Study of the effect of HFE gene mutations on iron overload in Egyptian thalassemia patients

Background: HFE gene mutations have been shown to be responsible for hereditaryhemochromatosis. Their effect on iron load in β-thalassemia patients and carriers remains controversial.Objectives: We aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in β-thalassemia patients and carriers and to investigate its effect on their serum ferritin levels.Patients and methods: A total of 100 β-thalassemia subjects; 75 patients and 25 carriers were screened for HFE gene mutations by PCR-RFLP. Serum ferritin measured by ELISA was evaluated in relation to HFE mutations.Results: Twenty-eight β-thalassemia patients (37.3%) were heterozygotes for H63D mutation (H/D), 8 (10.7%) were D/D and 39 (52%) were negative (H/H). Among carriers, 4 (16%) were D/D and 21 (84%) were H/H homozygotes. C282Y mutant allele was not detected in any of the subjects. Serum ferritin levels were significantly higher in β-thalassemia patients heterozygotes or homozygotes for H63D mutation compared to those without mutation (p= 0.000). Carriers homozygotes for H63D mutation showed significantly higher serum ferritin levels compared to those without mutation (p< 0.001).Conclusion: Homozygosity for H63D mutation tends to be associated with higher ferritin levels in beta-thalassemia patients and carriers suggesting its modulating effect on iron load in these cases

PENGARUH PEMBELAJARAN KEWIRAUSAHAAN DAN EKSTRAKURIKULER WAJIB KEPRAMUKAAN TERHADAP KARAKTER KEWIRAUSAHAAN (Studi Kasus Peserta Didik Kelas XI SMA YPI Bandung)

Penelitian ini bertujuan untuk memperoleh data mengenai 1. Pembinaan karakter kewirausahaan pada pembelajaran kewirausahaan pokok pembahasan produksi ikan konsumsi peserta didik kelas XI SMA YPI Bandung, 2. Pembinaan karakter kewirausahaan di Gugus depan 03021-03022 pangkalan SMA YPI Bandung, 3. Karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung, 4. Pengaruh pembinaan karakter kewirausahaan melalui pembelajaran kewirausahaan pokok bahasan produksi ikan konsumsi peserta didik kelas XI SMA YPI Bandung, 5. Pengaruh pembinaan karakter kewirausahaan dalam ekstrakurikuler wajib kepramukaan di Gugus depan 03021-03022 pangkalan SMA YPI Bandung. Metode penelitian yang dipergunakan metode survei tingkat eksplanasi asosiatif kausal. Teknik pengumpulan data dengan cara studi pustaka, kuesioner, dan observasi. Populasi pada penelitian ini, yaitu peserta didik kelas XI SMA YPI Bandung semester I yang berjumlah 22 orang. Hipotesis pada penelitian ini, yaitu 1. Terdapat pengaruh pembelajaran kewirausahaan terhadap karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung, 2 Terdapat pengaruh ekstrakurikuler kepramukaan terhadap karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung. Teknik pengolahan data menggunakan uji validitas, uji reliabilitas, uji normalitas data, analisis regresi linier sederhana, dan koefisien determinasi dengan menggunakan program SPSS 20.0 for windows. Hasil pengolahan data menunjukkan bahwa, 1. Pembinaan karakter kewirausahaan pada pembelajaran kewirausahaan peserta didik kelas XI SMA YPI menunjukkan kategori Baik dengan rata-rata 3,85, 2. Pembinaan karakter kewirausahaan di Gugus depan 03021-03022 pangkalan SMA YPI Bandung menunjukkan kategori Baik dengan rata-rata 3,78, 3. Karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung menujukkan kategori Sangat Baik dengan rata-rata 4,04, 4. T¬erdapat pengaruh pembelajaran kewirausahaan terhadap karakter kewirausahaan peserta didik senilai 4,7 % itu berarti Y sebagian kecil dipengaruhi oleh X1, arti Ha1 dapat diterima dan Ho1 ditolak, 5. Terdapat pengaruh ekstrakurikuler kepramukaan terhadap karakter kewirausahaan peserta didik senilai 27,6 % itu berarti Y hampir setengahnya dipengaruhi oleh X2, arti Ha2 dapat diterima dan Ho2 ditolak. Kesimpulan dari penelitian ini yaitu secara parsial terdapat pengaruh positif pembelajaran kewirausahaan dan ekstrakurikuler kepramukaan terhadap karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung. Sebagai akhir penelitian penulis menyampaikan saran kepada sekolah, guru, dan pembina Pramuka agar pembelajaran dan pelatihan dioptimalkan sebagai salah satu strategi untuk meningkatkan karakter kewirausahaan peserta didik. Kata kunci: Pembelajaran Kewirausahaan, Ekstrakurikuler Kepramukaan, Karakter Kewirausahaan

Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy

The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with ExjadeA (R). Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC < 7 or a parts per thousand yen7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2-magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC < 7 and a parts per thousand yen7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 A +/- 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 A +/- 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the < 7 versus a parts per thousand yen7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC < 7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation

Achieving treatment goals of reducing or maintaining body iron burden with deferasirox in patients with β-thalassaemia: results from the ESCALATOR study

This analysis evaluated the effects of deferasirox on liver iron concentration in moderate and heavily iron-overloaded patients with β-thalassaemia from the ESCALATOR trial (n = 231). Mean liver iron concentrations (LIC) decreased significantly from 21.1 ± 8.2 to 14.2 ± 12.1 mg Fe/g dry weight (dw) at 2 yr (P < 0.001) in patients with LIC ≥7 mg Fe/g dw at baseline; patients with LIC <7 mg Fe/g dw maintained these levels over the treatment period. The proportion of patients with LIC <7 mg Fe/g dw increased from 9.4% at core baseline to 39.3% by the end of year 2. The results showed that deferasirox enabled therapeutic goals to be achieved, by maintaining LIC in patients with LIC <7 mg Fe/g dw at a mean dose of 22.4 ± 5.2 mg/kg/d and significantly reducing LIC in patients with LIC ≥7 mg Fe/g dw at a mean dose of 25.7 ± 4.2 mg/kg/d, along with a manageable safety profile

Epistasis and the sensitivity of phenotypic screens for beta thalassaemia

Genetic disorders of haemoglobin, particularly the sickle cell diseases and the alpha and beta thalassaemias, are the commonest inherited disorders worldwide. The majority of affected births occur in low-income and lower-middle income countries. Screening programmes are a vital tool to counter these haemoglobinopathies by: (i) identifying individual carriers and allowing them to make informed reproductive choices, and (ii) generating population level gene-frequency estimates, to help ensure the optimal allocation of public health resources. For both of these functions it is vital that the screen performed is suitably sensitive. One popular first-stage screening option to detect carriers of beta thalassaemia in low-income countries is the One Tube Osmotic Fragility Test (OTOFT). Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts. We demonstrate that interactions between the carrier states for beta thalassaemia and alpha thalassaemia, glucose-6-phosphate dehydrogenase deficiency and Southeast Asian Ovalocytosis have the potential to reduce the sensitivity of OTOFTs for beta thalassaemia heterozygosity to below 70%. Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur

International sentinel site surveillance of patients with transfusional hemosiderosis treated with deferasirox in actual practice setting

Funding: This study was funded by Novartis Pharma AGObjective:The study evaluates the long-term deferasirox treatment of adult and pediatricpatients with chronic transfusional iron overload in clinical practice.Methods:In this non-interventional study, patients were observed for up to 3 years frominitiation of deferasirox treatment both prospectively and retrospectively for up to 1 yearprior to enrollment. The primary end points were the proportion of patients with≥1 notableincrease in serum creatinine (SCr), and≥1 notable increase in alanine aminotransferase (ALT).Results:Overall, 120 patients were enrolled and 51 completed the study, with a limited 3-yeardropout rate of 12.5% due to adverse events (AEs). Increase in SCr > 33% above baseline and theage-adjusted ULN (upper limit of normal) was observed in 14 patients (95%CI, 7.1-19.2). The ALTlevels >5 × ULN was observed in 1 patient. Most frequent AEs reported during treatment withdeferasirox include gastrointestinal disturbances.Conclusions:The long-term treatment with deferasirox was manageable in most transfusion-dependent patients with no unexpected safetyfindings. Regular monitoring and an adjusteddeferasirox dosing strategy per local labels allowed continued iron chelation treatment andcontrol of transfusional iron in the majority of patients on study

Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis

Data from the International Collaborative Gaucher Group Gaucher Registry were analysed to assess the relationship between enzyme replacement therapy with imiglucerase (ERT) and incidence of avascular necrosis (AVN) in type 1 Gaucher disease (GD1), and to determine whether the time interval between diagnosis and initiation of ERT influences the incidence rate of AVN. All patients with GD1 enrolled in the Gaucher Registry who received ERT and did not report AVN prior to starting therapy (n = 2700) were included. The incidence rate of AVN following initiation of ERT was determined. An incidence rate of AVN of 13·8 per 1000 person-years was observed in patients receiving ERT. Patients who initiated ERT within 2 years of diagnosis had an incidence rate of 8·1 per 1000 person-years; patients who started ERT ≥2 years after diagnosis had an incidence rate of 16·6 per 1000 person-years. The adjusted incidence rate ratio was 0·59 [95% confidence interval (CI) 0·36–0·96, P = 0·0343]. Splenectomy was an independent risk factor for AVN (adjusted incidence rate ratio 2·23, 95% CI 1·61–3·08, P < 0·0001). In conclusion, the risk of AVN was reduced among patients who initiated ERT within 2 years of diagnosis, compared to initiating treatment ≥2 years after diagnosis. A higher risk of AVN was observed among patients who had previously undergone splenectomy

Worldwide survey of T2* cardiovascular magnetic resonance in Thalassaemia

Introduction Thalassaemia major (TM) affects hundreds of thousands of patients worldwide but only a minority have access to regular blood transfusion and chelation therapy. Cardiovascular magnetic resonance (CMR) T2* measurement provides an accurate, reproducible measurement of cardiac iron which is the cause of heart failure and early death in many transfused TM patients. This technique has been adopted as part of routine management in many countries where survival is now approaching normal but little is known about the severity and effects of myocardial iron loading in different geographical regions. Purpose The aim of this study was to describe the burden of disease of myocardial siderosis (measured by T2*) in different populations throughout the world and to assess the relationship between T2* and outcome such as heart failure and cardiac death. Methods 34 worldwide centres were involved in this survey of 3376 patients from Europe, the Middle East, North America, South America, North Africa, Australia and Asia. Anonymised data on myocardial T2* values were analysed in conjunction with clinical outcomes (heart failure and death). Results Overall, 57.5% of patients had no significant iron loading (T2* >20ms), 22.6% had moderate cardiac iron (10ms50%) in South-East Asia had cardiac iron (T2* >20ms) at baseline. At the time of the first scan, 100 patients (3.3%) had confirmed heart failure, the majority of whom (77.0%) had myocardial T2* <10ms with almost all (99%) having T2* <20ms. There were 113 patients who subsequently developed heart failure. 92.0% of these had T2* <10ms and 99.1% had a T2* <20ms. There were 39 deaths. Cardiac T2* values were <10ms in 79.5%, with 92.3% <20ms. Conclusions Even in this well-treated cohort with access to transfusion, chelation and CMR, there is a large proportion of TM patients with moderate to severe cardiac iron loading. Low T2* (<10ms) is associated with cardiac failure and death. There is a huge unmet worldwide need in terms of access to specialist medical care (including transfusion and chelation therapy) together with advanced monitoring techniques (such as CMR)