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1.  Parental and Other Factors Associated with Hydroxyurea Use for Pediatric Sickle Cell Disease 
Pediatric blood & cancer  2012;60(4):653-658.
Background
Hydroxyurea (HU) is highly effective treatment for Sickle Cell Disease (SCD). While pediatric use of HU is accepted clinical practice, barriers to use may impede its potential benefit.
Procedure
A survey of parents of children ages 5–17 years with SCD was performed across five institutions to assess factors associated with HU use.
Results
Of the 173 parent responses, 65 (38%) had children currently taking HU. Among parents of children not taking HU, the most commonly cited reasons were that their hematology provider had not offered it, their child was not sufficiently symptomatic and concerns about potential side effects. Even parents of HU users reported widespread concern about effectiveness, long-term safety and off-label use. In bivariate analyses, children’s ages, parental demographics such as education level, or travel time to their hematology provider were not correlated with HU use. Bivariate analysis and multivariate logistic regression revealed three significant factors associated with current HU use: better parental knowledge about its major therapeutic effects (p<0.001), sickle genotype (p=0.005) and institution of clinical care (p=0.04).
Conclusions
Pervasive concerns about HU safety exist, even among parents of current users. Varying knowledge among parents appears to be independent of their demographics, and is associated with HU use. Inter-institutional variability in parental knowledge and drug uptake highlights potentially potent site-specific influences on likelihood of HU use. Overall, these survey data underscore the need for strategies to bolster parental understanding about benefits of HU and address concerns about its safety.
doi:10.1002/pbc.24381
PMCID: PMC3625668  PMID: 23129068
Hydroxyurea; sickle cell disease; knowledge; and barriers; outcomes research
2.  Macrophages support pathological erythropoiesis in Polycythemia Vera and Beta-Thalassemia 
Nature medicine  2013;19(4):437-445.
Regulation of erythropoiesis is achieved by integration of distinct signals. Among these, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages for physiological and pathological conditions of enhanced erythropoiesis. We utilized mouse models of induced anemia, Polycythemia vera and β-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively for recovery from induced anemia as well as the pathological progression of Polycythemia vera and β-thalassemia by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a critical direct impact of macrophages on proliferation and enucleation of erythroblasts from healthy individuals and Polycythemia vera or β-thalassemic patients. In summary, we identify a new mechanism that we named “Stress Erythropoiesis Macrophage-supporting Activity” (SEMA) that contributes to the pathophysiology of these disorders and will have critical scientific and therapeutic implications in the near future.
doi:10.1038/nm.3126
PMCID: PMC3618568  PMID: 23502961
3.  Hepcidin and Hfe in iron overload in β-thalassemia 
Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with β-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in β-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in β-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries.
doi:10.1111/j.1749-6632.2010.05595.x
PMCID: PMC3652388  PMID: 20712796
β-thalassemia; iron overload; hepcidin; Hfe; lentiviral vectors
4.  Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea 
PLoS ONE  2013;8(2):e55709.
Background
Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin.
Methodology/Principal Findings
In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels.
Conclusions/Significance
These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease.
doi:10.1371/journal.pone.0055709
PMCID: PMC3567082  PMID: 23409025
5.  Education and Employment Status of Children and Adults with Thalassemia in North America 
Pediatric blood & cancer  2010;55(4):678-683.
Background
Advances in the management of thalassemia have resulted in increased life expectancy and new challenges. We conducted the first survey of education and employment status of people with thalassemia in North America.
Procedures
A total of 633 patients (349 adults and 284 school age children) enrolled in the Thalassemia Clinical Research Network (TCRN) registry in Canada and the US were included in the data analysis. Predictors considered for analysis were age, gender, race/ethnicity, site of treatment (Canada vs. United States), transfusion and chelation status, serum ferritin, and clinical complications.
Results
Seventy percent of adults were employed of which 67 percent reported working full-time. Sixty percent had a college degree and 14% had achieved some post college education. Eighty-two percent of school age children were at expected grade level. In a multivariate analysis for adults, Whites (OR=2.76, 95% CI: 1.50-5.06) were more likely to be employed compared to Asians. Higher education in adults was associated with older age (OR=1.67, 95% CI: 1.29-2.15), female gender (OR=2.08, 95% CI: 1.32-3.23) and absence of lung disease (OR=14.3, 95% CI: 2.04-100). Younger children (OR=5.7 for 10 year increments, 95% CI: 2.0 – 16.7) and Canadian patients (OR=5.6, 95% CI: 1.5-20) were more likely to be at the expected education level. Neither transfusion nor chelation was associated with lower employment or educational achievement.
Conclusions
Individuals with thalassemia in North America can achieve higher education; however, full-time employment remains a problem. Transfusion and chelation do not affect employment or education status of this patient population.
doi:10.1002/pbc.22565
PMCID: PMC2932798  PMID: 20535817
Employment; Education; Thalassemia
6.  Relationship between Chronic Transfusion Therapy and Body Composition in Subjects with Thalassemia 
The Journal of pediatrics  2010;157(4):641-647.e2.
Objective
To measure body composition in patients with thalassemia and explore its relationship to abnormal growth and bone mass.
Study design
Cross-sectional, multi-center study. Fat, lean, and bone mineral density (BMD) were assessed by DXA. Medical history, food frequency and physical activity questionnaires were conducted in 257 transfused thalassemia patients (23.7 ± 11 yr, Mean±SD, 51% male) compared with 113 non-transfused patients (21.3 ± 13 yr, 44% male).
Results
Subjects with thalassemia were leaner compared with healthy Americans from NHANES III data. Transfused subjects had higher percentage body fat compared with non- transfused after controlling for age, sex and ethnicity; 11.8% of non-transfused pediatric subjects were considered underweight, significantly lower than NHANES data (p=0.03). Hemoglobin level was positively related to lean mass (p=0.008). Body fat and lean mass were positive predictors for both height and BMD Z-scores after adjustment for transfusion status, age, sex, ethnicity, calcium intake and physical activity (all p<0.001).
Conclusions
Though the majority of adult patients with thalassemia had healthy body composition with rare obesity, young, non-transfused patients appear at risk for being underweight. Optimizing physical activity and appropriate use of transfusion therapy may improve growth and bone health in these at risk patients.
doi:10.1016/j.jpeds.2010.04.064
PMCID: PMC2936667  PMID: 20547400
DXA; lean mass; fat mass; body mass index (BMI); calcium
7.  A preclinical approach for gene therapy of β-thalassemia 
Lentiviral-mediated β-globin gene transfer successfully treated β-thalassemic mice. Based on this result, clinical trials were initiated. To date, however, no study has investigated the efficacy of gene therapy in relation to the nature of the different β-globin mutations found in patients. Most mutations can be classified as β0 or β+, based on the amount of β-globin protein produced. Therefore, we propose that a screening in vitro is necessary to verify the efficacy of gene transfer prior to treatment of individual patients. We used a two-phase liquid culture system to expand and differentiate erythroid progenitor cells (ErPCs) transduced with lentiviral vectors. We propose the use of this system to test the efficiency of lentiviral vectors carrying the human β-globin gene, to correct the phenotype of ErPCs from patients preparing for gene therapy. This new approach might have profound implications for designing gene therapy and for understanding the genotype/phenotype variability observed in Cooley’s anemia patients.
doi:10.1111/j.1749-6632.2010.05594.x
PMCID: PMC3068625  PMID: 20712784
β-thalassemia; β-globin; gene therapy; lentiviral vectors; hemoglobin; erythroid progenitor cells
8.  Changes in bone micro-architecture and biomechanical properties in the th3 thalassemia mouse are associated with decreased bone turnover and occur during the period of bone accrual 
Calcified tissue international  2010;86(6):484-494.
Osteoporosis and fractures occur frequently in patients with beta thalassemias, a group of congenital hemolytic anemias characterized by decreased synthesis of the beta chain of hemoglobin. In this study, we determined the bone abnormalities of the th3 thalassemia mouse, generated by deletion of the mouse beta chain genes. The heterozygote th3/+ mouse has moderate anemia, and serves as a model of beta thalassemia intermedia (TI), which represents the mild thalassemia phenotype. The th3/th3 mouse has lethal anemia and is a model of beta thalassemia major (TM), which is characterized by life-threatening anemia requiring regular transfusions to sustain life.
Compared to controls: i) Micro-CT of trabecular bone showed decreased bone volume fraction, number of trabeculae and trabecular thickness in both th3/+ and th3/th3 (p<0.05). ii) Cortical bone analysis showed thinner cortices and increased marrow area in th3/+ animals (p<0.05). iii) Micro-CT abnormalities in th3/+ mice were present by 2 months and did not worsen with age. iv) Histomorphometry was significant for decreased bone formation and resorption in both th3/+ and th3/th3. Similarly, cathepsin K and osteocalcin expression from bone of both th3/+and th3/th3 animals was reduced (p<0.05). vi) Biomechanics showed reduced maximum load, maximum moment and structural stiffness in both th3/+and th3/th3 (p<0.01).
In conclusion, the th3 mouse model of thalassemia manifests bone changes reminiscent of those in humans, and can be used for further bone studies in thalassemia. Bone changes are associated with decreased bone turnover, and develop early on during the period of bone accrual.
doi:10.1007/s00223-010-9365-0
PMCID: PMC2917203  PMID: 20449578
9.  Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice 
The Journal of Clinical Investigation  2010;120(12):4466-4477.
Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.
doi:10.1172/JCI41717
PMCID: PMC2993583  PMID: 21099112
10.  Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem 
Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z-scores < −2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.
doi:10.1359/jbmr.080505
PMCID: PMC3276604  PMID: 18505376
DXA; BMD; fractures; vertebral morphometry; thalassemia
11.  Therapeutic Hemoglobin Levels after Gene Transfer in β-Thalassemia Mice and in Hematopoietic Cells of β-Thalassemia and Sickle Cells Disease Patients 
PLoS ONE  2012;7(3):e32345.
Preclinical and clinical studies demonstrate the feasibility of treating β-thalassemia and Sickle Cell Disease (SCD) by lentiviral-mediated transfer of the human β-globin gene. However, previous studies have not addressed whether the ability of lentiviral vectors to increase hemoglobin synthesis might vary in different patients.
We generated lentiviral vectors carrying the human β-globin gene with and without an ankyrin insulator and compared their ability to induce hemoglobin synthesis in vitro and in thalassemic mice. We found that insertion of an ankyrin insulator leads to higher, potentially therapeutic levels of human β-globin through a novel mechanism that links the rate of transcription of the transgenic β-globin mRNA during erythroid differentiation with polysomal binding and efficient translation, as reported here for the first time. We also established a preclinical assay to test the ability of this novel vector to synthesize adult hemoglobin in erythroid precursors and in CD34+ cells isolated from patients affected by β-thalassemia and SCD. Among the thalassemic patients, we identified a subset of specimens in which hemoglobin production can be achieved using fewer copies of the vector integrated than in others. In SCD specimens the treatment with AnkT9W ameliorates erythropoiesis by increasing adult hemoglobin (Hb A) and concurrently reducing the sickling tetramer (Hb S).
Our results suggest two major findings. First, we discovered that for the purpose of expressing the β-globin gene the ankyrin element is particularly suitable. Second, our analysis of a large group of specimens from β-thalassemic and SCD patients indicates that clinical trials could benefit from a simple test to predict the relationship between the number of vector copies integrated and the total amount of hemoglobin produced in the erythroid cells of prospective patients. This approach would provide vital information to select the best candidates for these clinical trials, before patients undergo myeloablation and bone marrow transplant.
doi:10.1371/journal.pone.0032345
PMCID: PMC3314006  PMID: 22479321

Results 1-11 (11)