Β-thalassemia Major Patients Research Articles

Relaxivity-iron calibration in hepatic iron overload: Predictions of a Monte Carlo model.

R2* (1/T2*) and single echo R2 (1/T2) have been calibrated to liver iron concentration (LIC) in patients with thalassemia and transfusion-dependent sickle cell disease at 1.5T. The R2*-LIC relationship is linear, whereas that of R2 is curvilinear. However, the increasing popularity of high-field scanners requires generalizing these relationships to higher field strengths. In this study, we tested the hypothesis that numerical simulation can accurately determine the field dependence of iron-mediated transverse relaxation rates. We previously replicated the calibration curves between R2 and R2* and iron at 1.5T using Monte Carlo models incorporating realistic liver structure, iron deposit susceptibility, and proton mobility. In this paper, we extend our model to predict relaxivity-iron calibrations at higher field strengths. Predictions were validated by measuring R2 and R2* at 1.5T and 3T in six β-thalassemia major patients. Predicted R2* increased twofold at 3T from 1.5T, whereas R2 increased by a factor of 1.47. Patient data exhibited a coefficient of variation of 3.6% and 7.2%, respectively, to the best-fit simulated data. Simulations over the range 0.25T-7T showed R2* increasing linearly with field strength, whereas R2 exhibited a concave-downward relationship. A model-based approach predicts alterations in relaxivity-iron calibrations with field strength without repeating imaging studies. The model may generalize to alternative pulse sequences and tissue iron distribution.

N-Acetylcysteine Supplementation Reduces Oxidative Stress and DNA Damage in Children with β-Thalassemia

There are several reports that increased oxidative stress and DNA damage were found in β-thalassemia major (β-TM) patients. In this study, we aimed to evaluate the effects of N-acetylcysteine (NAC) and vitamin E on total oxidative stress and DNA damage in children with β-TM. Seventy-five children with transfusion-dependent β-thalassemia (β-thal) were randomly chosen to receive 10 mg/kg/day of NAC or 10 IU/kg/day of vitamin E or no supplementation; 28 healthy controls were also included in the study. Serum total oxidant status (TOS) and total antioxidant capacity (TAC) were measured, oxidative stress index (OSI) was calculated, and mononuclear DNA damage was assessed by alkaline comet assay; they were determined before treatment and after 3 months of treatment. Total oxydent status, OSI, and DNA damage levels were significantly higher and TAC levels were significantly lower in the thalassemic children than in the healthy controls (p < 0.001). In both supplemented groups, mean TOS and OSI levels were decreased; TAC and pre transfusion hemoglobin (Hb) levels were significantly increased after 3 months (p ≤ 0.002). In the NAC group, DNA damage score decreased (p = 0.001). N-acetylcysteine and vitamin E may be effective in reducing serum oxidative stress and increase pre transfusion Hb levels in children with β-thal. N-acetylcysteine also can reduce DNA damage.

Expression of CD55 on Red Blood Cells of β-Thalassemia Patients

CD55 is a complement regulatory protein expressed by cells to protect them from bystander lysis by complement. It prevents the formation of C3/C5 convertase. In β-thalassemia (β-thal), the defective hemoglobin (Hb) production makes red blood cells (RBCs) lyse early and frequently. Loss of CD55 expression in those patients compromises the complement regulatory function, thereby accelerating RBC lysis. In this study, we aimed to evaluate the expression of CD55 on erythrocytes of β-thal patients. Flow cytometry analysis of CD55 was conducted on RBCs of 21 β-thalassemia major (β-TM) patients, 11 β-thalassemia intermedia (β-TI) patients and 10 healthy volunteers. The results showed a significant decrease in CD55 expression in β-TM (57.5 ± 16.7%), while there was a slight decrease in β-TI patients (81.8 ± 3.8%) in comparison with that of the normal controls (88.7 ± 0.8%). The diminished expression of CD55 was not accompanied by decrease in CD59 expression in β-thal patients (97.2 ± 2.3%). This could suggest a mechanism (could be genetic) responsible for low CD55 expression. It may be related to defective Hb genes in thalassemia, but it does not relate to cell membrane changes.

Immunological evaluation of β-thalassemia major patients receiving oral iron chelator deferasirox.

To determine the immune abnormalities and occurrence of infections in transfusion-dependent β-thalassemia major patients receiving oral iron chelator deferasirox (DFX). An observational study. Hematology Clinics, King Khalid University Hospital, Riyadh, Saudi Arabia, from July to December 2010. Seventeen patients with β-thalassemia major (12 females, median age 26 years) receiving deferasirox (DFX) for a median duration of 27 months were observed for any infections and had their immune status determined. Immune parameters studied included serum immunoglobulins and IgG subclasses, serum complement (C3 and C4) and anti-nuclear antibody (ANA) level, total B and T-lymphocytes, CD4+ and CD8+ counts, CD4+/CD8+ ratio, and natural killer (NK) cells. Immunological parameters of the patients were compared with age, gender, serum ferritin level and splenectomy status. Lymphocyte subsets were also compared with age and gender matched normal controls. A considerable reduction in serum ferritin was achieved by DFX from a median level of 2528 to 1875 μmol/l. Serum IgG levels were increased in 7 patients. Low C4 levels were found in 9 patients. Total B and T-lymphocytes were increased in 14 patients each, while CD4+, CD8+ and NK cells were increased in 13, 12 and 11 patients respectively. Absolute counts for all lymphocyte subsets were significantly higher compared to the normal controls (p ² 0.05 for all parameters). Raised levels of IgG were associated with older age, female gender, splenectomized status and higher serum ferritin levels but this did not reach statistical significance except for the higher ferritin levels (p=0.044). Increased tendency to infections was not observed. Patients with β-thalassemia major receiving DFX exhibited significant immune abnormalities. Changes observed have been described previously, but could be related to DFX. The immune abnormalities were not associated with increased tendency to infections.

Serum levels of TGFβ, IL-10, IL-17, and IL-23 cytokines in β-thalassemia major patients: the impact of silymarin therapy

Several immunological abnormalities have been characterized in β-thalassemia, many of which are linked to or identified with cytokines. In this study, we investigated the serum levels of TGF-β, IL-10, IL-17 and IL-23 in β-thalassemia major patients in comparison with healthy controls. The immunomodulatory effect of silymarin (a flavonoid complex obtained from Silybum marinum) on the serum levels of cytokines was further evaluated in thalassemia patients receiving silymarin (420 mg/day) and compared with patients treated with placebo for 6-month. Serum cytokines levels were measured by enzyme linked immunosorbent assay (ELISA). The results showed a significant higher concentration of TGF-β and IL-23 in the patient group than control group. Among studied cytokines, a significant reduction in serum IL-10 levels was found in patients treated with silymarin when compared with IL-10 values at baseline. However, no significant difference was observed between baseline values of cytokine compared with end values in placebo group. Our data suggest the presence of imbalanced immune condition involving inflammation and immunosuppression in thalassemia patients, which could be modulated to a more effective immune response by silymarin.

Orofacial Structural Changes in Iraqi Patients with β-Thalassaemia Major

Background : Thalassaemia is the most common single gene disorder in the world and represents a major health burden. Oro-facial changes occur during the disease process mainly because of marrow expansion to compensate anemia. The aim of this study :The aim of this study was to evaluate the orofacial structural changes in thalassaemia and to co-relate them to the duration of the disease process and to assess the bone density of both mandibular condyles in β-thalassaemia major patients . Patients,materials and methods: The control group consisted of (16) subjects and the study groups consisted of (52) , each of the study and control groups were divided into three sub groups according to their age and types of collecting data. A coronal view of the image was obtained , the bone density in Hounsfield units (HU) within each (region of interest) roi measured and five units at different locations on the body of condyle obtained , then divided into five ,this represented the mean number of hu of each body of condyle (both right and left head of condyle obtained). Results: The results of the study showed high degree of malocclusion in β-thalassemia patients. There was a significant difference in oral hygiene between thalassaemic patients and control group. The extraoral examination of thalassaemia major patients showed that the facial pigmentation and the saddle nose were significant in thalassemia major patients . In this study the mean value of DMFT index in the study group was (10.905) while the mean value of DMFT index in the control group was 7.875. In comparison between study and control group ,the results were significant for males (P<0.05 ) and highly significant for total (P<0.01), while for females ,the results were significant(P<0.05 ) . The orthopantomography(OPG) assessment of patients showed that the lamina dura around the roots was thinner than usual,enlarged bone marrow spaces ,spiky root of mandibular molars and taurodontism. The assessment of bone density of the head of condyles using quantitive computerised tomography (CT) scan in the study showed that the Hounsfield unit (H.U) of study group were lower than control group which mean that bone density was lower and the Hounsfield unit( H.U )and density of bone decreased with increase the age

Endocrinopathies in Turkish Children with Beta Thalassemia Major: Results from a Single Center Study

The endocrinological complications in β-thalassemia major patients do affect the life quality to a large extend. In this study, the endocrinological complications of 47 β-thalassemia patients, who have been followed-up at our hospital's pediatric hematology department, were evaluated. Out of β-thalassemia major cases included to this study, the 55.3% was male and 44.7% was female. The patients’ mean levels of ferritin, whose mean age was 10.0 ± 4.5 years (2–20 years), were 2497 ± 1469 ng/mL (472–8558 ng/mL). At least one endocrinological pathology in 27 out of 47 (57.4%) and more than one endocrinological pathology in 14 out of 47 (29.7%) thalassemia patients were observed. The most frequently observed complication in followed-up cases was vitamin D insufficiency and deficiency (78.2%). The other complications in decreasing order were pubertal failure (41.6%), growth retardation (25.5%), decreased bone-mineral density (22.2%), secondary hyperparathyroidism (11.5%), overt hypothyroidism (4.25%), subclinical hypothyroidism (2.12%), and impaired glucose tolerance (2.12%). There was no statistically significant difference between serum mean ferritin level and endocrin complications (P > .05). Four patients (8.5%) had decreased signal intensity in pituitary magnetic resonance imaging (MRI) but this finding was not associated with ferritin levels (P = .87). MRI parameters were similar between patients with and without gonadal dysfunction. Mean height of the pituitary gland was 4.98 ± 1.1 mm (3–9 mm) and this was similar to those normal values in the literature. Ferritin levels were not correlated with pituitary height (P > .05). Beta thalassemia major, having the potential of leading to multisystemic complications, is a chronic disease that should be treated and followed-up by a multidisciplinary approach. Due to frequently encountered endocrinological complications, beta thalassemic patients should be followed-up regularly by hematology and endocrinology departments in coordination.

Hematopoietic Stem Cell Transplantation for Thalassemia

Thalassemia is an autosomal recessive disorder associated with defective synthesis of the α- or β-chain of hemoglobin. For β-thalassemia major patients, therapeutic options are either monthly red cell transfusions and chelation therapy or allogeneic stem cell transplant. Stem cell transplant is the only curative approach and success is inversely correlated with the degree of iron overload and hepatic damage. Without transfusions, thalassemic patients have tremendous skeleton deformities, as well as hepatomegaly and splenomegaly due to expansion of the hematopoietic system with extramedullary hematopoiesis. Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) in thalassemia has been a cornerstone in the development of HSCT. The rational basis of HSCT in thalassemia consists of substituting the thalassemic HSC bearing ineffective erythropoiesis with an allogeneic one capable of effective erythropoiesis. This cellular replacement therapy is not limited to the diseased erythropoietic component, but leads to the replacement of the entire hematopoietic system. Nevertheless, it is an efficient way to obtain a long-lasting, probably permanent, clinically effective correction of hemolytic anemia, thus avoiding transfusion requirements and associated complications . The transplantation approach for a nonmalignant disease is much different from transplantation in malignancies. In the former setting, the detrimental immunologic proprieties [GVHD] of the engrafted HSC are not balanced by an antimalignancy effect. This characteristic must be always considered in determining the risk/benefit ratio and therapeutic decision such as the kind and intensity of the conditioning regimen, GVHD prophylaxis, source of HSC, and adoptive posttransplant therapies. The Pesaro group developed a prognostic scheme to predict transplant outcome in patients younger than age 17. This prognostic scheme included three variables all related to iron burden: quality of chelation received for the entire life before transplantation; hepatomegaly; and the presence of liver fibrosis at pretransplant hepatic biopsy examination. These variables stratified patients into three groups based on them having none, or one/two, or all three of the risk factors. Overall survival and thalassemia-free survival were significantly different in the three groups: 94% and 87% in the low-risk group, 84% and 81% in the intermediate-risk group, and 70% and 58% in the high-risk group, respectively. The rate of rejection/thalassemia recurrence was much higher in thalassemic patients than in patients transplanted because of malignancies. Several factors have been invoked to explain this difference: massive pretransplant exposure to blood products, not having received any chemotherapy before transplant, expanded erythropoietic marrow, and possibly splenomegaly. Key Words: Hematopoietic, Stem cell, Thalassemi.

A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA)

AbstractRandomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.

Adipocytokine concentrations in children with different types of beta-thalassemia

Background. Beta-thalassemia is an inherited blood disorder. It results from the impaired production of β-globin chains, leading to a relative excess of alpha-globin chains. Clinical severity separates this disease into three main subtypes: β- thalassemia major, β-thalassemia intermedia and β-thalassemia minor, the former two being clinically more significant. Inflammatory processes may play an important role in some of the complications of thalassemia. Adipose tissue is one of the most important endocrine and secretory organs that release adipocytokines like adiponectin, resistin and visfatin. Aim. The aim of our study was to analyze adipocytokine concentrations (adiponectin, resistin and visfatin) in different types of β-thalassemia patients and determine any possible correlations with disease severity. Methods. We recruited 29 patients who were transfusion-dependent β-thalassemia-major patients, 17 patients with β-thalassemia intermedia, 30 β-thalassemia minor patients. The control group consisted of 30 healthy children. Anthropometric measurements, complete blood count, biochemical parameters, serum concentrations of adiponectin, resistin, visfatin were performed for all subjects. Results. Resistin and visfatin concentrations were significantly higher in β-thalassemia minor patients than in controls. Adiponectin, resistin and visfatin concentrations were significantly higher in both β-thalassemia intermedia and major patients than in controls. The concentrations of adiponectin, resistin and visfatin were significantly higher in both β-thalassemia intermedia and major patients than in β-thalassemia minor patients. There was no significant difference between β-thalassemia intermedia and β-thalassemia major patients for adipocytokines concentrations. Conclusion. We speculate that these adipocytokines may play a role in the development of complications in β-thalassaemia.

Molecular characterisation of β-globin gene mutations in Penang and Kedah, Malaysia

IntroductionBeta-thalassaemia is an autosomal recessive disorder and it is a public health problem in the Malaysian Malays and Chinese. This disorder mainly results from point mutations, small insertion or deletions in the β-globin gene complex. Beta-thalassaemia major patients require life-long monthly blood transfusions and iron-chelation therapies to sustain their lives. Mutation characterisation is necessary for affected couples at risk of having a β-thalassaemia major child. Objective1. To develop the TaqMan genotyping platform as a time- and cost-effective approach for characterisation of β-globin gene mutations. 2. To characterise the mutations using the developed assays in transfusion-dependent patients in Penang and Kedah. MethodsTen sets of primers and TaqMan probes were designed to identify the common mutations in Malaysian Malays and Chinese: −28 (A→G), CD17 (A→T), CD19 (A→G), HbE (G→A), IVS1-1 (G→T), IVS1-5 (G→C), CD 41/42 (-CTTT), CD71/72 (+A), IVS2-654 (C→T) and Poly A (AATAAAHAATAGA). Another 7 sets of TaqMan genotyping assays were designed to identify the rare mutations in Malays and Chinese: −29 (A→G), Cap (+1) (A→C), CD8/9 (+G), CD16 (-C), CD27/28 (+C), IVS1-1 (G→A) and CD43 (G→T). The developed assays were used to screen 54 and 62 transfusion-dependent patients in Penang and Kedah respectively. Results & DiscussionThe developed assays detected 92.9% of mutations in the β-thalassaemia major patients. The remaining mutations were detected by ARMS, gap-PCR and DNA sequencing. The most common mutation in β-thalassaemia major patients in Penang is CD41/42 with a frequency of 20.9%. The most common mutation in β-thalassaemia major patients in Kedah is HbE with a frequency of 30.8%. ConclusionThe simplicity and reproducibility of the TaqMan genotyping assays enable rapid and cost-effective analysis of the β-globin gene mutations in Malaysia.

Assessment of Iron Overload in Very Young Children with Limited Thalassemia Care Resources in South China

Southern China has one of the world’s largest population of patients needing transfusions. Transfusion and chelation are not uniformly available and no magnetic resonance imaging (MRI) assessment data exists to date. A total of 153 young β-thalassemia major (β-TM) patients were assessed using a validated 1.5T scanner in Hong Kong, People’s Republic of China (PRC). Their median age was 13 (range 7 to 30), and most patients were young (22.0% age <10, 73.0% age <15, 88.0% age <18). Erratic health care made estimation of total transfusion and chelation exposure impossible. Despite their early age, 24.0% had severe cardiac hemosiderosis [T2*<10 milliseconds (ms)], at ages as early as 8 years old. Median heart iron was 1.68 mg/g dry weight (range 0.19–7.66) and increased with age (p = 0.017), while liver iron was 22.2 mg/g dry weight (range 3.15 to 39.2). Serum ferritin levels were poor predictors of heart and liver, or pancreatic R* and pituitary R* values. Magnetic resonance imaging scans are needed to screen very young β-TM patients with immediate risk of premature cardiac death in developing nations and triage them to more intensive treatment. This is particularly important in countries with a large number of patients and limited resources. Our data suggests that in developing countries, there is no lower limit for thalassemia MRI scanning programs.

Serum Angiogenin Level in Sickle Cell Disease and Beta Thalassemia Patients

Introduction: Angiogenesis has been investigated in different kinds of anemia. However, its role as a marker of angiogenesis has not been investigated in thalassemia or sickle cell disease (SCD). Objectives: We aimed to investigate serum angiogenin level in children and adolescents with beta thalassemia or SCD and its relation to possible risk factors of angiogenesis. Materials and Methods: This study included; 32 β-thalassemia major (β-TM) patients aged 14.2 ± 3.8 years, 20 β-thalassemia intermedia (β-TI) patients aged 14.3 ± 4.8 years, 20 SCD patients aged 14.1 ± 2.4 years; 8 with (HbSS) and 12 with sickle thalassemia (HbS/β-thalassemia) and 35 age and sex-matched controls. Data collected regarding; age, sex, disease duration, blood transfusion frequency, transfusion index, chelation type and duration, CBC, Hb electrophoresis, serum ferritin and serum angiogenin level (by ELISA). Results: Angiogenin level was significantly higher in patients with SCD [250 (100–300) pg/mL] compared to β-TM [180 (140–230) pg/mL] and controls [89 (80–103) pg/mL] (P < .001) especially those with HbSS (P = .06). There was a significant negative correlation between serum angiogenin and age of patients, age of onset and duration of chelation in β-TM (P < .01, P < .001, P = .003) and β-TI (P = .009, P = .03, P < .001) and with serum ferritin in β-TI group (r = −0.573, P = .008). In SCD, angiogenin level was negatively correlated with both frequency of blood transfusion (r = −0.731, P < .001) and duration of hydroxyurea therapy (P = .017). Conclusions: High angiogenin level detected among patients with SCD may be negatively influenced by regular blood transfusion and hydroxyurea therapy, while; early onset of chelation therapy may decrease angiogenin level in β-TM.

Efficacy and Safety of Deferasirox in β-Thalassemia Major Patients in Iran: A Prospective Study from a Single referral Center in Iran

Introduction: Herein, the results of a prospective study evaluating the efficacy and safety of treatment with deferasirox are studied in iron-overloaded patients with β-thalassemia major during an 18-month trial. Methods: Thirty patients who were previously chelated with deferoxamine with/without deferiprone, and fulfilled the inclusion criteria were recruited. Patients received an initial dose of 10–30 mg/kg/day. Liver and cardiac MRI T2* were evaluated before and after the trial. In addition, serum ferritin level was assessed every 3 months. Primary endpoint was regarded as significant improvement in the severity of liver and cardiac iron overload in severe and moderate cases, in addition to improvement or maintenance of the grade of severity in patients with mild iron overload or normal iron accumulation. Therapy was considered effective if primary endpoint was met in >50%. Results: Liver MRI values improved significantly (P = .002), achieving a 73.33% success rate. A successful outcome regarding myocardial iron overload was observed in 80%. Finally, an overall of 66.66% of patients met the success criteria. Secondary endpoint, regarded as safety and tolerability was reached by 93.33%. The most common adverse events were skin rash and gastrointestinal disturbance. A dose between 30 and 40 mg/kg/day, tailored to each patient was considered the optimal dose. Conclusion: Deferasirox proved as an efficient and safe chelating agent in our patients, specifically in mild to moderate iron overloaded patients.

Optimal method for early detection of cardiac disorders in thalassemia major patients: magnetic resonance imaging or echocardiography?

BackgroundHeart failure resulting from myocardial iron deposition is the most important cause of death in β-thalassemia major (TM) patients. Cardiac T2*magnetic resonance imaging (MRI), echocardiography, and serum ferritin level serve as diagnostic methods for detecting myocardial iron overload. In this study, we aimed to evaluate the relationship between the above-mentioned methods.MethodsT2*MRI and echocardiographic measurement of left ventricular (LV) systolic and diastolic function were performed in 63 patients. Serum ferritin level was measured. The relationships between all assessments were evaluated.ResultsThere were 40 women and 23 men with a mean age of 23.7±5.1 years (range, 15-35 years). There was no statistically significant correlation between serum ferritin level and LV systolic and diastolic function (P=0.994 and P=0.475, respectively). T2*MRI results had a significant correlation with ferritin level; 63.6% of patients with serum ferritin level >2,000 ng/mL had abnormal cardiac MRI, while none of the patients with ferritin level <1,000 ng/mL had abnormal cardiac MRI (P=0.001). There was no significant correlation between MRI findings and LV systolic function (P=1.00). However, we detected a significant difference between LV diastolic function and cardiac siderosis (P=0.03)ConclusionMRI findings are a good predictor of future cardiac dysfunction, even in asymptomatic TM patients; however, diastolic dysfunction may happen prior to cardiac siderosis in some patients, and echocardiography is able to diagnose this diastolic dysfunction while T2*MRI shows normal findings.

Comparison of effective α-tocopherol concentrations ameliorating reduced glucose transport and counteracting t-butylhydroxyperoxide-induced lipid peroxidation in isolated erythrocytes from ß-thalassemic patients

In thalassemia patients Red Blood Cell (RBC) membrane is the major target of oxidative stress caused by hemichrome radicals. Moreover, RBC membranes from thalassemic patients are more susceptible to oxidative stress, which causes lipid peroxidation, membrane rigidity, and dysfunction of membrane proteins. We investigated hemoglobin-free isolated RBC membranes (ghosts) from 28 β-thalassemia major patients and from 24 normal blood samples. Our research aimed to determine the effective concentrations of racemic α-tocopherol i) counteracting experimental oxidative stress induced by 2mM tertiary butylhydroperoxide (t-BHP) and ii) ameliorating impaired glucose transport in RBC ghosts from thalassemia patients. Reduced glucose transport in thalassemic ghosts was ameliorated significantly by tocopherol with a maximum effect at 75 ppm concentration. Furthermore, ghosts were pre-incubated with/without α-tocopherol up to 200 ppm before treated with t-BHP as the oxidative agent and reactive membrane thiols determined. As a parameter of lipid peroxidation (LPO) thiobarbiturate-reactive substances were measured and expressed as malondialdehyde levels. Tocopherol counteracted LPO continuously in a concentration-dependent way up 200 ppm. Hence, it is concluded that tocopherol acts at different concentrations as an antioxidant and on glucose transport by GLUT1 in RBC membranes.

Molecular basis of transfusion dependent beta-thalassemia major patients in Sabah

Beta-thalassemia is one of the most prevalent inherited diseases and a public health problem in Malaysia. Malaysia is geographically divided into West and East Malaysia. In Sabah, a state in East Malaysia, there are over 1000 estimated cases of β-thalassemia major patients. Accurate population frequency data of the molecular basis of β-thalassemia major are needed for planning its control in the high-risk population of Sabah. Characterization of β-globin gene defects was done in 252 transfusion dependent β-thalassemia patients incorporating few PCR techniques. The study demonstrates that β-thalassemia mutations inherited are ethnically dependent. It is important to note that 86.9% of transfusion-dependent β-thalassemia major patients in Sabah were of the indigenous population and homozygous for a single mutation. The Filipino β(0)-deletion was a unique mutation found in the indigenous population of Sabah. Mutations common in West Malaysia were found in 11 (4.3%) patients. Four rare mutations (Hb Monroe, CD 8/9, CD 123/124/125 and IVS I-2) were also found. This study is informative on the population genetics of β-thalassemia major in Sabah.

Joint Diabetes Thalassaemia Clinic: An Effective New Model of Care

Diabetes is a significant complication of β-thalassemia major (β-TM) and most patients receive fragmented diabetes care. In 2005, we developed a unique Joint Diabetes Thalassaemia Clinic, based at the Department of Diabetes, Whittington Health, London, UK, where patients were reviewed jointly by a multidisciplinary team, including Consultant Diabetologist and Hematologist. Study of the Joint Diabetes Thalassaemia Clinic (2005–2009) showed improvement in glycemic control with fructosamine reduction from 344 umol/L to 319 umol/L over a 1-year period as well as improvement in lipid profiles. The proportion of patients attending the Joint Clinic who achieved metabolic targets compared to the National Diabetes Audit for England was higher for glycemic control (73.0 Joint Diabetes Thalassaemia Clinic vs. 63.0% nationally), blood pressure control (58.0 Joint Diabetes Thalassaemia Clinic vs. 30.0% nationally) and cholesterol control (81.0 Joint Diabetes Thalassaemia Clinic vs. 78.0% nationally). Five patients (22.7%) had microvascular complications. A significant proportion of our patients had endocrinopathies (86.0% hypogonadism, 18.0% hypothyroidism, 23.0% hypoparathyroidism). The unique partnership of our Joint Diabetes Thalassaemia Clinic, allowed these very complex patients to be managed effectively.

Association between clinical expression and molecular heterogeneity in β-thalassemia Tunisian patients

Beta-thalassemia is the most frequent hereditary blood disorder in Tunisia because of its geographic localization and history. This pathology is characterized by a complex multisystem process with genetic and biochemical interactions. The aim of this work was to establish phenotype/genotype association through studying the distribution and the relationship between β-thalassemia and α-thalassemia mutations and three polymorphic markers: the C → T polymorphism at -158 of the Gγ gene, the RFLP haplotype and the repeated sequence (AT)xTy in the β globin silencer, in two groups of β-thalassemia major and β-thalassemia intermedia (TI) patients. Statistical analysis has shown that moderate expression seen in TI patients was significantly associated to β(+) -87 (C → G), -30 (T → A) and IVSI-6 (T → C) mutations, haplotypes VIII, IX and Nb and to XmnI polymorphism. The regression analysis of combined genotypes (mutation/XmnI/RFLP haplotype) revealed that they contribute to justify 17.1 % of clinical expression diversity (p < 0.05). Among the studied genotypes the XmnI polymorphism seems to be the most determinant modulating factor, followed by the β-thalassemia mutation and RFLP haplotype. Our findings highlight the heterogeneity of molecular background of β-thalassemia that would be responsible of clinical variability.

Three most common nonsynonymous UGT1A6*2 polymorphisms (Thr181Ala, Arg184Serand Ser7Ala) and therapeutic response to deferiprone in β-thalassemia major patients

Deferiprone is used as a chelation agent in chronic iron overload in β-thalassemia patients. Patients on deferiprone therapy show variable response to this drug in terms of reduction in iron overload as well as adverse drug reactions (ADRs). The pharmacogenetic studies on deferiprone have not carried out in patients with blood disorders in India. Therefore, the present study was carried out to evaluate the three most common nonsynonymous UGT1A6 polymorphisms Thr181Ala (541 A/G), Arg184Ser (552 A/C) and Ser7Ala (19 T/G) and therapeutic response to deferiprone in β-thalassemia major patients. Two hundred and eighty six (286) β-thalassemia major patients were involved in the study. Serum ferritin levels were estimated periodically to assess the status of the iron overload and the patients were grouped into responders and non-responders depending on the ferritin levels. The UGT1A6*2 polymorphisms were detected by PCR-RFLP methods. The association between the genotypes and outcome as well as ADRs was evaluated by Open EPI software. A significant difference was observed in the genotypic distribution of UGT1A6*2 Thr181Ala polymorphism in responders and non-responders. However, there was no difference in the genotypic distribution between patients with and without ADRs. As far as the UGT1A6*2 Arg184Ser polymorphism is concerned, no significant difference was observed between responders and non-responders. Further, evaluating the association of UGT1A6*2 Ser7Ala polymorphism with drug response, there was no significant difference in the genotypic distribution between responders and non-responders. However, there was a significant difference between responders with and without ADRs and non-responders with and without ADRs. In addition to this haplotype analysis was also carried out. However, we did not find any specific haplotype to be significantly associated with the deferiprone response in β-thalassemia major patients.