Annals of the New York Academy of Sciences
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Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with beta-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. ⋯ 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 beta-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 beta-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries.
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Ann. N. Y. Acad. Sci. · Aug 2010
ReviewThe challenge of obtaining therapeutic levels of genetically modified hematopoietic stem cells in beta-thalassemia patients.
Hematopoietic stem cells (HSCs) function to provide the individual with a continuing supply of blood cells over many decades. To this end, HSCs have evolved unique mechanisms for self-preservation, including resistance to viral infection. Unfortunately, this characteristic may impede the ability to achieve high levels of gene transfer mediated by HIV-based lentiviral vectors. ⋯ In particular, the study of beta-thalassemia patients that underwent allogeneic stem cell transplantation and developed stable, long-term mixed chimerism suggests that HSC gene transfer levels of greater than 25% will be needed for a robust therapeutic effect in such patients. Available pre-clinical and clinical trial lentiviral gene transfer studies suggest that improvements are needed to achieve this goal. Here, we review what level of gene transfer is needed in the context of varying degrees of beta-globin deficiency, what level is currently achievable, and the areas of research which may be fruitful in improving the likelihood of success for patients with the severest forms of beta-thalassemia.
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Ann. N. Y. Acad. Sci. · Aug 2010
Detection of the cardiovascular complications of thalassemia by echocardiography.
The thalassemia syndromes are associated with cardiovascular complications, which differ with the varying phenotypes encountered. The well-recognized paradigm of heart failure induced by myocardial iron overload, in thalassemia major (TM), has now been joined by pulmonary arterial hypertension (mostly seen in thalassemia intermedia) among other more subtle disorders of the cardiovascular system, including endothelial dysfunction. ⋯ Echocardiography remains an indispensable tool in the cardiovascular assessment of patients, it provides many insights into cardiovascular function, and its use allows improved management of patients. It is particularly suited to assess diastolic function, diagnose intracardiac masses (usually thrombus), and assess right ventricular function and pulmonary pressure.
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Ann. N. Y. Acad. Sci. · Aug 2010
Acute effects of motor vehicle traffic-related air pollution exposures on measures of oxidative stress in human airways.
Epidemiological studies have linked exposure to traffic-related air pollutants to increased respiratory and cardiovascular morbidity and mortality. Evidence from human, animal, and in vitro studies supports an important role for oxidative stress in the pathophysiological pathways underlying the adverse health effects of air pollutants. ⋯ Noninvasive measurement of biomarkers in breath and breath condensate may be particularly useful for evaluating the role of oxidative stress in acute responses to exposures that occur in vehicles or during near-roadway activities. Promising biomarkers include nitric oxide in exhaled breath, and nitrite/nitrate, malondialdehyde, and F2-isoprostanes in exhaled breath condensate.
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Ann. N. Y. Acad. Sci. · Aug 2010
Progress in hematopoietic stem cell transplantation as allogeneic cellular gene therapy in thalassemia.
Allogeneic hemopoietic stem cell transplantation (HSCT) represents one of the best cures for thalassemia. Currently, HSCT for thalassemia consists of allogeneic stem cell gene therapy and still awaits autologous genetically modified stem cell transplantation. HSCT for thalassemia has substantially improved over the last two decades, due in large part to improvements in preventive strategies, the effective control of transplant-related complications, and the development of new preparative regimens. ⋯ Adult thalassemia patients, who are higher risk patients for transplant-related toxicity due to an advanced phase of the disease, have a cure rate of 65% with current treatment protocol. Patients who do not have matched family or unrelated donors could benefit from haploidentical mother-to-child transplantation. Overall, the results of this type of transplantation appear encouraging.