk of acquiring HCV. IL28B gene polymorphisms have been associated with spontaneous HCV clearance. This study aims to determine the prevalence of HCV infection among children with SCD and to investigate the relation between IL28B gene polymorphisms and spontaneous HCV clearance. METHODS: Seventy SCD patients were screened for HCV antibody. HCV-positive patients were tested for the level of HCV RNA using quantitative real-time PCR. IL28B polymorphisms (rs 12979860 SNP and rs 12980275 SNP) were detected using TaqMan QRT-PCR and sequence-specific primers PCR respectively. RESULTS: Sixteen patients (23%) were HCV antibody positive, 9 of them (56.3%) had undetectable HCV RNA in serum, and 7 (43.7%) had persistent viremia. Genotypes CC/CT/TT of rs12979860 were found in 30 (42.9%), 29 (41.4%) and 11 (15.7%) patients and rs12980275 AA/AG/GG were found in 8 (11.4%), 59 (84.3%) and 3 (4.3%) patients. There was no significant difference in the frequency of IL28B (rs 12979860 and rs12980275) genotypes among HCV patients who cleared the virus and those with persistent viremia (p=0.308 and 0.724 respectively). CONCLUSION: Egyptian SCD patients have a high prevalence of HCV. Multi-transfused patients still exposed to the risk of transmission of HCV. IL28B gene polymorphismsare not associated with spontaneous clearance of HCV in this cohort of Egyptian children with SCD.
RESUMO
Sickle cell disease (SCD) complications are associated with oxidative stress. Glutathione S-transferases (GSTs) are a group of enzymes that protect against oxidative stress. The aims of this study was to evaluate the prevalence of GSTM1, GSTT1, and GSTP1 gene polymorphisms among homozygous sickle cell anemia patients and to investigate the possible association between the presence of these polymorphisms and SCD severity and complications. Genotyping the polymorphisms in GSTT1 and GSTM1 genes was performed using the multiplex polymerase chain reaction (PCR) method. The GSTP1 ILe105Val polymorphism was determined using PCR-restriction fragment length polymorphism. GSTM1 null genotype was significantly associated with increased risk of severe vaso-occlusive crises (VOC) (odds ratio â=â 1.52, 95% confidence interval â=â 0.42-5.56, P â=â 0.005). We found no significant association between GST genotypes and frequency of sickle cell-related pain, transfusion frequency, disease severity, or hydroxyurea treatment. GSTM1 gene polymorphism may be associated with risk of severe VOC among Egyptian SCD patients.
Assuntos
Anemia Falciforme/genética , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Polimorfismo Genético , Adolescente , Fatores Etários , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/enzimologia , Antidrepanocíticos/uso terapêutico , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Estudos Transversais , Progressão da Doença , Egito , Feminino , Frequência do Gene , Predisposição Genética para Doença , Homozigoto , Humanos , Hidroxiureia/uso terapêutico , Masculino , Razão de Chances , Medição da Dor , Fenótipo , Reação em Cadeia da Polimerase , Prognóstico , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: the present study was conducted to investigate the oxidant-antioxidant status in Egyptian children with sickle cell anemia. METHODS: the serum levels of total antioxidant capacity (TAO), paraoxonase (PON), vitamin E, nitrite, and malondialdehyde (MDA) were measured in 40 steady state children with homozygous sickle cell anemia (24 males and 16 females) and 20 apparently healthy age- and gender-matched controls. RESULTS: mean serum TAO, PON, vitamin E, and nitrite levels were significantly lower in the group with sickle cell anemia, whereas mean serum MDA was significantly higher in these children compared to controls. No significant differences in mean levels of TAO, PON, nitrite, vitamin E, and MDA were found in sickle cell anemia patients receiving hydroxyurea when compared with those not receiving hydroxyurea. A significant negative correlation between serum nitrite and the occurrence of vaso-occlusive crises (VOC) was observed (r=-0.3, p=0.04). PON level was found to be positively correlated with patients' weight and BMI (r=-0.4, p=0.01; r=-0.7, p<0.001, respectively), but not with frequency of VOC. The area under the curve of serum nitrite in predicting occurrence of VOC was 0.782, versus 0.701 for PON, and 0.650 for TAO (p=0.006). Serum MDA was not correlated with nitrite, PON, TAO, or vitamin E levels. No significant correlations were detected between serum nitrite and hemoglobin or antioxidant enzymes. CONCLUSION: children with sickle cell anemia have chronic oxidative stress that may result in increased VOC, and decreased serum nitrite may be associated with increases in VOC frequency. A novel finding in this study is the decrease in PON level in these patients, which is an interesting subject for further research.