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Sample records for cardiac iron overload

  1. Effects of digoxin on cardiac iron content in rat model of iron overload

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    Nasri, Hamid Reza; Shahouzehi, Beydolah; Masoumi-Ardakani, Yaser; Iranpour, Maryam

    2016-01-01

    BACKGROUND Plasma iron excess can lead to iron accumulation in heart, kidney and liver. Heart failure is a clinical widespread syndrome. In thalassemia, iron overload cardiomyopathy is caused by iron accumulation in the heart that leads to cardiac damage and heart failure. Digoxin increases the intracellular sodium concentration by inhibition of Na+/K+-ATPase that affects Na+/Ca2+ exchanger (NCX), which raises intracellular calcium and thus attenuates heart failure. The mechanism of iron upta...

  2. Secoisolariciresinol diglucoside abrogates oxidative stress-induced damage in cardiac iron overload condition.

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    Stephanie Puukila

    Full Text Available Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG, a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 μ5M iron for 24 hours and/or a 24 hour pre-treatment of 500 μ M SDG. Cardiac iron overload resulted in increased oxidative stress and gene expression of the inflammatory mediators tumor necrosis factor-α, interleukin-10 and interferon γ, as well as matrix metalloproteinases-2 and -9. Increased apoptosis was evident by increased active caspase 3/7 activity and increased protein expression of Forkhead box O3a, caspase 3 and Bax. Cardiac iron overload also resulted in increased protein expression of p70S6 Kinase 1 and decreased expression of AMP-activated protein kinase. Pre-treatment with SDG abrogated the iron-induced increases in oxidative stress, inflammation and apoptosis, as well as the increased p70S6 Kinase 1 and decreased AMP-activated protein kinase expression. The decrease in superoxide dismutase activity by iron treatment was prevented by pre-treatment with SDG in the presence of iron. Based on these findings we conclude that SDG was cytoprotective in an in vitro model of iron overload induced redox-inflammatory damage, suggesting a novel potential role for SDG in cardiac iron overload.

  3. Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome

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    de Montalembert, Mariane; Ribeil, Jean-Antoine; Brousse, Valentine; Guerci-Bresler, Agnes; Stamatoullas, Aspasia; Vannier, Jean-Pierre; Dumesnil, Cécile; Lahary, Agnès; Touati, Mohamed; Bouabdallah, Krimo; Cavazzana, Marina; Chauzit, Emmanuelle; Baptiste, Amandine; Lefebvre, Thibaud; Puy, Hervé; Elie, Caroline

    2017-01-01

    The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation. PMID:28257476

  4. Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil

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    WOOD, JOHN C.; OTTO-DUESSEL, MAYA; GONZALEZ, IGNACIO; AGUILAR, MICHELLE I.; SHIMADA, HIRO; NICK, HANSPETER; NELSON, MARVIN; MOATS, REX

    2010-01-01

    Introduction Deferasirox effectively controls liver iron concentration; however, little is known regarding its ability to remove stored cardiac iron. Deferiprone seems to have increased cardiac efficacy compared with traditional deferoxamine therapy. Therefore, the relative efficacy of deferasirox and deferiprone were compared in removing cardiac iron from iron-loaded gerbils. Methods Twenty-nine 8- to 10-week-old female gerbils underwent 10 weekly iron dextran injections of 200 mg/kg/week. Prechelation iron levels were assessed in 5 animals, and the remainder received deferasirox 100 mg/kg/D po QD (n = 8), deferiprone 375 mg/kg/D po divided TID (n = 8), or sham chelation (n = 8), 5 days/week for 12 weeks. Results Deferasirox reduced cardiac iron content 20.5%. No changes occurred in cardiac weight, myocyte hypertrophy, fibrosis, or weight-to-dry weight ratio. Deferasirox treatment reduced liver iron content 51%. Deferiprone produced comparable reductions in cardiac iron content (18.6% reduction). Deferiprone-treated hearts had greater mass (16.5% increase) and increased myocyte hypertrophy. Deferiprone decreased liver iron content 24.9% but was associated with an increase in liver weight and water content. Conclusion Deferasirox and deferiprone were equally effective in removing stored cardiac iron in a gerbil animal model, but deferasirox removed more hepatic iron for a given cardiac iron burden. PMID:17145573

  5. Spatial repolarization heterogeneity detected by magnetocardiography correlates with cardiac iron overload and adverse cardiac events in beta-thalassemia major.

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    Chun-An Chen

    Full Text Available BACKGROUND: Patients with transfusion-dependent beta-thalassemia major (TM are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events. METHODS AND RESULTS: Fifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc, a standard deviation of QTc (SD-QTc, and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values<0.001. Spatial repolarization heterogeneity was even more pronounced in patients with significant iron overload (T2*<20 ms, n = 20 compared to those with normal T2* (all p values<0.001. Loge cardiac T2* correlated with SI-QTc (r = -0.609, p<0.001, SD-QTc (r = -0.572, p<0.001, and QTc dispersion (r = -0.622, p<0.001, while all these indices had no relationship with measurements of the left ventricular geometry or function. At the time of study, 10 patients had either heart failure or arrhythmia. All 3 indices of repolarization heterogeneity were related to the presence of adverse cardiac events, with areas under the receiver operating characteristic curves (ranged between 0.79 and 0.86, similar to that of cardiac T2*. CONCLUSIONS: Multichannel MCG demonstrated that patients with TM had increased spatial repolarization heterogeneity, which is related to myocardial iron load and adverse cardiac events.

  6. Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

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    Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

    2017-01-01

    Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats. PMID:28287621

  7. Iron overload and immunity

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    Gra(c)a Porto; Maria De Sousa

    2007-01-01

    Progress in the characterization of genes involved in the control of iron homeostasis in humans and in mice has improved the definition of iron overload and of the cells affected by it. The cell involved in iron overload with the greatest effect on immunity is the macrophage.Intriguing evidence has emerged, however, in the last 12 years indicating that parenchymal iron overload is linked to genes classically associated with the immune system. This review offers an update of the genes and proteins relevant to iron metabolism expressed in cells of the innate immune system, and addresses the question of how this system is affected in clinical situations of iron overload. The relationship between iron and the major cells of adaptive immunity, the T lymphocytes,will also be reviewed. Most studies addressing this last question in humans were performed in the clinical model of Hereditary Hemochromatosis. Data will also be reviewed demonstrating how the disruption of molecules essentially involved in adaptive immune responses result in the spontaneous development of iron overload and how they act as modifiers of iron overload.

  8. Prooxidant Mechanisms in Iron Overload Cardiomyopathy

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    Ching-Feng Cheng

    2013-01-01

    Full Text Available Iron overload cardiomyopathy (IOC, defined as the presence of systolic or diastolic cardiac dysfunction secondary to increased deposition of iron, is emerging as an important cause of heart failure due to the increased incidence of this disorder seen in thalassemic patients and in patients of primary hemochromatosis. At present, although palliative treatment by regular iron chelation was recommended; whereas IOC is still the major cause for mortality in patient with chronic heart failure induced by iron-overloading. Because iron is a prooxidant and the associated mechanism seen in iron-overload heart is still unclear; therefore, we intend to delineate the multiple signaling pathways involved in IOC. These pathways may include organelles such as calcium channels, mitochondria; paracrine effects from both macrophages and fibroblast, and novel mediators such as thromboxane A2 and adiponectin; with increased oxidative stress and inflammation found commonly in these signaling pathways. With further understanding on these complex and inter-related molecular mechanisms, we can propose potential therapeutic strategies to ameliorate the cardiac toxicity induced by iron-overloading.

  9. Pathology of hepatic iron overload

    Institute of Scientific and Technical Information of China (English)

    Yves Deugnier; Bruno Turlin

    2007-01-01

    Although progress in imaging and genetics allow for a noninvasive diagnosis of most cases of genetic iron overload, liver pathology remains often useful (1) to assess prognosis by grading fibrosis and seeking for associated lesions and (2) to guide the etiological diagnosis, especially when no molecular marker is available.Then, the type of liver siderosis (parenchymal, mesenchymal or mixed) and its distribution throughout the lobule and the liver are useful means for suggesting its etiology: HLA-linked hemochromatosis gene (HFE) hemochromatosis or other rare genetic hemochromatosis,nonhemochromatotic genetic iron overload (ferroportin disease, aceruloplasminemia), or iron overload secondary to excessive iron supply, inflammatory syndrome,noncirrhotic chronic liver diseases including dysmetabolic iron overload syndrome, cirrhosis, and blood disorders.

  10. [Genetics of hereditary iron overload].

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    Le Gall, Jean-Yves; Jouanolle, Anne-Marie; Fergelot, Patricia; Mosser, Jean; David, Véronique

    2004-01-01

    The classification of hereditary abnormalities of iron metabolism was recently expanded and diversified. Genetic hemochromatosis now corresponds to six diseases, namely classical hemochromatosis HFE 1; juvenile hemochromatosis HFE 2 due to mutations in an unidentified gene on chromosome 1; hemochromatosis HFE 3 due to mutations in the transferrin receptor 2 (TfR2); hemochromatosis HFE 4 caused by a mutation in the H subunit of ferritin; and hemochromatosis HFE 6 whose gene is hepcidine (HAMP). Systemic iron overload is also associated with aceruloplasminemia, atransferrinemia and the "Gracile" syndrome caused by mutations in BCS1L. The genes responsible for neonatal and African forms of iron overload are unknown. Other genetic diseases are due to localized iron overload: Friedreich's ataxia results from the expansion of triple nucleotide repeats within the frataxin (FRDA) gene; two forms of X-linked sideroblastic anemia are due to mutations within the delta aminolevulinate synthetase (ALAS 2) or ABC-7 genes; Hallervorden-Spatz syndrome is caused by a pantothenate kinase 2 gene (PANK-2) defect; neuroferritinopathies; and hyperferritinemia--cataract syndrome due to a mutation within the L-ferritin gene. In addition to this wide range of genetic abnormalities, two other features characterize these iron disorders: 1) most are transmitted by an autosomal recessive mechanism, but some, including hemochromatosis type 4, have dominant transmission; and 2) most correspond to cytosolic iron accumulation while some, like Friedreich's ataxia, are disorders of mitochondrial metabolism.

  11. Iron age: novel targets for iron overload.

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    Casu, Carla; Rivella, Stefano

    2014-12-05

    Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

  12. Acetaminophen protects against iron-induced cardiac damage in gerbils.

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    Walker, Ernest M; Epling, Christopher P; Parris, Cordel; Cansino, Silvestre; Ghosh, Protip; Desai, Devashish H; Morrison, Ryan G; Wright, Gary L; Wehner, Paulette; Mangiarua, Elsa I; Walker, Sandra M; Blough, Eric R

    2007-01-01

    There are few effective agents that safely remove excess iron from iron-overloaded individuals. Our goal was to evaluate the iron-removing effectiveness of acetaminophen given ip or orally in the gerbil iron-overload model. Male gerbils were divided into 5 groups: saline controls, iron-overloaded controls, iron-overloaded treated with ip acetaminophen, iron-overloaded treated with oral acetaminophen, and iron-overloaded treated with ipdeferoxamine. Iron dextran was injected iptwice/wk for 8 wk. Acetaminophen and deferoxamine treatments were given on Mondays, Wednesdays, and Fridays during the same 8 wk and continued for 4 wk after completion of iron-overloading. Echocardiograms were performed after completion of the iron-overloading and drug treatments. Liver and cardiac iron contents were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Iron-overloaded controls had 232-fold and 16-fold increases in liver and cardiac iron content, respectively, compared to saline controls. In iron-overloaded controls, echocardiography showed cardiac hypertrophy, right and left ventricular distension, significant reduction in left ventricular ejection fraction (-22%), and fractional shortening (-31%) during systole. Treatments with acetaminophen (ip or oral) or deferoxamine (ip) were equally effective in reducing cardiac iron content and in preventing cardiac structural and functional changes. Both agents also significantly reduced excess hepatic iron content, although acetaminophen was less effective than deferoxamine. The results suggest that acetaminophen may be useful for treatment of iron-induced pathology.

  13. Iron chelating agents for iron overload diseases

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    Guido Crisponi

    2014-09-01

    Full Text Available Although iron is an essential element for life, an excessive amount may become extremely toxic both for its ability to generate reactive oxygen species, and for the lack in humans of regulatory mechanisms for iron excretion. Chelation therapy has been introduced in clinical practice in the seventies of last century to defend thalassemic patients from the effects of iron overload and, in spite of all its limitations, it has dramatically changed both life expectancy and quality of life of patients. It has to be considered that the drugs in clinical use present some disadvantages too, this makes urgent new more suitable chelating agents. The requirements of an iron chelator have been better and better defined over the years and in this paper they will be discussed in detail. As a final point the most interesting ligands studied in the last years will be presented.

  14. [Genetic iron overloads and hepatic insulin-resistance iron overload syndrome: an update].

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    Ruivard, M

    2009-01-01

    Hepcidin inhibits intestinal absorption of iron through internalisation of ferroportin. Its discovery helps to better understand the genetic iron overloads. The insulin resistance-hepatic iron overload (IR-HIO)--also coined as the dysmetabolic iron overload syndrome--is a common cause or iron overload. This article is a review about genetic iron overloads and IR-HIO. Type 1 haemochromatosis C282Y +/+ accounts for 95% of the haemochromatosis. Hepatic fibrosis may develop if serum ferritin is higher than 1000 microg/l but can be partially reversible with phlebotomies. Juvenile haemochromatosis (type 2) and type 3 haemochromatosis (mutation of the transferrin receptor 2) are very uncommon. Several mutations of the ferroportin gene can cause usually mild iron overload of autosomal dominant inheritance. Aceruleoplasminemia is an uncommon disorder involving cerebral iron overload. The causes and consequences of the IR-HIO are unknown. Treatment of IR-HIO is focused on metabolic syndrome and phlebotomies are questionable because the overload is moderate and intestinal absorption of iron seems to be low. MRI (or other non invasive methods) is needed to truly assess iron overload because serum ferritin overestimates it in metabolic syndrome. Several points have to be elucidated: how HFE interferes with hepcidin in type 1 haemochromatosis; the causes of variability of iron overload; the benefits of populations screening; the advantage of phlebotomies in IR-HIO; the use of new oral iron chelators.

  15. New rat models of iron sucrose-induced iron overload.

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    Vu'o'ng Lê, Bá; Khorsi-Cauet, Hafida; Villegier, Anne-Sophie; Bach, Véronique; Gay-Quéheillard, Jérôme

    2011-07-01

    The majority of murine models of iron sucrose-induced iron overload were carried out in adult subjects. This cannot reflect the high risk of iron overload in children who have an increased need for iron. In this study, we developed four experimental iron overload models in young rats using iron sucrose and evaluated different markers of iron overload, tissue oxidative stress and inflammation as its consequences. Iron overload was observed in all iron-treated rats, as evidenced by significant increases in serum iron indices, expression of liver hepcidin gene and total tissue iron content compared with control rats. We also showed that total tissue iron content was mainly associated with the dose of iron whereas serum iron indices depended essentially on the duration of iron administration. However, no differences in tissue inflammatory and antioxidant parameters from controls were observed. Furthermore, only rats exposed to daily iron injection at a dose of 75 mg/kg body weight for one week revealed a significant increase in lipid peroxidation in iron-treated rats compared with their controls. The present results suggest a correlation between iron overload levels and the dose of iron, as well as the duration and frequency of iron injection and confirm that iron sucrose may not play a crucial role in inflammation and oxidative stress. This study provides important information about iron sucrose-induced iron overload in rats and may be useful for iron sucrose therapy for iron deficiency anemia as well as for the prevention and diagnosis of iron sucrose-induced iron overload in pediatric patients.

  16. Deferasirox, an oral chelator in the treatment of iron overload

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    I. Portioli

    2013-05-01

    Full Text Available BACKGROUND Deferasirox is a once-daily oral iron chelator developed for treating iron overload complicating long-term transfusion therapy in patients with diseases such as beta-thalassemia and myelodysplastic syndromes. Iron overload can damage the liver, pancreas and the heart. Deferoxamine, the only other drug approved for iron chelation, can prevent these effects but requires parenteral administration. Deferasirox has been approved after a one-year, open-label trial in patients ≥ 2 years old with beta-thalassemia and transfusional emosiderosis randomized to once-daily oral 5, 10, 20, 30 mg/kg/day in comparison of subcutaneous deferoxamine 20-60 mg/mg/kg/day x 5/week. CONCLUSIONS Deferasirox 20-30 mg/kg/day produced reductions in liver iron concentration (LIC similar to those with deferoxamine. Adverse effect of deferasirox (increases of serum creatinine and aminotransferases, including the gastrointestinal ones, are similar but more frequent than those occurring with deferoxamine. Information is lacking on the effects of deferasirox on cardiac iron and cardiac dysfunction which is the most serious complication of transfusional iron overload.

  17. Iron overload thalassemic cardiomyopathy: Iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity

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    Lekawanvijit, Suree; Chattipakorn, Nipon

    2009-01-01

    Patients with thalassemia major have inevitably suffered from complications of the disease, due to iron overload. Among such complications, cardiomyopathy is the leading cause of morbidity and mortality (63.6% to 71%). The major causes of death in this group of patients are congestive heart failure and fatal cardiac tachyarrhythmias leading to sudden cardiac death. The free radical-mediated pathway is the principal mechanism of iron toxicity. The consequent series of events caused by iron ove...

  18. Update on the use of deferasirox in the management of iron overload

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    Ali Taher

    2009-10-01

    Full Text Available Ali Taher,1 Maria Domenica Cappellini21American University of Beirut, Beirut, Lebanon; 2Universitá di Milano, Policlinico Foundation IRCCS, Milan, ItalyAbstract: Regular blood transfusions as supportive care for patients with chronic anemia inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload cause significant morbidity and mortality if not effectively treated with chelation therapy. Based on a comprehensive clinical development program, the once-daily, oral iron chelator deferasirox (Exjade® is approved for the treatment of transfusional iron overload in adult and pediatric patients with various transfusion-dependent anemias, including β-thalassemia and the myelodysplastic syndromes. Deferasirox dose should be titrated for each individual patient based on transfusional iron intake, current iron burden and whether the goal is to decrease or maintain body iron levels. Doses of >30 mg/kg/day have been shown to be effective with a safety profile consistent with that observed at doses <30 mg/kg/day. Recent data have highlighted the ability of deferasirox to decrease cardiac iron levels and to prevent the accumulation of iron in the heart. The long-term efficacy and safety of deferasirox for up to 5 years of treatment have now been established. The availability of this effective and generally well tolerated oral therapy represents a significant advance in the management of transfusional iron overload. Keywords: deferasirox, Exjade, oral, iron chelation, iron overload, cardiac iron 

  19. Iron overload in a teenager with xerocytosis: the importance of nuclear magnetic resonance imaging

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    Assis, Reijâne Alves de; Kassab, Carolina; Seguro, Fernanda Salles [Hospital Israelita Albert Einstein, São Paulo, SP (Brazil); Costa, Fernando Ferreira [Universidade Estadual de Campinas, Campinas, SP (Brazil); Silveira, Paulo Augusto Achucarro [Hospital Israelita Albert Einstein, São Paulo, SP (Brazil); Wood, John [University of Southern California, California (United States); Hamerschlak, Nelson [Hospital Israelita Albert Einstein, São Paulo, SP (Brazil)

    2013-07-01

    To report a case of iron overload secondary to xerocytosis, a rare disease in a teenager, diagnosed, by T2* magnetic resonance imaging. We report the case of a symptomatic patient with xerocytosis, a ferritin level of 350ng/mL and a significant cardiac iron overload. She was diagnosed by T2* magnetic resonance imaging and received chelation therapy Ektacytometric analysis confirmed the diagnosis of hereditary xerocytosis. Subsequent T2* magnetic resonance imaging demonstrated complete resolution of the iron overload in various organs, as a new echocardiography revealed a complete resolution of previous cardiac alterations. The patient remains in chelation therapy. Xerocytosis is a rare autosomal dominant genetic disorder characterized by dehydrated stomatocytosis. The patient may present with intense fatigue and iron overload. We suggest the regular use of T2* magnetic resonance imaging for the diagnosis and control of the response to iron chelation in xerocytosis, and we believe it can be used also in other hemolytic anemia requiring transfusions.

  20. Screening for Iron Overload: Lessons from the HEmochromatosis and IRon Overload Screening (HEIRS Study

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    Paul C Adams

    2009-01-01

    Full Text Available BACKGROUND: The HEmochromatosis and IRon Overload Screening (HEIRS Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations.

  1. Myocardial iron overload in thalassaemia major. How early to check?

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    Borgna-Pignatti, Caterina; Meloni, Antonella; Guerrini, Giulia; Gulino, Letizia; Filosa, Aldo; Ruffo, Giovan B; Casini, Tommaso; Chiodi, Elisabetta; Lombardi, Massimo; Pepe, Alessia

    2014-02-01

    The age at which it is necessary to start Cardiovascular Magnetic Resonance (CMR) T2* screening in thalassaemia major (TM) is still uncertain. To clarify this point, we evaluated the prevalence of myocardial iron overload (MIO), function and fibrosis by CMR in TM patients younger than 10 years. We retrospectively selected 35 TM patients enrolled in the Myocardial Iron Overload in Thalassaemia network. MIO was measured by T2* multislice multiecho technique. Biventricular function parameters were evaluated by cine images. To detect myocardial fibrosis, late gadolinium enhancement images were acquired. Patients' age ranged from 4·2 to 9·7 years. All scans were performed without sedation. Nine patients showed no MIO, 22 patients had heterogeneous MIO with a T2* global value ≥20 ms; two patients had heterogeneous MIO with a T2* global value <20 ms and two patients showed homogeneous MIO. No patient showed myocardial fibrosis. Among the patients with heart T2*<20 ms, the youngest was 6 years old, none showed heart dysfunction and the iron transfused was <35 g in all cases. Cardiac iron loading can occur much earlier than previously described. The first cardiac T2* assessment should be performed as early as feasible without sedation, especially if chelation is started late or if poor compliance is suspected.

  2. Iron Overload Assessment in Adult Thalassaemic Patients Using MRI T2

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    Azita Azarkeivan

    2009-01-01

    Full Text Available "nd anemia in our country. Blood transfusion is the continual treatment of this disease. But transfusion causes a serious side effect which is iron overload in vital organs such as the heart, liver and the endocrine system. Accumulated iron in these organs may cause high risk secondary problems which threaten the patients' life. Early assessment of the iron overload in vital organs and applying for early treatment can be beneficial for increasing life quality in these patients. Assessment of cardiac and hepatic iron overload using MRI T2 technique and comparing it with serum ferritin level was the goal of this study. "nMaterials and Methods: The referred thalassaemic patients to Zafar adult thalassaemia clinic were the population of this study. Serum ferritin test was carried out for all these patients. Cardiac and hepatic iron overload assessment of these patients was performed in Noor medical imaging center using MRI T2 technique. The iron overload results of all patients were classified as normal, mild, moderate and severe. We compared them with the patients’ clinical parameters, especially the serum ferritin level. Results were analyzed by SPSS software. "nResults: 700 adult patients with the mean age of 25.76 (SD±10.4 were studied in this research project. There were 360 males (51.4% and 340 (48.6% females enrolled in this study. Among them, there were 502 (71.7% major thalassaemia, 158 (22.6% intermediate thalassaemia, 7 alpha thalassaemia, 9 sickle cell anemia and 10 hemochromatosis patients. The mean of serum ferritin level was 2327.6 mg/dl (SD±2095.8. Classified results of cardiac iron overload assessment were normal in 366 (66.5% patients, mild in 44 (8% patients, moderate in 64 (11.6% patients, and severe in 76 (13.8%patients. The classified results of hepatic iron overload assessment were: normal in 122 (22.2% patients, mild in 137 (25% patients, moderate in 235 (42.8% patients and severe in 55 (10% patients. Iron overload

  3. Iron overload in patients with acute leukemia or MDS undergoing myeloablative stem cell transplantation.

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    Armand, Philippe; Kim, Haesook T; Rhodes, Joanna; Sainvil, Marie-Michele; Cutler, Corey; Ho, Vincent T; Koreth, John; Alyea, Edwin P; Hearsey, Doreen; Neufeld, Ellis J; Fleming, Mark D; Steen, Hanno; Anderson, Damon; Kwong, Raymond Y; Soiffer, Robert J; Antin, Joseph H

    2011-06-01

    Patients with hematologic malignancies undergoing allogeneic stem cell transplantation (HSCT) commonly have an elevated serum ferritin prior to HSCT, which has been associated with increased mortality after transplantation. This has led to the suggestion that iron overload is common and deleterious in this patient population. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. We report a prospective study of 48 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS) undergoing myeloablative HSCT, using magnetic resonance imaging (MRI) to estimate liver iron content (LIC) and cardiac iron. The median (and range) pre-HSCT value of serum ferritin was 1549 ng/mL (20-6989); serum hepcidin, 59 ng/mL (10-468); labile plasma iron, 0 LPI units (0.0-0.9). Eighty-five percent of patients had hepatic iron overload (HIO), and 42% had significant HIO (LIC ≥5.0 mg/gdw). Only 1 patient had cardiac iron overload. There was a strong correlation between pre-HSCT serum ferritin and estimated LIC (r = .75), which was mostly dependent on prior transfusion history. Serum hepcidin was appropriately elevated in patients with HIO. Labile plasma iron elevation was rare. A regression calibration analysis supported the hypothesis that elevated pre-HSCT LIC is significantly associated with inferior post-HSCT survival. These results contribute to our understanding of the prevalence, mechanism, and consequences of iron overload in HSCT.

  4. Dysmetabolic Hyperferritinemia: All Iron Overload Is Not Hemochromatosis

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    Jasbir Makker

    2015-01-01

    Full Text Available Disturbances in iron metabolism can be genetic or acquired and accordingly manifest as primary or secondary iron overload state. Organ damage may result from iron overload and manifest clinically as cirrhosis, diabetes mellitus, arthritis, endocrine abnormalities and cardiomyopathy. Hemochromatosis inherited as an autosomal recessive disorder is the most common genetic iron overload disorder. Expert societies recommend screening of asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation (calculated as serum iron/total iron binding capacity × 100. Further testing for the hemochromatosis gene is recommended if transferrin saturation is >45% with or without hyperferritinemia. However, management of individuals with low or normal transferrin saturation is not clear. In patients with features of iron overload and high serum ferritin levels, low or normal transferrin saturation should alert the physician to other - primary as well as secondary - causes of iron overload besides hemochromatosis. We present here a possible approach to patients with hyperferritinemia but normal transferrin saturation.

  5. Dysmetabolic hyperferritinemia: all iron overload is not hemochromatosis.

    Science.gov (United States)

    Makker, Jasbir; Hanif, Ahmad; Bajantri, Bharat; Chilimuri, Sridhar

    2015-01-01

    Disturbances in iron metabolism can be genetic or acquired and accordingly manifest as primary or secondary iron overload state. Organ damage may result from iron overload and manifest clinically as cirrhosis, diabetes mellitus, arthritis, endocrine abnormalities and cardiomyopathy. Hemochromatosis inherited as an autosomal recessive disorder is the most common genetic iron overload disorder. Expert societies recommend screening of asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation (calculated as serum iron/total iron binding capacity × 100). Further testing for the hemochromatosis gene is recommended if transferrin saturation is >45% with or without hyperferritinemia. However, management of individuals with low or normal transferrin saturation is not clear. In patients with features of iron overload and high serum ferritin levels, low or normal transferrin saturation should alert the physician to other - primary as well as secondary - causes of iron overload besides hemochromatosis. We present here a possible approach to patients with hyperferritinemia but normal transferrin saturation.

  6. Iron overload following bone marrow transplantation in children: MR findings

    Energy Technology Data Exchange (ETDEWEB)

    Kornreich, L.; Horev, G.; Grunebaum, M. [Department of Imaging, Schneider Children`s Medical Center of Israel, Beilinson Medical Campus, 49202 Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University (Israel); Yaniv, I.; Stein, J.; Zaizov, R. [Department of Pediatric Hematology-Oncology, Schneider Children`s Medical Center of Israel, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University (Israel)

    1997-11-01

    Objective. The purpose of this study was to determine the incidence of post-transfusional iron overload in children after bone marrow transplantation by reviewing their magnetic resonance imaging (MR) findings. Materials and methods. We reviewed the abdominal MR studies of 13 children after autologous bone marrow transplantation. Nine of the children had also undergone MR prior to transplantation. Iron deposition in the liver, spleen and bone marrow was graded semi-quantitatively on both T1- and T2-weighted images. Serum ferritin levels and number of blood units given after bone marrow transplantation were recorded. Results. None of the pre-transplantation MR studies revealed iron overload. After bone marrow transplantation, three children showed normal liver and spleen. Iron overload in the liver was noted in ten patients (77 %), six of whom also showed iron overload in the spleen (46 %) and five in the bone marrow (38.5 %). The degree of hepatic iron overload was correlated significantly and splenic iron overload was correlated weakly with the number of blood transfusions (P = 0.01 and P > 0.01, respectively), but neither was correlated with the serum ferritin level. Conclusion. Iron overload commonly accompanies bone marrow transplantation. The observed pattern of iron deposition, in which the spleen was uninvolved in 40 % of patients demonstrating iron overload, is not typical of post-transfusional hemochromatosis. (orig.) With 1 fig., 2 tabs., 15 refs.

  7. Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats.

    Directory of Open Access Journals (Sweden)

    Suwakon Wongjaikam

    Full Text Available Iron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO, deferiprone (DFP and deferasirox (DFX or an antioxidant (N-acetyl cysteine (NAC with a combined DFP and NAC treatments on left ventricular (LV function with iron overload has not been investigated.Male Wistar rats were fed with either a normal diet or a high iron diet (HFe group for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day, DFP (75 mg/kg/day, DFX (20 mg/kg/day, NAC (100 mg/kg/day or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI, malondialdehyde (MDA, cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function.The combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats.

  8. Evaluation of a new tablet formulation of deferasirox to reduce chronic iron overload after long-term blood transfusions

    Directory of Open Access Journals (Sweden)

    Chalmers AW

    2016-02-01

    Full Text Available Anna W Chalmers, Jamile M Shammo Department of Internal Medicine, Division of Hematology/Oncology, Rush University Medical Center, Chicago, IL, USA Abstract: Transfusion-dependent anemia is a common feature in a wide array of hematological disorders, including thalassemia, sickle cell disease, aplastic anemia, myelofibrosis, and myelodysplastic syndromes. In the absence of a physiological mechanism to excrete excess iron, chronic transfusions ultimately cause iron overload. Without correction, iron overload can lead to end-organ damage, resulting in cardiac, hepatic, and endocrine dysfunction/failure. Iron chelating agents are utilized to reduce iron overload, as they form a complex with iron, leading to its clearance. Iron chelation has been proven to decrease organ dysfunction and improve survival in certain transfusion-dependent anemias, such as β-thalassemia. Several chelating agents have been approved by the United States Food and Drug Administration for the treatment of iron overload, including deferoxamine, deferiprone, and deferasirox. A variety of factors have to be considered when choosing an iron chelator, including dosing schedule, route of administration, tolerability, and side effect profile. Deferasirox is an orally administered iron chelator with proven efficacy and safety in multiple hematological disorders. There are two formulations of deferasirox, a tablet for suspension, and a new tablet form. This paper is intended to provide an overview of iron overload, with a focus on deferasirox, and its recently approved formulation Jadenu® for the reduction of transfusional iron overload in hematological disorders. Keywords: iron chelation therapy, transfusional iron overload, deferasirox

  9. Iron deficiency and overload in relation to nutrition

    NARCIS (Netherlands)

    Spanjersberg MQI; Jansen EHJM; LEO

    2000-01-01

    Nutritional iron intake in the Netherlands has been reviewed with respect to both iron deficiency and iron overload. In general, iron intake and iron status in the Netherlands are adequate and therefore no change in nutrition policy is required. The following aspects and developments, however, need

  10. Deferasirox, an oral chelator in the treatment of iron overload

    OpenAIRE

    I. Portioli

    2013-01-01

    BACKGROUND Deferasirox is a once-daily oral iron chelator developed for treating iron overload complicating long-term transfusion therapy in patients with diseases such as beta-thalassemia and myelodysplastic syndromes. Iron overload can damage the liver, pancreas and the heart. Deferoxamine, the only other drug approved for iron chelation, can prevent these effects but requires parenteral administration. Deferasirox has been approved after a one-year, open-label trial in patients ≥ 2 years o...

  11. Update on the use of deferasirox in the management of iron overload

    Science.gov (United States)

    Taher, Ali; Cappellini, Maria Domenica

    2009-01-01

    Regular blood transfusions as supportive care for patients with chronic anemia inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload cause significant morbidity and mortality if not effectively treated with chelation therapy. Based on a comprehensive clinical development program, the once-daily, oral iron chelator deferasirox (Exjade®) is approved for the treatment of transfusional iron overload in adult and pediatric patients with various transfusion-dependent anemias, including β-thalassemia and the myelodysplastic syndromes. Deferasirox dose should be titrated for each individual patient based on transfusional iron intake, current iron burden and whether the goal is to decrease or maintain body iron levels. Doses of >30 mg/kg/day have been shown to be effective with a safety profile consistent with that observed at doses <30 mg/kg/day. Recent data have highlighted the ability of deferasirox to decrease cardiac iron levels and to prevent the accumulation of iron in the heart. The long-term efficacy and safety of deferasirox for up to 5 years of treatment have now been established. The availability of this effective and generally well tolerated oral therapy represents a significant advance in the management of transfusional iron overload. PMID:19898650

  12. HFE gene in primary and secondary hepatic iron overload

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani; Ann P Walker

    2007-01-01

    Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and nonalcoholic fatty liver diseases and porphyria cutanea tarda.We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.

  13. Pathogenic Mechanisms Underlying Iron Deficiency and Iron Overload: New Insights for Clinical Application

    OpenAIRE

    Kotze, MJ; van Velden, DP; van Rensburg, SJ; Erasmus, R

    2009-01-01

    Iron uptake, utilisation, release and storage occur at the gene level. Individuals with variant forms of genes involved in iron metabolism may have different requirements for iron and are likely to respond differently to the same amount of iron in the diet, a concept termed nutrigenetics. Iron deficiency, iron overload and the anemia of inflammation are the commonest iron-related disorders. While at least four types of hereditary iron overload have been identified to date, our knowledge of th...

  14. Iron in Skin of Mice with Three Etiologies of Systemic Iron Overload

    OpenAIRE

    2005-01-01

    In human hemochromatosis, tissue toxicity is a function of tissue iron levels. Despite reports of skin toxicity in hemochromatosis, little is known about iron levels in skin of individuals with systemic iron overload. We measured skin iron and studied skin histology in three mouse models of systemic iron overload: mice with a deletion of the hemochromatosis (Hfe) gene, mice fed a high iron diet, and mice given parenteral injections of iron. In Hfe−/− mice, iron content in the epidermis and de...

  15. Thrombopoietin Protects Cardiomyocytes from Iron-Overload Induced Oxidative Stress and Mitochondrial Injury

    Directory of Open Access Journals (Sweden)

    Shing Chan

    2015-07-01

    Full Text Available Background/Aims: Thalassaemia accompanied with iron-overload is common in Hong Kong. Iron-overload induced cardiomyopathy is the commonest cause of morbidity and mortality in patients with β-thalassaemia. Chronic iron-overload due to blood transfusion can cause cardiac failure. Decreased antioxidant defence and increased ROS production may lead to oxidative stress and cell injury. Iron-overload may lead to heart tissue damage through lipid peroxidation in response to oxidative stress, and a great diversity of toxic aldehydes are formed when lipid hydroperoxides break down in heart and plasma. Methods: Iron entry into embryonic heart H9C2 cells was determined by calcein assay using a fluorometer. Reactive oxygen species (ROS production in cells treated with FeCl3 or thrombopoietin (TPO was monitored by using the fluorescent probe H2DCFDA. Changes in mitochondrial membrane potential of H9C2 cells were quantified by using flow cytometry. Results: We demonstrated that iron induced oxidative stress and apoptosis in cardiomyocytes, and that iron increased ROS production and reduced cell viability in a dose-dependent manner. Iron treatment increased the proportion of cells with JC-1 monomers, indicating a trend of drop in the mitochondrial membrane potential. TPO exerted a cardio-protective effect on iron-induced apoptosis. Conclusions: These findings suggest that iron-overload leads to the generation of ROS and further induces apoptosis in cardiomyocytes via mitochondrial pathways. TPO might exert a protective effect on iron-overload induced apoptosis via inhibiting oxidative stress and suppressing the mitochondrial pathways in cardiomyocytes.

  16. Influence of genetic polymorphisms and mutations in the cardiac pathology of iron overload in thalassemia and sickle cell anemia patients: a retrospective study

    Directory of Open Access Journals (Sweden)

    Veronica Agrigento

    2012-11-01

    Full Text Available Cardiac disease in thalassemia is determined by the accumulation of iron in the tissue. Genetic factors could influence the severity and the rapidity of the modifications of the cardiac tissue. Mutations or polymorphisms of genes have already been described as being implicated in cardiac disease. In particular, we studied the polymorphisms C1091T in the Connexin 37 gene (CX 37, 4G -668 5G in the Plasminogen Activator Inhibitor-1 gene (PAI 1 and 5A-1171 6A in the Stromelysin-1 gene (SL in 193 randomly selected patients affected by hemoglobinopathies and 100 normal subjects randomly selected from the general population. A retrospective analysis based on history, clinical data and imaging studies was carried out to assess the presence and type of heart disease. The results of our study do not demonstrate a close association between polymorphism in these candidate genes and cardiac disease, and in particular with myocardial infarction in a cohort of Sicilian patients affected by hemoglobinopathies. 地中海贫血心脏病的关键诱因是组织中的铁沉积。遗传因子可能影响心脏组织修复的严重程度和速度。基因突变或基因多态性与心脏病有关。尤其是,我们研究了193名随机选择的血红蛋白病患者以及从普通人群中随机选择的100名正常受试者的连接蛋白37基因(CX37)的C1091T、纤溶酶原激活物抑制剂-1基因(PAI1)的4G -668 5G 和基质分解素-1基因(SL)的5A-1171 6A等多态性。根据病史、临床资料和影像研究进行回顾性分析,以评估心脏病的存在情况和类型。我们的研究结果并没有表明这些候选基因的多态性和心脏疾病之间存在密切联系,尤其是与一组西西里岛血红蛋白病患者的心肌梗塞存在密切联系。

  17. Iron overload and apoptosis of HL-1 cardiomyocytes: effects of calcium channel blockade.

    Directory of Open Access Journals (Sweden)

    Mei-pian Chen

    Full Text Available Iron overload cardiomyopathy that prevails in some forms of hemosiderosis is caused by excessive deposition of iron into the heart tissue and ensuing damage caused by a raise in labile cell iron. The underlying mechanisms of iron uptake into cardiomyocytes in iron overload condition are still under investigation. Both L-type calcium channels (LTCC and T-type calcium channels (TTCC have been proposed to be the main portals of non-transferrinic iron into heart cells, but controversies remain. Here, we investigated the roles of LTCC and TTCC as mediators of cardiac iron overload and cellular damage by using specific Calcium channel blockers as potential suppressors of labile Fe(II and Fe(III ingress in cultured cardiomyocytes and ensuing apoptosis.Fe(II and Fe(III uptake was assessed by exposing HL-1 cardiomyocytes to iron sources and quantitative real-time fluorescence imaging of cytosolic labile iron with the fluorescent iron sensor calcein while iron-induced apoptosis was quantitatively measured by flow cytometry analysis with Annexin V. The role of calcium channels as routes of iron uptake was assessed by cell pretreatment with specific blockers of LTCC and TTCC.Iron entered HL-1 cardiomyocytes in a time- and dose-dependent manner and induced cardiac apoptosis via mitochondria-mediated caspase-3 dependent pathways. Blockade of LTCC but not of TTCC demonstrably inhibited the uptake of ferric but not of ferrous iron. However, neither channel blocker conferred cardiomyocytes with protection from iron-induced apoptosis.Our study implicates LTCC as major mediators of Fe(III uptake into cardiomyocytes exposed to ferric salts but not necessarily as contributors to ensuing apoptosis. Thus, to the extent that apoptosis can be considered a biological indicator of damage, the etiopathology of cardiosiderotic damage that accompanies some forms of hemosiderosis would seem to be unrelated to LTCC or TTCC, but rather to other routes of iron ingress present in

  18. Hepcidin and Hfe in iron overload in beta-thalassemia.

    Science.gov (United States)

    Gardenghi, Sara; Ramos, Pedro; Follenzi, Antonia; Rao, Niva; Rachmilewitz, Eliezer A; Giardina, Patricia J; Grady, Robert W; Rivella, Stefano

    2010-08-01

    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. 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 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.

  19. Hepcidin and Hfe in iron overload in β-thalassemia

    Science.gov (United States)

    Gardenghi, Sara; Ramos, Pedro; Follenzi, Antonia; Rao, Niva; Rachmilewitz, Eliezer A.; Giardina, Patricia J.; Grady, Robert W.; Rivella, Stefano

    2013-01-01

    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. PMID:20712796

  20. Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia.

    Science.gov (United States)

    Anderson, Erik R; Taylor, Matthew; Xue, Xiang; Ramakrishnan, Sadeesh K; Martin, Angelical; Xie, Liwei; Bredell, Bryce X; Gardenghi, Sara; Rivella, Stefano; Shah, Yatrik M

    2013-12-10

    Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including β-thalassemia major, which is characterized by a defective β-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In β-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in β-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2α (HIF2α) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of β-thalassemia and are essential for excess iron accumulation in mouse models of β-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2α. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2α/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2α signaling is critical for progressive iron overload in β-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.

  1. Cytoskeletal mechanics in pressure-overload cardiac hypertrophy

    Science.gov (United States)

    Tagawa, H.; Wang, N.; Narishige, T.; Ingber, D. E.; Zile, M. R.; Cooper, G. 4th

    1997-01-01

    We have shown that the cellular contractile dysfunction characteristic of pressure-overload cardiac hypertrophy results not from an abnormality intrinsic to the myofilament portion of the cardiocyte cytoskeleton but rather from an increased density of the microtubule component of the extramyofilament portion of the cardiocyte cytoskeleton. To determine how, in physical terms, this increased microtubule density mechanically overloads the contractile apparatus at the cellular level, we measured cytoskeletal stiffness and apparent viscosity in isolated cardiocytes via magnetic twisting cytometry, a technique by which magnetically induced force is applied directly to the cytoskeleton through integrin-coupled ferromagnetic beads coated with Arg-Gly-Asp (RGD) peptide. Measurements were made in two groups of cardiocytes from cats with right ventricular (RV) hypertrophy induced by pulmonary artery banding: (1) those from the pressure-overloaded RV and (2) those from the normally loaded same-animal control left ventricle (LV). Cytoskeletal stiffness increased almost twofold, from 8.53 +/- 0.77 dyne/cm2 in the normally loaded LV cardiocytes to 16.46 +/- 1.32 dyne/cm2 in the hypertrophied RV cardiocytes. Cytoskeletal apparent viscosity increased almost fourfold, from 20.97 +/- 1.92 poise in the normally loaded LV cardiocytes to 87.85 +/- 6.95 poise in the hypertrophied RV cardiocytes. In addition to these baseline data showing differing stiffness and, especially, apparent viscosity in the two groups of cardiocytes, microtubule depolymerization by colchicine was found to return both the stiffness and the apparent viscosity of the pressure overload-hypertrophied RV cells fully to normal. Conversely, microtubule hyperpolymerization by taxol increased the stiffness and apparent viscosity values of normally loaded LV cardiocytes to the abnormal values given above for pressure-hypertrophied RV cardiocytes. Thus, increased microtubule density constitutes primarily a viscous load on

  2. Effect of iron overload on exercise capacity in thalassemic patients with heart failure.

    Science.gov (United States)

    Mavrogeni, Sophie; Gotsis, Efstathios; Verganelakis, Dimitrios; Berdousis, Eleni; Dritsas, Athanasios; Kolovou, Genovefa; Toulas, Panagiotis; Ladis, Vassilios

    2009-12-01

    In b-thalassemia, myocardial iron overload contributes to heart failure, despite chelation treatment. We hypothesized that myocardial T2*, an index of iron overload, influences patients' physical activity. We assessed a thalassemic population by both cardiovascular magnetic resonance imaging (CMR) and ergospirometry test. Sixty-six thalassemic patients aged 27 (19-40) years, 30 without (NHF) and 36 with heart failure (HF), were studied. Cardiac T2* and left ventricular ejection fraction (LVEF) were evaluated using a 1.5 T system. VO(2max), AT, Mets and duration of exercise by ergospirometry were also assessed. Myocardial T2* was lower in HF compared to NHF patients (14.7 +/- 6.6 vs. 39 +/- 2 ms, P iron overloaded (HF-H) and the rest of them (n = 23) as (HF-L). Although LVEDV, LVESV, LVEF were similar in the two subgroups, the exercise parameters were significantly lower in the HF-H group (P Heart T2* correlated with all exercise parameters (P iron overload, expressed as T2*, has a direct influence on exercise capacity, independent of LV ejection fraction and functional class.

  3. Does rapidly progressive iron overload in a young girl with sideroblastic anemia also signify the presence of hereditary hemochromatosis?

    Science.gov (United States)

    Scimeca, P G; Weinblatt, M E; Kahn, E; Kochen, J A

    1994-01-01

    A severely anemic 3-year-old girl with refractory sideroblastic anemia and fulminant, fatal hemochromatosis is described. The patient had transfusion-dependent anemia with clinical cardiac, liver, and endocrine dysfunction that resulted from iron loading. The patient was minimally transfused, and deferoxamine chelation was started at age 34 months. Despite treatment, the patient died at age 46 months as a result of severe iron overload. Sideroblastic anemia and iron overload in childhood are reviewed, and a pathophysiologic mechanism for the patient's clinical course is postulated.

  4. Genetics Home Reference: African iron overload

    Science.gov (United States)

    ... instructions for making a protein called ferroportin. This protein is involved in the process of iron absorption in the body. Iron from the diet is absorbed through the walls of the small intestine. Ferroportin then transports iron from the small intestine ...

  5. Study on abnormal iron metabolism and iron overload in patients with aplastic anemia

    Institute of Scientific and Technical Information of China (English)

    金朋

    2013-01-01

    Objective To investigate the abnormalities of iron metabolism,the prevalence and risk factors of iron overload and clinical characteristics of patients with aplastic anemia (AA) .Methods A cross-sectional study was conducted on 520 newly diagnosed AA patients.Results Iron overload was observed in 66 (13%) of 520 AA patients,in which a higher prevalence of iron overload was seen not only in patients with infections (19/86,22%) than those without infections (47/434,11%,P<0.01) ,but also in patients with hepatitis associated AA

  6. Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats.

    Science.gov (United States)

    Du, Fang; Qian, Zhong-Ming; Luo, Qianqian; Yung, Wing-Ho; Ke, Ya

    2015-08-01

    Iron accumulates progressively in the brain with age, and iron-induced oxidative stress has been considered as one of the initial causes for Alzheimer's disease (AD) and Parkinson's disease (PD). Based on the role of hepcidin in peripheral organs and its expression in the brain, we hypothesized that this peptide has a role to reduce iron in the brain and hence has the potential to prevent or delay brain iron accumulation in iron-associated neurodegenerative disorders. Here, we investigated the effects of hepcidin expression adenovirus (ad-hepcidin) and hepcidin peptide on brain iron contents, iron transport across the brain-blood barrier, iron uptake and release, and also the expression of transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin 1 (Fpn1) in cultured microvascular endothelial cells and neurons. We demonstrated that hepcidin significantly reduced brain iron in iron-overloaded rats and suppressed transport of transferrin-bound iron (Tf-Fe) from the periphery into the brain. Also, the peptide significantly inhibited expression of TfR1, DMT1, and Fpn1 as well as reduced Tf-Fe and non-transferrin-bound iron uptake and iron release in cultured microvascular endothelial cells and neurons, while downregulation of hepcidin with hepcidin siRNA retrovirus generated opposite results. We concluded that, under iron-overload, hepcidin functions to reduce iron in the brain by downregulating iron transport proteins. Upregulation of brain hepcidin by ad-hepcidin emerges as a new pharmacological treatment and prevention for iron-associated neurodegenerative disorders.

  7. Fetal liver iron overload: the role of MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Cassart, Marie; Avni, Freddy Efraim [Erasme Hospital, Medical imaging, Brussels, Brabant (Belgium); Guibaud, Laurent [Hopital femme mere enfant, Imagerie Pediatrique et Foetale, Lyon-Bron (France); Molho, Marc [C.H.I Poissy/St Germain-en-Laye, Imagerie Medicale, Poissy (France); D' Haene, Nicky [Erasme Hospital, Anatomopathology Department, Brussels (Belgium); Paupe, Alain [C.H.I Poissy/St Germain-en-Laye, Pediatrie, Poissy (France)

    2011-02-15

    To assess the potential role of MR imaging in the diagnosis of fetal liver iron overload. We reviewed seven cases of abnormal liver signal in fetuses referred to MR imaging in a context of suspected congenital infection (n = 2), digestive tract anomalies (n = 3) and hydrops fetalis (n = 2). The average GA of the fetuses was 31 weeks. The antenatal diagnoses were compared with histological data (n = 6) and postnatal work-up (n = 1). Magnetic resonance imaging demonstrated unexpected abnormal fetal liver signal suggestive of iron overload in all cases. The iron overload was confirmed on postnatal biopsy (n = 2) and fetopathology (n = 4). The final diagnosis was hepatic hemosiderosis (haemolytic anaemia (n = 2) and syndromal anomalies (n = 2)) and congenital haemochromatosis (n = 3). In all cases, the liver appeared normal on US. Magnetic resonance is the only imaging technique able to demonstrate liver iron overload in utero. Yet, the study outlines the fundamental role of MR imaging in cases of congenital haemochromatosis. The antenatal diagnosis of such a condition may prompt ante - (in the case of recurrence) or neonatal treatment, which might improve the prognosis. (orig.)

  8. Epidemiology and diagnostic testing for hemochromatosis and iron overload.

    Science.gov (United States)

    Adams, P C

    2015-05-01

    Hemochromatosis is the most common genetic disease in northern European populations. Body iron stores progressively increase in most patients, which can lead to cirrhosis of the liver, hepatocellular carcinoma, heart failure, arthritis, and pigmentation. Simple blood tests such as the serum ferritin and transferrin saturation are useful to suggest the diagnosis which can be confirmed in most cases with a simple genetic test for the C282Y mutation of the HFE gene. However, these blood tests are often misinterpreted and there are rare patients with iron overload without HFE mutations. A diagnostic approach is presented based on a large referral practice and a population-based study (HEIRS) which screened for iron overload in 101,168 participants.

  9. Biological tissue magnetism in the frame of iron overload diseases

    Energy Technology Data Exchange (ETDEWEB)

    Lazaro, Francisco J. [Departamento de Ciencia y Tecnologia de Materiales y Fluidos, Universidad de Zaragoza, Zaragoza 50018 (Spain) and Instituto de Nanociencia de Aragon, Universidad de Zaragoza, Zaragoza 50009 (Spain)]. E-mail: osoro@unizar.es; Gutierrez, Lucia [Departamento de Ciencia y Tecnologia de Materiales y Fluidos, Universidad de Zaragoza, Zaragoza 50018 (Spain); Abadia, Ana R. [Departamento de Farmacologia y Fisiologia, Universidad de Zaragoza, Zaragoza 50013 (Spain); Romero, Maria S. [Departamento de Medicina y Psiquiatria, Universidad de Zaragoza, Zaragoza 50009 (Spain); Lopez, A. [CNAM-Salesianos Zaragoza, Zaragoza 50009 (Spain)

    2007-09-15

    The conspicuous magnetic properties of iron, paradoxically, rarely participate in the methods routinely employed in the clinical environment to detect iron containing species in tissues. In the organism iron is just a trace metal and it mostly occurs as part of haemoproteins or ferritin, which show paramagnetic, diamagnetic or antiferromagnetic behaviour, hence resulting in a very low contribution to the tissue susceptibility. Detailed magnetic measurements make it nowadays possible to identify such species in tissues that correspond to individuals with iron overload pathologies. Since, as alternatives to the conventional biopsy, magnetism-based noninvasive techniques to diagnose and manage such diseases are recently under development, the deep knowledge of the magnetic properties of the different forms of iron in tissues is of high applied interest.

  10. Pathogenic Mechanisms Underlying Iron Deficiency and Iron Overload: New Insights for Clinical Application.

    Science.gov (United States)

    Kotze, M J; van Velden, D P; van Rensburg, S J; Erasmus, R

    2009-08-01

    Iron uptake, utilisation, release and storage occur at the gene level. Individuals with variant forms of genes involved in iron metabolism may have different requirements for iron and are likely to respond differently to the same amount of iron in the diet, a concept termed nutrigenetics. Iron deficiency, iron overload and the anemia of inflammation are the commonest iron-related disorders. While at least four types of hereditary iron overload have been identified to date, our knowledge of the genetic basis and consequences of inherited iron deficiency remain limited. The importance of genetic risk factors in relation to iron overload was highlighted with the identification of the HFE gene in 1996. Deleterious mutations in this gene account for 80-90% of inherited iron overload and are associated with loss of iron homeostasis, alterations in inflammatory responses, oxidative stress and in its most severe form, the disorder hereditary haemochromatosis (HH). Elucidation of the genetic basis of HH has led to rapid clinical benefit through drastic reduction in liver biopsies performed as part of the diagnostic work-up of affected patients. Today, detection of a genetic predisposition in the presence of high serum ferritin and transferrin saturation levels is usually sufficient to diagnose HH, thereby addressing the potential danger of inherited iron overload which starts with the same symptoms as iron deficiency, namely chronic fatigue. This review provides the scientific back-up for application of pathology supported genetic testing, a new test concept that is well placed for optimizing clinical benefit to patients with regard to iron status.

  11. Ciprofloxacin: a novel therapeutic agent for iron overload?

    Directory of Open Access Journals (Sweden)

    Mitra Elmi

    2009-09-01

    Full Text Available Objective: Major thalassemia is one of the hematological diseases requiring multiple blood transfusions, which results in iron overload in the liver, heart and other organs. Current iron chelation therapy consists of intravenous (IV deferoxamine and oral deferasirox and deferiprone. Although these chelators are effective, many side effects are reported. In the present study, the iron-chelating effect of ciprofloxacin with good oral absorption was investigated. Material and Methods: Thirty male albino Wistar rats were used for the study. Ciprofloxacin (7 or 14 mg/kg per day was administered simultaneously with iron (0.03 g/kg per day or after one-month administration of iron. Ciprofloxacin effect on iron absorption in the liver and heart was studied carefully using atomic absorption. Results: A significant decrease in the liver and heart iron following the ciprofloxacin (14 mg/kg per day administration was observed, when compared with the control group. This ciprofloxacin-induced tissue iron depletion was more pronounced when it was administered simultaneously with iron, when it was administered for a longer duration (2 months rather than 1 month and when it was given in higher doses (14 mg/kg per day. Conclusion: Administration of ciprofloxacin may help to decrease the burden of parenteral administration, thereby improving compliance and also the life expectancy of thalassemic patients.

  12. Iron overload in the liver diagnostic and quantification

    Energy Technology Data Exchange (ETDEWEB)

    Alustiza, Jose M. [Osatek SA, P Dr. Beguiristain 109, 20014, San Sebastian, Guipuzcoa (Spain)]. E-mail: jmalustiza@osatek.es; Castiella, Agustin [Osatek SA, P Dr. Beguiristain 109, 20014, San Sebastian, Guipuzcoa (Spain); Juan, Maria D. de [Osatek SA, P Dr. Beguiristain 109, 20014, San Sebastian, Guipuzcoa (Spain); Emparanza, Jose I. [Osatek SA, P Dr. Beguiristain 109, 20014, San Sebastian, Guipuzcoa (Spain); Artetxe, Jose [Osatek SA, P Dr. Beguiristain 109, 20014, San Sebastian, Guipuzcoa (Spain); Uranga, Maite [Osatek SA, P Dr. Beguiristain 109, 20014, San Sebastian, Guipuzcoa (Spain)

    2007-03-15

    Hereditary Hemochromatosis is the most frequent modality of iron overload. Since 1996 genetic tests have facilitated significantly the non-invasive diagnosis of the disease. There are however many cases of negative genetic tests that require confirmation by hepatic iron quantification which is traditionally performed by hepatic biopsy. There are many studies that have demonstrated the possibility of performing hepatic iron quantification with Magnetic Resonance. However, a consensus has not been reached yet regarding the technique or the possibility to reproduce the same method of calculus in different machines. This article reviews the state of the art of the question and delineates possible future lines to standardise this non-invasive method of hepatic iron quantification.

  13. Continuing treatment with Salvia miltiorrhiza injection attenuates myocardial fibrosis in chronic iron-overloaded mice.

    Directory of Open Access Journals (Sweden)

    Ying Zhang

    Full Text Available Iron overload cardiomyopathy results from iron accumulation in the myocardium that is closely linked to iron-mediated myocardial fibrosis. Salvia miltiorrhiza (SM, also known as Danshen, a traditional Chinese medicinal herb, has been widely used for hundreds of years to treat cardiovascular diseases. Here, we investigated the effect and potential mechanism of SM on myocardial fibrosis induced by chronic iron overload (CIO in mice. Kunming male mice (8 weeks old were randomized to six groups of 10 animals each: control (CONT, CIO, low-dose SM (L-SM, high-dose SM (H-SM, verapamil (VRP and deferoxamine (DFO groups. Normal saline was injected in the CONT group. Mice in the other five groups were treated with iron dextran at 50 mg/kg per day intraperitoneally for 7 weeks, and those in the latter four groups also received corresponding daily treatments, including 3 g/kg or 6 g/kg of SM, 100 mg/kg of VRP, or 100 mg/kg of DFO. The iron deposition was estimated histologically using Prussian blue staining. Myocardial fibrosis was determined by Masson's trichrome staining and hydroxyproline (Hyp quantitative assay. Superoxide dismutase (SOD activity, malondialdehyde (MDA content and protein expression levels of type I collagen (COL I, type I collagen (COL III, transforming growth factor-β1 (TGF-β1 and matrix metalloproteinase-9 (MMP-9 were analyzed to investigate the mechanisms underlying the effects of SM against iron-overloaded fibrosis. Treatment of chronic iron-overloaded mice with SM dose-dependently reduced iron deposition levels, fibrotic area percentage, Hyp content, expression levels of COL I and COL III, as well as upregulated the expression of TGF- β1 and MMP-9 proteins in the heart. Moreover, SM treatment decreased MDA content and increased SOD activity. In conclusion, SM exerted activities against cardiac fibrosis induced by CIO, which may be attributed to its inhibition of iron deposition, as well as collagen metabolism and oxidative

  14. A Review on Iron Chelators in Treatment of Iron Overload Syndromes

    Science.gov (United States)

    Mobarra, Naser; Shanaki, Mehrnoosh; Ehteram, Hassan; Nasiri, Hajar; Sahmani, Mehdi; Saeidi, Mohsen; Goudarzi, Mehdi; Pourkarim, Hoda; Azad, Mehdi

    2016-01-01

    Iron chelation therapy is used to reduce iron overload development due to its deposition in various organs such as liver and heart after regular transfusion. In this review, different iron chelators implicated in treatment of iron overload in various clinical conditions have been evaluated using more up-to-date studies focusing on these therapeutic agents. Deferoxamine, Deferiprone and Deferasirox are the most important specific US FDA-approved iron chelators. Each of these chelators has their own advantages and disadvantages, various target diseases, levels of deposited iron and clinical symptoms of the afflicted patients which may affect their selection as the best modality. Taken together, in many clinical disorders, choosing a standard chelator does not have an accurate index which requires further clarifications. The aim of this review is to introduce and compare the different iron chelators regarding their advantages and disadvantages, usage dose and specific applications. PMID:27928480

  15. Phytochelators Intended for Clinical Use in Iron Overload, Other Diseases of Iron Imbalance and Free Radical Pathology

    Directory of Open Access Journals (Sweden)

    Christina N. Kontoghiorghe

    2015-11-01

    Full Text Available Iron chelating drugs are primarily and widely used in the treatment of transfusional iron overload in thalassaemia and similar conditions. Recent in vivo and clinical studies have also shown that chelators, and in particular deferiprone, can be used effectively in many conditions involving free radical damage and pathology including neurodegenerative, renal, hepatic, cardiac conditions and cancer. Many classes of phytochelators (Greek: phyto (φυτό—plant, chele (χηλή—claw of the crab with differing chelating properties, including plant polyphenols resembling chelating drugs, can be developed for clinical use. The phytochelators mimosine and tropolone have been identified to be orally active and effective in animal models for the treatment of iron overload and maltol for the treatment of iron deficiency anaemia. Many critical parameters are required for the development of phytochelators for clinical use including the characterization of the therapeutic targets, ADMET, identification of the therapeutic index and risk/benefit assessment by comparison to existing therapies. Phytochelators can be developed and used as main, alternative or adjuvant therapies including combination therapies with synthetic chelators for synergistic and or complimentary therapeutic effects. The development of phytochelators is a challenging area for the introduction of new pharmaceuticals which can be used in many diseases and also in ageing. The commercial and other considerations for such development have great advantages in comparison to synthetic drugs and could also benefit millions of patients in developing countries.

  16. Extramedullary hematopoiesis is associated with lower cardiac iron loading in chronically transfused thalassemia patients.

    Science.gov (United States)

    Ricchi, Paolo; Meloni, Antonella; Spasiano, Anna; Neri, Maria Giovanna; Gamberini, Maria Rita; Cuccia, Liana; Caruso, Vincenzo; Gerardi, Calogera; D'Ascola, Domenico Giuseppe; Rosso, Rosamaria; Campisi, Saveria; Rizzo, Michele; Terrazzino, Fabrizia; Vangosa, Alessandra Briatico; Chiodi, Elisabetta; Missere, Massimiliano; Mangione, Maurizio; Positano, Vincenzo; Pepe, Alessia

    2015-11-01

    The aim of this study was to evaluate, in a large cohort of chronically transfused patients, whether the presence of extramedullary hematopoiesis (EMH) accounts for the typical patterns of cardiac iron distribution and/or cardiac function parameters. We retrospectively selected 1,266 thalassemia major patients who had undergone regular transfusions (611 men and 655 women; mean age: 31.3 ± 8.9 years, range: 4.2-66.6 years) and were consecutively enrolled within the Myocardial Iron Overload in Thalassemia network. The presence of EMH was evaluated based on steady-state free precession sequences; cardiac and liver iron overloads were quantified using a multiecho T2* approach; cardiac function parameters and pulmonary diameter were quantified using the steady-state free precession sequences; and myocardial fibrosis was evaluated using the late gadolinium enhancement technique. EMH was detected in 167 (13.2%) patients. The EMH+ patients had significantly lower cardiac iron overload than that of the EMH- patients (P = 0.003). The patterns of cardiac iron distribution were significantly different in the EMH+ and EMH- patients (P < 0.0001), with a higher prevalence of patients with no myocardial iron overload and heterogeneous myocardial iron overload and no significant global heart iron in the EMH+ group EMH+ patients had a significantly higher left ventricle mass index (P = 0.001) and a significantly higher pulmonary artery diameter (P = 0.002). In conclusion, in regularly transfused thalassemia patients, EMH was common and was associated with a thalassemia intermedia-like pattern of cardiac iron deposition despite regular transfusion therapy.

  17. Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation

    Institute of Scientific and Technical Information of China (English)

    Yong-nan FU; Han XIAO; Xiao-wei MA; Sheng-yang JIANG; Ming XU; You-yi ZHANG

    2011-01-01

    Aim: To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect.Methods: Wild type and AMPKα2 knockout (AMPKα2-/-) littermates were subjected to left ventricular pressure overload caused by evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting.Results: Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKx2-/- mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKα2-/-mice.Conclusion: Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy.

  18. Revaluation of clinical and histological criteria for diagnosis of dysrnetabolic iron overload syndrome

    Institute of Scientific and Technical Information of China (English)

    Alessia Riva; Giorgio Bovo; Alberto Piperno; Paola Trombini; Raffaella Mariani; Alessandra Salvioni; Sabina Coletti; Silvia Bonfadini; Valentina Paolini; Matteo Pozzi; Rita Facchetti

    2008-01-01

    AIM: To re-evaluate the diagnostic criteria of insulin resistance hepatic iron overload based on clinical,biochemical and histopathological findings.METHODS: We studied 81 patients with hepatic iron overload not explained by known genetic and acquired causes.The metabolic syndrome (MS) was defined according to ATPⅢ criteria.Iron overload was assessed by liver biopsy.Liver histology was evaluated by Ishak's score and iron accumulation by Deugnier's score; steatosis was diagnosed when present in ≥ 5% of hepatocytes.RESULTS: According to transferrin saturation levels,we observed significant differences in the amount of hepatic iron overload and iron distribution,as well as the number of metabolic abnormalities.Using Receiving Operating Curve analysis,we found that the presence of two components of the MS differentiated two groups with a statistically significant different hepatic iron overload (P < 0.0001).Patients with ≥ 2 metabolic alterations and steatosis had lower amount of hepatic iron,lower transferrin saturation and higher sinusoidal iron than patients with < 2 MS components and absence of steatosis.CONCLUSION: In our patients,the presence of ≥2 alterations of the MS and hepatic steatosis was associated with a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation,suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation.These patients may have the typical dysmetabolic iron overload syndrome.By contrast,patients with transferrin saturation ≥ 60% had more severe iron overload,few or no metabolic abnormalities and a hemochromatosis-like pattern of iron overload.

  19. Iron overload in polytransfused patients without heart failure is associated with subclinical alterations of systolic left ventricular function using cardiovascular magnetic resonance tagging

    Directory of Open Access Journals (Sweden)

    Vanoverschelde Jean-Louis

    2011-04-01

    Full Text Available Abstract Background It remains incompletely understood whether patients with transfusion related cardiac iron overload without signs of heart failure exhibit already subclinical alterations of systolic left ventricular (LV dysfunction. Therefore we performed a comprehensive evaluation of systolic and diastolic cardiac function in such patients using tagged and phase-contrast CMR. Methods 19 patients requiring regular blood transfusions for chronic anemia and 8 healthy volunteers were investigated using cine, tagged, and phase-contrast and T2* CMR. LV ejection fraction, peak filling rate, end-systolic global midventricular systolic Eulerian radial thickening and shortening strains as well as left ventricular rotation and twist, mitral E and A wave velocity, and tissue e' wave and E/e' wave velocity ratio, as well as isovolumic relaxation time and E wave deceleration time were computed and compared to cardiac T2*. Results Patients without significant iron overload (T2* > 20 ms, n = 9 had similar parameters of systolic and diastolic function as normal controls, whereas patients with severe iron overload (T2* 20 ms or normal controls. Patients with moderate iron overload (T2* 10-20 ms, n = 5, had preserved ejection fraction (59 ± 6%, p = NS vs. pts. with T2* > 20 ms and controls, but showed reduced maximal LV rotational twist (1.8 ± 0.4 degrees. The magnitude of reduction of LV twist (r = 0.64, p Conclusion Multiple transfused patients with normal ejection fraction and without heart failure have subclinical alterations of systolic and diastolic LV function in direct relation to the severity of cardiac iron overload. Among all parameters, left ventricular twist is affected earliest, and has the highest correlation to log (T2*, suggesting that this parameter might be used to follow systolic left ventricular function in patients with iron overload.

  20. Treating thalassemia major-related iron overload: the role of deferiprone

    Directory of Open Access Journals (Sweden)

    Berdoukas V

    2012-10-01

    Full Text Available Vasilios Berdoukas,1 Kallistheni Farmaki,2 Susan Carson,1 John Wood,3 Thomas Coates11Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA, USA; 2Thalassemia Unit, General Hospital of Corinth, Corinth, Greece; 3Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, USAAbstract: Over the last 20 years, management for thalassemia major has improved to the point where we predict that patients' life expectancy will approach that of the normal population. These outcomes result from safer blood transfusions, the availability of three iron chelators, new imaging techniques that allow specific organ assessment of the degree of iron overload, and improvement in the treatment of hepatitis. In October 2011, the Food and Drug Administration licensed deferiprone, further increasing the available choices for iron chelation in the US. The ability to prescribe any of the three chelators as well as their combinations has led to more effective reduction of total body iron. The ability to determine the amount of iron in the liver and heart by magnetic resonance imaging allows the prescription of the most appropriate chelation regime for patients and to reconsider what our aims with respect to total body iron should be. Recent evidence from Europe has shown that by normalizing iron stores not only are new morbidities prevented but also reversal of many complications such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance, and type 2 diabetes can occur, improving survival and patients' quality of life. The most effective way to achieve normal iron stores seems to be with the combination of deferoxamine and deferiprone. Furthermore, outcomes should continue to improve in the future. Starting relative intensive chelation in younger children may prevent short stature and abnormal pubertal maturation as well as other iron-related morbidities. Also, further information should become available on the

  1. Mycobacterium avium Complex Infection in a Patient with Sickle Cell Disease and Severe Iron Overload

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    Kamal Shemisa

    2014-01-01

    Full Text Available A 34-year-old female with sickle cell anemia (hemoglobin SS disease and severe iron overload presented to our institution with the subacute presentation of recurrent pain crisis, fever of unknown origin, pancytopenia, and weight loss. A CT scan demonstrated both lung and liver nodules concerning for granulomatous disease. Subsequent biopsies of the liver and bone marrow confirmed the presence of noncaseating granulomas and blood cultures isolated Mycobacterium avium complex MAC. Disseminated MAC is considered an opportunistic infection typically diagnosed in the immunocompromised and rarely in immunocompetent patients. An appreciable number of mycobacterial infection cases have been reported in sickle cell disease patients without immune dysfunction. It has been reported that iron overload is known to increase the risk for mycobacterial infection in vitro and in vivo studies. While iron overload is primarily known to cause end organ dysfunction, the clinical relationship with sickle cell disease and disseminated MAC infection has not been reported. Clinical iron overload is a common condition diagnosed in the sub-Saharan African population. High dietary iron, genetic defects in iron trafficking, as well as hemoglobinopathy are believed to be the etiologies for iron overload in this region. Patients with iron overload in this region were 17-fold more likely to die from Mycobacterium tuberculosis. Both experimental and clinical evidence suggest a possible link to iron overload and mycobacterial infections; however larger observational studies are necessary to determine true causality.

  2. Postnatal iron overload destroys NA-DA functional interactions.

    Science.gov (United States)

    Fredriksson, A; Archer, T

    2007-02-01

    C57/BL6 mice were administered either postnatal iron (Fe(2+) 7.5 mg/kg, on postnatal days 10-12) or vehicle, followed by administration of either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, iron/vehicle treated, DSP4/vehicle treated mice were injected with either a low dose of MPTP (2 x 20 mg/kg, with a 24-hr interval between injections) or vehicle. Behaviour testing took place a further three weeks (spontaneous behaviour and L-Dopa induced) and two weeks (clonidine-L-Dopa induced) later. Postnatal iron administration exacerbated the bradykinesia induced by MPTP and virtually abolished all spontaneous motor activity in NA-denervated mice that were MPTP-treated. Postnatal iron administration reduced markedly the restoration of motor activity by suprathreshold L-Dopa (20 mg/kg) following a 60-min habituation to the test chambers. Pretreatment with DSP4 effectively eliminated the restorative effect of L-Dopa in the MPTP mice. The synergistic effects of co-administration of clinidine (1 mg/kg) with a subthreshold dose of L-Dopa (5 mg/kg) in elevating the motor activity of MPTP mice were reduced markedly by postnatal iron administration, as well as by pretreatment with DSP4. NA-denervation by DSP4, after postnatal iron treatment, totally abolished the activity-elevating effects of the alpha-adrenoceptor agonist + DA-precursor combination in MPTP mice, and virtually eliminated these effects in saline (non-MPTP) mice. Postnatal iron administration caused enduring higher levels of total iron content in all the groups with an increased level in mice treated with DSP4 followed by MPTP. These divergent findings confirm the direct influence of NA innervation upon dopaminergic functional expression and indicate a permanent vulnerability both in the noradrenergic and dopaminergic pathways following the postnatal infliction of an iron overload.

  3. Treating thalassemia major-related iron overload: the role of deferiprone.

    Science.gov (United States)

    Berdoukas, Vasilios; Farmaki, Kallistheni; Carson, Susan; Wood, John; Coates, Thomas

    2012-01-01

    Over the last 20 years, management for thalassemia major has improved to the point where we predict that patients' life expectancy will approach that of the normal population. These outcomes result from safer blood transfusions, the availability of three iron chelators, new imaging techniques that allow specific organ assessment of the degree of iron overload, and improvement in the treatment of hepatitis. In October 2011, the Food and Drug Administration licensed deferiprone, further increasing the available choices for iron chelation in the US. The ability to prescribe any of the three chelators as well as their combinations has led to more effective reduction of total body iron. The ability to determine the amount of iron in the liver and heart by magnetic resonance imaging allows the prescription of the most appropriate chelation regime for patients and to reconsider what our aims with respect to total body iron should be. Recent evidence from Europe has shown that by normalizing iron stores not only are new morbidities prevented but also reversal of many complications such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance, and type 2 diabetes can occur, improving survival and patients' quality of life. The most effective way to achieve normal iron stores seems to be with the combination of deferoxamine and deferiprone. Furthermore, outcomes should continue to improve in the future. Starting relative intensive chelation in younger children may prevent short stature and abnormal pubertal maturation as well as other iron-related morbidities. Also, further information should become available on the use of other combinations in chelation treatment, some of which have been used only in a very limited fashion to date. All these advances in management require absolute cooperation and understanding of parents, children, and, subsequently, the patients themselves. Only with such cooperation can normal long-term survival be achieved, as

  4. Right ventricular volumes and function in thalassemia major patients in the absence of myocardial iron overload

    Directory of Open Access Journals (Sweden)

    Porter John B

    2010-04-01

    Full Text Available Abstract Aim We aimed to define reference ranges for right ventricular (RV volumes, ejection fraction (EF in thalassemia major patients (TM without myocardial iron overload. Methods and results RV volumes, EF and mass were measured in 80 TM patients who had no myocardial iron overload (myocardial T2* > 20 ms by cardiovascular magnetic resonance. All patients were receiving deferoxamine chelation and none had evidence of pulmonary hypertension or other cardiovascular comorbidity. Forty age and sex matched healthy non-anemic volunteers acted as controls. The mean RV EF was higher in TM patients than controls (males 66.2 ± 4.1% vs 61.6 ± 6%, p = 0.0009; females 66.3 ± 5.1% vs 62.6 ± 6.4%, p = 0.017, which yielded a raised lower threshold of normality for RV EF in TM patients (males 58.0% vs 50.0% and females 56.4% vs 50.1%. RV end-diastolic volume index was higher in male TM patients (mean 98.1 ± 17.3 mL vs 88.4 ± 11.2 mL/m2, p = 0.027, with a higher upper limit (132 vs 110 mL/m2 but this difference was of borderline significance for females (mean 86.5 ± 13.6 mL vs 80.3 ± 12.8 mL/m2, p = 0.09, with upper limit of 113 vs 105 mL/m2. The cardiac index was raised in TM patients (males 4.8 ± 1.0 L/min vs 3.4 ± 0.7 L/min, p Conclusion The normal ranges for functional RV parameters in TM patients with no evidence of myocardial iron overload differ from healthy non-anemic controls. The new reference RV ranges are important for determining the functional effects of myocardial iron overload in TM patients.

  5. Iron overload in very low birth weight infants: Serum Ferritin and adverse outcomes

    LENUS (Irish Health Repository)

    Barrett, M

    2011-11-01

    Adequate iron isessential for growth and haematpoiesis. Oral iron supplementation is the standard of care in VLBW infants. Post mortem evidence has confirmed significant iron overload. Excessive free iron has been associated with free radical formation and brain injury in term infants.

  6. Mutation analysis of the transferrin receptor-2 gene in patients with iron overload.

    Science.gov (United States)

    Lee, P L; Halloran, C; West, C; Beutler, E

    2001-01-01

    Three mutations in the transferrin receptor-2 gene have recently been identified in four Sicilian families with iron overload who had a normal hemochromatosis gene, HFE (C. Camaschella, personal communication). To determine the extent to which mutations in the transferrin receptor-2 gene occur in other populations with iron overload, we have completely sequenced this gene in 17 whites, 10 Asians, and 8 African Americans with iron overload and a C282C/C282C HFE genotype, as well as 4 subjects without iron overload and homozygous for the mutant HFE C282Y genotype, 5 patients with iron overload and homozygous for the mutant HFE C282Y genotype, and 5 normal individuals. None of the individuals exhibited the Sicilian mutations, Y250X in exon 6, M172K in exon 4, and E60X in exon 2. One iron-overloaded individual of Asian descent exhibited a I238M mutation which was subsequently found to be a polymorphism present in the Asian population at a frequency of 0.0192. The presence of the I238M mutation was not associated with an increase in ferritin or transferrin saturation levels. Three silent polymorphisms were also identified, nt 1770 (D590D) and nt 1851 (A617A) and a polymorphism at nt 2255 in the 3' UTR. Thus, mutations in the transferrin receptor-2 gene were not responsible for the iron overload seen in our subjects.

  7. Uncoupling and oxidative stress in liver mitochondria isolated from rats with acute iron overload

    Energy Technology Data Exchange (ETDEWEB)

    Pardo Andreu, G.L. [Centro de Quimica Farmaceutica, Departamento de Investigaciones Biomedicas, Ciudad de La Habana (Cuba); Inada, N.M.; Vercesi, A.E. [Universidade Estadual de Campinas, Departamento de Patologia Clinica, Faculdade de Ciencias Medicas, Campinas, SP (Brazil); Curti, C. [Universidade de Sao Paulo, Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, SP (Brazil)

    2009-01-15

    One hypothesis for the etiology of cell damage arising from iron overload is that its excess selectively affects mitochondria. Here we tested the effects of acute iron overload on liver mitochondria isolated from rats subjected to a single dose of i.p. 500 mg/kg iron-dextran. The treatment increased the levels of iron in mitochondria (from 21{+-}4 to 130{+-}7 nmol/mg protein) and caused both lipid peroxidation and glutathione oxidation. The mitochondria of iron-treated rats showed lower respiratory control ratio in association with higher resting respiration. The mitochondrial uncoupling elicited by iron-treatment did not affect the phosphorylation efficiency or the ATP levels, suggesting that uncoupling is a mitochondrial protective mechanism against acute iron overload. Therefore, the reactive oxygen species (ROS)/H{sup +} leak couple, functioning as a mitochondrial redox homeostatic mechanism could play a protective role in the acutely iron-loaded mitochondria. (orig.)

  8. Danshen (Salvia miltiorrhiza injection suppresses kidney injury induced by iron overload in mice.

    Directory of Open Access Journals (Sweden)

    Shengjiang Guan

    Full Text Available OBJECTIVES: Excessive iron can accumulate in the kidney and induce tissue damage. Danshen (Salvia miltiorrhiza injection is a traditional Chinese medicinal preparation used for preventing and treating chronic renal failure. The aim of the present study was to evaluate the effects of treatment with Danshen injection on iron overload-induced kidney damage. METHODS: Mice were mock-treated with saline (control group or given a single dose of iron dextran without treatment (iron overload group, 50 mg/kg/day for 2 weeks or with daily treatments of low-dose Danshen (3 g/kg/day, high-dose Danshen (6 g/kg/day or deferoxamine (100 mg/kg/day. RESULTS: Treatment of iron-overloaded mice with Danshen injection led to significant improvements of body weight and decreased iron levels in the kidney. Danshen injection treatment also reduced concentrations of blood urea nitrogen, creatinine and malondialdehyde and enhanced glutathione peroxidase and superoxide dismutase activities. Histopathological examinations showed that Danshen injection ameliorated pathological changes and reduced iron deposition in kidneys of iron overloaded mice. Furthermore, the treatment was demonstrated to suppress apoptosis in nephrocytes. CONCLUSIONS: These results indicated that Danshen injection exerted significant renal protective effects in iron-overloaded mice, which were closely associated with the decrease of iron deposition and suppression of lipid peroxidation and apoptosis in the kidney.

  9. A free software for the calculation of T2* values for iron overload assessment.

    Science.gov (United States)

    Fernandes, Juliano Lara; Fioravante, Luciana Andrea Barozi; Verissimo, Monica P; Loggetto, Sandra R

    2016-01-01

    Background Iron overload assessment with magnetic resonance imaging (MRI) using T2* has become a key diagnostic method in the management of many diseases. Quantitative analysis of the MRI images with a cost-effective tool has been a limitation to increased use of the method. Purpose To provide a free software solution for this purpose comparing the results with a commercial solution. Material and Methods The free tool was developed as a standalone program to be directly downloaded and ran in a common personal computer platform without the need of a dedicated workstation. Liver and cardiac T2* values were calculated using both tools and the values obtained compared between them in a group of 56 patients with suspected iron overload using Bland-Altman plots and concordance correlation coefficients (CCC). Results In the heart, the mean T2* differences between the two methods was 0.46 ms (95% confidence interval [CI], -0.037 -0.965) and in the liver 0.49 ms (95% CI, 0.257-0.722). The CCC for both the heart and the liver were significantly high (0.98 [95% CI, 0.966-0.988] with a Pearson ρ of 0.9811 and 0.991 [95% CI, 0.986-0.994] with a Pearson ρ of 0.996, respectively. No significant differences were observed when analyzing only patients with abnormal concentrations of iron in both organs compared to the whole cohort. Conclusion The proposed free software tool is accurate for calculation of T2* values of the liver and heart and might be a solution for centers that cannot use paid commercial solutions.

  10. Liver cirrhosis as a consequence of iron overload caused by hereditary nonspherocytic hemolytic anemia

    Institute of Scientific and Technical Information of China (English)

    Philip Hilgard; Guido Gerken

    2005-01-01

    Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chronic liver d isease and severeiron overload due to chronic hereditary hemolysis. Both patients have had signs of liver cirrhosis and severe hemolysis since childhood. A hereditary pyruvate kinase deficiency (PKD) was discovered as the underlying reason for the hemolysis.Sequencing of the pyruvate kinase gene showed a mutation within exon 11. Liver histology in both patients revealed cirrhosis and a severe iron overload but primary hemochromatosis was excluded by HFE-gene analysis.An iron reduction therapy with desferrioxamine led to significant decrease of serum ferritin and sustained clinical improvement. PKD-induced hemolysis may cause severe iron overload even in the absence of HFE-genotype abnormalities. This secondary iron overload can lead to chronic liver disease and cirrhosis. Therefore, the iron metabolism of PKD patients has to be closely monitored and iron overload should be consequently treated.

  11. Whey protein inhibits iron overload-induced oxidative stress in rats.

    Science.gov (United States)

    Kim, Jungmi; Paik, Hyun-Dong; Yoon, Yoh-Chang; Park, Eunju

    2013-01-01

    In this study, we evaluated the effects of whey protein on oxidative stress in rats that were subjected to oxidative stress induced by iron overload. Thirty male rats were assigned to 3 groups: the control group (regular [50 mg/kg diet] dose of iron+20% casein), iron overload group (high [2,000 mg/kg] dose of iron+20% casein, IO), and whey protein group (high dose of iron+10% casein+10% whey protein, IO+whey). After 6 wk, the IO group showed a reduction in the plasma total radical trapping antioxidant parameter and the activity of erythrocyte superoxide dismutase and an increase in lipid peroxidation (determined from the proportion of conjugated dienes). However, whey protein ameliorated the oxidative changes induced by iron overload. The concentration of erythrocyte glutathione was significantly higher in the IO+whey group than in the IO group. In addition, whey protein supplementation fully inhibited iron overload-induced DNA damage in leukocytes and colonocytes. A highly significant positive correlation was observed between plasma iron levels and DNA damage in leukocytes and colonocytes. These results show the antioxidative and antigenotoxic effects of whey protein in an in vivo model of iron overload-induced oxidative stress.

  12. Randomised controlled trials of iron chelators for the treatment of cardiac siderosis in thalassaemia major

    Directory of Open Access Journals (Sweden)

    Arun John Baksi

    2014-09-01

    Full Text Available In conditions requiring repeated blood transfusion or where iron metabolism is abnormal, heart failure may result from accumulation of iron in the heart (cardiac siderosis. Death due to heart failure from cardiac iron overload has accounted for considerable early mortality in β-thalassemia major. The ability to detect iron loading in the heart by cardiovascular magnetic resonance using T2* sequences has created an opportunity to intervene in the natural history of such conditions. However, effective and well tolerated therapy is required to remove iron from the heart. There are currently 3 approved commercially available iron chelators: deferoxamine, deferiprone and deferasirox. We review the high quality randomised controlled trials in this area for iron chelation therapy in the management of cardiac siderosis.

  13. -Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload

    Directory of Open Access Journals (Sweden)

    Luca Melchiori

    2010-01-01

    Full Text Available -thalassemia encompasses a group of monogenic diseases that have in common defective synthesis of -globin. The defects involved are extremely heterogeneous and give rise to a large phenotypic spectrum, with patients that are almost asymptomatic to cases in which regular blood transfusions are required to sustain life. As a result of the inefficient synthesis of -globin, the patients suffer from chronic anemia due to a process called ineffective erythropoiesis (IE. The sequelae of IE lead to extramedullary hematopoiesis (EMH with massive splenomegaly and dramatic iron overload, which in turn is responsible for many of the secondary pathologies observed in thalassemic patients. The processes are intimately linked such that an ideal therapeutic approach should address all of the complications. Although -thalassemia is one of the first monogenic diseases to be described and represents a global health problem, only recently has the scientific community started to focus on the real molecular mechanisms that underlie this disease, opening new and exciting therapeutic perspectives for thalassemic patients worldwide.

  14. Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Ellervik, C; Tybjaerg-Hansen, A; Appleyard, M

    2010-01-01

    We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH).......We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH)....

  15. Clinical outcomes of transfusion-associated iron overload in patients with refractory chronic anemia

    Directory of Open Access Journals (Sweden)

    Gao C

    2014-04-01

    Full Text Available Chong Gao, Li Li, Baoan Chen, Huihui Song, Jian Cheng, Xiaoping Zhang, Yunyu SunDepartment of Hematology and Oncology, Key Department of Jiangsu Medicine, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of ChinaBackground: The purpose of this study was to evaluate the clinical outcomes of transfusion-associated iron overload in patients with chronic refractory anemia.Methods: Clinical manifestations, main organ function, results of computed tomography (CT, endocrine evaluation, and serum ferritin levels were analyzed retrospectively in 13 patients who were transfusion-dependent for more than 1 year (receiving >50 units of red blood cells to determine the degree of iron overload and efficacy of iron-chelating therapy.Results: Serum ferritin levels increased to 1,830–5,740 ng/mL in all patients. Ten patients had abnormal liver function. The CT Hounsfield units in the liver increased significantly in eleven patients, and were proportional to their serum ferritin levels. Skin pigmentation, liver dysfunction, and endocrine dysfunction were observed in nine patients with serum ferritin >3,500 ng/mL, eight of whom have since died. Interestingly, serum ferritin levels did not decrease significantly in nine transfusion-dependent patients who had received 15–60 days of iron-chelating therapy.Conclusion: Transfusion-dependent patients may progress to secondary iron overload with organ impairment, which may be fatal in those who are heavily iron-overloaded. The CT Hounsfield unit is a sensitive indicator of iron overload in the liver. Iron chelation therapy should be initiated when serum ferritin is >1,000 ng/mL and continued until it is <1,000 ng/mL in transfusional iron-overloaded patients.Keywords: anemia, aplastic, iron overload, myelodysplastic syndromes

  16. Management of transfusional iron overload – differential properties and efficacy of iron chelating agents

    Directory of Open Access Journals (Sweden)

    Kwiatkowski JL

    2011-09-01

    Full Text Available Janet L Kwiatkowski The Children's Hospital of Philadelphia, Division of Hematology and University of Pennsylvania School of Medicine, Philadelphia, PA, USA Abstract: Regular red cell transfusion therapy ameliorates disease-related morbidity and can be lifesaving in patients with various hematological disorders. Transfusion therapy, however, causes progressive iron loading, which, if untreated, results in endocrinopathies, cardiac arrhythmias and congestive heart failure, hepatic fibrosis, and premature death. Iron chelation therapy is used to prevent iron loading, remove excess accumulated iron, detoxify iron, and reverse some of the iron-related complications. Three chelators have undergone extensive testing to date: deferoxamine, deferasirox, and deferiprone (although the latter drug is not currently licensed for use in North America where it is available only through compassionate use programs and research protocols. These chelators differ in their modes of administration, pharmacokinetics, efficacy with regard to organ-specific iron removal, and adverse-effect profiles. These differential properties influence acceptability, tolerability and adherence to therapy, and, ultimately, the effectiveness of treatment. Chelation therapy, therefore, must be individualized, taking into account patient preferences, toxicities, ongoing transfusional iron intake, and the degree of cardiac and hepatic iron loading. Keywords: transfusion, iron, chelation, magnetic resonance imaging

  17. Assessment of Iron Overload in Homozygous and Heterozygous Beta Thalassemic Children below 5 Years of Age

    Directory of Open Access Journals (Sweden)

    Dhiraj J. Trivedi

    2014-07-01

    Full Text Available Background: Thalassemia is a genetic disease having 3-7% carrier rate in Indians. It is transfusion dependent anemia having high risk of iron overloading. A clinical symptom of iron overload becomes detectable in second decade causing progressive liver, heart and endocrine glands damage. There is a need to assess iron overload in thalassemics below 5 years of age to protect them from complications at later age of life. Aims and objectives: Present study was undertaken to estimate serum iron status and evaluate serum transferrin saturation in both homozygous & heterozygous form of thalassemia as an index of iron overload among children of one to five years of age. Materials and Methods: Clinically diagnosed thirty cases of β thalassemia major & thirty cases of β thalassemia minor having severe anemia, hepatospleenomegaly and between 1 year to 5 years of age were included in study group and same age matched healthy controls were included in the study. RBC indices and HbA, HbA2 and HbF were estimated along with serum iron & serum Total Iron Binding Capacity (TIBC and serum transferrin levels. Results: Significant difference was observed in hemoglobin levels between control and both beta thalassemia groups. Mean Corpuscular Volume (MCV and Mean Corpuscular Hemoglobin (MCH values were reduced. Hemoglobin electrophoresis showed the elevated levels of HbF and HbA2 in both beta thalassemia groups. Among serum iron parameters, serum iron, TIBC and transferrin saturation were elevated whereas serum transferrin levels were low in thalassemia major in children below 5 years of age. Conclusion: Although clinical symptoms of iron overload have been absent in thalassemic children below five years of age, biochemical iron overloading has started at much lower age which is of great concern.

  18. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

    Energy Technology Data Exchange (ETDEWEB)

    Guenancia, Charles [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cardiology Department, University Hospital, Dijon (France); Li, Na [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Hachet, Olivier [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cardiology Department, University Hospital, Dijon (France); Rigal, Eve [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cottin, Yves [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cardiology Department, University Hospital, Dijon (France); Dutartre, Patrick; Rochette, Luc [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Vergely, Catherine, E-mail: cvergely@u-bourgogne.fr [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France)

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15 mg/kg) for 3 weeks (D0–D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6 mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000 μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+ 22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. - Highlights: • The effects of iron on cardiomyocytes were opposite to those on cancer cell lines. • In our model, iron overload did not potentiate anthracycline cardiotoxicity. • Chronic oxidative stress induced by iron could mitigate doxorubicin cardiotoxicity. • The role of iron in

  19. Tomoregulin-1 prevents cardiac hypertrophy after pressure overload in mice by inhibiting TAK1-JNK pathways

    Directory of Open Access Journals (Sweden)

    Dan Bao

    2015-08-01

    Full Text Available Cardiac hypertrophy is associated with many forms of heart disease, and identifying important modifier genes involved in the pathogenesis of cardiac hypertrophy could lead to the development of new therapeutic strategies. Tomoregulin-1 is a growth factor that is primarily involved in embryonic development and adult central nervous system (CNS function, and it is expressed abnormally in a variety of CNS pathologies. Tomoregulin-1 is also expressed in the myocardium. However, the effects of tomoregulin-1 on the heart, particularly on cardiac hypertrophy, remains unknown. The aim of the study is to examine whether and by what mechanism tomoregulin-1 regulates the development of cardiac hypertrophy induced by pressure overload. In this study, we found that tomoregulin-1 was significantly upregulated in two cardiac hypertrophy models: cTnTR92Q transgenic mice and thoracic aorta constriction (TAC-induced cardiac hypertrophy mice. The transgenic overexpression of tomoregulin-1 increased the survival rate, improved the cardiac geometry and functional parameters of echocardiography, and decreased the degree of cardiac hypertrophy of the TAC mice, whereas knockdown of tomoregulin-1 expression resulted in an opposite phenotype and exacerbated phenotypes of cardiac hypertrophy induced by TAC. A possible mechanism by which tomoregulin-1 regulates the development of cardiac hypertrophy in TAC-induced cardiac hypertrophy is through inhibiting TGFβ non-canonical (TAK1-JNK pathways in the myocardium. Tomoregulin-1 plays a protective role in the modulation of adverse cardiac remodeling from pressure overload in mice. Tomoregulin-1 could be a therapeutic target to control the development of cardiac hypertrophy.

  20. Transformation rate between ferritin and hemosiderin assayed by serum ferritin kinetics in patients with normal iron stores and iron overload.

    Science.gov (United States)

    Saito, Hiroshi; Hayashi, Hisao

    2015-11-01

    Ferritin iron, hemosiderin iron, total iron stores and transformation rate were determined by serum ferritin kinetics. The transformation rate between ferritin and hemosiderin is motivated by the potential difference between them. The transformer determines transformation rate according to the potential difference in iron mobilization and deposition. The correlations between transformation rate and iron stores were studied in 11 patients with chronic hepatitis C (CHC), 1 patent with treated iron deficiency anemia (TIDA), 9 patients with hereditary hemochromatosis (HH) and 4 patients with transfusion-dependent anemia (TD). The power regression curve of approximation showed an inverse correlation between transformation rate and ferritin iron, hemosiderin iron in part and total iron stores in HH. Such an inverse correlation between transformation rate and iron stores implies that the larger the amount of iron stores, the smaller the transformation of iron stores. On the other hand, a minimal inverse correlation between transformation rate and ferritin iron and no correlation between transformation rate and hemosiderin iron or total iron stores in CHC indicate the derangement of storage iron metabolism in the cells with CHC. Radio-iron fixation on the iron storing tissue in iron overload was larger than that in normal subjects by ferrokinetics. This is consistent with the inverse correlation between transformation rate and total iron stores in HH. The characteristics of iron turnover between ferritin and hemosiderin were disclosed from the correlation between transformation rate and ferritin iron, hemosiderin iron or total iron stores.

  1. Effect of mild iron overload on liver and kidney lipid peroxidation.

    Science.gov (United States)

    Galleano, M; Puntarulo, S

    1994-10-01

    1. Hepatotoxicity is the most common finding in patients with iron overload since the liver is the major recipient of iron excess, even though the kidney could be a target of iron toxicity. The effect of iron overload was studied in the early stages after iron-dextran injection in rats, as a model for secondary hemocromatosis. 2. Total hepatic and kidney iron content was markedly elevated over control values 20 h after the iron administration. Plasma GOT, GPT and LDH activities were not affected, suggesting that liver cell permeability was not affected by necrosis. 3. Spontaneous liver chemiluminescence was measured as an indicator of oxidative stress and lipid peroxidation. Light emission was increased four-fold 6 h after iron supplementation. 4. Increases in the generation of thiobarbituric acid reactive substances (TBARS in liver and kidney homogenates were detected after iron administration. 5. The activities of catalase, SOD and glutathione peroxidase were determined. Enzymatic activities declined in liver homogenates by 25, 36 and 32%, respectively, 20 h after iron injection. These activities were not affected in kidney as compared to control values, except for SOD activity that was decreased by 26%. 6. The content of alpha-tocopherol was decreased by 31% in whole kidney homogenates and by 40% in plasma. 7. Our data indicate that lipid peroxidation occurs after mild iron overload both in liver and kidney. Enzymatic antioxidants are consumed significantly in liver and alpha-tocopherol content decreases in kidney, suggesting an organ-specific antioxidant effect.

  2. Extracellular high-mobility group box 1 mediates pressure overload-induced cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Zhang, Lei; Liu, Ming; Jiang, Hong; Yu, Ying; Yu, Peng; Tong, Rui; Wu, Jian; Zhang, Shuning; Yao, Kang; Zou, Yunzeng; Ge, Junbo

    2016-03-01

    Inflammation plays a key role in pressure overload-induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High-mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload-induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild-type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin-embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up-regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

  3. Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

    Directory of Open Access Journals (Sweden)

    Qing Tian

    2016-11-01

    Full Text Available Background Iron overload is recognized as a new pathogenfor osteoporosis. Various studies demonstrated that iron overload could induce apoptosis in osteoblasts and osteoporosis in vivo. However, the exact molecular mechanisms involved in the iron overload-mediated induction of apoptosis in osteoblasts has not been explored. Purpose In this study, we attempted to determine whether the mitochondrial apoptotic pathway is involved in iron-induced osteoblastic cell death and to investigate the beneficial effect of N-acetyl-cysteine (NAC in iron-induced cytotoxicity. Methods The MC3T3-E1 osteoblastic cell line was treated with various concentrations of ferric ion in the absence or presence of NAC, and intracellular iron, cell viability, reactive oxygen species, functionand morphology changes of mitochondria and mitochondrial apoptosis related key indicators were detected by commercial kits. In addition, to further explain potential mechanisms underlying iron overload-related osteoporosis, we also assessed cell viability, apoptosis, and osteogenic differentiation potential in bone marrow-derived mesenchymal stemcells(MSCs by commercial kits. Results Ferric ion demonstrated concentration-dependent cytotoxic effects on osteoblasts. After incubation with iron, an elevation of intracelluar labile iron levels and a concomitant over-generation of reactive oxygen species (ROS were detected by flow cytometry in osteoblasts. Nox4 (NADPH oxidase 4, an important ROS producer, was also evaluated by western blot. Apoptosis, which was evaluated by Annexin V/propidium iodide staining, Hoechst 33258 staining, and the activation of caspase-3, was detected after exposure to iron. Iron contributed to the permeabilizatio of mitochondria, leading to the release of cytochrome C (cyto C, which, in turn, induced mitochondrial apoptosis in osteoblasts via activation of Caspase-3, up-regulation of Bax, and down-regulation of Bcl-2. NAC could reverse iron-mediated mitochondrial

  4. Modulation of Pseudomonas aeruginosa lipopolysaccharide-induced lung inflammation by chronic iron overload in rat.

    Science.gov (United States)

    Lê, Bá Vuong; Khorsi-Cauet, Hafida; Bach, Véronique; Gay-Quéheillard, Jérôme

    2012-03-01

    Iron constitutes a critical nutrient source for bacterial growth, so iron overload is a risk factor for bacterial infections. This study aimed at investigating the role of iron overload in modulating bacterial endotoxin-induced lung inflammation. Weaning male Wistar rats were intraperitoneally injected with saline or iron sucrose [15 mg kg(-1) body weight (bw), 3 times per week, 4 weeks]. They were then intratracheally injected with Pseudomonas aeruginosa lipopolysaccharide (LPS) (5 μg kg(-1) bw) or saline. Inflammatory indices were evaluated 4 or 18 h post-LPS/saline injection. At 4 h, LPS-treated groups revealed significant increases in the majority of inflammatory parameters (LPS-binding protein (LBP), immune cell recruitment, inflammatory cytokine synthesis, myeloperoxidase activity, and alteration of alveolar-capillary permeability), as compared with control groups. At 18 h, these parameters reduced strongly with the exception for LBP content and interleukin (IL)-10. In parallel, iron acted as a modulator of immune cell recruitment; LBP, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant 3, and IL-10 synthesis; and alveolar-capillary permeability. Therefore, P. aeruginosa LPS may only act as an acute lung inflammatory molecule, and iron overload may modulate lung inflammation by enhancing different inflammatory parameters. Thus, therapy for iron overload may be a novel and efficacious approach for the prevention and treatment of bacterial lung inflammations.

  5. Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans.

    Science.gov (United States)

    Wang, Haizhen; Jiang, Xue; Wu, Jieyu; Zhang, Linqiang; Huang, Jingfei; Zhang, Yuru; Zou, Xiaoju; Liang, Bin

    2016-05-01

    The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases.

  6. Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS Study initial screening

    OpenAIRE

    Barton, James C.; Acton, Ronald T; Leiendecker-Foster, Catherine; Lovato, Laura; Adams, Paul C; Eckfeldt, John H.; Mclaren, Christine E.; Reiss, Jacob A.; McLaren, Gordon D; Reboussin, David M.; Gordeuk, Victor R.; Speechley, Mark R; Press, Richard D.; Dawkins, Fitzroy W.

    2008-01-01

    There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25–29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1,...

  7. Iron overload complicating sideroblastic anemia--is the gene for hemochromatosis responsible?

    Science.gov (United States)

    Barron, R; Grace, N D; Sherwood, G; Powell, L W

    1989-04-01

    Idiopathic hemochromatosis is a hereditary disease that is associated with human leucocytic antigens A3, B7, and B14. A genetic association between human leucocytic antigen-linked hemochromatosis and idiopathic refractory sideroblastic anemia has been suggested that may predispose some patients with idiopathic refractory sideroblastic anemia to develop gross iron overload. Study of the family of a patient with idiopathic refractory sideroblastic anemia and hemochromatosis revealed that 2 of 5 first-degree relatives had significant elevations of serum ferritin, and a shared human leucocytic antigen haplotype, supporting the concept that patients with idiopathic refractory sideroblastic anemia and significant iron overload have at least one allele for hemochromatosis.

  8. Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review.

    LENUS (Irish Health Repository)

    Dwyer, Jeremy P

    2011-11-01

    Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.

  9. Rat liver antioxidant response to iron and copper overloads.

    Science.gov (United States)

    Musacco-Sebio, Rosario; Saporito-Magriñá, Christian; Semprine, Jimena; Torti, Horacio; Ferrarotti, Nidia; Castro-Parodi, Mauricio; Damiano, Alicia; Boveris, Alberto; Repetto, Marisa G

    2014-08-01

    The rat liver antioxidant response to Fe and Cu overloads (0-60mg/kg) was studied. Dose- and time-responses were determined and summarized by t1/2 and C50, the time and the liver metal content for half maximal oxidative responses. Liver GSH (reduced glutathione) and GSSG (glutathione disulfide) were determined. The GSH content and the GSH/GSSG ratio markedly decreased after Fe (58-66%) and Cu (79-81%) loads, with t1/2 of 4.0 and 2.0h. The C50 were in a similar range for all the indicators (110-124μgFe/g and 40-50μgCu/g) and suggest a unique free-radical mediated process. Hydrophilic antioxidants markedly decreased after Fe and Cu (60-75%; t1/2: 4.5 and 4.0h). Lipophilic antioxidants were also decreased (30-92%; t1/2: 7.0 and 5.5h) after Fe and Cu. Superoxide dismutase (SOD) activities (Cu,Zn-SOD and Mn-SOD) and protein expression were adaptively increased after metal overloads (Cu,Zn-SOD: t1/2: 8-8.5h and Mn-SOD: t1/2: 8.5-8.0h). Catalase activity was increased after Fe (65%; t1/2: 8.5h) and decreased after Cu (26%; t1/2: 8.0h), whereas catalase expression was increased after Fe and decreased after Cu overloads. Glutathione peroxidase activity decreased after metal loads by 22-39% with a t1/2 of 4.5h and with unchanged protein expression. GSH is the main and fastest responder antioxidant in Fe and Cu overloads. The results indicate that thiol (SH) content and antioxidant enzyme activities are central to the antioxidant defense in the oxidative stress and damage after Fe and Cu overloads.

  10. Iron overload and cofactors with special reference to alcohol, hepatitis C virus infection and steatosis/insulin resistance

    Institute of Scientific and Technical Information of China (English)

    Yutaka Kohgo; Katsuya Ikuta; Takaaki Ohtake; Yoshihiro Torimoto; Junji Kato

    2007-01-01

    There are several cofactors which affect body iron metabolism and accelerate iron overload. Alcohol and hepatic viral infections are the most typical examples for clarifying the role of cofactors in iron overload. In these conditions, iron is deposited in hepatocytes and Kupffer cells and reactive oxygen species (ROS) produced through Fenton reaction have key role to facilitate cellular uptake of transferrin-bound iron. Furthermore,hepcidin, antimicrobial peptide produced mainly in the liver is also responsible for intestinal iron absorption and reticuloendothelial iron release. In patients with ceruloplasmin deficiency, anemia and secondary iron overload in liver and neurodegeneration are reported.Furthermore, there is accumulating evidence that fatty acid accumulation without alcohol and obesity itself modifies iron overload states. Ineffective erythropoiesis is also an important factor to accelerate iron overload,which is associated with diseases such as thalassemia and myelodysplastic syndrome. When this condition persists, the dietary iron absorption is increased due to the increment of bone marrow erythropoiesis and tissue iron overload will thereafter occurs. In porphyria cutanea tarda, iron is secondarily accumulated in the liver.

  11. Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders.

    Science.gov (United States)

    de Swart, Louise; Hendriks, Jan C M; van der Vorm, Lisa N; Cabantchik, Z Ioav; Evans, Patricia J; Hod, Eldad A; Brittenham, Gary M; Furman, Yael; Wojczyk, Boguslaw; Janssen, Mirian C H; Porter, John B; Mattijssen, Vera E J M; Biemond, Bart J; MacKenzie, Marius A; Origa, Raffaella; Galanello, Renzo; Hider, Robert C; Swinkels, Dorine W

    2016-01-01

    Non-transferrin-bound iron and its labile (redox active) plasma iron component are thought to be potentially toxic forms of iron originally identified in the serum of patients with iron overload. We compared ten worldwide leading assays (6 for non-transferrin-bound iron and 4 for labile plasma iron) as part of an international inter-laboratory study. Serum samples from 60 patients with four different iron-overload disorders in various treatment phases were coded and sent in duplicate for analysis to five different laboratories worldwide. Some laboratories provided multiple assays. Overall, highest assay levels were observed for patients with untreated hereditary hemochromatosis and β-thalassemia intermedia, patients with transfusion-dependent myelodysplastic syndromes and patients with transfusion-dependent and chelated β-thalassemia major. Absolute levels differed considerably between assays and were lower for labile plasma iron than for non-transferrin-bound iron. Four assays also reported negative values. Assays were reproducible with high between-sample and low within-sample variation. Assays correlated and correlations were highest within the group of non-transferrin-bound iron assays and within that of labile plasma iron assays. Increased transferrin saturation, but not ferritin, was a good indicator of the presence of forms of circulating non-transferrin-bound iron. The possibility of using non-transferrin-bound iron and labile plasma iron measures as clinical indicators of overt iron overload and/or of treatment efficacy would largely depend on the rigorous validation and standardization of assays.

  12. Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Haipeng; Zhang, Xin [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Cui, Yuqian [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Zhou, Heng [Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan (China); Xu, Dachun [Department of Cardiology, Shanghai Tenth People' s Hospital of Tongji University, Shanghai (China); Shan, Tichao; Zhang, Fan [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Guo, Yuan [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Chen, Yuguo, E-mail: chen919085@163.com [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Department of Emergency, Qilu Hospital of Shandong University, Jinan (China); Wu, Dawei, E-mail: wdwu55@163.com [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China)

    2015-09-01

    Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and β-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis. - Highlights: • We focus on the protective effect of taxifolin on cardiac remodeling. • Taxifolin inhibited cardiac hypertrophy and attenuated ventricular fibrosis. • Taxifolin

  13. Effect of Hereditary Hemochromatosis Gene H63D and C282Y Mutations on Iron Overload in Sickle Cell Disease Patients

    Directory of Open Access Journals (Sweden)

    Yunus Kasım Terzi

    2016-12-01

    Full Text Available Objective: Hemochromatosis is an autosomal recessive disease that is one of the most important reasons for iron overload. Sickle cell disease is a hemoglobinopathy that occurs as a result of a homozygous mutation in the hemoglobin gene. Erythrocyte transfusion is frequently used in the treatment of this disease. Iron overload as a result of transfusion is important in the mortality and morbidity of sickle cell anemia patients as well as in other hemoglobinopathies. In this study, the effect of hemochromatosis gene (HFE p.H63D and p.C282Y mutations on transfusion-related cardiac and liver iron overload in sickle cell disease patients who carry homozygous hemoglobin S mutation has been investigated. Materials and Methods: This is a prospective single-center crosssectional study in patients with homozygous hemoglobin S mutation between the years 2008 and 2013. The patients were divided into two groups. The first group (group A, n=31 was receiving chelation therapy and the second group (group B, n=13 was not. Direct and indirect iron loads were analyzed by magnetic resonance imaging and biochemically, respectively. HFE gene mutations were analyzed by polymerase chain reaction-restriction fragment length polymorphism method. Statistical analyses were performed by independent samples t-test. Results: p.H63D mutation was detected in 10 (32.3% patients in group A and in only 1 patient (7.7% in group B. When the 2 groups were compared for iron overload, iron deposition in the liver was significantly higher in group B (p=0.046. In addition, in group A, iron deposition was significantly higher in HFE mutation carriers compared to patients without the mutation (p=0.05. Conclusion: Results of this study showed that HFE gene mutations are important in iron deposition in the liver in patients with sickle cell disease.

  14. Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload

    Institute of Scientific and Technical Information of China (English)

    Xian-hui Dong; Cong Liu; Jiang-tao Bai; Wei-na Kong; Xiao-ping He; Peng Yan; Tie-mei Shao; Wen-guo Yu; Xi-qing Chai; Yan-hua Wu

    2015-01-01

    Abnormally increased levels of iron in the brain trigger cascade ampliifcation in Alzheimer’s dis-ease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer’s disease patients. An APPswe/PS1ΔE9 double transgenic mouse model of Alzheimer’s disease was used. The intragas-tric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer’s disease. These com-pounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer’s disease.

  15. Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload

    Directory of Open Access Journals (Sweden)

    Xian-hui Dong

    2015-01-01

    Full Text Available Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer′s disease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer′s disease patients. An APP swe/PS1ΔE9 double transgenic mouse model of Alzheimer′s disease was used. The intragastric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer′s disease. These compounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer′s disease.

  16. Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

    Science.gov (United States)

    Millot, Sarah; Delaby, Constance; Moulouel, Boualem; Lefebvre, Thibaud; Pilard, Nathalie; Ducrot, Nicolas; Ged, Cécile; Lettéron, Philippe; de Franceschi, Lucia; Deybach, Jean Charles; Beaumont, Carole; Gouya, Laurent; De Verneuil, Hubert; Lyoumi, Saïd; Puy, Hervé; Karim, Zoubida

    2017-01-01

    Hemolysis occurring in hematologic diseases is often associated with an iron loading anemia. This iron overload is the result of a massive outflow of hemoglobin into the bloodstream, but the mechanism of hemoglobin handling has not been fully elucidated. Here, in a congenital erythropoietic porphyria mouse model, we evaluate the impact of hemolysis and regenerative anemia on hepcidin synthesis and iron metabolism. Hemolysis was confirmed by a complete drop in haptoglobin, hemopexin and increased plasma lactate dehydrogenase, an increased red blood cell distribution width and osmotic fragility, a reduced half-life of red blood cells, and increased expression of heme oxygenase 1. The erythropoiesis-induced Fam132b was increased, hepcidin mRNA repressed, and transepithelial iron transport in isolated duodenal loops increased. Iron was mostly accumulated in liver and spleen macrophages but transferrin saturation remained within the normal range. The expression levels of hemoglobin-haptoglobin receptor CD163 and hemopexin receptor CD91 were drastically reduced in both liver and spleen, resulting in heme- and hemoglobin-derived iron elimination in urine. In the kidney, the megalin/cubilin endocytic complex, heme oxygenase 1 and the iron exporter ferroportin were induced, which is reminiscent of significant renal handling of hemoglobin-derived iron. Our results highlight ironbound hemoglobin urinary clearance mechanism and strongly suggest that, in addition to the sequestration of iron in macrophages, kidney may play a major role in protecting hepatocytes from iron overload in chronic hemolysis. PMID:28143953

  17. Iron Overload Leading to Torsades de Pointes in β-Thalassemia and Long QT Syndrome

    DEFF Research Database (Denmark)

    Refaat, Marwan M; El Hage, Lea; Steffensen, Annette Buur

    2016-01-01

    The authors present a unique case of torsades de pointes in a β-thalassemia patient with early iron overload in the absence of any structural abnormalities as seen in hemochromatosis. Genetic testing showed a novel KCNQ1 gene mutation 1591C>T [Gln531Ter(X)]. Testing of the gene mutation in Xenopu...

  18. Deubiquitinase BRCC36 protects heart against chronic pressure overload-induced cardiac remodeling in mice

    Institute of Scientific and Technical Information of China (English)

    LI Ru-jun; FANG Wei; ZHU Hua-jiang; ZHANG Feng-xia; XU Ou-fang; XU Li-juan; ZHANG Zhen-gang; GONG Kai-zheng

    2016-01-01

    Emerging evidence has indicated that BRCC 36-mediated K63-linked ubiquitination modification was involved in diverse cellular functions , including endocytosis , apoptosis and DNA damage repair .We previously showed that activation of cGMP/PKG pathway con-tributed to the binding of BRCC36 and the pro-fibrotic factor Smad3.The current study tested the hypothesis that BRCC 36 functions as a negative regulator of transforming growth factor-beta ( TGF-β)/Smad3 pathway and participates in cardiac remodeling .In isolated adult mouse cardiac fibroblasts , we have demonstrated that TGF-β1 treatment significantly increased the expression of BRCC 36.Over-expression BRCC36 suppressed TGF-β1-induced Smad3 phosphorylation, nuclear translocation, extracellular matrix molecular expres-sion and cell proliferation .On the contrary, silencing BRCC36 by transfection of adenovirus-carrying BRCC36 shRNA potentiated to enhance the pro-fibrotic effect of TGF-β.In vivo, under chronic pressure overload condition-induced by transverse aortic constriction , myocardial pro-survival protein Bcl-2 and Mcl-1 expression were significantly decreased and the pro-apoptosis protein Puma was in-creased.However, the cardiac-specific over-expression of BRCC36 significantly increased myocardial Bcl-2 and Mcl-1 and inhibited Puma expression .Interestingly , we also found that sustained pressure overload resulted in a significant myocardial DNA injury in wild type mice, which was characterized by the increase of γH2AX level.However, cardiac-specific BRCC36 over-expression significantly decreased the level of γH2AX in the pressure overloaded heart in the transgenic mice , while effectively enhanced myocardial RAD 51 expression, a marker of DNA damage repair.Furthermore, BRCC36 over-expression effectively attenuated TAC-induced cardiac fibro-sis and remodeling in the transgenic mice , compared with the wild type mice .Collectively , the results have suggested that BRCC 36 ef-fectively protected heart

  19. Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of β-thalassemia

    Science.gov (United States)

    Jackson, Laurence H.; Vlachodimitropoulou, Evangelia; Shangaris, Panicos; Roberts, Thomas A.; Ryan, Thomas M.; Campbell-Washburn, Adrienne E.; David, Anna L.; Porter, John B.; Lythgoe, Mark F.; Stuckey, Daniel J.

    2017-01-01

    β-thalassemia (βT) is a genetic blood disorder causing profound and life threatening anemia. Current clinical management of βT is a lifelong dependence on regular blood transfusions, a consequence of which is systemic iron overload leading to acute heart failure. Recent developments in gene and chelation therapy give hope of better prognosis for patients, but successful translation to clinical practice is hindered by the lack of thorough preclinical testing using representative animal models and clinically relevant quantitative biomarkers. Here we demonstrate a quantitative and non-invasive preclinical Magnetic Resonance Imaging (MRI) platform for the assessment of βT in the γβ0/γβA humanized mouse model of βT. Changes in the quantitative MRI relaxation times as well as severe splenomegaly were observed in the heart, liver and spleen in βT. These data showed high sensitivity to iron overload and a strong relationship between quantitative MRI relaxation times and hepatic iron content. Importantly these changes preceded the onset of iron overload cardiomyopathy, providing an early biomarker of disease progression. This work demonstrates that multiparametric MRI is a powerful tool for the assessment of preclinical βT, providing sensitive and quantitative monitoring of tissue iron sequestration and cardiac dysfunction- parameters essential for the preclinical development of new therapeutics. PMID:28240317

  20. Effects of iron and copper overload on the human liver: an ultrastructural study.

    Science.gov (United States)

    Fanni, D; Fanos, V; Gerosa, C; Piras, M; Dessi, A; Atzei, A; Van, Eyken P; Gibo, Y; Faa, G

    2014-01-01

    Iron and copper ions play important roles in many physiological functions of our body, even though the exact mechanisms regulating their absorption, distribution and excretion are not fully understood. Metal-related human pathology may be observed in two different clinical settings: deficiency or overload. The overload in liver cells of both trace elements leads to multiple cellular lesions. Here we report the main pathological changes observed at transmission electron microscopy in the liver of subjects affected by Beta-thalassemia and by Wilson's disease. The hepatic iron overload in beta-thalassemia patients is associated with haemosiderin storage both in Kupffer cells and in the cytoplasm of hepatocytes. Haemosiderin granules are grouped inside voluminous lysosomes, also called siderosomes. Other ultrastructural changes are fat droplets, proliferation of the smooth endoplasmic reticulum and fibrosis. Apoptosis of hepatocytes and infiltration of sinusoids by polymorphonucleates is also detected in beta-thalassemia. Ultrastructural changes in liver biopsies from Wilson's disease patients are characterized by severe mitochondrial changes, associated with an increased number of perossisomes, cytoplasmic lipid droplets and the presence of lipolysosomes, characteristic cytoplasmic bodies formed by lipid vacuoles surrounded by electron-dense lysosomes. In patients affected by Wilson's disease, nuclei are frequently involved, with disorganization of the nucleoplasm and with glycogen inclusions. On the contrary, no significant changes are detected in Kupffer cells. Our data show that iron and copper, even though are both transition metals, are responsible of different pathological changes at ultrastructural level. In particular, copper overload is associated with mitochondrial damage, whereas iron overload only rarely may cause severe mitochondrial changes. These differences underlay the need for further studies in which biochemical analyses should be associated with

  1. Loss of Bmx nonreceptor tyrosine kinase prevents pressure overload-induced cardiac hypertrophy.

    Science.gov (United States)

    Mitchell-Jordan, Scherise A; Holopainen, Tanja; Ren, Shuxun; Wang, Sujing; Warburton, Sarah; Zhang, Michael J; Alitalo, Kari; Wang, Yibin; Vondriska, Thomas M

    2008-12-05

    Bmx nonreceptor tyrosine kinase has an established role in endothelial and lymphocyte signaling; however, its role in the heart is unknown. To determine whether Bmx participates in cardiac growth, we subjected mice deficient in the molecule (Bmx knockout mice) to transverse aortic constriction (TAC). In comparison with wild-type mice, which progressively developed massive hypertrophy following TAC, Bmx knockout mice were resistant to TAC-induced cardiac growth at the organ and cell level. Loss of Bmx preserved cardiac ejection fraction and decreased mortality following TAC. These findings are the first to demonstrate a necessary role for the Tec family of tyrosine kinases in the heart and reveal a novel regulator (Bmx) of pressure overload-induced hypertrophic growth.

  2. Hepatic iron overload and fibrosis in patients with beta thalassemia major after hematopoietic stem cell transplantation: A pilot study.

    Science.gov (United States)

    Ghavamzadeh, Ardeshir; Mirzania, Mehrzad; Kamalian, Naser; Sedighi, Nahid; Azimi, Parisima

    2015-04-01

    Currently, hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with beta-thalassemia major, but liver iron overload in these patients will not decrease and hepatic fibrosis may still progress despite successful HSCT. Liver biopsy samples were taken from 14 patients (Out of 25 patients) who underwent HSCT. All patients met three criteria: negative HCV antibody, liver fibrosis in samples before HSCT and lack of regular treatment for iron overload after HSCT (Because patients did not consent to phlebotomy or they had not regular follow-up). We evaluated liver fibrosis and liver iron overload by a semi quantitative method, Perls' Prussian blue staining, before and after HSCT. HSCT was successful in all the patients. Liver iron overload did not change after transplant (P=0.61), but hepatic fibrosis progressed after transplant (P=0.01). In patients with beta thalassemia major who previously had some degree of liver fibrosis, HSCT alone cannot reduce liver iron overload and liver fibrosis will increase. We recommend that regardless of the amount of iron overload in patients with beta thalassemia major that have shown some degree of fibrosis in their liver biopsy before transplantation, appropriate steps should be taken to reduce iron overload as soon as possible after successful transplantation.

  3. Hepatic iron overload in thalassemic patients: proposal and validation of an MRI method of assessment

    Energy Technology Data Exchange (ETDEWEB)

    Bonetti, M.G. [Servicio di Radiologia e Diagnostica per Immagini, Ancona (Italy)]|[IRCCS, San Giovanni Rotondo (Italy). Dipt. di Diagnostica per Immagini; Castriota-Scanderberg, A. [IRCCS, San Giovanni Rotondo (Italy). Dipt. di Diagnostica per Immagini; Criconia, G.M. [IRCCS, San Giovanni Rotondo (Italy). Reparto di Cardiologia; Mazza, P. [Servizio di Ematologia, Ospedale SS. Annunziata., Taranto (Italy); Sacco, M. [IRCCS, San Giovanni Rotondo (Italy). Reparto di Pediatria; Amurri, B. [Servizio di Ematologia, Ospedale SS. Annunziata., Taranto (Italy); Masi, C. [Servizio di Ematologia, Ospedale SS. Annunziata., Taranto (Italy)

    1996-09-01

    Background. A simple, accurate reproducible and noninvasive method of body iorn overload assessment whoul be of great clinical use. Objective. The purpose of the study was the implementation of a 0.5-T MRI method for liver iron overload measurement. Materials and methods. Thirty paptients with thalassemia major took part in the study. Liver and paraspinal muscle signal intensity (SI) measurements were performed on T1-weighted images and normalized on a standard phantom, and a subjective hemochromatosis grading scale was made on both T1- and T2-weighted images. Serum ferritin levels and tissue iron from liver biopsy specimes were determined for comparison. Results. A close correlation was found between biotopic liver iron and both the liver-to-phantom SI ratio (r=-0.88) and the subjective grading scale (rho=0.89). Serum ferritin correlated poorly with liver iron deposition, whether assesssed by biopsy (r=0.62) of MRI (r=-0.69). Conclusions. Both the subjective and the quantitative MRI methods proposed here are clinicaly valuable, with the former being adequate for a gross, the latter for an accurate estimation of tissue iron overload.

  4. Clinical Impact and Cellular Mechanisms of Iron Overload-Associated Bone Loss

    Science.gov (United States)

    Jeney, Viktória

    2017-01-01

    Diseases/conditions with diverse etiology, such as hemoglobinopathies, hereditary hemochromatosis and menopause, could lead to chronic iron accumulation. This condition is frequently associated with a bone phenotype; characterized by low bone mass, osteoporosis/osteopenia, altered microarchitecture and biomechanics, and increased incidence of fractures. Osteoporotic bone phenotype constitutes a major complication in patients with iron overload. The purpose of this review is to summarize what we have learnt about iron overload-associated bone loss from clinical studies and animal models. Bone is a metabolically active tissue that undergoes continuous remodeling with the involvement of osteoclasts that resorb mineralized bone, and osteoblasts that form new bone. Growing evidence suggests that both increased bone resorption and decreased bone formation are involved in the pathological bone-loss in iron overload conditions. We will discuss the cellular and molecular mechanisms that are involved in this detrimental process. Fuller understanding of this complex mechanism may lead to the development of improved therapeutics meant to interrupt the pathologic effects of excess iron on bone. PMID:28270766

  5. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload.

    Science.gov (United States)

    Camaschella, Clara; Campanella, Alessandro; De Falco, Luigia; Boschetto, Loredana; Merlini, Roberta; Silvestri, Laura; Levi, Sonia; Iolascon, Achille

    2007-08-15

    Inherited microcytic-hypochromic anemias in rodents and zebrafish suggest the existence of corresponding human disorders. The zebrafish mutant shiraz has severe anemia and is embryonically lethal because of glutaredoxin 5 (GRLX5) deletion, insufficient biogenesis of mitochondrial iron-sulfur (Fe/S) clusters, and deregulated iron-regulatory protein 1 (IRP1) activity. This leads to stabilization of transferrin receptor 1 (TfR) RNA, repression of ferritin, and ALA-synthase 2 (ALAS2) translation with impaired heme synthesis. We report the first case of GLRX5 deficiency in a middle-aged anemic male with iron overload and a low number of ringed sideroblasts. Anemia was worsened by blood transfusions but partially reversed by iron chelation. The patient had a homozygous (c.294A>G) mutation that interferes with intron 1 splicing and drastically reduces GLRX5 RNA. As in shiraz, aconitase and H-ferritin levels were low and TfR level was high in the patient's cells, compatible with increased IRP1 binding. Based on the biochemical and clinical phenotype, we hypothesize that IRP2, less degraded by low heme, contributes to the repression of the erythroblasts ferritin and ALAS2, increasing mitochondrial iron. Iron chelation, redistributing iron to the cytosol, might relieve IRP2 excess, improving heme synthesis and anemia. GLRX5 function is highly conserved, but at variance with zebrafish, its defect in humans leads to anemia and iron overload.

  6. Oxidative damage to rat brain in iron and copper overloads.

    Science.gov (United States)

    Musacco-Sebio, Rosario; Ferrarotti, Nidia; Saporito-Magriñá, Christian; Semprine, Jimena; Fuda, Julián; Torti, Horacio; Boveris, Alberto; Repetto, Marisa G

    2014-08-01

    This study reports on the acute brain toxicity of Fe and Cu in male Sprague-Dawley rats (200 g) that received 0 to 60 mg kg(-1) (ip) FeCl2 or CuSO4. Brain metal contents and time-responses were determined for rat survival, in situ brain chemiluminescence and phospholipid and protein oxidation products. Metal doses hyperbolically defined brain metal content. Rat survival was 91% and 60% after Fe and Cu overloads. Brain metal content increased from 35 to 114 μg of Fe per g and from 3.6 to 34 μg of Cu per g. Brain chemiluminescence (10 cps cm(-2)) increased 3 and 2 times after Fe and Cu overloads, with half maximal responses (C50) of 38 μg of Fe per g of brain and 15 μg of Cu per g of brain, and with half time responses (t1/2) of 12 h for Fe and 20 h for Cu. Phospholipid peroxidation increased by 56% and 31% with C50 of 40 μg of Fe per g and 20 μg of Cu per g and with t1/2 of 9 h and 14 h. Protein oxidation increased by 45% for Fe with a C50 of 40 μg of Fe per g and 18% for Cu with a C50 of 10 μg of Cu per g and a t1/2 of 12 h for both metals. Fe and Cu brain toxicities are likely mediated by Haber-Weiss type HO˙ formation with subsequent oxidative damage.

  7. Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis.

    Science.gov (United States)

    Schneider, Johanna; Lother, Achim; Hein, Lutz; Gilsbach, Ralf

    2011-06-01

    Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.

  8. Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

    Science.gov (United States)

    McLaren, Gordon D; Gordeuk, Victor R

    2009-01-01

    Hemochromatosis comprises a group of inherited disorders resulting from mutations of genes involved in regulating iron metabolism. The multicenter, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study screened approximately 100,000 participants in the US and Canada, testing for HFE mutations, serum ferritin and transferrin saturation. As in other studies, HFE C282Y homozygosity was common in Caucasians but rare in other ethnic groups, and there was a marked heterogeneity of disease expression in C282Y homozygotes. Nevertheless, this genotype was often associated with elevations of serum ferritin and transferrin saturation and with iron stores of more than four grams in men but not in women. If liver biopsy was performed, in some cases because of evidence of hepatic dysfunction, fibrosis or cirrhosis was often found. Combined elevations of serum ferritin and transferrin saturation were observed in non-C282Y homozygotes of all ethnic groups, most prominently Asians, but not often with iron stores of more than four grams. Future studies to discover modifier genes that affect phenotypic expression in C282Y hemochromatosis should help identify patients who are at greatest risk of developing iron overload and who may benefit from continued monitoring of iron status to detect progressive iron loading.

  9. Iron distribution and histopathological study of the effects of deferoxamine and deferiprone in the kidneys of iron overloaded β-thalassemic mice.

    Science.gov (United States)

    Yatmark, Paranee; Morales, Noppawan Phumala; Chaisri, Urai; Wichaiyo, Surasak; Hemstapat, Warinkarn; Srichairatanakool, Somdet; Svasti, Saovaros; Fucharoen, Suthat

    2016-09-01

    Renal glomerular and tubular dysfunctions have been reported with high prevalence in β-thalassemia. Iron toxicity is implicated in the kidney damage, which may be reversed by iron chelation therapy. To mimic heavy iron overload and evaluate the efficacy of iron chelators in the patients, iron dextran (180mg iron/mouse) was intraperitoneally (i.p.) injected in heterozygous β-globin knockout mice ((muβth-3/+), BKO) and wild type mice (C57BL/6J, WT) over a period of 2 weeks, followed by daily i.p. injection of deferoxamine (DFO) or deferiprone (L1) for 1 week. In BKO mice, iron preferentially accumulated in the proximal tubule with a grading score of 0-1 and increased to grade 3 after iron loading. In contrast, iron mainly deposited in the glomerulus and interstitial space in iron overloaded WT mice. Increased levels of kidney lipid peroxidation, glomerular and medullar damage and fibrosis in iron overloaded mice were reversed by treatment with iron chelators. L1 showed higher efficacy than DFO in reduction of glomerular iron, which was supported by a significantly decreased the amount of glomerular damage. Notably, DFO and L1 demonstrated a distinct pattern of iron distribution in the proximal tubule of BKO mice. In conclusion, chelation therapy has beneficial effects in iron-overloaded kidneys. However, the defect of kidney iron metabolism in thalassemia may be a determining factor of the treatment outcome in individual patients.

  10. Combination Iron Chelation Therapy with Deferiprone and Deferasirox in Iron-Overloaded Patients with Transfusion-Dependent β-Thalassemia Major

    Science.gov (United States)

    Karami, Hossein; Kosaryan, Mehrnoush; Amree, Arash Hadian; Darvishi-Khezri, Hadi; Mousavi, Masoomeh

    2017-01-01

    There are few papers on the combination therapy of deferiprone (DFP) and deferasirox (DFX) in iron-overloaded patients with transfusion-dependent β-thalassemia major (β-TM). A total of 6 patients with β-TM (5 males and 1 female) with a mean age of 23.8±5.8 years (ranging from 17 to 31) used this treatment regimen. The mean doses of DFP and DFX were 53.9±22.2 and 29.3±6.8 mg/kg/day, respectively. The duration of treatment was 11.5±4.6 months. Their serum ferritin levels were measured to be 2800±1900 and 3400±1600 ng/mL before and after treatment, respectively (p<0.6). Their cardiac magnetic resonance imaging (MRI) T2* values were 16.69±15.35 vs 17.38±5.74 millisecond (ms) before and after treatment, respectively (p < 0.9). Although there was no significant difference between their cardiac MRI T2* values before and after treatment statistically, the values improved after combination therapy with DFP and DFX in most of the patients. Liver MRI T2 * values were changed from 2.12±0.98 to 3.03±1.51 ms after treatment (p < 0.01); Further, their liver T2* values and liver iron concentration (LIC) were improved after treatment. Our study found that cardiac MRI T2* values, liver MRI T2* values, and LIC were improved after combination therapy with DFP and DFX in β-TM patients and that DFP and DFX combination therapy could be used to alleviate cardiac and liver iron loading. PMID:28243431

  11. VARIATION AND SIGNIFICANCE OF C-MYC PROTEIN IN RAT CARDIAC VOLUME-OVERLOAD HYP ERTROPHY

    Institute of Scientific and Technical Information of China (English)

    刘华胜; 马爱群; 王一理; 刘勇; 李恒力; 田红燕

    2002-01-01

    Objective To investigate the change of c-myc protein, which was chosen as the response indicator to volume-overload. Methods The time and spatial course of c-myc protein expressi on on the model of rat cardiac volume-overload hyper trophy was examined by immunohistochemical study. Results The immunohistochemica l study indicated the expression of c-myc protein was increased obviously at 4 -6 hours (62.73%) than that of control (45.41%, P<0.01) after the volume-o verload, then decreased gradually along with development of volume-overload hyp ertrophy and was decreased extremely at 5 months(r=-0.514,P<0.01).Conclusion There are disorders in the signal transduction pathways governing the hypertrophic respon se of cardiomyocytes in hypertrophic myocardium. C-myc gene and the product of it may be only the promoter gene of myocardial hypertrophy. Once switching on, c-myc gene and the product of it do not act anymore;While it may be that c-my c gene and the product of it increased following with myocardial hypertrophy, an d have not direct relation to the occurrence and development of myocardial hyper trophy.

  12. VARIATION AND SIGNIFICANCE OF C-MYC PROTEIN IN RAT CARDIAC VOLUME-OVERLOAD HYPERTROPHY

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Objective:To investigate the change of c-myc protein,which was chosen as the response indicator to volume-overloab.Methods:The time and spatial course of c-myc protein expression on the model of rat cardiac volume-overload hypertrophy was examined by immunohistochemical study.Results:The immunohistochemical study indicated the expression of c-myc protein was increased obviously at 4-6 hours(62.73%)than that of control(45.41%,P<0.01) after the volume-overload,then decreased gradually along with development of volume-overload hypertrophy and was decreased extremely at 5 months(r=-0.514,p<0.01),Conclusion:There are disorders in the signal transduction pathways governing the hypertrophic response of cardiomyocytes in hypertrophic myocardium.C-myc gene and the product of it may be only the promoter gene of myocardial hypertrophy.Once switching on,c-myc gene and the product of it do not act anymore;While it may be that c-myc gene and the product of it increased following with myocardial hypertrophy,and have not direct relation to the occurrence and development of myocardial hypertrophy.

  13. Desferrioxamine treatment of iron overload secondary to RH isoimmunization and intrauterine transfusion in a newborn infant.

    Science.gov (United States)

    Yalaz, Mehmet; Bilgin, Betül Siyah; Köroğlu, Ozge Altun; Ay, Yılmaz; Arıkan, Ciğdem; Sagol, Sermet; Akısü, Mete; Kültürsay, Nilgün

    2011-11-01

    Intrauterine transfusion is the standard of care in the management of severe Rh isoimmunization. Desferrioxamine has been used for the treatment of iron overload secondary to hemolysis and intrauterine transfusions in Rh isoimmunization cases. Here, we report a preterm infant born at 34 weeks of gestational age who had formerly received intrauterine transfusions for Rhesus hemolytic disease and presented with severe hyperferritinemia and elevated liver enzymes in the first week of life. Desferrioxamine treatment was started due to a ferritin level of 28,800 ng/ml and continued for 13 weeks. Although the treatment was successful, we observed resistant leukopenia which resolved after the cessation of treatment. In conclusion, iron overload secondary to intrauterine transfusions can be treated successfully with desferrioxamine; however, neonatologists must be aware of the possible side effects of this drug which has been used in only a limited number of newborns.

  14. Evidence for a novel mechanism independent of myocardial iron in β-thalassemia cardiac pathogenesis.

    Directory of Open Access Journals (Sweden)

    Ekatherina Stoyanova

    Full Text Available Human β-thalassemia major is one of the most prevalent genetic diseases characterized by decrease/absence of β-globin chain production with reduction of erythrocyte number. The main cause of death of treated β-thalassemia major patients with chronic blood transfusion is early cardiac complications that have been attributed to secondary iron overload despite optimal chelation. Herein, we investigated pathophysiological mechanisms of cardiovascular dysfunction in a severe murine model of β-thalassemia from 6 to 15-months of age in the absence of confounding effects related to transfusion. Our longitudinal echocardiography analysis showed that β-thalassemic mice first display a significant increase of cardiac output in response to limited oxygen-carrying erythrocytes that progressed rapidly to left ventricular hypertrophy and structural remodeling. Following this compensated hypertrophy, β-thalassemic mice developed age-dependent deterioration of left ventricular contractility and dysfunction that led toward decompensated heart failure. Consistently, murine β-thalassemic hearts histopathology revealed cardiac remodeling with increased interstitial fibrosis but virtual absence of myocardial iron deposits. Importantly, development of thalassemic cardiac hypertrophy and dysfunction independently of iron overload has uncoupled these cardiopathogenic processes. Altogether our study on β-thalassemia major hemoglobinopathy points to two successive phases resulting from severe chronic anemia and from secondarily induced mechanisms as pathophysiologic contributors to thalassemic cardiopathy.

  15. Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

    DEFF Research Database (Denmark)

    Christoffersen, Tue E.H.; Aplin, Mark; Strom, Claes C.

    2006-01-01

    Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system...... also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg.kg(-1).day(-1)) to investigate a possible role of the renin-angiotensin system...

  16. Efficacy of curcuminoids in alleviation of iron overload and lipid peroxidation in thalassemic mice.

    Science.gov (United States)

    Thephinlap, C; Phisalaphong, C; Fucharoen, S; Porter, J B; Srichairatanakool, S

    2009-09-01

    Non-transferrin bound iron (NTBI) is detectable in plasma of beta-thalassemia patients and participates in free-radical formation and oxidative tissue damage. Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are iron chelators used for treatment of iron overload; however they may cause adverse effects. Curcuminoids (CUR) exhibits many pharmacological activities and presents beta-diketone group to bind metal ions. Iron-chelating capacity of CUR was investigated in thalassemic mice. The mice (C57BL/6 stain); wild type ((mu)beta(+/+)) and heterozygous beta-knockout ((mu)beta(th-3/+)) were fed with ferrocene-supplemented diet for 2 months, and coincidently intervened with CUR (200 mg/kg/day) and DFP (50 mg/kg/day). Plasma NTBI was quantified using NTA chelation/HPLC method, and MDA concentration was analyzed by TBARS-based HPLC. Hepatic iron content (HIC) and total glutathione concentration were measured colorimetrically. Tissue iron accumulation was determined by Perl's staining. Ferrocene-supplemented diet induced occurrence of NTBI in plasma of thalassemic mice as well as markedly increased iron deposition in spleen and liver. Treatment with CUR and DFP decreased levels of the NTBI and MDA effectively. Hepatic MDA and nonheme iron content was also decreased in liver of the treated mice whilst total glutathione levels were increased. Importantly, the CUR and DFP reduced liver weight index and iron accumulation. Clearly, CUR is effective in chelation of plasma NTBI in iron-loaded thalassemic mice. Consequently, it can alleviate iron toxicity and harmfulness of free radicals. In prospective, efficacy of curcumin in removal of labile iron pool (LIP) in hepatocytes and cardiomyocytes are essential for investigation.

  17. Temporal alterations in cardiac fibroblast function following induction of pressure overload

    Science.gov (United States)

    Stewart, James A.; Massey, Erin P.; Fix, Charity; Zhu, Jinyu; Goldsmith, Edie C.

    2014-01-01

    Increases in cardiovascular load (pressure overload) are known to elicit ventricular remodeling including cardiomyocyte hypertrophy and interstitial fibrosis. While numerous studies have focused on the mechanisms of myocyte hypertrophy, comparatively little is known regarding the response of the interstitial fibroblasts to increased cardiovascular load. Fibroblasts are the most numerous cell type in the mammalian myocardium and have long been recognized as producing the majority of the myocardial extracellular matrix. It is only now becoming appreciated that other aspects of fibroblast behavior are important to overall cardiac function. The present studies were performed to examine the temporal alterations in fibroblast activity in response to increased cardiovascular load. Rat myocardial fibroblasts were isolated at specific time-points (3, 7, 14, and 28 days) after induction of pressure overload by abdominal aortic constriction. Bioassays were performed to measure specific parameters of fibroblast function including remodeling and contraction of 3-dimensional collagen gels, migration, and proliferation. In addition, the expression of extracellular matrix receptors of the integrin family was examined. Myocardial hypertrophy and fibrosis were evident within 7 days after constriction of the abdominal aorta. Collagen gel contraction, migration, and proliferation were enhanced in fibroblasts from pressure-overloaded animals compared to fibroblasts from sham animals. Differences in fibroblast function and protein expression were evident within 7 days of aortic constriction, concurrent with the onset of hypertrophy and fibrosis of the intact myocardium. These data provide further support for the idea that rapid and dynamic changes in fibroblast phenotype accompany and contribute to the progression of cardiovascular disease. PMID:20217135

  18. Tetrahydrocurcumin in combination with deferiprone attenuates hypertension, vascular dysfunction, baroreflex dysfunction, and oxidative stress in iron-overloaded mice.

    Science.gov (United States)

    Sangartit, Weerapon; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Donpunha, Wanida; Shibahara, Shigeki; Kukongviriyapan, Upa

    2016-12-01

    Excessive iron can generate reactive oxygen species (ROS), leading to oxidative stress that is closely associated with cardiovascular dysfunction. Iron overload was induced in male ICR mice by injection of iron sucrose (10mg/kg/day) for eight weeks. Iron overload was evidenced by increased serum iron indices. The mice developed increased blood pressure, impaired vascular function and blunted response of the autonomic nervous system. These effects were accompanied by increased malondialdehyde levels in various tissues, increased nitric oxide metabolites in plasma and urine, and decreased blood glutathione. Tetrahydrocurcumin (THU, 50mg/kg/day), deferiprone (or L1, 50mg/kg/day) or both was orally administered throughout the period of iron sucrose injection. The treatments significantly alleviated the deleterious cardiovascular effects of iron overload, and were associated with modulation of nitric oxide levels. An imbalance between endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) expression in response to iron overload was normalized by THU, L1 or the combination treatment. Moreover, the treatment decreased the upregulated expression levels of gp91(phox), p47(phox) and HO-1. The combination of THU and L1 exerted a greater effect than THU or L1 monotherapy. These results suggest beneficial effects of THU and L1 on iron-induced oxidative stress, hypertension, and vascular dysfunction.

  19. TLc-A, the leading nanochelating-based nanochelator, reduces iron overload in vitro and in vivo.

    Science.gov (United States)

    Kalanaky, Somayeh; Hafizi, Maryam; Safari, Sepideh; Mousavizadeh, Kazem; Kabiri, Mahboubeh; Farsinejad, Alireza; Fakharzadeh, Saideh; Nazaran, Mohammad Hassan

    2016-03-01

    Iron chelation therapy is an effective approach to the treatment of iron overload conditions, in which iron builds up to toxic levels in the body and may cause organ damage. Treatments using deferoxamine, deferasirox and deferiprone have been introduced and despite their disadvantages, they remain the first-line therapeutics in iron chelation therapy. Our study aimed to compare the effectiveness of the iron chelation agent TLc-A, a nano chelator synthetized based on the novel nanochelating technology, with deferoxamine. We found that TLc-A reduced iron overload in Caco2 cell line more efficiently than deferoxamine. In rats with iron overload, very low concentrations of TLc-A lowered serum iron level after only three injections of the nanochelator, while deferoxamine was unable to reduce iron level after the same number of injections. Compared with deferoxamine, TLc-A significantly increased urinary iron excretion and reduced hepatic iron content. The toxicity study showed that the intraperitoneal median lethal dose for TLc-A was at least two times higher than that for deferoxamine. In conclusion, our in vitro and in vivo studies indicate that the novel nano chelator compound, TLc-A, offers superior performance in iron reduction than the commercially available and widely used deferoxamine.

  20. Anemia, ineffective erythropoiesis, and hepcidin: interacting factors in abnormal iron metabolism leading to iron overload in β-thalassemia.

    Science.gov (United States)

    Gardenghi, Sara; Grady, Robert W; Rivella, Stefano

    2010-12-01

    β-Thalassemia is a genetic disorder caused by mutations in the β-globin gene and characterized by chronic anemia caused by ineffective erythropoiesis, and accompanied by a variety of serious secondary complications such as extramedullary hematopoiesis, splenomegaly, and iron overload. In the past few years, numerous studies have shown that such secondary disease conditions have a genetic basis caused by the abnormal expression of genes with a role in controlling erythropoiesis and iron metabolism. In this article, the most recent discoveries related to the mechanism(s) responsible for anemia/ineffective erythropoiesis and iron overload are discussed in detail. Particular attention is paid to the pathway(s) controlling the expression of hepcidin, which is the main regulator of iron metabolism, and the Epo/EpoR/Jak2/Stat5 signaling pathway, which regulates erythropoiesis. Better understanding of how these pathways function and are altered in β-thalassemia has revealed several possibilities for development of new therapeutic approaches to treat of the complications of this disease.

  1. Inositol hexa phosphoric acid (phytic acid), a nutraceuticals, attenuates iron-induced oxidative stress and alleviates liver injury in iron overloaded mice.

    Science.gov (United States)

    Bhowmik, Anwesha; Ojha, Durbadal; Goswami, Debayan; Das, Rashmi; Chandra, Nidhi S; Chatterjee, Tapan K; Chakravarty, Amit; Chakravarty, Sudipa; Chattopadhyay, Debprasad

    2017-03-01

    Inositol hexa phosphoric acid (IP6) or Phytic acid, a natural antioxidant of some leguminous plants, known to act as a protective agent for seed storage in plants by suppressing iron catalyzed oxidative process. Following the same mechanism, we have tested the effect of IP6 on iron overloaded in vitro oxidative stress, and studied it's in vivo hepatoprotective ability in iron-dextran (injection)-induced iron overloaded liver injury in mice (intraperitoneal). Our results showed that IP6 had in vitro iron chelation (IC50 38.4μg/ml) activity, with the inhibition of iron-induced lipid peroxidation (IC50 552μg/ml), and deoxyribose sugar degrading hydroxyl radicals (IC50 448.6μg/ml). Oral administration of IP6 (0-200mg/kg) revealed significant decrease in biochemical markers such as serum iron, total iron binding, serum ferritin and serum enzymes. Histopathology of liver stained with hematoxylin-eosin and Prussian blue showed reduced hepatocellular necrosis, ballooning and inflammation, indicating the restoration of normal cellular integrity. Interestingly, the IP6 was found to down-regulate the mRNA expression of tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, and IL-6 in iron overloaded liver tissues. Thus, we provide an insight that IP6, a natural food component, can serve as an iron chelator against iron overload diseases like Thalassemia, and also as a dietary hepatoprotective supplement.

  2. Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations

    Institute of Scientific and Technical Information of China (English)

    Ajay Duseja; Reena Das; Mohit Nanda; Ashim Das; Gurjeewan Garewal; Yogesh Chawla

    2005-01-01

    AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH.METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Peris' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined.RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients.On histology, 71% of the patients had negative iron staining,21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P = 0.55) and fibrosis stage (P = 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation.CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.

  3. Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane.

    Directory of Open Access Journals (Sweden)

    Leilismara Sousa

    Full Text Available Iron is an essential chemical element for human life. However, in some pathological conditions, such as hereditary hemochromatosis type 1 (HH1, iron overload induces the production of reactive oxygen species that may lead to lipid peroxidation and a change in the plasma-membrane lipid profile. In this study, we investigated whether iron overload interferes with the Na,K-ATPase activity of the plasma membrane by studying erythrocytes that were obtained from the whole blood of patients suffering from iron overload. Additionally, we treated erythrocytes of normal subjects with 0.8 mM H2O2 and 1 μM FeCl3 for 24 h. We then analyzed the lipid profile, lipid peroxidation and Na,K-ATPase activity of plasma membranes derived from these cells. Iron overload was more frequent in men (87.5% than in women and was associated with an increase (446% in lipid peroxidation, as indicated by the amount of the thiobarbituric acid reactive substances (TBARS and an increase (327% in the Na,K-ATPase activity in the plasma membrane of erythrocytes. Erythrocytes treated with 1 μM FeCl3 for 24 h showed an increase (132% in the Na,K-ATPase activity but no change in the TBARS levels. Iron treatment also decreased the cholesterol and phospholipid content of the erythrocyte membranes and similar decreases were observed in iron overload patients. In contrast, erythrocytes treated with 0.8 mM H2O2 for 24 h showed no change in the measured parameters. These results indicate that erythrocytes from patients with iron overload exhibit higher Na,K-ATPase activity compared with normal subjects and that this effect is specifically associated with altered iron levels.

  4. Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane

    Science.gov (United States)

    Sousa, Leilismara; Garcia, Israel J. P.; Costa, Tamara G. F.; Silva, Lilian N. D.; Renó, Cristiane O.; Oliveira, Eneida S.; Tilelli, Cristiane Q.; Santos, Luciana L.; Cortes, Vanessa F.; Santos, Herica L.; Barbosa, Leandro A.

    2015-01-01

    Iron is an essential chemical element for human life. However, in some pathological conditions, such as hereditary hemochromatosis type 1 (HH1), iron overload induces the production of reactive oxygen species that may lead to lipid peroxidation and a change in the plasma-membrane lipid profile. In this study, we investigated whether iron overload interferes with the Na,K-ATPase activity of the plasma membrane by studying erythrocytes that were obtained from the whole blood of patients suffering from iron overload. Additionally, we treated erythrocytes of normal subjects with 0.8 mM H2O2 and 1 μM FeCl3 for 24 h. We then analyzed the lipid profile, lipid peroxidation and Na,K-ATPase activity of plasma membranes derived from these cells. Iron overload was more frequent in men (87.5%) than in women and was associated with an increase (446%) in lipid peroxidation, as indicated by the amount of the thiobarbituric acid reactive substances (TBARS) and an increase (327%) in the Na,K-ATPase activity in the plasma membrane of erythrocytes. Erythrocytes treated with 1 μM FeCl3 for 24 h showed an increase (132%) in the Na,K-ATPase activity but no change in the TBARS levels. Iron treatment also decreased the cholesterol and phospholipid content of the erythrocyte membranes and similar decreases were observed in iron overload patients. In contrast, erythrocytes treated with 0.8 mM H2O2 for 24 h showed no change in the measured parameters. These results indicate that erythrocytes from patients with iron overload exhibit higher Na,K-ATPase activity compared with normal subjects and that this effect is specifically associated with altered iron levels. PMID:26197432

  5. Iron overload alters glucose homeostasis, causes liver steatosis, and increases serum triacylglycerols in rats.

    Science.gov (United States)

    Silva, Maísa; Silva, Marcelo E; de Paula, Heberth; Carneiro, Cláudia Martins; Pedrosa, Maria Lucia

    2008-06-01

    The objective of this study was to investigate the effect of iron overload with a hyperlipidemic diet on the histologic feature of hepatic tissue, the lipid and glycemic serum profiles, and the markers of oxidative damage and stress in a rat model. Twenty-four male Fischer rats, purchased from Experimental Nutrition Laboratory, Federal University of Ouro Preto, were assigned to 4 equal groups, 2 were fed a standard cholesterol-free diet (group C or control and CI or control with iron) containing 8.0% soybean oil and 2 were fed a hyperlipidemic diet (group H or hyperlipidemic and HI or hyperlipidemic with iron) containing 1.0% cholesterol and 25.0% soybean oil. A total of 50 mg of iron was administered to rats in groups CI and HI in 5 equal doses (1 every 3 weeks for a 16-week period) by intraperitoneal injections of 0.1 mL of iron dextran solution (100 g Fe(2+)/L; Sigma, St Louis, Mo). The other rats in groups C and H were treated in a similar manner but with sterile saline (0.1 mL). Irrespective of the diet, iron excess enhanced serum triacylglycerols (P .05) were observed in paraoxonase activities or in serum levels of free or total sulfhydryl radicals, malondialdehyde, or total antioxidants. The findings suggest that iron excess in the rat probably modifies lipid metabolism and, as a consequence, alters glucose homeostasis and increases the level of serum triacylglycerols but not of cholesterol.

  6. Virtual iron concentration imaging based on dual-energy CT for noninvasive quantification and grading of liver iron content: An iron overload rabbit model study

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Xian Fu; Yang, Yi; Xie, Xue Qian; Zhang, Huan; Chai, Wei Min; Yan, Fu Hua [Shanghai Jiao Tong University School of Medicine, Department of Radiology, Ruijin Hospital, Shanghai (China); Yan, Jing [Siemens Shanghai Medical Equipment Ltd., Shanghai (China); Wang, Li [Fudan University, Center of Analysis and Measurement, Shanghai (China); Schmidt, Bernhard [Siemens AG, Healthcare Sector, Forchheim (Germany)

    2015-09-15

    To assess the accuracy of liver iron content (LIC) quantification and grading ability associated with clinical LIC stratification using virtual iron concentration (VIC) imaging on dual-energy CT (DECT) in an iron overload rabbit model. Fifty-one rabbits were prepared as iron-loaded models by intravenous injection of iron dextran. DECT was performed at 80 and 140 kVp. VIC images were derived from an iron-specific algorithm. Postmortem LIC assessments were conducted on an inductively coupled plasma (ICP) spectrometer. Correlation between VIC and LIC was analyzed. VIC were stratified according to the corresponding clinical LIC thresholds of 1.8, 3.2, 7.0, and 15.0 mg Fe/g. Diagnostic performance of stratification was evaluated by receiver operating characteristic analysis. VIC linearly correlated with LIC (r = 0.977, P < 0.01). No significant difference was observed between VIC-derived LICs and ICP (P > 0.05). For the four clinical LIC thresholds, the corresponding cutoff values of VIC were 19.6, 25.3, 36.9, and 61.5 HU, respectively. The highest sensitivity (100 %) and specificity (100 %) were achieved at the threshold of 15.0 mg Fe/g. Virtual iron concentration imaging on DECT showed potential ability to accurately quantify and stratify hepatic iron accumulation in the iron overload rabbit model. (orig.)

  7. Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Keith Dadson

    Full Text Available Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM remodeling in response to pressure overload (PO. Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO and wild-type (WT mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson's trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1α1 and collagen 1α3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1α only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects.

  8. Impact of Oxidative Stress in Premature Aging and Iron Overload in Hemodialysis Patients

    Science.gov (United States)

    Hernández Vázquez, Wendy Ivett; Solorio-Meza, Sergio; Albarrán-Tamayo, Froylán; Ramos-Rodríguez, Edna; Benítez- Bribiesca, Luis

    2016-01-01

    Background. Increased oxidative stress is a well described feature of patients in hemodialysis. Their need for multiple blood transfusions and supplemental iron causes a significant iron overload that has recently been associated with increased oxidation of polyunsaturated lipids and accelerated aging due to DNA damage caused by telomere shortening. Methods. A total of 70 patients were evaluated concomitantly, 35 volunteers with ferritin levels below 500 ng/mL (Group A) and 35 volunteers with ferritin levels higher than 500 ng/mL (Group B). A sample of venous blood was taken to extract DNA from leukocytes and to measure relative telomere length by real-time PCR. Results. Patients in Group B had significantly higher plasma TBARS (p = 0.008), carbonyls (p = 0.0004), and urea (p = 0.02) compared with those in Group A. Telomeres were significantly shorter in Group B, 0.66 (SD, 0.051), compared with 0.75 (SD, 0.155) in Group A (p = 0.0017). We observed a statistically significant association between relative telomere length and ferritin levels (r = −0.37, p = 0.001). Relative telomere length was inversely related to time on hemodialysis (r = −0.27, p = 0.02). Conclusions. Our findings demonstrate that iron overload was associated with increased levels of oxidative stress and shorter relative telomere length. PMID:27800120

  9. Astragalus Polysaccharide Attenuated Iron Overload-Induced Dysfunction of Mesenchymal Stem Cells via Suppressing Mitochondrial ROS

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    Fan Yang

    2016-09-01

    Full Text Available Background/Aims: Bone marrow-derived mesenchymal stem cells (BMSCs have the ability to differentiate into multilineage cells such as osteoblasts, chondrocytes, and cardiomyocytes. Dysfunction of BMSCs in response to pathological stimuli participates in the development of diseases such as osteoporosis. Astragalus polysaccharide (APS is a major active ingredient of Astragalus membranaceus, a commonly used anti-aging herb in traditional Chinese medicine. The aim of this study was to investigate whether APS protects against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. Methods: BMSCs were exposed to ferric ammonium citrate (FAC with or without different concentrations of APS. The viability and proliferation of BMSCs were assessed by CCK-8 assay and EdU staining. Cell apoptosis, senescence and pluripotency were examined utilizing TUNEL staining, β-galactosidase staining and qRT-PCR respectively. The reactive oxygen species (ROS level was assessed in BMSCs with a DCFH-DA probe and MitoSOX Red staining. Results: Firstly, we found that iron overload induced by FAC markedly reduced the viability and proliferation of BMSCs, but treatment with APS at 10, 30 and 100 μg/mL was able to counter the reduction of cell proliferation. Furthermore, exposure to FAC led to apoptosis and senescence in BMSCs, which were partially attenuated by APS. The pluripotent genes Nanog, Sox2 and Oct4 were shown to be downregulated in BMSCs after FAC treatment, however APS inhibited the reduction of Nanog, Sox2 and Oct4 expression. Further study uncovered that APS treatment abrogated the increase of intracellular and mitochondrial ROS level in FAC-treated BMSCs. Conclusion: Treatment of BMSCs with APS to impede mitochondrial ROS accumulation can remarkably inhibit apoptosis, senescence, and the reduction of proliferation and pluripotency of BMSCs caused by FAC-induced iron overload.

  10. Iron Chelation Therapy with Deferasirox Results in Improvement of Liver Enzyme Level in Patients with Iron Overload-Associated Liver Dysfunction

    Science.gov (United States)

    Miura, Yasuo; Matsui, Yusuke; Kaneko, Hitomi; Watanabe, Mitsumasa; Tsudo, Mitsuru

    2010-01-01

    Iron chelation therapy (ICT) has been applied for the patients with iron overload-associated liver dysfunction since it is one of the causes of death in patients with intractable hematological diseases requiring multiple red blood cell transfusions. Recently, deferasirox (DSX), a novel, once-daily oral iron chelator, was demonstrated to have similar efficacy to the conventional continuous infusion of deferoxamine on a decrease in serum ferritin (SF) level in heavily transfused patients. We show three cases of transfusion-mediated iron-overloaded patients with an elevated serum alanine aminotransaminase (ALT). All three patients who received the ICT with DSX showed a decrease in ALT level in association with a decrease in SF level. It is suggested that DSX therapy could be considered to expect the improvement of liver damage for iron-overloaded patients with an abnormal ALT level. PMID:20592762

  11. Iron Chelation Therapy with Deferasirox Results in Improvement of Liver Enzyme Level in Patients with Iron Overload-Associated Liver Dysfunction

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    Yasuo Miura

    2010-01-01

    Full Text Available Iron chelation therapy (ICT has been applied for the patients with iron overload-associated liver dysfunction since it is one of the causes of death in patients with intractable hematological diseases requiring multiple red blood cell transfusions. Recently, deferasirox (DSX, a novel, once-daily oral iron chelator, was demonstrated to have similar efficacy to the conventional continuous infusion of deferoxamine on a decrease in serum ferritin (SF level in heavily transfused patients. We show three cases of transfusion-mediated iron-overloaded patients with an elevated serum alanine aminotransaminase (ALT. All three patients who received the ICT with DSX showed a decrease in ALT level in association with a decrease in SF level. It is suggested that DSX therapy could be considered to expect the improvement of liver damage for iron-overloaded patients with an abnormal ALT level.

  12. Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded β-thalassemic mice

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    Supranee Upanan

    2015-12-01

    Conclusions: The GTE + DFP treatment could ameliorate iron overload and liver oxidative damage in non-transfusion dependent β-thalassemic mice, by chelating toxic iron in plasma and tissues, and increasing hepcidin expression to inhibit duodenal iron absorption and iron release from hepatocytes and macrophages in the spleen. There is probably an advantage in giving GTE with DFP when treating patients with iron overload.

  13. Deferasirox: a review of its use for chronic iron overload in patients with non-transfusion-dependent thalassaemia.

    Science.gov (United States)

    Shirley, Matt; Plosker, Greg L

    2014-06-01

    Deferasirox (Exjade(®)) is a once-daily orally administered iron chelator which has been approved for use in the treatment of transfusional-dependent chronic iron overload since 2005. Based primarily on the findings of the THALASSA (Assessment of Exjade(®) in Non-Transfusion-Dependent THALASSemiA) trial, the approval for deferasirox has recently been expanded to include the management of chronic iron overload in patients with non-transfusion-dependent thalassaemia (NTDT) syndromes. Despite the lack of regular blood transfusions, NTDT patients can still develop clinically relevant iron overload, primarily due to increased gastrointestinal absorption secondary to ineffective erythropoiesis, and may require chelation therapy. The THALASSA trial, the first placebo-controlled clinical trial of an iron chelator in NTDT patients, demonstrated that deferasirox was effective in reducing liver iron and serum ferritin levels in this population. Deferasirox has an acceptable tolerability profile, with the most common adverse events reported in the THALASSA trial being related to mild to moderate gastrointestinal disorders. Although further long-term studies will be required to clearly demonstrate the clinical benefit of chelation therapy in NTDT patients, deferasirox presents a useful tool in the management of iron overload in this population.

  14. Effects of pressure- or volume-overload hypertrophy on passive stiffness in isolated adult cardiac muscle cells

    Science.gov (United States)

    Kato, S.; Koide, M.; Cooper, G. 4th; Zile, M. R.

    1996-01-01

    It has been hypothesized that the changes in myocardial stiffness induced by chronic hemodynamic overloading are dependent on changes in the passive stiffness of the cardiac muscle cell (cardiocyte). However, no previous studies have examined the passive constitutive properties of cardiocytes isolated from animals with myocardial hypertrophy. Accordingly, changes in relative passive stiffness of cardiocytes isolated from animals with chronic pressure- or volume-overload hypertrophy were determined by examining the effects of anisosmotic stress on cardiocyte size. Anisosmotic stress was produced by altering superfusate osmolarity. Hypertrophied cardiocytes were enzymatically isolated from 16 adult cats with right ventricular (RV) pressure-overload hypertrophy induced by pulmonary artery banding (PAB) and from 6 adult cats with RV volume-overload hypertrophy induced by creating an atrial septal defect (ASD). Left ventricular (LV) cardiocytes from each cat served as nonhypertrophied, normally loaded, same-animal controls. Superfusate osmolarity was decreased from 305 +/- 3 to 135 +/- 5 mosM and increased to 645 +/- 4 mosM. During anisosmotic stress, there were no significant differences between hypertrophied RV and normal LV cardiocytes in pressure overload PAB cats with respect to percent change in cardiocyte area (47 +/- 2% in RV vs. 48 +/- 2% in LV), diameter (46 +/- 3% in RV vs. 48 +/- 2% in LV), or length (2.4 +/- 0.2% in RV vs. 2.0 +/- 0.3% in LV), or sarcomere length (1.5 +/- 0.1% in RV vs. 1.3 +/- 0.3% in LV). Likewise, there were no significant differences in cardiocyte strain between hypertrophied RV and normal LV cardiocytes from ASD cats. In conclusion, chronic pressure-overload hypertrophy and chronic volume-overload hypertrophy did not alter the cardiocyte response to anisosmotic stress. Thus chronic overload hypertrophy did not alter relative passive cardiocyte stiffness.

  15. Dasatinib Attenuates Pressure Overload Induced Cardiac Fibrosis in a Murine Transverse Aortic Constriction Model.

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    Sundaravadivel Balasubramanian

    Full Text Available Reactive cardiac fibrosis resulting from chronic pressure overload (PO compromises ventricular function and contributes to congestive heart failure. We explored whether nonreceptor tyrosine kinases (NTKs play a key role in fibrosis by activating cardiac fibroblasts (CFb, and could potentially serve as a target to reduce PO-induced cardiac fibrosis. Our studies were carried out in PO mouse myocardium induced by transverse aortic constriction (TAC. Administration of a tyrosine kinase inhibitor, dasatinib, via an intraperitoneally implanted mini-osmotic pump at 0.44 mg/kg/day reduced PO-induced accumulation of extracellular matrix (ECM proteins and improved left ventricular geometry and function. Furthermore, dasatinib treatment inhibited NTK activation (primarily Pyk2 and Fak and reduced the level of FSP1 positive cells in the PO myocardium. In vitro studies using cultured mouse CFb showed that dasatinib treatment at 50 nM reduced: (i extracellular accumulation of both collagen and fibronectin, (ii both basal and PDGF-stimulated activation of Pyk2, (iii nuclear accumulation of Ki67, SKP2 and histone-H2B and (iv PDGF-stimulated CFb proliferation and migration. However, dasatinib did not affect cardiomyocyte morphologies in either the ventricular tissue after in vivo administration or in isolated cells after in vitro treatment. Mass spectrometric quantification of dasatinib in cultured cells indicated that the uptake of dasatinib by CFb was greater that that taken up by cardiomyocytes. Dasatinib treatment primarily suppressed PDGF but not insulin-stimulated signaling (Erk versus Akt activation in both CFb and cardiomyocytes. These data indicate that dasatinib treatment at lower doses than that used in chemotherapy has the capacity to reduce hypertrophy-associated fibrosis and improve ventricular function.

  16. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

    Science.gov (United States)

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

    2015-01-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

  17. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice.

    Science.gov (United States)

    Gardenghi, Sara; Ramos, Pedro; Marongiu, Maria Franca; Melchiori, Luca; Breda, Laura; Guy, Ella; Muirhead, Kristen; Rao, Niva; Roy, Cindy N; Andrews, Nancy C; Nemeth, Elizabeta; Follenzi, Antonia; An, Xiuli; Mohandas, Narla; Ginzburg, Yelena; Rachmilewitz, Eliezer A; Giardina, Patricia J; Grady, Robert W; Rivella, Stefano

    2010-12-01

    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.

  18. Heart Rate Variability for Early Detection of Cardiac Iron Deposition in Patients with Transfusion-Dependent Thalassemia

    Science.gov (United States)

    Silvilairat, Suchaya; Charoenkwan, Pimlak; Saekho, Suwit; Tantiworawit, Adisak; Phrommintikul, Arintaya; Srichairatanakool, Somdet; Chattipakorn, Nipon

    2016-01-01

    Background Iron overload cardiomyopathy remains the major cause of death in patients with transfusion-dependent thalassemia. Cardiac T2* magnetic resonance imaging is costly yet effective in detecting cardiac iron accumulation in the heart. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and is depressed in cases of thalassemia. We evaluated whether HRV could be used as an indicator for early identification of cardiac iron deposition. Methods One hundred and one patients with transfusion-dependent thalassemia were enrolled in this study. The correlation between recorded HRV and hemoglobin, non-transferrin bound iron (NTBI), serum ferritin and cardiac T2* were evaluated. Results The median age was 18 years (range 8–59 years). The patient group with a 5-year mean serum ferritin >5,000 ng/mL included significantly more homozygous β-thalassemia and splenectomized patients, had lower hemoglobin levels, and had more cardiac iron deposit than all other groups. Anemia strongly influenced all domains of HRV. After adjusting for anemia, neither serum ferritin nor NTBI impacted the HRV. However cardiac T2* was an independent predictor of HRV, even after adjusting for anemia. For receiver operative characteristic (ROC) curve analysis of cardiac T2* ≤20 ms, only mean ferritin in the last 12 months and the average of the standard deviation of all R-R intervals for all five-minute segments in the 24-hour recording were predictors for cardiac T2* ≤20 ms, with area under the ROC curve of 0.961 (p<0.0001) and 0.701 (p = 0.05), respectively. Conclusions Hemoglobin and cardiac T2* as significant predictors for HRV indicate that anemia and cardiac iron deposition result in cardiac autonomic imbalance. The mean ferritin in the last 12 months could be useful as the best indicator for further evaluation of cardiac risk. The ability of serum ferritin to predict cardiac risk is stronger than observed in other thalassemia cohorts. HRV might be a

  19. MR marrow signs of iron overload in transfusion-dependent patients with sickle cell disease

    Energy Technology Data Exchange (ETDEWEB)

    Levin, T.L. [Department of Pediatric Radiology, Babies and Children`s Hospital, Columbia-Presbyterian Medical Center, New York, NY (United States); Sheth, S.S. [Department of Pediatrics, Babies and Children`s Hospital, Columbia-Presbyterian Medical Center, 3959 Broadway, New York, NY 10032 (United States); Hurlet, A. [Department of Pediatrics, Babies and Children`s Hospital, Columbia-Presbyterian Medical Center, 3959 Broadway, New York, NY 10032 (United States); Comerci, S.C. [Department of Pediatric Radiology, Babies and Children`s Hospital, Columbia-Presbyterian Medical Center, New York, NY (United States); Ruzal-Shapiro, C. [Department of Pediatric Radiology, Babies and Children`s Hospital, Columbia-Presbyterian Medical Center, New York, NY (United States); Piomelli, S. [Department of Pediatrics, Babies and Children`s Hospital, Columbia-Presbyterian Medical Center, 3959 Broadway, New York, NY 10032 (United States); Berdon, W.E. [Department of Pediatric Radiology, Babies and Children`s Hospital, Columbia-Presbyterian Medical Center, New York, NY (United States)

    1995-11-01

    Magnetic resonance (MR) marrow signal in the axial and appendicular skeleton of 13 transfusion-dependent and chelated pediatric patients with sickle cell anemia (SSD) was compared with marrow signal in six non-transfusion-dependent patients with SSD. Hepatic, pancreatic, and renal MR signal were also evaluated. Indication for hypertransfusion therapy was primarily prior history of stroke. Transfusion-dependent patients had evidence of iron deposition throughout the imaged marrow and the liver, despite deferoxamine chelation therapy. Non-transfusion-dependent patients did not demonstrate grossly apparent signs of iron overload. Red marrow restoration was present in the spine, pelvis, and long bones and, in some patients, within the epiphyses. Marrow edema secondary to vaso-occlusive crises was evident in the metaphyses and diaphyses of long bones in areas of both red and fatty marrow and was best seen using fat-saturated T2-weighted imaging techniques. (orig.). With 4 figs., 2 tabs.

  20. Phlebotomy improves histology in chronic hepatitis C males with mild iron overload

    Science.gov (United States)

    Sartori, Massimo; Andorno, Silvano; Rossini, Angelo; Boldorini, Renzo; Bozzola, Cristina; Carmagnola, Stefania; Piano, Mario Del; Albano, Emanuele

    2010-01-01

    AIM: To investigate the usefulness of mild iron depletion and the factors predictive for histological improvement following phlebotomy in Caucasians with chronic hepatitis C (CHC). METHODS: We investigated 28 CHC Caucasians with persistently elevated serum aminotransferase levels and non responders to, or unsuitable for, antiviral therapy who underwent mild iron depletion (ferritin ≤ 70 ng/mL) by long-term phlebotomy. Histological improvement, as defined by at least one point reduction in the staging score or, in case of unchanged stage, as at least two points reduction in the grading score (Knodell), was evaluated in two subsequent liver biopsies (before and at the end of phlebotomy, 48 ± 16 mo apart). RESULTS: Phlebotomy showed an excellent safety profile. Histological improvement occurred in 12/28 phlebotomized patients. Only males responded to phlebotomy. At univariate logistic analysis alcohol intake (P = 0.034), high histological grading (P = 0.01) and high hepatic iron concentration (HIC) (P = 0.04) before treatment were associated with histological improvement. Multivariate logistic analysis showed that in males high HIC was the only predictor of histological improvement following phlebotomy (OR = 1.41, 95% CI: 1.03-1.94, P = 0.031). Accordingly, 12 out of 17 (70%) patients with HIC ≥ 20 μmol/g showed histological improvements at the second biopsy. CONCLUSION: Male CHC Caucasian non-responders to antiviral therapy with low-grade iron overload can benefit from mild iron depletion by long-term phlebotomy. PMID:20128028

  1. MicroRNAs and liver cancer associated with iron overload: therapeutic targets unravelled.

    Science.gov (United States)

    Greene, Catherine M; Varley, Robert B; Lawless, Matthew W

    2013-08-28

    Primary liver cancer is a global disease that is on the increase. Hepatocellular carcinoma (HCC) accounts for most primary liver cancers and has a notably low survival rate, largely attributable to late diagnosis, resistance to treatment, tumour recurrence and metastasis. MicroRNAs (miRNAs/miRs) are regulatory RNAs that modulate protein synthesis. miRNAs are involved in several biological and pathological processes including the development and progression of HCC. Given the poor outcomes with current HCC treatments, miRNAs represent an important new target for therapeutic intervention. Several studies have demonstrated their role in HCC development and progression. While many risk factors underlie the development of HCC, one process commonly altered is iron homeostasis. Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised. Aberrant miRNA expression in hepatic fibrosis and injury response have been reported, as have dysregulated miRNA expression patterns affecting cell cycle progression, evasion of apoptosis, invasion and metastasis. In 2009, miR-26a delivery was shown to prevent HCC progression, highlighting its therapeutic potential. Several studies have since investigated the clinical potential of other miRNAs with one drug, Miravirsen, currently in phase II clinical trials. miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy. Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years, yielding improved HCC survival rates and patient outcomes.

  2. Association of cardiac injury with iron-increased oxidative and nitrative modifications of the SERCA2a isoform of sarcoplasmic reticulum Ca(2+)-ATPase in diabetic rats.

    Science.gov (United States)

    Li, Xueli; Li, Wenliang; Gao, Zhonghong; Li, Hailing

    2016-08-01

    The role of iron in the etiology of diabetes complications is not well established. Thus, this study was performed to test whether the iron-induced increase of oxidative/nitrative damage is involved in SERCA2a-related diabetic heart complication. Four randomly divided groups of rats were used: normal control group; iron overload group; diabetes group, and diabetic plus iron overload group. Iron supplementation stimulated cardiomyocyte hypertrophy and led to an increase in cardiac protein carbonyls, nitrotyrosine (3-NT) formation, and iNOS protein expression, thus resulting in abnormal myocardium calcium homeostasis of diabetic rats. The levels of SECA2a oxidation/nitration were significantly increased in the iron overload diabetic rats, along with a decrease in SECA2a expression and activity. In order to elucidate the possible role of iron in SERCA2a dysfunction, the effects of iron (Fe(3+) or hemin) on peroxynitrite (ONOO(-)) induced SERCA2a oxidation and nitration were further investigated in vitro. It was found that tyrosine nitration played more important role in SERCA2a inactivation than thiol oxidation. These results present a potential mechanism in which iron exacerbates the diabetes-induced oxidative/nitrative modification of SERCA2a, which may cause functional deficits in the myocyte associated with diabetic cardiac dysfunction. Our findings may help to further understand the role of iron in the pathogenesis of diabetic complications.

  3. Effect of co-inheritance of β-thalassemia and hemochromatosis mutations on iron overload.

    Science.gov (United States)

    López-Escribano, Herminio; Ferragut, Joana F; Parera, Maria M; Guix, Pilar; Castro, José A; Ramon, M Misericòrdia; Picornell, Antònia

    2012-01-01

    Co-inheritance of mutations in the HFE gene underlying hereditary hemocromatosis (HH) may play a role in the variability of iron status in patients with β-thalassemia (β-thal) minor. Different studies have yielded conflicting results: some suggest iron overload might arise from the interaction of the β-thal trait with homozygosity or even heterozygosity for HFE mutations and others that it was unrelated to the HFE genotype. Because of the high frequency of HFE mutations in the Balearic Islands, where the β-thal trait is also moderately common, it is of interest to evaluate the effect of the co-inheritance of mutations in both genes on the severity of iron loading. A retrospective analysis of 142 individuals heterozygous for β-thal was performed to investigate the effect of HFE mutations on iron status of these patients. No significant differences were detected between β-thal carriers with and without HFE mutations. These results suggest that in the Balearic population the β-thal trait does not tend to be aggravated by the co-inheritance of HFE mutations.

  4. EGCG inhibits cardiomyocyte apoptosis in pressure overload-induced cardiac hypertrophy and protects cardiomyocytes from oxidative stress in rats

    Institute of Scientific and Technical Information of China (English)

    Rui SHENG; Zhen-lun GU; Mei-lin XIE; Wen-xuan ZHOU; Ci-yi GUO

    2007-01-01

    Aim: To investigate the effects of epigallocatechin gallate (EGCG) on pressure overload and hydrogen peroxide (H2O2) induced cardiac myocyte apoptosis. Methods: Cardiac hypertrophy was established in rats by abdominal aortic constriction. EGCG 25, 50 and 100 mg/kg were administered intragastrically (ig). Cultured newborn rat cardiomyocytes were preincubated with EGCG, and oxidative stress injury was induced by H2O2. Results: In cardiac hypertrophy induced by AC in rats, relative to the model group, EGCG 25, 50 and 100 mg/kg ig for 6weeks dose-dependently reduced systolic blood pressure (SBP) and heart weight indices, decreased malondialdehyde (MDA) content, and increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity, both in serum and in the myocardium. Also, treatment with EGCG 50 and 100 mg/kg markedly improved cardiac structure and inhibited fibrosis in HE and van Gieson (VG) stain, and reduced apoptotic myocytes in the hypertrophic myocardium detected by terminal transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay. Inthe Western blot analysis, EGCG significantly inhibited pressure overload-inducedp53 increase and bcl-2 decrease. In H2O2-induced cardiomyocyte injury, when preincubated with myocytes for 6-48 h, EGCG 12.5-200 mg/L increased cell viability determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. EGCG also attenuated H2O2-induced lactate dehydrogenase (LDH) release and MDA formation. Meanwhile, EGCG 50 and 100 mg/L significantly inhibited the cardiomyocyte apoptotic rate in flow cytometry. Conclusion: EGCG inhibits cardiac myocyte apoptosis and oxidative stress in pressure overload in-duced cardiac hypertrophy. Also, EGCG prevented cardiomyocyte apoptosis from oxidative stress in vitro. The mechanism might be related to the inhibitory effects of EGCG on p53 induction and bcl-2 decrease.

  5. Assessment of the role of α-lipoic acid against the oxidative stress of induced iron overload

    Directory of Open Access Journals (Sweden)

    Yasser F. Ali

    2015-01-01

    Full Text Available This work was aimed to study the protective role of α-lipoic acid against the oxidative damage of induced iron overload. Iron (Fe overload is a complication of the treatment, by chronic transfusion, of a number of genetic diseases associated with inadequate red cell production (anemias and of other genetic diseases that lead to excessive iron absorption from the diet. Male rats were injected ip with 5 mg/kg body weight ferrous sulfate for 50 days. The animals were injected ip with α-lipoic acid 20 mg per kg body weight for 21 days. Serum iron, Total Iron Binding Capacity (TIBC, Malonyldialdehyde (MDA, Electron paramagnetic resonance (EPR spectroscopy, UV-visible absorption spectrum of hemoglobin and osmotic fragility were studied. Results showed significant increase in serum iron, total iron binding capacity, and malonyldialdehyde levels in iron-loaded rats. Treatment with lipoic acid (LA resulted in decreasing serum iron and TIBC levels by 47%and 29% respectively. At the same time the lipoic acid decreased the level of the MDA in liver, brain and plasma by 54%, 42% and 74% respectively. Also LA diminished the effect of iron-induced free radicals on erythrocyte membrane integrity; it decreased the elevated average osmotic fragility and decreased the elevated rate of hemolysis. Results from UV-visible spectrophotometric measurement of hemoglobin revealed that no oxidative changes of hemoglobin occurred in iron-loaded rats. EPR spectra showed increased in non-heme ferric ions Fe+3 and free radicals in iron-loaded rats. Whereas the injection of the lipoic acid leads to decreased in such toxic result. In conclusion, these observations suggested that lipoic acid might be a beneficial antioxidant that can be effective for limiting damage from oxidative stress of iron overload.

  6. Comparison of Deferoxamine, Activated Charcoal, and Vitamin C in Changing the Serum Level of Fe in Iron Overloaded Rats

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    Reza Ghafari

    2014-02-01

    Full Text Available Background: Iron is an essential mineral for normal cellular physiology but its overload can lead to cell injury. For many years, deferoxamine injection has been used as an iron chelator for treatment of iron overload. The aim of this study is to compare oral deferoxamine, activated charcoal, and vitamin C, as an absorbent factor of Fe, in changing the serum level of iron in iron overload rats. Methods: In this experimental study, all groups were administered 150 mg iron dextran orally by gavage. After eight hours, rats in the first group received oral deferoxamine while those in the second and third groups received oral activated charcoal 1 mg/kg and oral vitamin C 150 mg, respectively. Then, serum levels of iron ware measured in all rats. Results: The mean serum level of iron in rats that received oral deferoxamine was 258.11±10.49 µg/dl, whereas mean levels of iron in charcoal and vitamin C groups were 380.88±11.21 µg/dl and 401.22±13.28 µg/dl, respectively. None of the measurements were within safety limits of serum iron. Conclusion: It seems that oral deferoxamine per se may not help physicians in the management of cases presented with iron toxicity. Activated charcoal did not reduce serum iron significantly in this study and further investigations may be warranted to assess the potential clinical utility of its mixture with oral deferoxamine as an adjunct in the clinical management of iron ingestions.

  7. The impact of iron overload and its treatment on quality of life: results from a literature review

    Directory of Open Access Journals (Sweden)

    Jones Paula

    2006-09-01

    Full Text Available Abstract Background To assess the literature for the impact of iron overload and infusion Iron Chelation Therapy (ICT on patients' quality of life (QoL, and the availability of QoL instruments for patients undergoing infusion ICT. Also, to obtain patients' experiences of having iron overload and receiving infusion ICT, and experts' clinical opinions about the impact of treatment on patients' lives. Methods A search of studies published between 1966 and 2004 was conducted using Medline and the Health Economic Evaluation Database (HEED. Qualitative results from patient and expert interviews were analysed. Hand searching of relevant conference abstracts completed the search. Results Few studies measuring the impact of ICT with deferoxamine (DFO on patients QoL were located (n = 15. QoL domains affected included: depression; fatigue; dyspnoea; physical functioning; psychological distress; decrease in QoL during hospitalization. One theme in all articles was that oral ICT should improve QoL. No iron overload or ICT-specific QoL instruments were located in the articles. Interviews revealed that the impact of ICT on patients with thalassemia, sickle cell disease, and myelodysplastic syndromes is high. Conclusion A limited number of studies assessed the impact of ICT or iron overload on QoL. All literature suggested a need for easily administered, efficacious and well tolerated oral iron overload treatments, given the impact of current ICT on adherence. Poor adherence to ICT was documented to negatively impact survival. Further research is warranted to continue the qualitative and quantitative study of QoL using validated instruments in patients receiving ICT to further understanding the issues and improve patients QoL.

  8. Apocynum Tablet Protects against Cardiac Hypertrophy via Inhibiting AKT and ERK1/2 Phosphorylation after Pressure Overload.

    Science.gov (United States)

    Qi, Jianyong; Liu, Qin; Gong, Kaizheng; Yu, Juan; Wang, Lei; Guo, Liheng; Zhou, Miao; Wu, Jiashin; Zhang, Minzhou

    2014-01-01

    Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy. Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot. Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P < 0.05). Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT.

  9. Cardiac Myocyte De Novo DNA Methyltransferases 3a/3b Are Dispensable for Cardiac Function and Remodeling after Chronic Pressure Overload in Mice.

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    Thomas G Nührenberg

    Full Text Available Recent studies reported altered DNA methylation in failing human hearts. This may suggest a role for de novo DNA methylation in the development of heart failure. Here, we tested whether cardiomyocyte-specific loss of de novo DNA methyltransferases Dnmt3a and Dnmt3b altered cardiac function and remodeling after chronic left ventricular pressure overload.Mice with specific ablation of Dnmt3a and Dnmt3b expression in cardiomyocytes were generated by crossing floxed Dnmt3afl and Dnmt3bfl alleles with mice expressing Cre recombinase under control of the atrial myosin light chain gene promoter. The efficacy of combined Dnmt3a/3b ablation (DKO was characterized on cardiomyocyte-specific genomic DNA and mRNA levels. Cardiac phenotyping was carried out without (sham or with left ventricular pressure overload induced by transverse aortic constriction (TAC. Under similar conditions, cardiac genome-wide transcriptional profiling was performed and DNA methylation levels of promoters of differentially regulated genes were assessed by pyrosequencing.DKO cardiomyocytes showed virtual absence of targeted Dnmt3a and Dnmt3b mRNA transcripts. Cardiac phenotyping revealed no significant differences between DKO and control mice under sham and TAC conditions. Transcriptome analyses identified upregulation of 44 and downregulation of 9 genes in DKO as compared with control sham mice. TAC mice showed similar changes with substantial overlap of regulated genes compared to sham. Promoters of upregulated genes were largely unmethylated in DKO compared to control mice.The absence of cardiac pathology in the presence of the predicted molecular phenotype suggests that de novo DNA methylation in cardiomyocytes is dispensable for adaptive mechanisms after chronic cardiac pressure overload.

  10. SUBCHRONIC PULMONARY PATHOLOGY, IRON-OVERLOAD AND TRANSCRIPTIONAL ACTIVITY AFTER LIBBY AMPHIBOLE EXPOSURE IN RAT MODELS OF CARDIOVASCULAR DISEASE

    Science.gov (United States)

    Background: Surface-available iron (Fe) is proposed to contribute to asbestos-induced toxicity through the production of reactive oxygen species.Objective: Our goal was to evaluate the hypothesis that rat models of cardiovascular disease with coexistent Fe overload would be incre...

  11. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

    OpenAIRE

    Vichinsky, Elliott; Onyekwere, Onyinye; Porter, John; Swerdlow, Paul; Eckman, James; Lane, Peter; Files, Beatrice; Hassell, Kathryn; Kelly, Patrick; Wilson, Felicia; Bernaudin, Françoise; Forni, Gian Luca; Okpala, Iheanyi; Ressayre-Djaffer, Catherine; Alberti, Daniele

    2007-01-01

    Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change i...

  12. Glutathione S transferase polymorphisms influence on iron overload in β-thalassemia patients

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    Serena Sclafani

    2013-11-01

    Full Text Available In patients with β-thalassemia iron overload that leads to damage to vital organs is observed. Glutathione S transferase (GST enzymes have an antioxidant role in detoxification processes of toxic substances. This role is determined genetically. In this study, we correlated GSTT1 and GSTM1 genotypes with iron overload measured with direct and indirect non-invasive methods; in particular, we used serum ferritin and signal intensity of the magnetic resonance image (MRI in 42 patients with β-thalassemia, which were regularly subjected to chelation and transfusion therapy. Multiplex polymerase chain reaction was used to determine the genotype. The loss of both alleles leads to a decreased value of liver and heart MRI-signal intensity with a consequent iron accumulation in these organs; the loss of only one allele doesn’t lead to relevant overload. Serum ferritin doesn’t appear to be correlated to iron overload instead. 对于β-地中海贫血患者,由于铁过量而造成重要器官受损的情况也在观察之中。谷胱甘肽S转移酶(GST 酶类在对有毒物质进行解毒的过程中有着抗氧化剂的作用。该作用是由基因决定的。 在这份研究中,我们运用了直接和间接非侵入性的方法对基因型铁过量GSTT1 和GSTM1进行了相关性测量;特别地,我们对42位定期接受螯合和输血治疗的β-地中海贫血患者进行了血清铁蛋白和磁共振强度图像(MRI 的测试。 多重聚合酶链反应的测试也被运用来确定该基因型。 该两种等位基因的缺失,导致了肝功能减损及心脏磁共振强度的下降,并造成了在这些器官中铁含量的积累;其中一种等位基因的缺失并不会导致过度的铁含量。血清蛋白和铁过量之间,看起来并不存在相关性。

  13. Diagnosis of iron overload and heart disease by magnetic resonance imaging

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    J.C. Wood

    2011-12-01

    Full Text Available The use of Magnetic resonance imaging (MRI to estimate tissue iron was initiated nearly three decades ago but has only become a practical reality in the last ten years. MRI is most often used to estimate hepatic and cardiac iron in patients with thalassemia or sickle cell disease and has largely replaced liver biopsy for liver iron quantification. The ability of MRI to image extra hepatic organs has really transformed our understanding of iron mediated toxicity in transfusional siderosis. For decades, iron cardiomyopathy was the leading cause of death in thalassemia major, but it is now relatively rare in centers with regular MRI screening. Early recognition of cardiac iron loading allows more gentle modifications of iron chelation therapy prior to life threatening organ dysfunction. Serial MRI evaluations have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration increase the risk of cardiac and endocrine toxicities, extra hepatic iron deposition and toxicity occurs in many patients despite having low total body iron stores; there is no safe liver iron level in chronically transfused patients. Instead, the type, dose, and pattern of iron chelation therapy all contribute to whether cardiac iron accumulation will occur. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. With the decline in cardiac mortality, future frontiers in MRI monitoring including better prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes. These organs also serve as early warning signals for inadequate control of non-transferrin bound iron, a risk factor for cardiac iron loading. Thus MRI assessment of extra hepatic iron stores is a

  14. SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis.

    Science.gov (United States)

    Jenkitkasemwong, Supak; Wang, Chia-Yu; Coffey, Richard; Zhang, Wei; Chan, Alan; Biel, Thomas; Kim, Jae-Sung; Hojyo, Shintaro; Fukada, Toshiyuki; Knutson, Mitchell D

    2015-07-01

    Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14(-/-) mice with Hfe(-/-) and Hfe2(-/-) mice, animal models of type 1 and type 2 (juvenile) hemochromatosis, respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders.

  15. Relationship between labile plasma iron, liver iron concentration and cardiac response in a deferasirox monotherapy trial

    Science.gov (United States)

    Wood, John C.; Glynos, Tara; Thompson, Alexis; Giardina, Patricia; Harmatz, Paul; Kang, Barinder P.; Paley, Carole; Coates, Thomas D.

    2011-01-01

    The US04 trial was a multicenter, open-label, single arm trial of deferasirox monotherapy (30–40 mg/kg/day) for 18 months. Cardiac iron response was bimodal with improvements observed in patients with mild to moderate initial somatic iron stores; relationship of cardiac response to labile plasma iron is now presented. Labile plasma iron was measured at baseline, six months, and 12 months. In patients having a favorable cardiac response at 18 months, initial labile plasma iron was elevated in only 31% of patients at baseline and no patient at six or 12 months. Cardiac non-responders had elevated labile plasma iron in 50% of patients at baseline, 50% patients at six months, and 38% of patients at 12 months. Risk of abnormal labile plasma iron and cardiac response increased with initial liver iron concentration. Persistently increased labile plasma iron predicts cardiac non-response to deferasirox but labile plasma iron suppression does not guarantee favorable cardiac outcome. Study registered at www.clinicaltrials.gov (NCT00447694). PMID:21393329

  16. Effect of Erythropoietin, Iron Deficiency and Iron Overload on Liver Matriptase-2 (TMPRSS6) Protein Content in Mice and Rats.

    Science.gov (United States)

    Frýdlová, Jana; Přikryl, Petr; Truksa, Jaroslav; Falke, Lucas L; Du, Xin; Gurieva, Iuliia; Vokurka, Martin; Krijt, Jan

    2016-01-01

    Matriptase-2 (TMPRSS6) is an important negative regulator of hepcidin expression; however, the effects of iron overload or accelerated erythropoiesis on liver TMPRSS6 protein content in vivo are largely unknown. We determined TMPRSS6 protein content in plasma membrane-enriched fractions of liver homogenates by immunoblotting, using a commercial antibody raised against the catalytic domain of TMPRSS6. Plasma membrane-enriched fractions were obtained by centrifugation at 3000 g and washing. TMPRSS6 was detected in the 3000 g fraction as a 120 kDa full-length protein in both mice and rats. Feeding of iron-deficient diet as well as erythropoietin treatment increased TMPRSS6 protein content in rats and mice by a posttranscriptional mechanism; the increase in TMPRSS6 protein by erythropoietin was also observed in Bmp6-mutant mice. Administration of high doses of iron to mice (200, 350 and 700 mg/kg) decreased TMPRSS6 protein content. Hemojuvelin was detected in the plasma membrane-enriched fractions of control animals as a full length protein of approximately 52 kDa; in iron deficient animals, the full length protein was partially cleaved at the N-terminus, resulting in an additional weak band of approximately 47 kDa. In livers from hemojuvelin-mutant mice, TMPRSS6 protein content was strongly decreased, suggesting that intact hemojuvelin is necessary for stable TMPRSS6 expression in the membrane. Overall, the results demonstrate posttranscriptional regulation of liver TMPRSS6 protein by iron status and erythropoietin administration, and provide support for the interaction of TMPRSS6 and hemojuvelin proteins in vivo.

  17. Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats

    Science.gov (United States)

    Stewart, James A.; Gardner, Jason D.; Brower, Gregory L.

    2013-01-01

    Previous studies have established integrins as cell surface receptors that mediate cardiomyocyte-extracellular matrix (ECM) attachments. This study sought to determine the contributions of the myocardial β1- and β3-integrin subunits to ventricular dilatation and coronary flow regulation using a blood-perfused isolated heart preparation. Furthermore, cardiomyocyte adhesion to collagen types I and IV, fibronectin, and laminin with and without a β1-integrin subunit neutralizing antibody was assessed during the course of remodeling secondary to a sustained cardiac volume overload, including the onset of heart failure. Isolated cardiomyocytes were obtained during the initial, compensated, and decompensated phases of remodeling resulting from an aortocaval fistula created in 8-wk-old male Sprague-Dawley rats. Blocking the β1-integrin subunit in isolated normal hearts produced ventricular dilatation, whereas this was not the case when the β3-subunit was blocked. Substantial reductions in cardiomyocyte adhesion coincided with the previously documented development of ventricular dilatation and decreased contractility postfistula, with the β1-integrin contribution to adhesion ranging from 28% to 73% over the course of remodeling being essentially substrate independent. In contrast, both integrin subunits were found to be involved in regulating coronary vascular resistance. It is concluded that marked reductions in integrin-mediated cardiomyocyte adhesion to the ECM play a significant role in the progression of adverse myocardial remodeling that leads to heart failure. Furthermore, although both the β1- and β3-integrin subunits were involved in regulating coronary vascular resistance, only inhibition of β1-integrin-mediated adhesion resulted in ventricular dilatation of the normal heart. PMID:24163072

  18. Effect of Combined versus Monotherapy with Deferoxamine and Deferiprone in Iron Overloaded Thalassemia Patients: a Randomized Clinical Trial

    Directory of Open Access Journals (Sweden)

    Sasan Hejazi

    2016-06-01

    Full Text Available Background: Patients with transfusional iron overload have depended on iron chelation therapy and improving chelation regimens have been of the highest priority. The aim of this study was to compare effect of combined versus monotherapy with Deferoxamine (DFO and Deferiprone (DFP in iron overloaded beta thalassemia (BT major patients Materials and Methods We studied 36 BT major patients (mean age 7.6±4.6; range 3–16 years attending the Ormieh Motahari hospital for regular transfusional support. Patients were randomly allocated to receive one of the following two treatments: DFO in combination with DFP (n=12, DFO alone (n=12 and DFP alone (n=12. Serum ferritin level, liver enzymes, blood urea nitrogen, and creatinine and side effects were monitored over a 12 months period. Results: After one year, serum ferritin decreased more significantly in patients on DFO+DFP therapy compared to patients who only received DFO or DFP alone (P

  19. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).

    Science.gov (United States)

    Iolascon, Achille; d'Apolito, Maria; Servedio, Veronica; Cimmino, Flora; Piga, Antonio; Camaschella, Clara

    2006-01-01

    Divalent metal transporter 1 (DMT1) mediates apical iron uptake in duodenal enterocytes and iron transfer from the transferrin receptor endosomal cycle into the cytosol in erythroid cells. Both mk mice and Belgrade rats, which carry an identical DMT1 mutation, exhibit severe microcytic anemia at birth and defective intestinal iron use and erythroid iron use. We report the hematologic phenotype of a child, compound heterozygote for 2 DMT1 mutations, who was affected by severe anemia since birth and showed hepatic iron overload. The novel mutations were a 3-bp deletion in intron 4 (c.310-3_5del CTT) resulting in a splicing abnormality and a C>T transition at nucleotide 1246(p. R416C). A striking reduction of DMT1 protein in peripheral blood mononuclear cells was demonstrated by Western blot analysis. The proband required blood transfusions until erythropoietin treatment allowed transfusion independence when hemoglobin levels between 75 and 95 g/L (7.5 and 9.5 g/dL) were achieved. Hematologic data of this patient at birth and in the first years of life strengthen the essential role of DMT1 in erythropoiesis. The early onset of iron overload indicates that, as in animal models, DMT1 is dispensable for liver iron uptake, whereas its deficiency in the gut is likely bypassed by the up-regulation of other pathways of iron use.

  20. Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels

    Science.gov (United States)

    Rossi, Francesca; Perrotta, Silverio; Bellini, Giulia; Luongo, Livio; Tortora, Chiara; Siniscalco, Dario; Francese, Matteo; Torella, Marco; Nobili, Bruno; Di Marzo, Vincenzo; Maione, Sabatino

    2014-01-01

    The pathogenesis of bone resorption in β-thalassemia major is multifactorial and our understanding of the underlying molecular and cellular mechanisms remains incomplete. Considering the emerging importance of the endocannabinoid/endovanilloid system in bone metabolism, it may be instructive to examine a potential role for this system in the development of osteoporosis in patients with β-thalassemia major and its relationship with iron overload and iron chelation therapy. This study demonstrates that, in thalassemic-derived osteoclasts, tartrate-resistant acid phosphatase expression inversely correlates with femoral and lumbar bone mineral density, and directly correlates with ferritin levels and liver iron concentration. The vanilloid agonist resiniferatoxin dramatically reduces cathepsin K levels and osteoclast numbers in vitro, without affecting tartrate-resistant acid phosphatase expression. The iron chelators deferoxamine, deferiprone and deferasirox decrease both tartrate-resistant acid phosphatase and cathepsin K expression, as well as osteoclast activity. Taken together, these data show that transient receptor potential vanilloid type 1 activation/desensitization influences tartrate-resistant acid phosphatase expression and activity, and this effect is dependent on iron, suggesting a pivotal role for iron overload in the dysregulation of bone metabolism in patients with thalassemia major. Our applied pharmacology provides evidence for the potential of iron chelators to abrogate these effects by reducing osteoclast activity. Whether iron chelation therapy is capable of restoring bone health in humans requires further study, but the potential to provide dual benefits for patients with β-thalassemia major –preventing iron-overload and alleviating associated osteoporotic changes – is exciting. PMID:25216685

  1. Clinically approved iron chelators influence zebrafish mortality, hatching morphology and cardiac function.

    Directory of Open Access Journals (Sweden)

    Jasmine L Hamilton

    Full Text Available Iron chelation therapy using iron (III specific chelators such as desferrioxamine (DFO, Desferal, deferasirox (Exjade or ICL-670, and deferiprone (Ferriprox or L1 are the current standard of care for the treatment of iron overload. Although each chelator is capable of promoting some degree of iron excretion, these chelators are also associated with a wide range of well documented toxicities. However, there is currently very limited data available on their effects in developing embryos. In this study, we took advantage of the rapid development and transparency of the zebrafish embryo, Danio rerio to assess and compare the toxicity of iron chelators. All three iron chelators described above were delivered to zebrafish embryos by direct soaking and their effects on mortality, hatching and developmental morphology were monitored for 96 hpf. To determine whether toxicity was specific to embryos, we examined the effects of chelator exposure via intra peritoneal injection on the cardiac function and gene expression in adult zebrafish. Chelators varied significantly in their effects on embryo mortality, hatching and morphology. While none of the embryos or adults exposed to DFO were negatively affected, ICL -treated embryos and adults differed significantly from controls, and L1 exerted toxic effects in embryos alone. ICL-670 significantly increased the mortality of embryos treated with doses of 0.25 mM or higher and also affected embryo morphology, causing curvature of larvae treated with concentrations above 0.5 mM. ICL-670 exposure (10 µL of 0.1 mM injection also significantly increased the heart rate and cardiac output of adult zebrafish. While L1 exposure did not cause toxicity in adults, it did cause morphological defects in embryos at 0.5 mM. This study provides first evidence on iron chelator toxicity in early development and will help to guide our approach on better understanding the mechanism of iron chelator toxicity.

  2. Long-Term Sodium Ferulate Supplementation Scavenges Oxygen Radicals and Reverses Liver Damage Induced by Iron Overloading

    Directory of Open Access Journals (Sweden)

    Yang Qiao

    2016-09-01

    Full Text Available Ferulic acid is a polyphenolic compound contained in various types of fruits and wheat bran. As a salt of the active ingredient, sodium ferulate (SF has potent free radical scavenging activity and can effectively scavenge ROS. In this study, we examined the effect of SF on iron-overloaded mice in comparison to a standard antioxidant, taurine (TAU. We determined the protective role of SF against liver injury by examining liver-to-body ratio (%, transaminase and hepatocyte apoptosis in rats supplied with 10% dextrose intraperitoneal injection. In addition, antioxidative enzymes activities, ROS formation, mitochondrial swelling, and mitochondrial membrane potential (MMP were all evaluated to clarify the mechanism of protective effect of SF associated with oxidative stress. After 15 weeks of SF treatment, we found a significant reduction in liver-to-body weight radio and elevation in both transaminase and hepatocyte apoptosis associated with iron-injected to levels comparable to those achieved with TAU. Both SF and TAU significantly attenuated the impaired liver function associated with iron-overloaded in mice, whereas neither showed any significant effect on the iron uptake. Furthermore, treatment with either SF or TAU in iron-overloaded mice attenuated oxidative stress, associated with elevated oxidant enzymes activities, decreased ROS production, prevented mitochondrial swelling and dissipation of MMP and then inhibited hepatic apoptosis. Taken together, the current study shows that, SF alleviated oxidative stress and liver damage associated with iron-overload conditions compared to the standard ROS scavenger (TAU, and potentially could encourage higher consumption and utilization as healthy and sustainable ingredients by the food and drink.

  3. Hyperferritinemia without iron overload in patients with bilateral cataracts: a case series

    Directory of Open Access Journals (Sweden)

    Mumford Andrew

    2011-09-01

    Full Text Available Abstract Introduction Hepatologists and internists often encounter patients with unexplained high serum ferritin concentration. After exclusion of hereditary hemochromatosis and hemosiderosis, rare disorders like hereditary hyperferritinemia cataract syndrome should be considered in the differential diagnosis. This autosomal dominant syndrome, that typically presents with juvenile bilateral cataracts, was first described in 1995 and has an increasing number of recognized molecular defects within a regulatory region of the L-ferritin gene (FTL. Case presentation Two patients (32 and 49-year-old Caucasian men from our ambulatory clinic were suspected as having this syndrome and a genetic analysis was performed. In both patients, sequencing of the FTL 5' region showed previously described mutations within the iron responsive element (FTL c.33 C > A and FTL c.32G > C. Conclusion Hereditary hyperferritinemia cataract syndrome should be considered in all patients with unexplained hyperferritinemia without signs of iron overload, particularly those with juvenile bilateral cataracts. Liver biopsy and phlebotomy should be avoided in this disorder.

  4. Heart and liver T2* assessment for iron overload using different software programs

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes, Juliano L. [University of Campinas, Unicamp, Campinas (Brazil); Radiologia Clinica de Campinas, Campinas (Brazil); Cardiology, Department of Internal Medicine, Campinas, SP (Brazil); Sampaio, Erika Fontana; Coelho, Otavio R. [University of Campinas, Unicamp, Campinas (Brazil); Verissimo, Monica; Pereira, Fabricio B. [Centro Infantil Boldrini, Campinas (Brazil); Silva, Jose Alvaro da; Figueiredo, Gabriel S. de; Kalaf, Jose M. [Radiologia Clinica de Campinas, Campinas (Brazil)

    2011-12-15

    To assess the level of agreement and interchangeability among different software programs for calculation of T2* values for iron overload. T2* images were analysed in 60 patients with thalassaemia major using the truncation method in three software programs. Levels of agreement were assessed using Pearson correlation and Bland-Altman plots. Categorical classification for levels of iron concentration by each software program was also compared. For the heart, all correlation coefficients were significant among the software programs (P < 0.001 for all coefficients). The mean differences and 95% limits of agreement were 0.2 (-4.73 to 5.0); 0.1 (-4.0 to 3.9); and -0.1 (-4.3 to 4.8). For the liver all correlations were also significant with P < 0.001. Bland-Altman plots showed differences of -0.02 (-0.7 to 0.6); 0.01 (-0.4 to 0.4); and -0.02 (-0.6 to 0.6). There were no significant differences in clinical classification among the software programs. All tools used in this study provided very good agreement among heart and liver T2* values. The results indicate that interpretation of T2* data is interchangeable with any of the software programs tested. (orig.)

  5. Chelation Therapy with Oral Solution of Deferiprone in Transfusional Iron-Overloaded Children with Hemoglobinopathies

    Directory of Open Access Journals (Sweden)

    Alexandros Makis

    2013-01-01

    Full Text Available Iron overload in hemoglobinopathies is secondary to blood transfusions, chronic hemolysis, and increased iron absorption and leads to tissue injury requiring the early use of chelating agents. The available agents are parenteral deferoxamine and oral deferiprone and deferasirox. There are limited data on the safety and efficacy of deferiprone at a very young age. The aim of our study was the presentation of data regarding the use of oral solution of deferiprone in 9 children (mean age 6.5, range 2–10 with transfusion dependent hemoglobinopathies (6 beta thalassemia major, 1 thalassemia intermedia, and 2 sickle cell beta thalassemia. The mean duration of treatment was 21.5 months (range 15–31. All children received the oral solution without any problems of compliance. Adverse reactions were temporary abdominal discomfort and diarrhea (1 child, mild neutropenia (1 child that resolved with no need of discontinuation of treatment, and transient arthralgia (1 child that resolved spontaneously. The mean ferritin levels were significantly reduced at the end of 12 months (initial 2440 versus final 1420 μg/L, . This small study shows that oral solution of deferiprone was well tolerated by young children and its use was not associated with major safety concerns. Furthermore, it was effective in decreasing serum ferritin.

  6. Decitabine treatment could ameliorate primary iron-overload in myelodysplastic syndrome patients.

    Science.gov (United States)

    Shucheng, Gu; Chunkang, Chang; Youshan, Zhao; Juan, Guo; Chengming, Fei; Xi, Zhang; Chao, Xiao; Xiao, Li

    2015-04-01

    In order to research how does hypomethylating agents ameliorate iron metabolism in myelodysplastic syndrome (MDS), we performed methylation-specific, polymerase chain reaction (MSP), bisulfate genomic sequencing polymerase chain reaction (BSP), quantitative real-time PCR and western blot of hemojuvelin (HJV) and ELISA assay for hepcidin before and after demethylating therapy (decitabine) to determine whether the change of HJV methylation status would have an influence on hepcidin expression. Eleven of 22 MDS patients achieved CR or PR according to IWG criteria (50%). HJV mRNA was induced in decitabine responders (p = .006 comparing pre/post decitabine treatment) but not in non-responders (p = .121). Similarly, hepcidin serum expression increased from 320.77 ± 34.8 μg/L to 366.77 ± 21.90 μg/L (p = .012) in responders but did not significantly change in non-responders (p = .058), while no difference of adjusted serum ferritin (ASF) was found. In conclusion, hypermethylation of HJV promoter region could silence the gene expression and demethylating therapy might ameliorate iron-overload through HJV demethylation.

  7. Comparison of myocardial T1 and T2 values in 3 T with T2* in 1.5 T in patients with iron overload and controls.

    Science.gov (United States)

    Camargo, Gabriel C; Rothstein, Tamara; Junqueira, Flavia P; Fernandes, Elsa; Greiser, Andreas; Strecker, Ralph; Pessoa, Viviani; Lima, Ronaldo S L; Gottlieb, Ilan

    2016-05-01

    Myocardial iron quantification remains limited to 1.5 T systems with T2* measurement. The present study aimed at comparing myocardial T2* values at 1.5 T to T1 and T2 mapping at 3.0 T in patients with iron overload and healthy controls. A total of 17 normal volunteers and seven patients with a history of myocardial iron overload were prospectively enrolled. Mid-interventricular septum T2*, native T1 and T2 times were quantified on the same day, using a multi-echo gradient-echo sequence at 1.5 T and T1 and T2 mapping sequences at 3.0 T, respectively. Subjects with myocardial iron overload (T2* iron overload quantification.

  8. Deferasirox Decreases Liver Iron Concentration in Iron-Overloaded Patients with Myelodysplastic Syndromes, Aplastic Anemia and Other Rare Anemias.

    Science.gov (United States)

    Kohgo, Yutaka; Urabe, Akio; Kilinç, Yurdanur; Agaoglu, Leyla; Warzocha, Krzysztof; Miyamura, Koichi; Lim, Lay Cheng; Glaser, Sabine; Wang, Candace; Wiktor-Jedrzejczak, Wieslaw

    2015-01-01

    Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10–40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was –10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and –13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).

  9. Frequency of primary iron overload and HFE gene mutations (C282Y, H63D and S65C) in chronic liver disease patients in north India

    Institute of Scientific and Technical Information of China (English)

    Barjinderjit Kaur Dhillon; Reena Das; Gurjeewan Garewal; Yogesh Chawla; RK Dhiman; Ashim Das; Ajay Duseja; GR Chandak

    2007-01-01

    AIM: To identify the frequency of iron overload and study the three mutations in the HFE gene (C282Y,H63D, and S65C) in patients with chronic liver disorders (CLD) and controls.METHODS: To identify patients with iron overload (transferrin saturation > 45% in females and > 50% in males and serum ferritin > 1000 ng/mL) we evaluated 236 patients with CLD, including 59 with non-alcoholic steatohepatitis (NASH), 22 with alcoholic liver disease (ALD), 19 of cirrhosis due to viruses (HBV, HCV), and 136 with cryptogenic cirrhosis. Mutations of the HFE gene were analyzed by PCR-RE. hundred controls were screened for iron status and the mutations.RESULTS: Seventeen patients with CLD showed evidence of iron overload. Fifteen cases of iron overload had cryptogenic cirrhosis and two had ALD. None of the controls showed iron overload. We did not find any individual with 282Y or 65C either in the cases or in the controls. The prevalence of H63D heterozygosity was 12% in normal individuals, 14.8% in 236 patients (16.9% in NASH, 13.6% in ALD, 26.3% in viral and 12.5% in cryptogenic cirrhosis) and the overall prevalence was 13.98%. Only two of the 17 patients with primary iron overload were heterozygous for H63D. One patient with NASH and one normal individual who were homozygous for H63D showed no iron overload.CONCLUJSION: Primary iron overload in Indians is nonHFE type, which is different from that in Europeans and further molecular studies are required to determine the defect in various iron regulatory genes.

  10. Spatial learning, monoamines and oxidative stress in rats exposed to 900 MHz electromagnetic field in combination with iron overload.

    Science.gov (United States)

    Maaroufi, Karima; Had-Aissouni, Laurence; Melon, Christophe; Sakly, Mohsen; Abdelmelek, Hafedh; Poucet, Bruno; Save, Etienne

    2014-01-01

    The increasing use of mobile phone technology over the last decade raises concerns about the impact of high frequency electromagnetic fields (EMF) on health. More recently, a link between EMF, iron overload in the brain and neurodegenerative disorders including Parkinson's and Alzheimer's diseases has been suggested. Co-exposure to EMF and brain iron overload may have a greater impact on brain tissues and cognitive processes than each treatment by itself. To examine this hypothesis, Long-Evans rats submitted to 900 MHz exposure or combined 900 MHz EMF and iron overload treatments were tested in various spatial learning tasks (navigation task in the Morris water maze, working memory task in the radial-arm maze, and object exploration task involving spatial and non spatial processing). Biogenic monoamines and metabolites (dopamine, serotonin) and oxidative stress were measured. Rats exposed to EMF were impaired in the object exploration task but not in the navigation and working memory tasks. They also showed alterations of monoamine content in several brain areas but mainly in the hippocampus. Rats that received combined treatment did not show greater behavioral and neurochemical deficits than EMF-exposed rats. None of the two treatments produced global oxidative stress. These results show that there is an impact of EMF on the brain and cognitive processes but this impact is revealed only in a task exploiting spontaneous exploratory activity. In contrast, there are no synergistic effects between EMF and a high content of iron in the brain.

  11. HFE MUTATIONS AND IRON OVERLOAD IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

    Directory of Open Access Journals (Sweden)

    Luis COSTA-MATOS

    2013-03-01

    Full Text Available Context Alcoholic liver disease (ALD is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE gene mutations and the severity of liver disease in alcoholic patients. Objectives To compare the prevalence of mutations in the hemochromatosis (HFE gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity. Methods Liver biopsy specimens were obtained from 63 ALD patients (during routine treatment and 52 healthy controls (during elective cholecystectomy. All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations. Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis. Results ALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P<0.05, but the distribution of HFE mutations was similar between the two groups. For ALD patients, the odds ratio for having at least one HFE mutation and excessive liver iron stores was 17.23 (95% confidence interval (CI: 2.09-142.34, P = 0.008. However, the presence of at least one HFE mutation was not associated with an increased risk of liver fibrosis or necroinflammatory activity. Active alcohol ingestion showed the strongest association to increased serum ferritin (OR = 8.87, 95% CI: 2.11-34.78, P = 0.003. Conclusions ALD patients do not present with a differential profile of HFE mutations from healthy controls. In ALD patients, however, the presence of at least one HFE mutation increases the risk of having excessive liver iron stores but has no

  12. Postnatal ablation of Foxm1 from cardiomyocytes causes late onset cardiac hypertrophy and fibrosis without exacerbating pressure overload-induced cardiac remodeling.

    Science.gov (United States)

    Bolte, Craig; Zhang, Yufang; York, Allen; Kalin, Tanya V; Schultz, Jo El J; Molkentin, Jeffery D; Kalinichenko, Vladimir V

    2012-01-01

    Heart disease remains a leading cause of morbidity and mortality in the industrialized world. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and the most common cause of sudden cardiac death. Foxm1 transcription factor (also known as HFH-11B, Trident, Win or MPP2) plays an important role in the pathogenesis of various cancers and is a critical mediator of post-injury repair in multiple organs. Foxm1 has been previously shown to be essential for heart development and proliferation of embryonic cardiomyocytes. However, the role of Foxm1 in postnatal heart development and in cardiac injury has not been evaluated. To delete Foxm1 in postnatal cardiomyocytes, αMHC-Cre/Foxm1(fl/fl) mice were generated. Surprisingly, αMHC-Cre/Foxm1(fl/fl) mice exhibited normal cardiomyocyte proliferation at postnatal day seven and had no defects in cardiac structure or function but developed cardiac hypertrophy and fibrosis late in life. The development of cardiomyocyte hypertrophy and cardiac fibrosis in aged Foxm1-deficient mice was associated with reduced expression of Hey2, an important regulator of cardiac homeostasis, and increased expression of genes critical for cardiac remodeling, including MMP9, αSMA, fibronectin and vimentin. We also found that following aortic constriction Foxm1 mRNA and protein were induced in cardiomyocytes. However, Foxm1 deletion did not exacerbate cardiac hypertrophy or fibrosis following chronic pressure overload. Our results demonstrate that Foxm1 regulates genes critical for age-induced cardiomyocyte hypertrophy and cardiac fibrosis.

  13. Study of the effect of iron overload on the function of endocrine glands in male thalassemia patients

    Directory of Open Access Journals (Sweden)

    Abdulzahra Mohammed

    2011-01-01

    Full Text Available Background: Iron overload is an important issue in the state of thalassemic patients due to the harmful effect of high concentration of iron deposited in different tissues in human body including endocrine glands. In the present work, an attempt is carried out to estimate the effect of iron overload in thalassemic patients on the function of endocrine glands through the estimation of their ability to secrete adequate amounts of certain hormones. Materials and Methods: Seventy eight male children with beta-thalassemia, in the age-group of 4-11 years, were enrolled for this research. These children were being treated with frequent transfusions and long-term iron chelation therapy. Thirty age and sex matched children without thalassemia constituted the control group. Ferritin and different hormones were estimated by ELISA technique. Results: The results showed a mild reduction in the function of endocrine glands through the decrease in the level of some hormones. These changes due mainly to the hypoxia and precipitation of iron in certain glands and overlapping with the synthesis or secretion of the hormones. Conclusion: There is a different hormonal disturbances in beta thalassemia patients. Reduction of total body iron store is an important goal of the treatment of thalassemia and measuring the hormones concentration is necessary for the follow up of the thalassemic patients especially during puberty.

  14. Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis

    OpenAIRE

    Ye, Qi; Kim, Jonghan

    2015-01-01

    Manganese in excess promotes unstable emotional behavior. Our previous study showed that olfactory manganese uptake into the brain is altered in Hfe−/− mice, a model of iron overload hemochromatosis, suggesting that Hfe deficiency could modify the neurotoxicity of airborne manganese. We determined anxiety-related behavior and monoaminergic protein expression after repeated intranasal instillation of MnCl2 to Hfe−/− mice. Compared with manganese-instilled wild-type mice, Hfe−/− mice showed dec...

  15. β-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload

    Science.gov (United States)

    Melchiori, Luca; Gardenghi, Sara; Rivella, Stefano

    2010-01-01

    β-thalassemia encompasses a group of monogenic diseases that have in common defective synthesis of β-globin. The defects involved are extremely heterogeneous and give rise to a large phenotypic spectrum, with patients that are almost asymptomatic to cases in which regular blood transfusions are required to sustain life. As a result of the inefficient synthesis of β-globin, the patients suffer from chronic anemia due to a process called ineffective erythropoiesis (IE). The sequelae of IE lead to extramedullary hematopoiesis (EMH) with massive splenomegaly and dramatic iron overload, which in turn is responsible for many of the secondary pathologies observed in thalassemic patients. The processes are intimately linked such that an ideal therapeutic approach should address all of the complications. Although β-thalassemia is one of the first monogenic diseases to be described and represents a global health problem, only recently has the scientific community started to focus on the real molecular mechanisms that underlie this disease, opening new and exciting therapeutic perspectives for thalassemic patients worldwide. PMID:20508726

  16. beta-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload.

    Science.gov (United States)

    Melchiori, Luca; Gardenghi, Sara; Rivella, Stefano

    2010-01-01

    beta-thalassemia encompasses a group of monogenic diseases that have in common defective synthesis of beta-globin. The defects involved are extremely heterogeneous and give rise to a large phenotypic spectrum, with patients that are almost asymptomatic to cases in which regular blood transfusions are required to sustain life. As a result of the inefficient synthesis of beta-globin, the patients suffer from chronic anemia due to a process called ineffective erythropoiesis (IE). The sequelae of IE lead to extramedullary hematopoiesis (EMH) with massive splenomegaly and dramatic iron overload, which in turn is responsible for many of the secondary pathologies observed in thalassemic patients. The processes are intimately linked such that an ideal therapeutic approach should address all of the complications. Although beta-thalassemia is one of the first monogenic diseases to be described and represents a global health problem, only recently has the scientific community started to focus on the real molecular mechanisms that underlie this disease, opening new and exciting therapeutic perspectives for thalassemic patients worldwide.

  17. Effects of iron overload on the bone marrow microenvironment in mice.

    Directory of Open Access Journals (Sweden)

    Yuchen Zhang

    Full Text Available OBJECTIVE: Using a mouse model, Iron Overload (IO induced bone marrow microenvironment injury was investigated, focusing on the involvement of reactive oxygen species (ROS. METHODS: Mice were intraperitoneally injected with iron dextran (12.5, 25, or 50 mg every three days for two, four, and six week durations. Deferasirox(DFX125 mg/ml and N-acetyl-L-cysteine (NAC 40 mM were co-administered. Then, bone marrow derived mesenchymal stem cells (BM-MSCs were isolated and assessed for proliferation and differentiation ability, as well as related gene changes. Immunohistochemical analysis assessed the expression of haematopoietic chemokines. Supporting functions of BM-MSCs were studied by co-culture system. RESULTS: In IO condition (25 mg/ml for 4 weeks, BM-MSCs exhibited proliferation deficiencies and unbalanced osteogenic/adipogenic differentiation. The IO BM-MSCs showed a longer double time (2.07±0.14 days than control (1.03±0.07 days (P<0.05. The immunohistochemical analysis demonstrated that chemokine stromal cell-derived factor-1, stem cell factor -1, and vascular endothelial growth factor-1 expression were decreased. The co-cultured system demonstrated that bone marrow mononuclear cells (BMMNCs co-cultured with IO BM-MSCs had decreased colony forming unit (CFU count (p<0.01, which indicates IO could lead to decreased hematopoietic supporting functions of BM-MSCs. This effect was associated with elevated phosphatidylinositol 3 kinase (PI3K and reduced of Forkhead box protein O3 (FOXO3 mRNA expression, which could induce the generation of ROS. Results also demonstrated that NAC or DFX treatment could partially attenuate cell injury and inhibit signaling pathway striggered by IO. CONCLUSION: These results demonstrated that IO can impair the bone marrow microenvironment, including the quantity and quality of BM-MSCs.

  18. Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study.

    Science.gov (United States)

    Cançado, Rodolfo; Melo, Murilo R; de Moraes Bastos, Roberto; Santos, Paulo C J L; Guerra-Shinohara, Elivira M; Chiattone, Carlos; Ballas, Samir K

    2015-12-01

    This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.

  19. Iron Chelation Therapy with Deferasirox in the Management of Iron Overload in Primary Myelofibrosis

    Science.gov (United States)

    Elli, Elena Maria; Belotti, Angelo; Aroldi, Andrea; Parma, Matteo; Pioltelli, Pietro; Pogliani, Enrico Maria

    2014-01-01

    Deferasirox (DSX) is the principal option currently available for iron-chelation-therapy (ICT), principally in the management of myelodysplastic syndromes (MDS), while in primary myelofibrosis (PMF) the expertise is limited. We analyzed our experience in 10 PMF with transfusion-dependent anemia, treated with DSX from September 2010 to December 2013. The median dose tolerated of DSX was 750 mg/day (10 mg/kg/day), with 3 transient interruption of treatment for drug-related adverse events (AEs) and 3 definitive discontinuation for grade 3/4 AEs. According to IWG 2006 criteria, erythroid responses with DSX were observed in 4/10 patients (40%), 2 of them (20%) obtaining transfusion independence. Absolute changes in median serum ferritin levels (Delta ferritin) were greater in hematologic responder (HR) compared with non-responder (NR) patients, already at 6 months of ICT respect to baseline. Our preliminary data open new insights regarding the benefit of ICT not only in MDS, but also in PMF with the possibility to obtain an erythroid response, overall in 40 % of patients. HR patients receiving DSX seem to have a better survival and a lower incidence of leukemic transformation (PMF-BP). Delta ferritin evaluation at 6 months could represent a significant predictor for a different survival and PMF-BP. However, the tolerability of the drug seems to be lower compared to MDS, both in terms of lower median tolerated dose and for higher frequency of discontinuation for AEs. The biological mechanism of action of DSX in chronic myeloproliferative setting through an independent NF-κB inhibition could be involved, but further investigations are required. PMID:24959339

  20. IRON CHELATION THERAPY WITH DEFERASIROX IN THE MANAGEMENT OF IRON OVERLOAD IN PRIMARY MYELOFIBROSIS

    Directory of Open Access Journals (Sweden)

    Elena Maria Elli

    2014-05-01

    Full Text Available Deferasirox (DSX is the principal option currently available for iron-chelation-therapy (ICT, principally in the management of myelodysplastic syndromes (MDS, while in primary myelofibrosis (PMF the expertise is limited. We analyzed our experience in 10 PMF with transfusion-dependent anemia, treated with DSX from September 2010 to December 2013. The median dose tolerated of DSX was 750 mg/day (10 mg/kg/day, with 3 transient interruption of treatment for drug-related adverse events (AEs and 3 definitive discontinuation for grade 3/4 AEs. According to IWG 2006 criteria, erythroid responses with DSX were observed in 4/10 patients (40%, 2 of them (20% obtaining transfusion independence. Absolute changes in median serum ferritin levels (Delta ferritin were greater in hematologic responder (HR compared with non-responder (NR  patients, already at 6 months of ICT respect to baseline. Our preliminary data open new insights regarding the benefit of ICT not only in MDS, but also in PMF with the possibility to obtain an erythroid response, overall in 40 % of patients. HR patients receiving DSX seem to have a better survival and a lower incidence of leukemic transformation (PMF-BP. Delta ferritin evaluation at 6 months could represent a significant predictor for a different survival and PMF-BP.  However, the tolerability of the drug seems to be lower compared to MDS, both in terms of lower median tolerated dose and for higher frequency of discontinuation for AEs. The biological mechanism of action of DSX in chronic myeloproliferative setting through an independent NF-κB inhibition could be involved, but further investigations are required.

  1. Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy

    Science.gov (United States)

    Li, Wei; Goodwin, Charles B.; Richine, Briana; Acton, Anthony; Chan, Rebecca J.; Peacock, Munro; Muhoberac, Barry B.; Ghetti, Bernardino; Vidal, Ruben

    2016-01-01

    Mutations in the ferritin light chain (FTL) gene cause the neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic iron-containing ferritin inclusion bodies (IBs) in glia and neurons throughout the central nervous system (CNS) and in tissues of multiple organ systems. Herein, using primary mouse embryonic fibroblasts from a mouse model of HF, we show significant intracellular accumulation of ferritin and an increase in susceptibility to oxidative damage when cells are exposed to iron. Treatment of the cells with the iron chelator deferiprone (DFP) led to a significant improvement in cell viability and a decrease in iron content. In vivo, iron overload and DFP treatment of the mouse model had remarkable effects on systemic iron homeostasis and ferritin deposition, without significantly affecting CNS pathology. Our study highlights the role of iron in modulating ferritin aggregation in vivo in the disease HF. It also puts emphasis on the potential usefulness of a therapy based on chelators that can target the CNS to remove and redistribute iron and to resolubilize or prevent ferritin aggregation while maintaining normal systemic iron stores. PMID:27574973

  2. Long Non-Coding RNA Malat-1 Is Dispensable during Pressure Overload-Induced Cardiac Remodeling and Failure in Mice.

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    Tim Peters

    Full Text Available Long non-coding RNAs (lncRNAs are a class of RNA molecules with diverse regulatory functions during embryonic development, normal life, and disease in higher organisms. However, research on the role of lncRNAs in cardiovascular diseases and in particular heart failure is still in its infancy. The exceptionally well conserved nuclear lncRNA Metastasis associated in lung adenocarcinoma transcript 1 (Malat-1 is a regulator of mRNA splicing and highly expressed in the heart. Malat-1 modulates hypoxia-induced vessel growth, activates ERK/MAPK signaling, and scavenges the anti-hypertrophic microRNA-133. We therefore hypothesized that Malat-1 may act as regulator of cardiac hypertrophy and failure during cardiac pressure overload induced by thoracic aortic constriction (TAC in mice.Absence of Malat-1 did not affect cardiac hypertrophy upon pressure overload: Heart weight to tibia length ratio significantly increased in WT mice (sham: 5.78±0.55, TAC 9.79±1.82 g/mm; p<0.001 but to a similar extend also in Malat-1 knockout (KO mice (sham: 6.21±1.12, TAC 8.91±1.74 g/mm; p<0.01 with no significant difference between genotypes. As expected, TAC significantly reduced left ventricular fractional shortening in WT (sham: 38.81±6.53%, TAC: 23.14±11.99%; p<0.01 but to a comparable degree also in KO mice (sham: 37.01±4.19%, TAC: 25.98±9.75%; p<0.05. Histological hallmarks of myocardial remodeling, such as cardiomyocyte hypertrophy, increased interstitial fibrosis, reduced capillary density, and immune cell infiltration, did not differ significantly between WT and KO mice after TAC. In line, the absence of Malat-1 did not significantly affect angiotensin II-induced cardiac hypertrophy, dysfunction, and overall remodeling. Above that, pressure overload by TAC significantly induced mRNA levels of the hypertrophy marker genes Nppa, Nppb and Acta1, to a similar extend in both genotypes. Alternative splicing of Ndrg2 after TAC was apparent in WT (isoform ratio

  3. Velvet antler peptide prevents pressure overload-induced cardiac fibrosis via transforming growth factor (TGF)-β1 pathway inhibition.

    Science.gov (United States)

    Zhao, Lihong; Mi, Yang; Guan, Hongya; Xu, Yan; Mei, Yingwu

    2016-07-15

    Velvet antlers (VAs) are commonly used in traditional Chinese medicine and invigorant and contain many functional components for health promotion. The velvet antler peptide sVAP32 is one of active components in VAs; based on structural study, the sVAP32 interacts with TGF-β1 receptors and disrupts the TGF-β1 pathway. We hypothesized that sVAP32 prevents cardiac fibrosis from pressure overload by blocking TGF-β1 signaling. Sprague-Dawley rats underwent transverse aortic constriction (TAC) or a sham operation. After one month, rats received either sVAP32 (15mg/kg/day) or vehicle for an additional one month. TAC surgery induced significant cardiac dysfunction, fibroblast activation and fibrosis; these effects were improved by treatment with sVAP32. In the heart tissue, TAC remarkably increased the expression of TGF-β1 and connective tissue growth factor (CTGF), reactive oxygen species levels, and the phosphorylation levels of Smad2/3 and extracellular signal-regulated kinases 1/2 (ERK1/2). SVAP32 inhibited the increases in reactive oxygen species levels, CTGF expression and the phosphorylation of Smad2/3 and ERK1/2, but not TGF-β1 expression. In cultured cardiac fibroblasts, angiotensin II (Ang II) had similar effects compared to TAC surgery, such as increases in α-SMA-positive cardiac fibroblasts and collagen synthesis. SVAP32 eliminated these effects by disrupting TGF-β1 binding to its receptors and blocking Ang II/TGF-β1 downstream signaling. These results demonstrated that sVAP32 has anti-fibrotic effects by blocking the TGF-β1 pathway in cardiac fibroblasts.

  4. Temporal evaluation of cardiac myocyte hypertrophy and hyperplasia in male rats secondary to chronic volume overload.

    Science.gov (United States)

    Du, Yan; Plante, Eric; Janicki, Joseph S; Brower, Gregory L

    2010-09-01

    The temporal myocardial remodeling induced by chronic ventricular volume overload in male rats was examined. Specifically, left ventricular (LV) cardiomyocyte length and width, sarcomere length, and number of nuclei were measured in male rats (n = 8 to 17) at 1, 3, 5, 7, 21, 35, and 56 days after creation of an infrarenal aortocaval fistula. In contrast to previously published reports of progressive increases in cardiomyocyte length and cross-sectional area at 5 days post-fistula and beyond in female hearts, cardiomyocyte length and width did not increase significantly in males during the first 35 days of volume overload. Furthermore, a significant decrease in cardiomyocyte length relative to age-matched controls, together with a reduced number of sarcomeres per cell, was noted in male hearts at 5 days post-fistula. There was a concurrent increase in the percentage of mononucleated cardiomyocytes from 11.6% to 18% at 5 days post-fistula. These initial differences could not be attributed to cardiomyocyte proliferation, and treatment with a microtubule stabilizing agent prevented them from occurring. The subsequent significant increase in LV weight without corresponding increases in cardiomyocyte dimensions is indicative of hyperplasia. Thus, these findings indicate hyperplasia resulting from cytokinesis of cardiomyocytes is a key mechanism, independent of hypertrophy, that contributes to the significant increase in LV mass in male hearts subjected to chronic volume overload.

  5. CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload

    NARCIS (Netherlands)

    Fontes, Magda S C; Kessler, Elise L; van Stuijvenberg, Leonie; Brans, Maike A; Falke, LL; Kok, Bart; Leask, Andrew; van Rijen, HVM; Vos, MA; Goldschmeding, Roel; van Veen, AAB

    2015-01-01

    BACKGROUND: One of the main contributors to maladaptive cardiac remodeling is fibrosis. Connective tissue growth factor (CTGF), a matricellular protein that is secreted into the cardiac extracellular matrix by both cardiomyocytes and fibroblasts, is often associated with development of fibrosis. How

  6. Assessment and management of iron overload in β-thalassaemia major patients during the 21st century: a real-life experience from the Italian WEBTHAL project.

    Science.gov (United States)

    Piga, Antonio; Longo, Filomena; Musallam, Khaled M; Cappellini, Maria Domenica; Forni, Gian Luca; Quarta, Giovanni; Chiavilli, Francesco; Commendatore, Francesca; Mulas, Sergio; Caruso, Vincenzo; Galanello, Renzo

    2013-06-01

    We conducted a cross-sectional study on 924 β-thalassaemia major patients (mean age 30·1 years) treated at nine Italian centres using the WEBTHAL software, to evaluate real-life application of iron overload assessment and management standards. Serum ferritin 2 years. Patients who never had a cardiac MRI (CMR) T2* measurement were 2 years. Deferoxamine (22·8%) was more commonly used in patients with Hepatitis C Virus or high serum creatinine. Deferiprone (20·6%) was less commonly prescribed in patients with elevated alanine aminotransferase; while a deferoxamine + deferiprone combination (17·9%) was more commonly used in patients with serum ferritin >2500 ng/ml or CMR T2* <20 ms. Deferasirox (38·3%) was more commonly prescribed in patients <18 years, but less commonly used in those with heart disease or high iron intake. These observations largely echoed guidelines at the time, although some practices are expected to change in light of evolving evidence.

  7. T lymphocytes and iron overload: novel correlations of possible significance to the biology of the immunological system

    Directory of Open Access Journals (Sweden)

    Maria de Sousa

    1992-01-01

    Full Text Available This paper is written in the context of our changing preception of the immunological system as a system with possible biological roles exceding the prevailung view of a system concerned principally with the defense against external pathogens. The view discussed here relates the immunological system inextricably to the metabolism of iron, the circulation of the blood and the resolution of the evolutionary paradox created by oxygen and iron. Indirect evidence for this inextricable relationship between the two systems can be derived from the discrepancy between the theoretical quasi-impossibility of the existence of an iron deficiency state in the adult and the reality of the WHO numbers of people in the world with iron deficiency anemia. With mounting evidence that TNF, IL-1, and T lymphocyte cytokines affect hemopoieisis and iron metabolism it is possible that the reported discrepancy is a reflection of that inextricable interdependence between the two systems in the face of infection. Further direct evidence for a relationship between T cell subset numbers and iron metabolism is presented from the results of a study of T cell populations in patients with hereditary hemochromatosis. The recent finding of a correlation between low CD8+ lymphocite numbers, liver demage associated with HCVpositivity and severity of iron overload in B-thalassemia major patients (umpublished data of RW Grandy; P. Giardina, M. Hilgartner concludes this review.

  8. Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease.

    Science.gov (United States)

    Becerril-Ortega, Javier; Bordji, Karim; Fréret, Thomas; Rush, Travis; Buisson, Alain

    2014-10-01

    Iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model mice, respectively. In both systems, we observed iron-induced disruptions of amyloid precursor protein (APP) processing, neuronal signaling, and cognitive behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting the effect was N-methyl-D-aspartate receptor (NMDAR) dependent. Calcium imaging confirmed that 24 hours iron exposure led to disrupted synaptic signaling by augmenting GluN2B-containing NMDAR expression-GluN2B messenger RNA and protein levels were increased and promoting excessing extrasynaptic NMDAR signaling. The disrupted GluN2B expression was concurrent with diminished expression of the splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led to hastened progression of cognitive impairment with the novel object recognition discrimination index, revealing a deficit at the age of 4 months, concomitant with augmented GluN2B expression. Together, these data suggest iron-induced APP misprocessing and hastened cognitive decline occur through inordinate extrasynaptic NMDAR activation.

  9. THE DIAGNOSTIC VALUE OF PULSED WAVE TISSUE DOPPLER IMAGING IN ASYMPTOMATIC BETA- THALASSEMIA MAJOR CHILDREN AND YOUNG ADULTS ; RELATION TO CHEMICAL BIOMARKERS OF LEFT VENTRICULAR FUNCTION AND IRON OVERLOAD .

    Directory of Open Access Journals (Sweden)

    Seham Ragab

    2015-08-01

    Full Text Available Background: Cardiac iron toxicity is the leading cause of death among  β-halassaemia major (TM  patients.  Once  heart failure becomes overt , it will be  difficult to reverse . Objectives: To investigate non overt cardiac dysfunctions  in TM patients using  pulsed wave Tissue Doppler  Imaging (TD I and its relation to the iron overload and brain natruritic peptide (BNP. Methods: Thorough  clinical , conventional echo and  pulsed  wave TDI  parameters were compared between  asymtomatic 25 β-TM  patients  and 20 age and gender matched individuals. Serum ferritin and plasma BNP  levels were assayed by  ELISA .  Results: TM patients had significant higher mitral inflow early diastolic (E wave and  non significant other conventional echo  parameters. Pulsed wave TDI revealed systolic and diastolic dysfunctions in the form of significant higher  isovolumetric contraction time (ICT , ejection time ( E T and  isovolumetric relaxation time (IRT with significantly lower  mitral annulus  early diastolic velocity E` (12.07 ±2.06 vs 15.04±2.65 ,P= 0.003  in patients compared to  controls. Plasma BNP was higher in patients compared to the controls.  Plasma BNP and serum ferritin had significant correlation with each other and with pulsed wave conventional and TDI indices of systolic and diastolic functions.  Patients with E/E` ≥ 8 had  significant higher  serum ferritin  and plasma BNP levels compared to those with E/E` ratio < 8 without difference in Hb levels .Conclusion:  Pulsed wave TDI  is an  important diagnostic tool for latent cardiac dysfunction in iron loaded TM patients and is related to iron overload and BNP .

  10. Iron Chelation

    Science.gov (United States)

    Skip to main content Menu Donate Treatments Therapies Iron Chelation Iron chelation therapy is the main treatment ... have iron overload and need treatment. What is iron overload? Iron chelation therapy is used when you ...

  11. Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway

    Science.gov (United States)

    Rani, Shilpa; Sreenivasaiah, Pradeep Kumar; Cho, Chunghee; Kim, Do Han

    2017-01-01

    Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit (p-eIF2)-α, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal (0.5 mg·kg−1·day−1) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling. PMID:28152298

  12. Effect of cardiac glycosides on action potential characteristics and contractility in cat ventricular myocytes: role of calcium overload.

    Science.gov (United States)

    Ruch, Stuart R; Nishio, Manabu; Wasserstrom, J Andrew

    2003-10-01

    There is increasing evidence that cardiac glycosides act through mechanisms distinct from inhibition of the sodium pump but which may contribute to their cardiac actions. To more fully define differences between agents indicative of multiple sites of action, we studied changes in contractility and action potential (AP) configuration in cat ventricular myocytes produced by six cardiac glycosides (ouabain, ouabagenin, dihydroouabain, actodigin, digoxin, and resibufogenin). AP shortening was observed only with ouabain and actodigin. There was extensive inotropic variability between agents, with some giving full inotropic effects before automaticity occurred whereas others produced minimal inotropy before toxicity. AP shortening was not a result of alterations in calcium current or the inward rectifier potassium current, but correlated with an increase in steady-state outward current (Iss), which was sensitive to KB-R7943, a Na+-Ca2+ exchange (NCX) inhibitor. Interestingly, Iss was observed following exposure to ouabain and dihydroouabain, suggesting that an additional mechanism is operative with dihydroouabain that prevents AP shortening. Further investigation into differences in inotropy between ouabagenin, dihydroouabain and ouabain revealed almost identical responses under AP voltage clamp. Thus all agents appear to act on the sodium pump and thereby secondarily increase the outward reverse mode NCX current, but the extent of AP duration shortening and positive inotropy elicited by each agent is limited by development of their toxic actions. The quantitative differences between cardiac glycosides suggest that mechanisms independent of sodium pump inhibition may result from an altered threshold for calcium overload possibly involving direct or indirect effects on calcium release from the sarcoplasmic reticulum.

  13. Loss of Bmx Non-Receptor Tyrosine Kinase Prevents Pressure Overload-Induced Cardiac Hypertrophy

    OpenAIRE

    2008-01-01

    Bmx non-receptor tyrosine kinase has an established role in endothelial and lymphocyte signaling, however its role in the heart is unknown. To determine whether Bmx participates in cardiac growth, we subjected mice deficient in the molecule (Bmx KO mice) to transverse aortic constriction (TAC). In comparison to WT mice, which progressively developed massive hypertrophy following TAC, Bmx KO mice were resistant to TAC-induced cardiac growth at the organ and cell level. Loss of Bmx preserved ca...

  14. Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with β-thalassaemia: the ESCALATOR study

    Science.gov (United States)

    Taher, Ali; El-Beshlawy, Amal; Elalfy, Mohsen S; Al Zir, Kusai; Daar, Shahina; Habr, Dany; Kriemler-Krahn, Ulrike; Hmissi, Abdel; Al Jefri, Abdullah

    2009-01-01

    Objective: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake. Methods: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients ≥2 yr with β-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of ≥3 mg Fe/g dry weight (dw) if baseline LIC was ≥10 mg Fe/g dw, or final LIC of 1–7 mg Fe/g dw for patients with baseline LIC of 2 to <10 mg Fe/g dw. Results: Overall, 233/237 enrolled patients completed 1 yr’s treatment. Mean baseline LIC was 18.0 ± 9.1 mg Fe/g dw, while median serum ferritin was 3356 ng/mL. After 1 yr’s deferasirox treatment, the intent-to-treat population experienced a significant treatment success rate of 57.0% (P = 0.016) and a mean reduction in LIC of 3.4 mg Fe/g dw. Changes in serum ferritin appeared to parallel dose increases at around 24 wk. Most patients (78.1%) underwent dose increases above 20 mg/kg/d, primarily to 30 mg/kg/d. Drug-related adverse events were mostly mild to moderate and resolved without discontinuing treatment. Conclusions: The results of the ESCALATOR study in primarily heavily iron-overloaded patients confirm previous observations in patients with β-thalassaemia, highlighting the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure patients achieve their therapeutic goal of maintenance or reduction in iron burden

  15. Glutathione synthesis inhibitor butathione sulfoximine regulates ceruloplasmin by dual but opposite mechanism: Implication in hepatic iron overload.

    Science.gov (United States)

    Tapryal, Nisha; Mukhopadhyay, Chaitali; Mishra, Manoj Kumar; Das, Dola; Biswas, Sudipta; Mukhopadhyay, Chinmay K

    2010-06-01

    Glutathione (GSH) depletion is often detected in chronic pathological conditions like hepatitis C infection, alcohol consumption or xenobiotic assault with simultaneous reactive oxygen species (ROS) generation and hepatic iron overload. However, relation between GSH depletion and regulators of iron homeostasis is not clear so far. To determine that hepatic HepG2 cells were treated with GSH synthesis inhibitor butathione sulfoximine (BSO) and a dual regulation of ceruloplasmin (Cp) that involves in hepatic iron release was detected unlike other iron homeostasis regulators. BSO treatment that caused marginal GSH deficiency increased Cp synthesis due to increased transcription mediated by activator protein (AP)-1-binding site. In higher GSH deficiency (> 40 %) with increased ROS generation, Cp expression was decreased due to promotion of Cp mRNA decay mediated by 3'untranslated region (3'UTR) as found by transfecting chimera of chloramphenicol acetyl transferase (CAT) gene with Cp 3'UTR. RNA gel shift assay showed significant reduction in 3'UTR binding protein complex in similar condition. Decreased CAT expression and RNA-protein complex binding are reversed by pretreatment with antioxidant N-acetyl cysteine suggesting 3'UTR binding protein complex is redox-sensitive. This unique and opposite regulation of Cp provides a mechanism of hepatic iron-deposition during glutathione deficiency detected in chronic pathological conditions.

  16. Sobrecarga e quelação de ferro na anemia falciforme Iron overload and iron chelation in sickle cell disease

    Directory of Open Access Journals (Sweden)

    Rodolfo D. Cançado

    2007-09-01

    Full Text Available Pacientes cronicamente transfundidos desenvolvem sobrecarga de ferro que ocasiona lesão orgânica e morte. Nos últimos trinta anos, pacientes com sobrecarga de ferro transfusional dependem de infusões noturnas de desferroxamina para quelação de ferro. Apesar da dramática melhora da expectativa de vida na era da desferroxamina para pacientes com anemias dependentes de transfusão, 50% dos pacientes com talassemia maior morrem antes dos 30 anos de idade, predominantemente devido à insuficiência cardíaca induzida pelo ferro. A difícil natureza desse tratamento com infusão subcutânea prolongada por meio de aparelho infusor portátil motivou o desenvolvimento de formas alternativas de tratamento que facilitasse a aderência do paciente. Estratégias para reduzir a sobrecarga de ferro e suas conseqüências, através da melhora dos regimes de quelação, foram as prioridades mais importantes nos últimos anos. Nesta revisão, descrevemos os avanços mais importantes da terapia quelante de ferro. Em particular, analisamos os dois quelantes de ferro ativos por via oral: deferiprona e o novo quelante de ferro oral deferasirox.Patients who are chronically dependent on transfusions will develop iron overload that leads to organ damage and eventually to death. For nearly 30 years, patients with transfusional iron overload have been subject to overnight deferoxamine infusions for iron chelation. Despite dramatic gains in terms of life expectancy in the deferoxamine era for patients with transfusion-dependent anemias, 50% of patients with thalassemia major die before the age of 35 years, predominantly due to iron-induced heart failure. The very demanding nature of this treatment with prolonged subcutaneous infusion via portable pump infusions has been the motivation for attempts to develop alternative forms of treatment that would facilitate the patients' compliance. Strategies to reduce iron overload and its consequences by improving chelation

  17. Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in Native Americans and whites in the Hemochromatosis and Iron Overload Screening Study

    OpenAIRE

    Barton, JC; Acton, RT; Lovato, L; Speechley, MR; McLaren, CE; Harris, EL; Reboussin, DM; Adams, PC; Dawkins, FW; Gordeuk, VR; Walker, AP; Dixon, D.; Ferguson, S; Jones, R.; McKnight, J

    2006-01-01

    We compared initial screening transferrin saturation (TfSat) and serum ferritin (SF) phenotypes and HFE C282Y and H63D genotypes of 645 Native American and 43,453 white Hemochromatosis and Iron Overload Screening Study participants who did not report a previous diagnosis of hemochromatosis or iron overload. Elevated measurements were defined as TfSat >50% in men and >45% in women and SF>300 ng/ml in men and >200 ng/ml in women. Mean TfSat was 31% in Native American men and 32% in white men (p...

  18. Transformation rate between ferritin and hemosiderin assayed by serum ferritin kinetics in patients with normal iron stores and iron overload

    OpenAIRE

    Saito, Hiroshi; Hayashi, Hisao

    2015-01-01

    ABSTRACT Ferritin iron, hemosiderin iron, total iron stores and transformation rate were determined by serum ferritin kinetics. The transformation rate between ferritin and hemosiderin is motivated by the potential difference between them. The transformer determines transformation rate according to the potential difference in iron mobilization and deposition. The correlations between transformation rate and iron stores were studied in 11 patients with chronic hepatitis C (CHC), 1 patent with ...

  19. Al-hijamah and oral honey for treating thalassemia, conditions of iron overload, and hyperferremia: toward improving the therapeutic outcomes.

    Science.gov (United States)

    El Sayed, Salah Mohamed; Baghdadi, Hussam; Abou-Taleb, Ashraf; Mahmoud, Hany Salah; Maria, Reham A; Ahmed, Nagwa S; Helmy Nabo, Manal Mohamed

    2014-01-01

    Iron overload causes iron deposition and accumulation in the liver, heart, skin, and other tissues resulting in serious tissue damages. Significant blood clearance from iron and ferritin using wet cupping therapy (WCT) has been reported. WCT is an excretory form of treatment that needs more research efforts. WCT is an available, safe, simple, economic, and time-saving outpatient modality of treatment that has no serious side effects. There are no serious limitations or precautions to discontinue WCT. Interestingly, WCT has solid scientific and medical bases (Taibah mechanism) that explain its effectiveness in treating many disease conditions differing in etiology and pathogenesis. WCT utilizes an excretory physiological principle (pressure-dependent excretion) that resembles excretion through renal glomerular filtration and abscess evacuation. WCT exhibits a percutaneous excretory function that clears blood (through fenestrated skin capillaries) and interstitial fluids from pathological substances without adding a metabolic or detoxification burden on the liver and the kidneys. Interestingly, WCT was reported to decrease serum ferritin (circulating iron stores) significantly by about 22.25% in healthy subjects (in one session) and to decrease serum iron significantly to the level of causing iron deficiency (in multiple sessions). WCT was reported to clear blood significantly of triglycerides, low-density lipoprotein (LDL) cholesterol, total cholesterol, uric acid, inflammatory mediators, and immunoglobulin antibodies (rheumatoid factor). Moreover, WCT was reported to enhance the natural immunity, potentiate pharmacological treatments, and to treat many different disease conditions. There are two distinct methods of WCT: traditional WCT and Al-hijamah (WCT of prophetic medicine). Both start and end with skin sterilization. In traditional WCT, there are two steps, skin scarification followed by suction using plastic cups (double S technique); Al-hijamah is a three

  20. HFE MUTATIONS AND IRON OVERLOAD IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

    Directory of Open Access Journals (Sweden)

    Luís COSTA-MATOS

    2013-03-01

    Full Text Available Context Alcoholic liver disease (ALD is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE gene mutations and the severity of liver disease in alcoholic patients. Objectives To compare the prevalence of mutations in the hemochromatosis (HFE gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity. Methods Liver biopsy specimens were obtained from 63 ALD patients (during routine treatment and 52 healthy controls (during elective cholecystectomy. All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations. Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis. Results ALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P Contexto A doença hepática alcoólica (DHA está geralmente associada à sobrecarga de ferro, que pode contribuir para a sua patogênese, através do aumento do estresse oxidativo e dano celular. As descrições existentes na literatura sobre a associação entre mutações HFE e a gravidade da DHA nem sempre são concordantes. Objetivos Comparar a prevalência de mutações HFE entre um grupo de pacientes com DHA e uma população de controle. Avaliar a relação entre mutações HFE e os depósitos de ferro hepático. Avaliar se a presença dessas mutações está associada com a gravidade da DHA. Métodos Compararam-se 63 pacientes com DHA que efetuaram biopsia hepática com 52 controles saudáveis. A genotipagem HFE (wild type, C282Y, H63D, S65C, E

  1. Deferasirox for Treating Patients Who Have Undergone Allogeneic Stem Cell Transplant and Have Iron Overload

    Science.gov (United States)

    2012-07-16

    Iron Overload; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult

  2. Synergistic Interaction of Light Alcohol Administration in the Presence of Mild Iron Overload in a Mouse Model of Liver Injury: Involvement of Triosephosphate Isomerase Nitration and Inactivation

    Science.gov (United States)

    Gao, Wanxia; Zhao, Jie; Gao, Zhonghong

    2017-01-01

    It is well known that iron overload promotes alcoholic liver injury, but the doses of iron or alcohol used in studies are usually able to induce liver injury independently. Little attention has been paid to the coexistence of low alcohol consumption and mild iron overload when either of them is insufficient to cause obvious liver damage, although this situation is very common among some people. We studied the interactive effects and the underlining mechanism of mild doses of iron and alcohol on liver injury in a mouse model. Forty eight male Kunming mice were randomly divided into four groups: control, iron (300 mg/kg iron dextran, i.p.), alcohol (2 g/kg/day ethanol for four weeks i.g.), and iron plus alcohol group. After 4 weeks of treatment, mice were sacrificed and blood and livers were collected for biochemical analysis. Protein nitration level in liver tissue was determined by immunoprecipitation and Western blot analysis. Although neither iron overload nor alcohol consumption at our tested doses can cause severe liver injury, it was found that co-administration of the same doses of alcohol and iron resulted in liver injury and hepatic dysfunction, accompanied with elevated ratio of NADH/NAD+, reduced antioxidant ability, increased oxidative stress, and subsequent elevated protein nitration level. Further study revealed that triosephosphate isomerase, an important glycolytic enzyme, was one of the targets to be oxidized and nitrated, which was responsible for its inactivation. These data indicate that even under low alcohol intake, a certain amount of iron overload can cause significant liver oxidative damage, and the modification of triosephosphate isomerasemight be the important underlining mechanism of hepatic dysfunction. PMID:28103293

  3. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

    Science.gov (United States)

    Vichinsky, Elliott; Onyekwere, Onyinye; Porter, John; Swerdlow, Paul; Eckman, James; Lane, Peter; Files, Beatrice; Hassell, Kathryn; Kelly, Patrick; Wilson, Felicia; Bernaudin, Françoise; Forni, Gian Luca; Okpala, Iheanyi; Ressayre-Djaffer, Catherine; Alberti, Daniele; Holland, Jaymes; Marks, Peter; Fung, Ellen; Fischer, Roland; Mueller, Brigitta U; Coates, Thomas

    2007-01-01

    Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease. PMID:17233848

  4. Iron uptake and homeostasis related genes in potato cultivated in vitro under iron deficiency and overload.

    Science.gov (United States)

    Legay, Sylvain; Guignard, Cédric; Ziebel, Johanna; Evers, Danièle

    2012-11-01

    Potato is one of the most important staple food in the world because it is a good source of vitamin C, vitamin B6 but also an interesting source of minerals including mainly potassium, but also magnesium, phosphorus, manganese, zinc and iron to a lesser extent. The lack of iron constitutes the main form of micronutrient deficiency in the world, namely iron deficiency anemia, which strongly affects pregnant women and children from developing countries. Iron biofortification of major staple food such as potato is thus a crucial issue for populations from these countries. To better understand mechanisms leading to iron accumulation in potato, we followed in an in vitro culture experiment, by qPCR, in the cultivar Désirée, the influence of media iron content on the expression of genes related to iron uptake, transport and homeostasis. As expected, plantlets grown in a low iron medium (1 mg L(-1) FeNaEDTA) displayed a decreased iron content, a strong induction of iron deficiency-related genes and a decreased expression of ferritins. Inversely, plantlets grown in a high iron medium (120 mg L(-1) FeNaEDTA) strongly accumulated iron in roots; however, no significant change in the expression of our set of genes was observed compared to control (40 mg L(-1) FeNaEDTA).

  5. Diagnostic value of real-time elastography in the assessment of hepatic fibrosis in patients with liver iron overload

    Energy Technology Data Exchange (ETDEWEB)

    Paparo, Francesco [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Cevasco, Luca [School of Radiology, University of Genoa, Via Leon Battista Alberti 4, 16132 Genoa (Italy); Zefiro, Daniele [Medical Physics Department, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Biscaldi, Ennio; Bacigalupo, Lorenzo [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Balocco, Manuela [Unit of Microcitemia and Hereditary Anaemias, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Pongiglione, Marta; Banderali, Simone [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Forni, Gian Luca [Unit of Microcitemia and Hereditary Anaemias, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy); Rollandi, Gian Andrea, E-mail: gian.andrea.rollandi@galliera.it [Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa (Italy)

    2013-12-01

    Objective: The objective of our prospective monocentric work was to determine the diagnostic value of real-time elastography (RTE) in the assessment of liver fibrosis in patients with iron overload, using transient elastography (TE) as reference standard. Methods: Sixty-seven consecutive patients with MRI detectable iron overload (T2* < 6.3 ms) were enrolled. TE and RTE were performed on the same day as MRI. Elastograms were acquired by an experienced operator and analyzed by calculating the elastic ratio between perihepatic soft tissues and liver parenchyma. An elliptical ROI of 1 cm{sup 2} (Z{sub 1}) was positioned in the liver parenchyma and a smaller elliptical ROI of 2 mm{sup 2} (Z{sub 2}) was positioned in a homogeneously soft (red) region of the diaphragm, which was considered as internal control to calculate the elastic ratio Z{sub 2}/Z{sub 1}. Results: Seven patients were excluded because of invalid TE or RTE examinations. The remaining 60 patients were 57% males and 43% females (mean age: 42 [21–76] years), including 37 homozygous-β-thalassemics, 13 patients with β-thalassemia intermedia, 6 with primary hemochromatosis, and 4 with myelodysplastic syndrome. Increasing elastic ratios were significantly correlated with increasing TE values (r = 0.645, 95% CI 0.468–0.772, P < 0.0001). The mean elastic ratios for each METAVIR group were as follows: F0/1 = 1.9 ± 0.4; F2 = 2.2 ± 0.4; F3 = 2.9 ± 0.5; F4 = 3.2 ± 0.4. The diagnostic accuracy of RTE for F ≥ 2 evaluated by AUC-ROC analysis was 0.798 (95% CI 0.674–0.890). The diagnostic accuracy of RTE for F ≥ 3 was 0.909 (95% CI 0.806–0.968). At a cut-off ≥ 2.75, RTE showed a sensitivity of 70% (95% CI 45.7–88.1) and a specificity of 97.5% (95% CI 86.8–99.9). Conclusions: In patients with MRI-detectable liver iron-overload RTE allows to discriminate between F0/1–F2 and F3–F4 with a reasonable diagnostic accuracy.

  6. Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis : The HEmochromatosis FAmily Study

    NARCIS (Netherlands)

    Jacobs, Esther M. G.; Hendriks, Jan C. M.; van Deursen, Cees Th. B. M.; Kreeftenberg, Herman G.; de Vries, Richard A.; Marx, Joannes J. M.; Stalenhoef, Anton F. H.; Verbeek, Andre L. M.; Swinkels, Dorine W.

    2009-01-01

    Background/Aims: In families of patients with clinically detected hereditary hemochromatosis (HH) early screening has been suggested to prevent morbidity and mortality. Here, we aim to identify determinants for iron overload in first-degree family members of C282Y homozygous probands with clinically

  7. Iron status in Danish women, 1984-1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload

    DEFF Research Database (Denmark)

    Milman, N.; Byg, K.E.; Ovesen, Lars;

    2003-01-01

    Background and objectives: From 1954 to 1986, flour in Denmark was fortified with 30 mg carbonyl iron per kilogram. This mandatory enrichment of cereal products was abolished in 1987. The aim was to evaluate iron status in the Danish female population before and after abolishment of iron...... fortification. Methods: Iron status, serum ferritin and haemoglobin, was assessed in population surveys in 1983-1984 comprising 1221 Caucasian women (1089 non-blood-donors, 130 donors) and in 1993-1994 comprising 1261 women (1155 non-blood-donors, 104 donors) equally distributed in age cohorts of 40, 50, 60......, postmenopausal women had median ferritin of 75 mug/L and in 1994 of 93 mug/L (P iron stores (ferritin iron stores (ferritin less...

  8. Evaluation of MR imaging with T1 and T2* mapping for the determination of hepatic iron overload

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, B.; Kremser, C.; Rauch, S.; Eder, R.; Schocke, M. [Innsbruck Medical University, Department of Radiology, Innsbruck (Austria); Zoller, H.; Finkenstedt, A. [Innsbruck Medical University, Department of Internal Medicine, Innsbruck (Austria); Michaely, H.J. [Medical Faculty Mannheim - Heidelberg University, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Mannheim (Germany)

    2012-11-15

    To evaluate MRI using T1 and T2* mapping sequences in patients with suspected hepatic iron overload (HIO). Twenty-five consecutive patients with clinically suspected HIO were retrospectively studied. All underwent MRI and liver biopsy. For the quantification of liver T2* values we used a fat-saturated multi-echo gradient echo sequence with 12 echoes (TR = 200 ms, TE = 0.99 ms + n x 1.41 ms, flip angle 20 ). T1 values were obtained using a fast T1 mapping sequence based on an inversion recovery snapshot FLASH sequence. Parameter maps were analysed using regions of interest. ROC analysis calculated cut-off points at 10.07 ms and 15.47 ms for T2* in the determination of HIO with accuracy 88 %/88 %, sensitivity 84 %/89.5 % and specificity 100 %/83 %. MRI correctly classified 20 patients (80 %). All patients with HIO only had decreased T1 and T2* relaxation times. There was a significant difference in T1 between patients with HIO only and patients with HIO and steatohepatitis (P = 0.018). MRI-based T2* relaxation diagnoses HIO very accurately, even at low iron concentrations. Important additional information may be obtained by the combination of T1 and T2* mapping. It is a rapid, non-invasive, accurate and reproducible technique for validating the evidence of even low hepatic iron concentrations. (orig.)

  9. A comparative study of deferasirox and deferiprone in the treatment of iron overload in patients with myelodysplastic syndromes.

    Science.gov (United States)

    Cermak, Jaroslav; Jonasova, Anna; Vondrakova, Jana; Cervinek, Libor; Belohlavkova, Petra; Neuwirtova, Radana

    2013-12-01

    One hundred thirteen patients with myelodysplastic syndromes (MDS) with deferasirox in a daily dose of 10-40 mg/kg (65 patients). Median duration of treatment was 10,9 months for deferiprone and 13,7 months for deferasirox. A substantial reduction of iron stores evaluated as a decrease in serum ferritin of more than 50% of pretreatment level was achieved in 18 patients in deferasirox group (27.7%) but not in any patient treated with deferiprone, The incidence of adverse effects (mostly gastrointestinal symptoms) was similar after administration of both the drugs. The symptoms of deferasirox toxicity were mild and mostly transient and no drug related myelosuppresive effect was observed in contrast to deferiprone where agranulocytosis occurred in 4% of patients and the treatment had to be discontinued due to side effects in 20% of patients. The results confirmed the usefulness of deferasirox as an effective and safe iron chelator in MDS patients and indication of deferiprone as an alternative treatment only in patients with mild or moderate iron overload clearly not indicated for deferasirox.

  10. Deficiencia y sobrecarga de hierro: implicaciones en el estado oxidativo y la salud cardiovascular Iron deficiency and overload: Implications in oxidative stress and cardiovascular health

    Directory of Open Access Journals (Sweden)

    L. Toxqui

    2010-06-01

    exceptionally preserved. Disorders of iron metabolism could lead to iron overload, mainly causing the rare disease hereditary hemochromatosis, or on the other hand, iron deficiency and iron deficiency anaemia. Currently, these alterations constitute an important problem of public health. The genetic variation implicated in iron overload and iron deficiency anaemia, involves mutations in several genes such as HFE, TFR2,HAMP, HJV, Tf and TMPRSS6. Iron has the capacity to accept and donate electrons easily and can catalyze reactions of free radicals production. Therefore, iron overload causes lipid peroxidation and increases cardiovascular risk. Recently, a relationship between iron metabolism and insulin resistance and obesity has been described. In contrast, regarding a possible relationship between iron deficiency anaemia and cardiovascular disease, many aspects remain controversial. This review presents an overview of the most recent information concerning iron metabolism, iron bioavailability and iron overload/deficiency related diseases. The relation between iron and cardiovascular risk, in iron overload and in iron deficiency situations, is also examined. Finally, strategies to modify dietary iron bioavailability in order to prevent iron deficiency or alleviate iron overload are suggested.

  11. Severe iron overload and hyporegenerative anemia in a case with rhesus hemolytic disease: therapeutic approach to rare complications

    Directory of Open Access Journals (Sweden)

    Fatih Demircioğlu

    2010-09-01

    Full Text Available A 33 weeks’ gestation, a baby with rhesus hemolytic disease (RHD, who had received intrauterine transfusions twice, developed cholestatic hepatic disease and late hyporegenerative anemia. Her serum ferritin and bilirubin levels increased to 8842 ng/ml and 17.9 mg/dl, respectively. Liver biopsy showed cholestasis and severe iron overload. Treatment with recombinant erythropoietin (rHuEPO decreased the transfusion need, and intravenous deferoxamine resulted in a marked decreased in serum ferritin levels and normalization of liver function. In patients who have undergone intrauterine transfusions due to RHD, hyperferritinemia and late hyporegenerative anemia should be kept in mind. Chelation therapy in cases with symptomatic hyperferritinemia and rHuEPO treatment in cases with severe hyporegenerative anemia should be considered.

  12. Overview of iron overload and the new iron chelator deferasirox%铁过载概述及口服祛铁新药地拉罗司

    Institute of Scientific and Technical Information of China (English)

    刘容容

    2011-01-01

    规则输血是维持重度慢性贫血患者生命的重要治疗手段,患者长期依赖输血治疗不可避免地引起体内铁沉积增加.输血相关性铁过载可导致多脏器的损害,特别是沉积在肝脏或心脏,甚至可危及生命.作为传统的铁螯合剂,去铁酮和去铁胺因其不良反应或治疗依从性差等问题无法满足临床治疗需要.地拉罗司是一种新型的口服铁螯合剂,多个Ⅱ期或Ⅲ期试验证实其在输血依赖性患者中可获得与去铁胺相似的疗效.近期前瞻性、多中心EPIC研究也证实了其祛铁疗效,且有助于改善地中海贫血患者的心脏铁沉积.本文就铁过载的临床特征、危害性以及祛铁新药地拉罗司对比传统药物的优势做一综述.%For many patients with severe chronic anemia, regular blood transfusion is the important lifesav-ing therapy available. Long-term blood transfusions will unavoidably and invariably produce accumulation of iron (iron overload) , and thereby induced iron toxicity. Transfusional hemosiderosis, particularly in the liver or heart, can cause considerable morbidity that may be fatal eventually. Traditionally, iron chelating agents include def-eriprone and deferoxamine, but they are not the satisfied treatment choice due to their side effects or non-convenience for administration. Deferasirox, a rationally-designed oral iron chelator, is validated as defined by several phase II trials. Moreover, a pivotal phase III trial revealed that its efficacy is similar to that of deferoxamine in transfusion-dependent patients. Recently reported results from the large, prospective, multicenter EPIC study confirmed its efficacy, and in this study deferasirox was also found to be capable of removing iron from the heart in patients with p-thalassemia and myocardial hemosiderosis. This review summarized the morbidity, mortality, and clinical features of iron overload, and introduced the advantages of the new chelator deferasirox over

  13. EVALUATION OF SERUM FERRITIN AND SERUM IRON IN FREE-RANGING BLACK RHINOCEROS (DICEROS BICORNIS) AS A TOOL TO UNDERSTAND FACTORS AFFECTING IRON-OVERLOAD DISORDER.

    Science.gov (United States)

    Miller, Michele; Chavey, Patricia Sue; Hofmeyr, Jennifer; Mathebula, Nomkhosi; Doering, Alyssa; Buss, Peter; Olea-Popelka, Francisco

    2016-09-01

    Iron overload disorder (IOD) is a significant health issue for captive black rhinoceros ( Diceros bicornis ). Measurement of serum ferritin with a validated rhinoceros ferritin ELISA has been used extensively to detect animals in U.S. zoos that are at risk of developing IOD. However, there is limited information on serum ferritin levels in free-ranging black rhinoceros using this same assay. Serum ferritin, iron, and gamma-glutamyl transpeptidase (GGT) were determined in 194 black rhinoceros from southern Africa. Mean ferritin in free-ranging black rhinoceros (290.54 ±247.4 ng/ml) was significantly higher than in free-ranging white rhinoceros (64.0 ± 102.4 ng/ml) sampled in this study from Kruger National Park, South Africa. However, there were no significant differences between genders or age groups. Ferritin values varied with geographical location of the black rhinoceros, although this was not clinically significant. Serum iron values were also higher in black rhinoceros (40.4 ± 19.1 μmol/L) compared to white rhinoceros (29.7 ± 10.7 μmol/L). There was no association between ferritin and GGT. This study provides serum ferritin, iron, and GGT values from free-ranging black rhinoceros that can be used for as comparative target values for captive animals.

  14. Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded b-thalassemic mice

    Institute of Scientific and Technical Information of China (English)

    Supranee; Upanan; Kanjana; Pangjit; Chairat; Uthaipibull; Suthat; Fucharoen; Andrew; T.Mc; Kie; Somdet; Srichairatanakool

    2015-01-01

    Objective:To evaluate the efficacy of deferiprone(DFP),1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one(CM1)or green tea extract(GTE)in enhancing expression of hepatic hepcidin1(Hamp1)m RNA and relieving iron overload in b-globin knockout thalassemic mice.Methods:The b-globin knockout thalassemic mice were fed with a ferrocenesupplemented diet for 2 months and oral administration of deionized water,DFP(50 mg/kg),CM1(50 mg/kg),GTE(50 mg epigallocatechin 3-gallate equivalent/kg),GTE along with DFP(50 mg/kg),and GTE along with CM1(50 mg/kg)every day for 3months.Levels of hepatic Hamp1 m RNA,plasma non-transferrin bound iron,plasma alanine aminotransferase activity and tissue iron content were determined.Results:All chelation treatments could reduce plasma non-transferrin bound iron concentrations.Additionally,hepatic Hamp1 m RNA expression was significantly upregulated in the mice in a GTE+DFP combined treatment,correlating with a decrease in the plasma alanine aminotransferase activity and tissue iron deposition.Conclusions:The GTE+DFP treatment could ameliorate iron overload and liver oxidative damage in non-transfusion dependent b-thalassemic mice,by chelating toxic iron in plasma and tissues,and increasing hepcidin expression to inhibit duodenal iron absorption and iron release from hepatocytes and macrophages in the spleen.There is probably an advantage in giving GTE with DFP when treating patients with iron overload.

  15. Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded b-thalassemic mice

    Institute of Scientific and Technical Information of China (English)

    Supranee Upanan; Kanjana Pangjit; Chairat Uthaipibull; Suthat Fucharoen; Andrew T McKie; Somdet Srichairatanakool

    2015-01-01

    Objective: To evaluate the efficacy of deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) or green tea extract (GTE) in enhancing expres-sion of hepatic hepcidin1 (Hamp1) mRNA and relieving iron overload in b-globin knockout thalassemic mice. Methods: The b-globin knockout thalassemic mice were fed with a ferrocene-supplemented diet for 2 months and oral administration of deionized water, DFP (50 mg/kg), CM1 (50 mg/kg), GTE (50 mg epigallocatechin 3-gallate equivalent/kg), GTE along with DFP (50 mg/kg), and GTE along with CM1 (50 mg/kg) every day for 3 months. Levels of hepatic Hamp1 mRNA, plasma non-transferrin bound iron, plasma alanine aminotransferase activity and tissue iron content were determined. Results: All chelation treatments could reduce plasma non-transferrin bound iron con-centrations. Additionally, hepatic Hamp1 mRNA expression was significantly up-regulated in the mice in a GTE+DFP combined treatment, correlating with a decrease in the plasma alanine aminotransferase activity and tissue iron deposition. Conclusions: The GTE + DFP treatment could ameliorate iron overload and liver oxidative damage in non-transfusion dependent b-thalassemic mice, by chelating toxic iron in plasma and tissues, and increasing hepcidin expression to inhibit duodenal iron absorption and iron release from hepatocytes and macrophages in the spleen. There is probably an advantage in giving GTE with DFP when treating patients with iron overload.

  16. Al-hijamah and oral honey for treating thalassemia, conditions of iron overload, and hyperferremia: toward improving the therapeutic outcomes

    Directory of Open Access Journals (Sweden)

    El Sayed SM

    2014-10-01

    Full Text Available Salah Mohamed El Sayed,1,2 Hussam Baghdadi,2 Ashraf Abou-Taleb,3 Hany Salah Mahmoud,4 Reham A Maria,2,5 Nagwa S Ahmed,1 Manal Mohamed Helmy Nabo6,71Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Sohag, Egypt; 2Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Kingdom of Saudi Arabia; 3Department of Pediatrics, Sohag Faculty of Medicine, Sohag University, Sohag; 4World Federation of Alternative and Complementary Medicine, Cairo Regional Headquarter, Cairo; 5Department of Medical Biochemistry, Tanta Faulty of Medicine, Tanta University, Tanta; 6Department of Pediatrics, Sohag Teaching Hospital, Sohag, Egypt; 7Division of Pediatric Cardiology, Department of Pediatrics, Maternity and Children Hospital, King Abdullah Medical City, Al-Madinah Al-Munawwarah, Kingdom of Saudi ArabiaAbstract: Iron overload causes iron deposition and accumulation in the liver, heart, skin, and other tissues resulting in serious tissue damages. Significant blood clearance from iron and ferritin using wet cupping therapy (WCT has been reported. WCT is an excretory form of treatment that needs more research efforts. WCT is an available, safe, simple, economic, and time-saving outpatient modality of treatment that has no serious side effects. There are no serious limitations or precautions to discontinue WCT. Interestingly, WCT has solid scientific and medical bases (Taibah mechanism that explain its effectiveness in treating many disease conditions differing in etiology and pathogenesis. WCT utilizes an excretory physiological principle (pressure-dependent excretion that resembles excretion through renal glomerular filtration and abscess evacuation. WCT exhibits a percutaneous excretory function that clears blood (through fenestrated skin capillaries and interstitial fluids from pathological substances without adding a metabolic or detoxification burden on the

  17. Suppression of hepcidin expression and iron overload mediate Salmonella susceptibility in ankyrin 1 ENU-induced mutant.

    Directory of Open Access Journals (Sweden)

    Kyoko E Yuki

    Full Text Available Salmonella, a ubiquitous Gram-negative intracellular bacterium, is a food borne pathogen that infects a broad range of hosts. Infection with Salmonella Typhimurium in mice is a broadly recognized experimental model resembling typhoid fever in humans. Using a N-ethyl-N-nitrosurea (ENU mutagenesis recessive screen, we report the identification of Ity16 (Immunity to Typhimurium locus 16, a locus responsible for increased susceptibility to infection. The position of Ity16 was refined on chromosome 8 and a nonsense mutation was identified in the ankyrin 1 (Ank1 gene. ANK1 plays an important role in the formation and stabilization of the red cell cytoskeleton. The Ank1(Ity16/Ity16 mutation causes severe hemolytic anemia in uninfected mice resulting in splenomegaly, hyperbilirubinemia, jaundice, extramedullary erythropoiesis and iron overload in liver and kidneys. Ank1(Ity16/Ity16 mutant mice demonstrated low levels of hepcidin (Hamp expression and significant increases in the expression of the growth differentiation factor 15 (Gdf15, erythropoietin (Epo and heme oxygenase 1 (Hmox1 exacerbating extramedullary erythropoiesis, tissue iron deposition and splenomegaly. As the infection progresses in Ank1(Ity16/Ity16, the anemia worsens and bacterial load were high in liver and kidneys compared to wild type mice. Heterozygous Ank1(+/Ity16 mice were also more susceptible to Salmonella infection although to a lesser extent than Ank1(Ity16/Ity16 and they did not inherently present anemia and splenomegaly. During infection, iron accumulated in the kidneys of Ank1(+/Ity16 mice where bacterial loads were high compared to littermate controls. The critical role of HAMP in the host response to Salmonella infection was validated by showing increased susceptibility to infection in Hamp-deficient mice and significant survival benefits in Ank1(+/Ity16 heterozygous mice treated with HAMP peptide. This study illustrates that the regulation of Hamp and iron balance are

  18. Suppression of hepcidin expression and iron overload mediate Salmonella susceptibility in ankyrin 1 ENU-induced mutant.

    Science.gov (United States)

    Yuki, Kyoko E; Eva, Megan M; Richer, Etienne; Chung, Dudley; Paquet, Marilène; Cellier, Mathieu; Canonne-Hergaux, François; Vaulont, Sophie; Vidal, Silvia M; Malo, Danielle

    2013-01-01

    Salmonella, a ubiquitous Gram-negative intracellular bacterium, is a food borne pathogen that infects a broad range of hosts. Infection with Salmonella Typhimurium in mice is a broadly recognized experimental model resembling typhoid fever in humans. Using a N-ethyl-N-nitrosurea (ENU) mutagenesis recessive screen, we report the identification of Ity16 (Immunity to Typhimurium locus 16), a locus responsible for increased susceptibility to infection. The position of Ity16 was refined on chromosome 8 and a nonsense mutation was identified in the ankyrin 1 (Ank1) gene. ANK1 plays an important role in the formation and stabilization of the red cell cytoskeleton. The Ank1(Ity16/Ity16) mutation causes severe hemolytic anemia in uninfected mice resulting in splenomegaly, hyperbilirubinemia, jaundice, extramedullary erythropoiesis and iron overload in liver and kidneys. Ank1(Ity16/Ity16) mutant mice demonstrated low levels of hepcidin (Hamp) expression and significant increases in the expression of the growth differentiation factor 15 (Gdf15), erythropoietin (Epo) and heme oxygenase 1 (Hmox1) exacerbating extramedullary erythropoiesis, tissue iron deposition and splenomegaly. As the infection progresses in Ank1(Ity16/Ity16), the anemia worsens and bacterial load were high in liver and kidneys compared to wild type mice. Heterozygous Ank1(+/Ity16) mice were also more susceptible to Salmonella infection although to a lesser extent than Ank1(Ity16/Ity16) and they did not inherently present anemia and splenomegaly. During infection, iron accumulated in the kidneys of Ank1(+/Ity16) mice where bacterial loads were high compared to littermate controls. The critical role of HAMP in the host response to Salmonella infection was validated by showing increased susceptibility to infection in Hamp-deficient mice and significant survival benefits in Ank1(+/Ity16) heterozygous mice treated with HAMP peptide. This study illustrates that the regulation of Hamp and iron balance are crucial

  19. Effect of deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload

    Directory of Open Access Journals (Sweden)

    Gotsis Efstathios D

    2011-07-01

    Full Text Available Abstract Background Thalassaemia major (TM patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV function but little is known of their relative effects on the right ventricle (RV, which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT comparing these chelators was retrospectively analysed to assess the RV responses to these drugs. Methods In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment. Results From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV from 37.7 to 34.2 mL (p = 0.008, whilst RV ejection fraction (EF increased from 69.6 to 72.2% (p = 0.001. This was associated with a 27% increase in T2* (p Conclusion In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.

  20. Pyridoxine responsive hereditary sideroblastic erythropoiesis and iron overload: two microcytic subpopulations in the affected male, one normocytic and one microcytic subpopulation in the obligate female carrier.

    Science.gov (United States)

    Harris, J W; Danish, E H; Brittenham, G M; McLaren, C E

    1993-04-01

    Mild hepatic iron overload has been demonstrated by magnetic susceptibility measurements in a 22-year-old man with hereditary sideroblastic erythropoiesis despite hemoglobin levels in the normal range and a normal erythropoietin level. His grandfather's sideroblastic anemia has been found to be responsive to pyridoxine; his mother's hemoglobin has persisted in the normal range but red cell volume distribution analysis demonstrated two subpopulations; 30% with estimated geometric mean of 68 fl and 70% an estimated mean of 93 fl. Red cell distribution analysis of the grandson demonstrated two microcytic subpopulations; 46% with an estimated geometric mean of 45 fl and 54% an estimated mean of 70 fl. A therapeutic regimen is outlined to reduce to normal his iron stores and to prevent the future development of excessive iron overload.

  1. Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload

    OpenAIRE

    Xian-hui Dong; Jiang-tao Bai; Wei-na Kong; Xiao-ping He; Peng Yan; Tie-mei Shao; Wen-guo Yu; Xi-qing Chai; Yan-hua Wu; Cong LIu

    2015-01-01

    Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer′s disease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer′s disease patients. An APP swe/PS1ΔE9 double transgenic mouse model of Alzheimer′s disease was used. The intragastric administration of compound...

  2. Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload

    OpenAIRE

    Dong, Xian-Hui; Bai, Jiang-tao; Kong, Wei-Na; He, Xiao-Ping; Yan, Peng; Shao, Tie-mei; Yu, Wen-guo; Chai, Xi-qing; Wu, Yan-hua; Liu, Cong

    2015-01-01

    Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer’s disease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer’s disease patients. An APPswe /PS1ΔE9 double transgenic mouse model of Alzheimer’s disease was used. The intragastric administration of compound...

  3. Pressure overload-induced mild cardiac hypertrophy reduces leftventricular transmural differences in mitochondrial respiratory chainactivity and increases oxidative stress

    Directory of Open Access Journals (Sweden)

    Michel eKINDO

    2012-08-01

    Full Text Available Objective: Increased mechanical stress and contractility characterizes normal left ventricular subendocardium (Endo but whether Endo mitochondrial respiratory chain complex activities is reduced as compared to subepicardium (Epi and whether pressure overload-induced left ventricular hypertrophy (LVH might modulate transmural gradients through increased reactive oxygen species (ROS production is unknown. Methods: LVH was induced by 6 weeks abdominal aortic banding and cardiac structure and function were determined with echocardiography and catheterization in sham-operated and LVH rats (n=10 for each group. Mitochondrial respiration rates, coupling, content and ROS production were measured in LV Endo and Epi, using saponin-permeabilised fibres, Amplex Red fluorescence and citrate synthase activity.Results: In sham, a transmural respiratory gradient was observed with decreases in endo maximal oxidative capacity (-36.7%, P<0.01 and complex IV activity (-57.4%, P<0.05. Mitochondrial hydrogen peroxide (H2O2 production was similar in both LV layers.Aortic banding induced mild LVH (+31.7% LV mass, associated with normal LV fractional shortening and end diastolic pressure. LVH reduced maximal oxidative capacity (-23.6 and -33.3%, increased mitochondrial H2O2 production (+86.9 and +73.1%, free radical leak (+27.2% and +36.3% and citrate synthase activity (+27.2% and +36.3% in Endo and Epi, respectively.Transmural mitochondrial respiratory chain complex IV activity was reduced in LVH (-57.4 vs –12.2%; P=0.02. Conclusions: Endo mitochondrial respiratory chain complexes activities are reduced compared to LV Epi. Mild LVH impairs mitochondrial oxidative capacity, increases oxidative stress and reduces transmural complex IV activity. Further studies will be helpful to determine whether reduced LV transmural gradient in mitochondrial respiration might be a new marker of a transition from uncomplicated toward complicated LVH.

  4. 铁代谢及铁过载%Iron Metabolism and Overload

    Institute of Scientific and Technical Information of China (English)

    孟昭升; 贾红英; 吴学琼; 盛玲玲

    2012-01-01

    人体缺乏有效的铁"排泄机制",机体铁稳态的维持主要通过调控其吸收、转运与储存来实现.现总结近10年铁调控的相关研究成果,从肠道铁的吸收,铁在细胞、组织及血浆中的相互转运,铁的储存,铁调控激素hepcidin及其相关调控因子等方面探讨维持铁稳态的分子学机制,并简述遗传性血色病相关的发病机制,为理解铁代谢疾病提供线索.%The iron homeostasis is maintained by regulating its absorption,transferring and storing,because humans have no physiologic pathway for excretion. Here is to make a review on the research achievements about iron regulating in the last ten years, and discuss the molecular mechanism associated with iron homeostasis in iron absorption,transferring,storing and hormone associated with iron controlling,and state the pathogenesis of hereditary hemochromatosis,provide clue to comprehend the iron metabolic disease.

  5. Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging

    Science.gov (United States)

    Pepe, Alessia; Meloni, Antonella; Capra, Marcello; Cianciulli, Paolo; Prossomariti, Luciano; Malaventura, Cristina; Putti, Maria Caterina; Lippi, Alma; Romeo, Maria Antonietta; Bisconte, Maria Grazia; Filosa, Aldo; Caruso, Vincenzo; Quarta, Antonella; Pitrolo, Lorella; Missere, Massimiliano; Midiri, Massimo; Rossi, Giuseppe; Positano, Vincenzo; Lombardi, Massimo; Maggio, Aurelio

    2011-01-01

    Background Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare the effectiveness of deferasirox, deferiprone and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function in thalassemia major patients by means of quantitative magnetic resonance imaging. Design and Methods From the first 550 thalassemia subjects enrolled in the Myocardial Iron Overload in Thalassemia network, we retrospectively selected thalassemia major patients who had been receiving one chelator alone for longer than one year. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferiprone and 89 treated with desferrioxamine. Myocardial iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron concentrations were measured by T2* multiecho technique. Results The global heart T2* value was significantly higher in the deferiprone (34±11ms) than in the deferasirox (21±12 ms) and the desferrioxamine groups (27±11 ms) (P=0.0001). We found higher left ventricular ejection fractions in the deferiprone and the desferrioxamine versus the deferasirox group (P=0.010). Liver iron concentration, measured as T2* signal, was significantly lower in the desferrioxamine versus the deferiprone and the deferasirox group (P=0.004). Conclusions The cohort of patients treated with oral deferiprone showed less myocardial iron burden and better global systolic ventricular function compared to the patients treated with oral deferasirox or subcutaneous desferrioxamine. PMID:20884710

  6. Protective effects of Phellinus linteus extract against iron overload-mediated oxidative stress in cultured rat hepatocytes.

    Science.gov (United States)

    Ye, She-Fang; Hou, Zhen-Qing; Zhang, Qi-Qing

    2007-10-01

    Phellinus linteus (PL) mushroom has been reported to possess antioxidant activity. The present study was designed to investigate whether an ethanol extract obtained from PL might ameliorate oxidative stress and enhance antioxidant enzyme activities in primary rat hepatocytes, which were overloaded with iron using ferric nitrilotriacetate (FeNTA) complex. FeNTA enables hepatocytes to accumulate substantially redox-active iron and stimulates the production of injurious hydroxyl radicals, which in turn, initiate oxidative stress-mediated cytotoxicity. The results showed that pretreatment of hepatocytes with PL extract (50, 100 and 200 microg/mL) for 24 h significantly reversed FeNTA-induced cell viability loss, lactate dehydrogenase leakage (LDH), lipid peroxidation (LPO) and protein carbonyl formation in a dose-dependent manner. It was further observed that PL extract produced an inhibitory effect on intracellular reactive oxygen species (ROS) formation caused by FeNTA. Concomitantly, the amount of GSH content and the activities of glutathione reductase (GSH Rd) and glutathione peroxidase (GSH Px) in hepatocytes pretreated with PL extract increased substantially compared with those treated with FeNTA alone. These results suggest that PL may be useful in protecting against FeNTA-induced oxidative damage and also be capable of attenuating cytotoxicity of other oxidants.

  7. Hepatic magnetic resonance imaging with T2* mapping of ovariectomized rats: correlation between iron overload and postmenopausal osteoporosis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Lingshan; Peng, Xingui; Wang, Yuancheng; Wang, Yaling; Chen, Min; Wang, Qi; Jin, Jiyang [Zhongda Hospital of Southeast University, Department of Radiology, Nanjing (China); Zhu, Zhengqiu [Zhongda Hospital of Southeast University, Department of Endocrinology, Nanjing (China)

    2014-07-15

    To explore the correlation between liver iron overload and bone mineral density (BMD) in an ovariectomy (OVX) rat model, using liver magnetic resonance (MR)-T2* and dual-energy X-ray absorptiometry (DEXA). Sprague-Dawley rats received deferoxamine (DFO) or phosphate-buffered saline 3 months after bilateral OVX. MRI and DEXA were performed pre- and postoperatively. Five rats per group were killed every month for micro-CT, histopathology and biochemical examinations. Statistical analysis was performed with independent-samples t tests, box plots and Pearson's correlation analysis. At 2 months postoperatively, BMD was significantly lower in the OVX group than in the control group (P < 0.01), corresponding to the increased serum ferritin concentration (SFC; P < 0.01) and liver iron concentration (LIC; P < 0.01). Liver T2* values significantly differed between the two groups at 1 month postoperatively (P < 0.001) and improved 1 month after DFO injection (P < 0.05). These values were significantly and positively correlated with BMD in the control (r = 0.527, P < 0.001) and OVX (r = 0.456, P < 0.001) groups. Liver MRI T2* changed markedly earlier than BMD, LIC and SFC, and correlated well with osteoporosis; it may thus be a valuable early indicator of osteoporosis. (orig.)

  8. Association of hepcidin promoter c.-582 A>G variant and iron overload in thalassemia major.

    Science.gov (United States)

    Andreani, Marco; Radio, Francesca Clementina; Testi, Manuela; De Bernardo, Carmelilia; Troiano, Maria; Majore, Silvia; Bertucci, Pierfrancesco; Polchi, Paola; Rosati, Renata; Grammatico, Paola

    2009-09-01

    Hepcidin is a 25-amino acid peptide, derived from cleavage of an 84 amino acid pro-peptide produced predominantly by hepatocytes. This molecule, encoded by the hepcidin antimicrobial peptide (HAMP) gene shows structural and functional properties consistent with a role in innate immunity. Moreover, as demonstrated in mice and humans, hepcidin is a major regulator of iron metabolism, and acts by binding to ferroportin and controlling its concentration and trafficking. In this study we investigated the influence that mutations in HAMP and/or hemocromatosis (HFE) genes might exert on iron metabolism in a group of poly-transfused thalassemic patients in preparation for bone marrow transplantation. Our results showed that the presence of the c.-582 A>G polymorphism (rs10421768) placed in HAMP promoter (HAMP-P) might play a role in iron metabolism, perhaps varying the transcriptional activation that occurs through E-boxes located within the promoter.

  9. Phlebotomy improves histology in chronic hepatitis C males with mild iron overload

    Institute of Scientific and Technical Information of China (English)

    Massimo; Sartori; Silvano; Andorno; Angelo; Rossini; Renzo; Boldorini; Cristina; Bozzola; Stefania; Carmagnola; Mario; Del; Piano; Emanuele; Albano

    2010-01-01

    AIM:To investigate the usefulness of mild iron depletion and the factors predictive for histological improvement following phlebotomy in Caucasians with chronic hepatitis C(CHC). METHODS:We investigated 28 CHC Caucasians with persistently elevated serum aminotransferase levels and non responders to,or unsuitable for,antiviral therapy who underwent mild iron depletion(ferritin≤70 ng/mL) by long-term phlebotomy.Histological improvement,as defined by at least one point reduction in the staging score or,in case...

  10. Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study.

    Science.gov (United States)

    Kim, Beom-Jun; Ahn, Seong Hee; Bae, Sung Jin; Kim, Eun Hee; Lee, Seung-Hun; Kim, Hong-Kyu; Choe, Jae Won; Koh, Jung-Min; Kim, Ghi Su

    2012-11-01

    Despite extensive experimental and animal evidence about the detrimental effects of iron and its overload on bone metabolism, there have been no clinical studies relating iron stores to bone loss, especially in nonpathologic conditions. In the present study, we performed a large longitudinal study to evaluate serum ferritin concentrations in relation to annualized changes in bone mineral density (BMD) in healthy Koreans. A total of 1729 subjects (940 postmenopausal women and 789 middle-aged men) aged 40 years or older who had undergone comprehensive routine health examinations with an average 3 years of follow-up were enrolled. BMD in proximal femur sites (ie, the total femur, femur neck, and trochanter) was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. The mean age of women and men in this study was 55.8 ± 6.0 years and 55.5 ± 7.8 years, respectively, and serum ferritin levels were significantly higher in men than in women (p men. After adjustment for potential confounders, the rates of bone loss in all proximal femur sites in both genders were significantly accelerated in a dose-response fashion across increasing ferritin quartile categories (p for trend = 0.043 to <0.001). Consistently, compared with subjects in the lowest ferritin quartile category, those in the third and/or highest ferritin quartile category showed significantly faster bone loss in the total femur and femur neck in both genders (p = 0.023 to <0.001). In conclusion, these data provide the first clinical evidence that increased total body iron stores could be an independent risk factor for accelerated bone loss, even in healthy populations.

  11. Liver steatosis correlates with iron overload but not with HFE gene mutations in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Katarzyna Sikorska; Piotr Stalke; Tomasz Romanowski

    2013-01-01

    BACKGROUND: Liver  steatosis  and  iron  overload,  which are  frequently  observed  in  chronic  hepatitis  C  (CHC),  may contribute to the progression of liver injury. This study aimed to  evaluate  the  correlation  between  liver  steatosis  and  iron overload  in  Polish  patients  with  CHC  compared  to  non-alcoholic  fatty  liver  disease  (NAFLD)  and  HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67  NAFLD  and  21  HH  patients.  Liver  function  tests,  serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis  stages  were  assessed  in  liver  specimens.  HFE  gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver  steatosis  was  associated  with  obesity  and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC  patients,  most  of  whom  were  infected  with  genotype  1. The average grade of  steatosis  was higher  in  NAFLD  patients. CHC  patients  had  significantly  higher  iron  concentrations and  transferrin  saturations  than  NAFLD  patients.  Compared with  CHC  patients,  HH  patients  had  higher  values  of  serum iron  parameters  and  more  intensive  hepatocyte  iron  deposits without  differences  in  the  prevalence  and  intensity  of  liver steatosis. In the CHC group, lipids accumulation in hepatocytes was  significantly  associated  with  the  presence  of  serum markers of iron overload. No correlation between the HFE gene

  12. Mitogen-activated protein kinases (p38 and c-Jun NH2-terminal kinase) are differentially regulated during cardiac volume and pressure overload hypertrophy.

    Science.gov (United States)

    Sopontammarak, Somkiat; Aliharoob, Assad; Ocampo, Catherina; Arcilla, Rene A; Gupta, Mahesh P; Gupta, Madhu

    2005-01-01

    -MHC expression was downregulated in PO but remained unchanged in VO hypertrophy hearts. Thus, these results demonstrate differential activation of MAPKs in two types of cardiac hypertrophy and this, in part, may contribute to differential expression of cardiac muscle gene expression, giving rise to unique cardiac phenotype associated with different hemodynamic overloads.

  13. Two kinds of ferritin protect ixodid ticks from iron overload and consequent oxidative stress.

    Science.gov (United States)

    Galay, Remil Linggatong; Umemiya-Shirafuji, Rika; Bacolod, Eugene T; Maeda, Hiroki; Kusakisako, Kodai; Koyama, Jiro; Tsuji, Naotoshi; Mochizuki, Masami; Fujisaki, Kozo; Tanaka, Tetsuya

    2014-01-01

    Ticks are obligate hematophagous parasites that have successfully developed counteractive means against their hosts' immune and hemostatic mechanisms, but their ability to cope with potentially toxic molecules in the blood remains unclear. Iron is important in various physiological processes but can be toxic to living cells when in excess. We previously reported that the hard tick Haemaphysalis longicornis has an intracellular (HlFER1) and a secretory (HlFER2) ferritin, and both are crucial in successful blood feeding and reproduction. Ferritin gene silencing by RNA interference caused reduced feeding capacity, low body weight and high mortality after blood meal, decreased fecundity and morphological abnormalities in the midgut cells. Similar findings were also previously reported after silencing of ferritin genes in another hard tick, Ixodes ricinus. Here we demonstrated the role of ferritin in protecting the hard ticks from oxidative stress. Evaluation of oxidative stress in Hlfer-silenced ticks was performed after blood feeding or injection of ferric ammonium citrate (FAC) through detection of the lipid peroxidation product, malondialdehyde (MDA) and protein oxidation product, protein carbonyl. FAC injection in Hlfer-silenced ticks resulted in high mortality. Higher levels of MDA and protein carbonyl were detected in Hlfer-silenced ticks compared to Luciferase-injected (control) ticks both after blood feeding and FAC injection. Ferric iron accumulation demonstrated by increased staining on native HlFER was observed from 72 h after iron injection in both the whole tick and the midgut. Furthermore, weak iron staining was observed after Hlfer knockdown. Taken together, these results show that tick ferritins are crucial antioxidant molecules that protect the hard tick from iron-mediated oxidative stress during blood feeding.

  14. Two kinds of ferritin protect ixodid ticks from iron overload and consequent oxidative stress.

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    Remil Linggatong Galay

    Full Text Available Ticks are obligate hematophagous parasites that have successfully developed counteractive means against their hosts' immune and hemostatic mechanisms, but their ability to cope with potentially toxic molecules in the blood remains unclear. Iron is important in various physiological processes but can be toxic to living cells when in excess. We previously reported that the hard tick Haemaphysalis longicornis has an intracellular (HlFER1 and a secretory (HlFER2 ferritin, and both are crucial in successful blood feeding and reproduction. Ferritin gene silencing by RNA interference caused reduced feeding capacity, low body weight and high mortality after blood meal, decreased fecundity and morphological abnormalities in the midgut cells. Similar findings were also previously reported after silencing of ferritin genes in another hard tick, Ixodes ricinus. Here we demonstrated the role of ferritin in protecting the hard ticks from oxidative stress. Evaluation of oxidative stress in Hlfer-silenced ticks was performed after blood feeding or injection of ferric ammonium citrate (FAC through detection of the lipid peroxidation product, malondialdehyde (MDA and protein oxidation product, protein carbonyl. FAC injection in Hlfer-silenced ticks resulted in high mortality. Higher levels of MDA and protein carbonyl were detected in Hlfer-silenced ticks compared to Luciferase-injected (control ticks both after blood feeding and FAC injection. Ferric iron accumulation demonstrated by increased staining on native HlFER was observed from 72 h after iron injection in both the whole tick and the midgut. Furthermore, weak iron staining was observed after Hlfer knockdown. Taken together, these results show that tick ferritins are crucial antioxidant molecules that protect the hard tick from iron-mediated oxidative stress during blood feeding.

  15. Hyperferritinemia is associated with insulin resistance and fatty liver in patients without iron overload.

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    Robert Brudevold

    Full Text Available OBJECTIVE: During the last 10 years we have experienced an increasing number of referrals due to hyperferritinemia. This is probably due to increased awareness of hereditary hemochromatosis, and the availability of a genetic test for this condition. Most of these referred patients were over-weight middle-aged men with elevated ferritin levels, but without the hemochromatosis-predisposing gene mutations. We evaluated the relationship between hyperferritinemia and the metabolic syndrome in 40 patients. METHODS: Forty consecutive patients referred for hyperferritinemia were investigated. The examination programme included medical history, clinical investigation and venous blood samples drawn after an overnight fast. This resulted in 34 patients with unexplained hyperferritinemia, which were further examined. Liver biopsy was successfully performed in 29 subjects. Liver iron stores were assessed morphologically, and by quantitative phlebotomy in 16 patients. RESULTS: The majority of the patients had markers of the metabolic syndrome, and 18 patients (52% fulfilled the IDF-criteria for the metabolic syndrome. Mean body mass index was elevated (28.8+/-4.2, mean diastolic blood pressure was 88.5+/-10.5 mmHg, and mean fasting insulin C-peptide 1498+/-539 pmol/l. Liver histology showed steatosis and nuclear glycogen inclusions in most patients (19 out of 29. Only four patients had increased iron stores by histology, of which two could be explained by alcohol consumption. Fourteen of 16 patients normalized ferritin levels after phlebotomy of a cumulative blood amount corresponding to normal iron stores. Ferritin levels were significantly related to insulin C-peptide level (p<0.002 and age (p<0.002. CONCLUSION: The present results suggest that liver steatosis and insulin resistance but not increased iron load is frequently seen in patients referred for suspected hemochromatosis on the basis of hyperferritinemia. The ferritin level seems to be positively

  16. Wild Edible Fruit of Prunus nepalensis Ser. (Steud), a Potential Source of Antioxidants, Ameliorates Iron Overload-Induced Hepatotoxicity and Liver Fibrosis in Mice.

    Science.gov (United States)

    Chaudhuri, Dipankar; Ghate, Nikhil Baban; Panja, Sourav; Das, Abhishek; Mandal, Nripendranath

    2015-01-01

    The antioxidant and restoration potentials of hepatic injury by Prunus nepalensis Ser. (Steud), a wild fruit plant from the Northeastern region of India, were investigated. The fruit extract (PNME) exhibited excellent antioxidant and reducing properties and also scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical (IC50 = 30.92 ± 0.40 μg/ml). PNME demonstrated promising scavenging potency, as assessed by the scavenging of different reactive oxygen and nitrogen species. Moreover, the extract revealed an exceptional iron chelation capacity with an IC50 of 25.64 ± 0.60 μg/ml. The extract induced significant improvement of hepatic injury and liver fibrosis against iron overload induced hepatotoxicity in mice in a dose-dependent manner, and this effect was supported by different histopathological studies. The phytochemical constitutions and their identification by HPLC confirmed the presence of purpurin, tannic acid, methyl gallate, reserpine, gallic acid, ascorbic acid, catechin and rutin. The identified compounds were investigated for their individual radical scavenging and iron chelation activity; some compounds exhibited excellent radical scavenging and iron chelation properties, but most were toxic towards normal cells (WI-38). On the other hand, crude PNME was found to be completely nontoxic to normal cells, suggesting its feasibility as a safe oral drug. The above study suggests that different phytochemicals in PNME contributed to its free radical scavenging and iron chelation activity; however, further studies are required to determine the pathway in which PNME acts to treat iron-overload diseases.

  17. Terapia quelante oral com deferiprona em pacientes com sobrecarga de ferro Oral iron chelator therapy with deferiprone in patients with overloaded iron

    Directory of Open Access Journals (Sweden)

    Antonio Fabron Jr

    2003-01-01

    . For these patients, the orally active iron chelator deferiprone is an attractive alternative to control the overloaded iron. It has been estimated that more than six thousands patients have already been treated with deferiprone, with some of them taking the chelator for 10 years or more. The deferiprone-induced iron excretion is directly related to the dose of deferiprone and the patient's iron load. In most of transfusion-dependent patients, a dose of 75 mg/kg/day is sufficient to offset the transfusional iron-load. Recently, it has been demonstrated that desferrioxamine and deferiprone exhibit different chelating capabilities for the removal of iron from the various body iron pools and that the use of both chelators promote an additive or synergistic iron excretion with rapid reduction in the body iron load. It now is possible to consider tailor-made chelation regimens based on individual patient needs.

  18. Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload.

    Science.gov (United States)

    Badar, Sadaf; Busti, Fabiana; Ferrarini, Alberto; Xumerle, Luciano; Bozzini, Paolo; Capelli, Paola; Pozzi-Mucelli, Roberto; Campostrini, Natascia; De Matteis, Giovanna; Marin Vargas, Sergio; Giorgetti, Alejandro; Delledonne, Massimo; Olivieri, Oliviero; Girelli, Domenico

    2016-06-01

    Hereditary hemochromatosis, one of the commonest genetic disorder in Caucasians, is mainly associated to homozygosity for the C282Y mutation in the HFE gene, which is highly prevalent (allele frequency up to near 10% in Northern Europe) and easily detectable through a widely available "first level" molecular test. However, in certain geographical regions like the Mediterranean area, up to 30% of patients with a HH phenotype has a negative or non-diagnostic (i.e. simple heterozygosity) test, because of a known heterogeneity involving at least four other genes (HAMP, HJV, TFR2, and SLC40A1). Mutations in such genes are generally rare/private, making the diagnosis of atypical HH essentially a matter of exclusion in clinical practice (from here the term of "non-HFE" HH), unless cumbersome traditional sequencing is applied. We developed a Next Generation Sequencing (NGS)-based test targeting the five HH genes, and applied it to patients with clinically relevant iron overload (IO) and a non-diagnostic first level genetic test. We identified several mutations, some of which were novel (i.e. HFE W163X, HAMP R59X, and TFR2 D555N) and allowed molecular reclassification of "non-HFE" HH clinical diagnosis, particularly in some highly selected IO patients without concurring acquired risk factors. This NGS-based "second level" genetic test may represent a useful tool for molecular diagnosis of HH in patients in whom HH phenotype remains unexplained after the search of common HFE mutations.

  19. Effects of acute dietary iron overload in pigs (Sus scrofa) with induced type 2 diabetes mellitus.

    Science.gov (United States)

    Espinoza, A; Morales, S; Arredondo, M

    2014-06-01

    Epidemiological studies have reported an association between high iron (Fe) levels and elevated risk of developing type 2 diabetes mellitus (T2D). It is believed that the formation of Fe-catalyzed hydroxyl radicals may contribute to the development of diabetes. Our goal was to determine the effect of a diet with a high Fe content on type 2 diabetic pigs. Four groups of piglets were studied: (1) control group, basal diet; (2) Fe group, basal diet with 3,000 ppm ferrous sulfate; (3) diabetic group (streptozotocin-induced type 2 diabetes) with basal diet; (4) diabetic/Fe group, diabetic animals/3,000 ppm ferrous sulfate. For 2 months, biochemical and hematological parameters were evaluated. Tissue samples of liver and duodenum were obtained to determine mRNA relative abundance of DMT1, ferroportin (Fpn), ferritin (Fn), hepcidin (Hpc), and transferrin receptor by qRT-PCR. Fe group presented increased levels of hematological (erythrocytes, hematocrit, and hemoglobin) and iron parameters. Diabetic/Fe group showed similar behavior as Fe group but in lesser extent. The relative abundance of different genes in the four study groups yielded a different expression pattern. DMT1 showed a lower expression in the two iron groups compared with control and diabetic animals, and Hpc showed an increased on its expression in Fe and diabetic/Fe groups. Diabetic/Fe group presents greater expression of Fn and Fpn. These results suggest that there is an interaction between Fe nutrition, inflammation, and oxidative stress in the diabetes development.

  20. EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy.

    Science.gov (United States)

    Esposito, Giovanni; Perrino, Cinzia; Cannavo, Alessandro; Schiattarella, Gabriele G; Borgia, Francesco; Sannino, Anna; Pironti, Gianluigi; Gargiulo, Giuseppe; Di Serafino, Luigi; Franzone, Anna; Scudiero, Laura; Grieco, Paolo; Indolfi, Ciro; Chiariello, Massimo

    2011-06-01

    Urotensin II (UTII) and its seven trans-membrane receptor (UTR) are up-regulated in the heart under pathological conditions. Previous in vitro studies have shown that UTII trans-activates the epidermal growth factor receptor (EGFR), however, the role of such novel signalling pathway stimulated by UTII is currently unknown. In this study, we hypothesized that EGFR trans-activation by UTII might exert a protective effect in the overloaded heart. To test this hypothesis, we induced cardiac hypertrophy by transverse aortic constriction (TAC) in wild-type mice, and tested the effects of the UTII antagonist Urantide (UR) on cardiac function, structure, and EGFR trans-activation. After 7 days of pressure overload, UR treatment induced a rapid and significant impairment of cardiac function compared to vehicle. In UR-treated TAC mice, cardiac dysfunction was associated with reduced phosphorylation levels of the EGFR and extracellular-regulated kinase (ERK), increased apoptotic cell death and fibrosis. In vitro UTR stimulation induced membrane translocation of β-arrestin 1/2, EGFR phosphorylation/internalization, and ERK activation in HEK293 cells. Furthermore, UTII administration lowered apoptotic cell death induced by serum deprivation, as shown by reduced TUNEL/Annexin V staining and caspase 3 activation. Interestingly, UTII-mediated EGFR trans-activation could be prevented by UR treatment or knockdown of β-arrestin 1/2. Our data show, for the first time in vivo, a new UTR signalling pathway which is mediated by EGFR trans-activation, dependent by β-arrestin 1/2, promoting cell survival and cardioprotection.

  1. 肝脏铁过载的评估及治疗新进展%Progress in evaluation and treatment of hepatic iron overload

    Institute of Scientific and Technical Information of China (English)

    丁蕊; 贾继东

    2014-01-01

    铁过载为铁在体内过度沉积并导致肝脏、胰腺、心脏、内分泌器官等结构损害和功能障碍的一种病理状态。肝脏为机体储存铁的主要部位,过度铁沉积可诱发肝内炎症及纤维组织增生,后期可发展为肝硬化,甚至肝癌,影响预后。正确的评估及有效的治疗可在一定程度上改善铁过载引起的肝组织损伤,提高患者生存率。%Iron overload is a metabolic disorder characterized by excessive iron deposition in the liver,pancreas,heart,endocrine organs, etc.,resulting in structural damage and dysfunction.The liver is the primary organ for iron storage,and excessive iron deposition induces liver inflammation and fibrosis,which may progress to cirrhosis and even liver cancer,with a poor prognosis.Accurate evaluation and effec-tive treatment can reduce liver injury caused by iron overload and improve patients′survival.

  2. Is iron overload in alcohol-related cirrhosis mediated by hepcidin?

    Institute of Scientific and Technical Information of China (English)

    Tariq Iqbal; Azzam Diab; Douglas G Ward; Matthew J Brookes; Chris Tselepis; Jim Murray; Elwyn Elias

    2009-01-01

    In this case report we describe the relationship between ferritin levels and hepcidin in a patient with alcohol-related spur cell anemia who underwent liver transplantation. We demonstrate a reciprocal relationship between serum or urinary hepcidin and serum ferritin, which indicates that inadequate hepcidin production by the diseased liver is associated with elevated serum ferritin. The ferritin level falls with increasing hepcidin production after transplantation. Neither inflammatory indices (IL6) nor erythropoietin appear to be related to hepcidin expression in this case. We suggest that inappropriately low hepcidin production by the cirrhotic liver may contribute substantially to elevated tissue iron stores in cirrhosis and speculate that hepcidin replacement in these patients may be of therapeutic benefit in the future.

  3. Alteration of Mevalonate Pathway Related Enzyme Expressions in Pressure Overload-Induced Cardiac Hypertrophy and Associated Heart Failure with Preserved Ejection Fraction

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    Bin Chen

    2013-12-01

    Full Text Available Background: Abnormalities of the mevalonate pathway, an important cellular metabolic pathway, are common in many diseases including cardiovascular disease. The mevalonate pathway related enzyme expressions in pressure overload-induced cardiac hypertrophy and associated diastolic dysfunction remains largely unknown. This study aims to investigate whether the expression of mevalonate pathway related enzyme is altered during the progression of cardiac hypertrophy and associated diastolic dysfunction induced by pressure overload. Methods: Male Sprague-Dawley (SD rats were randomly divided into two groups: the suprarenal abdominal aortic coarctation (AAC group and the sham group. Results: Histological and echocardiographic assessments showed that there was a significant cardiovascular remodeling in the AAC group compared with the sham group after 3 weeks post-operatively, and the left ventricular (LV diastolic function was reduced at 8 and 14 weeks post-operatively in the AAC group, without any change in systolic function during the study. The tissue of the heart and the abdominal aorta proximal to the coarctation showed over-expression of several enzymes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR, farnesyl diphosphate synthase (FDPS, farnesyltransferase-α (FNTA, farnesyltransferase-β (FNTB, geranylgeranyltransferase type I (GGTase-I and the activation of their downstream proteins was enhanced. Conclusions: AAC induced compensatory LV hypertrophy to decompensatory diastolic dysfunction, accompanied by altered expression of several key enzymes in the mevalonate pathway.

  4. Effect of GDF15 on Iron Overloading and Erythropoiesis——Review%GDF15在铁过载及红系生成中的作用

    Institute of Scientific and Technical Information of China (English)

    赵佑山

    2011-01-01

    Ineffective erythropoiesis is recognized as the principal reason of non-transfusional iron overload. In the process of expanded erythropoiesis, the apoptosis of erythroblasts induces the up-regulation of GDF15. GDF15 suppresses hepcidin production by the hepatocytes. Subsequently, low hepcidin levels increase iron absorption from the intestine resulting in iron overload. Physiological dose of GDF15 can promote the growth and differentiation of erythroid progenitors, but the high dose of GDF15 can suppress the secretion of hepcidin. The regulation of GDF15 may also be related to iron levels, epigenetic regulation and hypoxia. In this article the GDF15 and its expression and distribution,roles of GDF15 in exythropoiesis and iron overload, as well as the regulation factors of GDF15 are reviewed.%无效红细胞生成被认为是非输注性铁过载患者铁过载的主要原因,在扩增的红系生成过程中原始红细胞的凋亡诱导转化生长因子15(GDF15)上调,后者抑制肝细胞铁调素的分泌,从而增加肠道铁吸收,引发铁过载.生理剂量的GDF15能促进原始红细胞的分化成熟,而高剂量的GDF15抑制铁调素的分泌.机体内铁水平、表现遗传修饰及组织缺氧均可能与GDF15的调控相关,本文就GDF15的表达与分布,GDF15在红系生成和铁过载中的作用以及GDF15的调控因素等问题进行综述.

  5. Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study.

    Science.gov (United States)

    Taher, Ali T; Porter, John B; Viprakasit, Vip; Kattamis, Antonis; Chuncharunee, Suporn; Sutcharitchan, Pranee; Siritanaratkul, Noppadol; Galanello, Renzo; Karakas, Zeynep; Lawniczek, Tomasz; Habr, Dany; Ros, Jacqueline; Zhu, Zewen; Cappellini, M Domenica

    2013-11-01

    Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was -7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of -6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.

  6. Liver, bone marrow, pancreas and pituitary gland iron overload in young and adult thalassemic patients: a T2 relaxometry study

    Energy Technology Data Exchange (ETDEWEB)

    Argyropoulou, Maria I.; Astrakas, Loukas; Metafratzi, Zafiria; Efremidis, Stavros C. [University of Ioannina, Department of Radiology, Medical School, Ioannina (Greece); Kiortsis, Dimitrios N. [University of Ioannina, Laboratory of Physiology, Medical School, Ioannina (Greece); Chalissos, Nikolaos [University of Ioannina, Department of Radiology, Medical School, Ioannina (Greece); University of Ioannina, Laboratory of Physiology, Medical School, Ioannina (Greece)

    2007-12-15

    Thirty-seven patients with {beta}-thalassemia major, including 14 adolescents (15.2 {+-} 3.0 years) and 23 adults (26.4 {+-} 6.9 years), were studied. T2 relaxation time (T2) of the liver, bone marrow, pancreas and pituitary gland was measured in a 1.5-Tesla magnetic resonance (MR) imager, using a multiecho spin-echo sequence (TR/TE 2,000/20, 40, 60, 80, 100, 120, 140, 160 ms). Pituitary gland height was evaluated in a midline sagittal scan of a spin-echo sequence (TR/TE, 500/20 ms). The T2 of the pituitary gland was higher in adolescents (59.4 {+-} 15 ms) than in adults (45.3 {+-} 10.4 ms), P < 0.05. The T2 of the pancreas was lower in adolescents (43.6 {+-} 10.3 ms) than in adults (54.4 {+-} 10.4 ms). No difference among groups was found in the T2 of the liver and bone marrow. There was no significant correlation of the T2 among the liver, pancreas, pituitary gland and bone marrow. There was no significant correlation between serum ferritin and T2 of the liver, pancreas and bone marrow. Pituitary T2 showed a significant correlation with pituitary gland height (adolescents: R = 0.63, adults: R = 0.62, P < 0.05) and serum ferritin (adolescents: R = -0.60, adults: R = -0.50, P < 0.05). In conclusion, iron overload evaluated by T2 is organ specific. After adolescence, age-related T2 changes are predominantly associated with pituitary siderosis and fatty degeneration of the pancreas. Pituitary size decreases with progressing siderosis. (orig.)

  7. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study.

    Science.gov (United States)

    Taher, Ali T; Porter, John; Viprakasit, Vip; Kattamis, Antonis; Chuncharunee, Suporn; Sutcharitchan, Pranee; Siritanaratkul, Noppadol; Galanello, Renzo; Karakas, Zeynep; Lawniczek, Tomasz; Ros, Jacqueline; Zhang, Yiyun; Habr, Dany; Cappellini, Maria Domenica

    2012-08-02

    Nontransfusion-dependent thalassemia (NTDT) patients may develop iron overload and its associated complications despite receiving only occasional or no transfusions. The present 1-year, randomized, double-blind, placebo-controlled THALASSA (Assessment of Exjade in Nontransfusion-Dependent Thalassemia) trial assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients. A total of 166 patients were randomized in a 2:1:2:1 ratio to starting doses of 5 or 10 mg/kg/d of deferasirox or placebo. The means ± SD of the actual deferasirox doses received over the duration of the study in the 5 and 10 mg/kg/d starting dose cohorts were 5.7 ± 1.4 and 11.5 ± 2.9 mg/kg/d, respectively. At 1 year, the liver iron concentration (LIC) decreased significantly compared with placebo (least-squares mean [LSM] ± SEM, -2.33 ± 0.7 mg Fe/g dry weight [dw], P = .001, and -4.18 ± 0.69 mg Fe/g dw, P deferasirox groups, respectively (baseline values [means ± SD], 13.11 ± 7.29 and 14.56 ± 7.92 mg Fe/g dw, respectively). Similarly, serum ferritin decreased significantly compared with placebo by LSM -235 and -337 ng/mL for the deferasirox 5 and 10 mg/kg/d groups, respectively (P deferasirox significantly reduces iron overload in NTDT patients with a frequency of overall adverse events similar to placebo.

  8. Can hydroxyurea serve as a free radical scavenger and reduce iron overload in β-thalassemia patients?

    Science.gov (United States)

    Italia, Khushnooma; Chandrakala, S; Ghosh, Kanjaksha; Colah, Roshan

    2016-09-01

    In this study, we hypothesize that hydroxyurea could provide an additional benefit as a free radical scavenger and/or iron chelator in β-thalassemia patients with iron overload. Twenty-one β-thalassemia intermedia patients who presented between 3 and 17 years but later required regular blood transfusions were enrolled for hydroxyurea therapy for a year. Fourteen patients responded to the therapy with hemoglobin levels maintained above 7.5 g/dl without transfusions. Hydroxyurea was discontinued after 6 months in seven patients who did not respond to the therapy and had to be continued on regular blood transfusions. We observed a statistically significant decrease in serum ferritin levels from 4194 ± 4850 ng/ml to 2129 ± 2380 ng/ml among the responders and from 2955 ± 2909 ng/ml to 2040 ± 2432 ng/ml among the non-responders and statistically significant decrease in labile iron pool from 18678.7 ± 10067.4 mean fluorescence intensity (MFI) to 14888.5 ± 5284.0 MFI among responders and from 17986.3 ± 9079.8 MFI to 15634.8 ± 8976.9 MFI among the non-responders after therapy. Phosphatidylserine externalization also showed a statistically significant decrease from 44.2 ± 22.2 MFI to 16.6 ± 6.7 MFI among the responders and from 46.9 ± 33.1 MFI to 39.8 ± 7.4 MFI among the non-responders along with a statistically significant decrease in the levels of reactive oxygen species from 72.8 ± 35.5 MFI to 29.0 ± 8.3 MFI among the responders and from 80.9 ± 41.4 MFI to 40.5 ± 15.8 MFI among the non-responders after therapy. A statistically significant increase in reduced glutathione levels was also observed from 430.8 ± 201.1 MFI to 715.5 ± 292.4 MFI among the responders and from 359.6 ± 165.6 MFI to 450.3 ± 279.5 MFI among the non-responders after therapy. This suggests the possible additional role of hydroxyurea as a free radical scavenger and

  9. Wild Edible Fruit of Prunus nepalensis Ser. (Steud, a Potential Source of Antioxidants, Ameliorates Iron Overload-Induced Hepatotoxicity and Liver Fibrosis in Mice.

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    Dipankar Chaudhuri

    Full Text Available The antioxidant and restoration potentials of hepatic injury by Prunus nepalensis Ser. (Steud, a wild fruit plant from the Northeastern region of India, were investigated. The fruit extract (PNME exhibited excellent antioxidant and reducing properties and also scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH radical (IC50 = 30.92 ± 0.40 μg/ml. PNME demonstrated promising scavenging potency, as assessed by the scavenging of different reactive oxygen and nitrogen species. Moreover, the extract revealed an exceptional iron chelation capacity with an IC50 of 25.64 ± 0.60 μg/ml. The extract induced significant improvement of hepatic injury and liver fibrosis against iron overload induced hepatotoxicity in mice in a dose-dependent manner, and this effect was supported by different histopathological studies. The phytochemical constitutions and their identification by HPLC confirmed the presence of purpurin, tannic acid, methyl gallate, reserpine, gallic acid, ascorbic acid, catechin and rutin. The identified compounds were investigated for their individual radical scavenging and iron chelation activity; some compounds exhibited excellent radical scavenging and iron chelation properties, but most were toxic towards normal cells (WI-38. On the other hand, crude PNME was found to be completely nontoxic to normal cells, suggesting its feasibility as a safe oral drug. The above study suggests that different phytochemicals in PNME contributed to its free radical scavenging and iron chelation activity; however, further studies are required to determine the pathway in which PNME acts to treat iron-overload diseases.

  10. The impact of anaemia and intravenous iron replacement therapy on outcomes in cardiac surgery.

    Science.gov (United States)

    Hogan, Maurice; Klein, Andrew A; Richards, Toby

    2015-02-01

    Anaemia is common in patients with cardiac disease and also in those undergoing cardiac surgery. There is increasing evidence that preoperative anaemia is associated with increased patient morbidity and mortality following surgery. We performed a systematic literature review to assess the impact of anaemia and intravenous (IV) iron supplementation on outcomes in cardiac surgery. Sixteen studies examined preoperative anaemia in detail. One study examined the role of preoperative IV iron administration and a further three, the effect of postoperative iron supplementation on haemoglobin (Hb) levels and the need for transfusion. Preoperative anaemia was associated with higher mortality, more postoperative blood transfusions, longer intensive care unit (ICU) and total hospital stay and also a greater incidence of postoperative cardiovascular events. In the single study that examined preoperative IV iron in combination with erythropoietin treatment, there was decreased blood transfusion, shorter hospital stay and an increase in patient survival. However, this was a small retrospective cohort study, with the observation and treatment groups analysed over different time periods. Postoperative administration of IV iron therapy, either alone or in combination with erythropoietin, was not effective in raising Hb levels or reducing red cell concentrate transfusion. On the basis of currently available evidence, the effect of perioperative administration of IV iron to cardiac surgery patients, alone or in combination with erythropoietin, remains unproven. Well-designed and appropriately powered prospective randomized controlled trials are needed to evaluate perioperative iron supplementation in the context of cardiac surgery.

  11. Cardiac protection by preconditioning is generated via an iron-signal created by proteasomal degradation of iron proteins.

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    Baruch E Bulvik

    Full Text Available Ischemia associated injury of the myocardium is caused by oxidative damage during reperfusion. Myocardial protection by ischemic preconditioning (IPC was shown to be mediated by a transient 'iron-signal' that leads to the accumulation of apoferritin and sequestration of reactive iron released during the ischemia. Here we identified the source of this 'iron signal' and evaluated its role in the mechanisms of cardiac protection by hypoxic preconditioning. Rat hearts were retrogradely perfused and the effect of proteasomal and lysosomal protease inhibitors on ferritin levels were measured. The iron-signal was abolished, ferritin levels were not increased and cardiac protection was diminished by inhibition of the proteasome prior to IPC. Similarly, double amounts of ferritin and better recovery after ex vivo ischemia-and-reperfusion (I/R were found in hearts from in vivo hypoxia pre-conditioned animals. IPC followed by normoxic perfusion for 30 min ('delay' prior to I/R caused a reduced ferritin accumulation at the end of the ischemia phase and reduced protection. Full restoration of the IPC-mediated cardiac protection was achieved by employing lysosomal inhibitors during the 'delay'. In conclusion, proteasomal protein degradation of iron-proteins causes the generation of the 'iron-signal' by IPC, ensuing de-novo apoferritin synthesis and thus, sequestering reactive iron. Lysosomal proteases are involved in subsequent ferritin breakdown as revealed by the use of specific pathway inhibitors during the 'delay'. We suggest that proteasomal iron-protein degradation is a stress response causing an expeditious cytosolic iron release thus, altering iron homeostasis to protect the myocardium during I/R, while lysosomal ferritin degradation is part of housekeeping iron homeostasis.

  12. Research progress in iron overload and neurodegenerative diseases%脑内铁过载与神经退行性疾病的研究进展

    Institute of Scientific and Technical Information of China (English)

    潘科; 陶国才

    2014-01-01

    背景 铁是人体内极其重要的微量元素,参与了许多生物大分子的构成和基本的生命活动.人体内有一套精密完善的储存、转运、调控系统来维持铁稳态,当这一复杂的网络系统出现障碍时将会导致铁代谢紊乱. 目的 综述脑内铁过载在神经退行性疾病发生发展中的重要作用. 内容 通过对近年来相关文献的总结,主要对铁的转运相关蛋白、铁稳态的调节系统、转运机制等方面对铁过载的形成及其与神经退行性疾病的关系进行了初步探讨,脑内异常高浓度的铁参与了阿尔茨海默病、帕金森病等多种神经退行性疾病的病理过程. 趋向 脑内铁过载引起神经退行性变的机制正被逐步阐明,但仍有许多问题有待解决.通过利用铁螫合剂来降低脑内铁过载可能是治疗这类疾病的一个潜在靶点.%Background As a crucial trace element in human body,iron is a component of many biological macromolecules and takes part in some basic life events.A sophisticated and sound system including iron storage,transport,regulation and control maintains iron homeostasis in the body.It will lead to iron metabolism disorder when the complex network is in problems.Objective To review the important roles of iron overload in brain during the genesis and development process of neurodegenerative diseases.Content The formation of iron overload in brain and its relationship with neurodegenerative diseases have be discussed by mainly concluding the issues in iron transporters,homeostatic regulatory system and transport mechanism.Aberrant high iron content in brain participates in pathological process of diverse neurodegenerative diseases,such as Alzheimer's disease and Parkinson's disease.Trend The mechanism of iron overload causing neurodegeneration is being clarifying,but remains many puzzles to be explored.It may become a potential target for neurodegeneration treatment by using iron chelators to reverse

  13. The efficacy of iron chelator regimes in reducing cardiac and hepatic iron in patients with thalassaemia major: a clinical observational study

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    Berdoussi Eleni

    2009-06-01

    Full Text Available Abstract Background Available iron chelation regimes in thalassaemia may achieve different changes in cardiac and hepatic iron as assessed by MR. The aim of this study was to assess the efficacy of four available iron chelator regimes in 232 thalassaemia major patients by assessing the rate of change in repeated measurements of cardiac and hepatic MR. Results For the heart, deferiprone and the combination of deferiprone and deferoxamine significantly reduced cardiac iron at all levels of iron loading. As patients were on deferasirox for a shorter time, a second analysis ("Initial interval analysis" assessing the change between the first two recorded MR results for both cardiac and hepatic iron (minimum interval 12 months was made. Combination therapy achieved the most rapid fall in cardiac iron load at all levels and deferiprone alone was significantly effective with moderate and mild iron load. In the liver, deferasirox effected significant falls in iron load and combination therapy resulted in the most rapid decline. Conclusion With the knowledge of the efficacy of the different available regimes and the specific iron load in the heart and the liver, appropriate tailoring of chelation therapy should allow clearance of iron. Combination therapy is best in reducing both cardiac and hepatic iron, while monotherapy with deferiprone or deferasirox are effective in the heart and liver respectively. The outcomes of this study may be useful to physicians as to the chelation they should prescribe according to the levels of iron load found in the heart and liver by MR.

  14. Ratiometric measurements of adiponectin by mass spectrometry in bottlenose dolphins (Tursiops truncatus with iron overload reveal an association with insulin resistance and glucagon

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    Benjamin A Neely

    2013-09-01

    Full Text Available High molecular weight (HMW adiponectin levels are reduced in humans with type 2 diabetes and insulin resistance. Similar to humans with insulin resistance, managed bottlenose dolphins (Tursiops truncatus diagnosed with hemochromatosis (iron overload have higher levels of 2 h post-prandial plasma insulin than healthy controls. A parallel reaction monitoring assay for dolphin serum adiponectin was developed based on tryptic peptides identified by mass spectrometry. Using identified post-translational modifications, a differential measurement was constructed. Total and unmodified adiponectin levels were measured in sera from dolphins with (n=4 and without (n=5 iron overload. This measurement yielded total adiponectin levels as well as site specific percent unmodified adiponectin that may inversely correlate with HMW adiponectin. Differences in insulin levels between iron overload cases and controls were observed 2 h post-prandial, but not during the fasting state. Thus, post-prandial as well as fasting serum adiponectin levels were measured to determine whether adiponectin and insulin would follow similar patterns. There was no difference in total adiponectin or percent unmodified adiponectin from case or control fasting animals. There was no difference in post-prandial total adiponectin levels between case and control dolphins (mean ± S.D. at 763 ± 298 and 727 ± 291 pmol/ml, respectively (p = 0.91; however, percent unmodified adiponectin was significantly higher in post-prandial cases compared controls (30.0 ± 6.3 versus 17.0 ± 6.6%, respectively; p = 0.016. Interestingly, both total and percent unmodified adiponectin were correlated with glucagon levels in controls (r = 0.999, p < 0.001, but not in cases, which is possibly a reflection of insulin resistance. Although total adiponectin levels were not significantly different, the elevated percent unmodified adiponectin follows a trend similar to HMW adiponectin reported for humans with

  15. 输血相关性铁过载的临床结果%Clinical outcomes of transfution-associated iron overload

    Institute of Scientific and Technical Information of China (English)

    高冲; 陈宝安; 孙耘玉; 程坚

    2011-01-01

    目的 探讨依赖输血的慢性血液病铁过载临床结果.方法 回顾性分析依赖输血(1年以上,≥50单位/例)的骨髓增乍异常综合征(MDS)和再生障碍性贫血(AA)患者10例的临床表现、重婴脏器功能、影像学变化、内分泌改变和血清铁蛋白(SF)浓度,了解体内铁负荷程度,去铁治疗及临床转归.结果 SF均明显增高(1830~4586 ng/ml);8例患者肝功能异常,7例肝脏CT值增高.SF>3500 ng/ml患者合并皮肤色素沉着,肝脾肿大和内分泌异常,其中的6例已经死亡.7例患者接受了 15~60d去铁治疗,持续依赖输血者SF无下降.结论 低危MDS和AA长期输血会导致输血性铁过载,严重者合并重要脏器功能及影像的异常,甚至死亡.去铁治疗宜在适时(SF>1000ng/ml)开始,并持续给予直到SF<1000 ng/ml.%Objective To evaluate the clinical outcomes of transfution-associated iron overload. iron overload in patients with myelodysplastic syndromes(MDS) and aplastic anemia(AA). Methods The clinical manifestations,main organ functions, CT imaging, endocrine evaluation and serum ferritin (SF) levels were analyzed retrospectively in 10 patients with transfusion-dependent for more than one year (≥50 units of red blood cells) for evaluating the degree of iron overload and efficacy of ironchelating therapy. Results SF levels of all patients increased to 1830-4586 ng mi. Eight patients had abnormal liver function. The attenuation coefficients of livers assessed by CT examination significantly increased in 7 patients. Skin pigmentation, splenohepatomegaly and endocrine dysfunction were common in the patients with SF>3500 ng/ml, of whom 6 cases were dead. Seven transfusiondependent patients received 15 to 60 days iron-chelating therapy without any decrease of SF. Conclution Transfusion-dependent patients with low-risk MDS and AA may progress secondary iron overload with organ impairment and abnormal CT imaging, even mortality in these heavily ironoverloaded

  16. CARDIAC FUNCTION AND IRON CHELATION IN THALASSEMIA MAJOR AND INTERMEDIA: A REVIEW OF THE UNDERLYING PATHOPHYSIOLOGY AND APPROACH TO CHELATION MANAGEMENT

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    Athanasios Aessopos

    2009-07-01

    Full Text Available Heart disease is the leading cause of mortality and one of the main causes of morbidity in beta-thalassemia. Patients with homozygous thalassemia may have either a severe phenotype which is usually transfusion dependent or a milder form that is thalassemia intermedia.  The two main factors that determine cardiac disease in homozygous β thalassemia are the high output state that results from chronic tissue hypoxia, hypoxia-induced compensatory reactions and iron overload.  The high output state playing a major role in thalassaemia intermedia and the iron load being more significant in the major form. Arrhythmias, vascular involvement that leads to an increased pulmonary vascular resistance and an increased systemic vascular stiffness and valvular abnormalities also contribute to the cardiac dysfunction in varying degrees according to the severity of the phenotype.  Endocrine abnormalities, infections, renal function and medications can also play a role in the overall cardiac function.  For thalassaemia major, regular and adequate blood transfusions and iron chelation therapy are the mainstays of management. The approach to thalassaemia intermedia, today, is aimed at monitoring for complications and initiating, timely, regular transfusions and/or iron chelation therapy.  Once the patients are on transfusions, then they should be managed in the same way as the thalassaemia major patients.  If cardiac manifestations of dysfunction are present in either form of thalassaemia, high pre transfusion Hb levels need to be maintained in order to reduce cardiac output and appropriate intensive chelation therapy needs to be instituted.  In general recommendations on chelation, today, are usually made according to the Cardiac Magnetic Resonance findings, if available.  With the advances in the latter technology and the ability to tailor chelation therapy according to the MRI findings as well as the availability of three iron chelators, together with

  17. Postoperative Fluid Overload is a Useful Predictor of the Short-Term Outcome of Renal Replacement Therapy for Acute Kidney Injury After Cardiac Surgery.

    Science.gov (United States)

    Xu, Jiarui; Shen, Bo; Fang, Yi; Liu, Zhonghua; Zou, Jianzhou; Liu, Lan; Wang, Chunsheng; Ding, Xiaoqiang; Teng, Jie

    2015-08-01

    To analyze the predictive value of postoperative percent fluid overload (PFO) of renal replacement therapy (RRT) for acute kidney injury (AKI) patients after cardiac surgery.Data from 280 cardiac surgery patients between 2005 January and 2012 April were collected for retrospective analyses. A receiver operating characteristic (ROC) curve was used to compare the predictive values of cumulative PFO at different times after surgery for 90-day mortality.The cumulative PFO before RRT initiation was 7.9% ± 7.1% and the median PFO 6.1%. The cumulative PFO before and after RRT initiation in intensive care unit (ICU) was higher in the death group than in the survival group (8.8% ± 7.6% vs 6.1% ± 5.6%, P = 0.001; -0.5[-5.6, 5.1]% vs 6.9[2.2, 14.6]%, P 731, and 0.752. PFO during the whole ICU stay ≥7.2% was determined as the cut-off point for 90-day mortality prediction with a sensitivity of 77% and a specificity of 64%. Kaplan-Meier survival estimates showed a significant difference in survival among patients with cumulative PFO ≥ 7.2% and PFO < 7.2% after cardiac surgery (log-rank P < 0.001).Postoperative cumulative PFO during the whole ICU stay ≥7.2% would have an adverse effect on 90-day short-term outcome, which may provide a strategy for the volume control of AKI-RRT patients after cardiac surgery.

  18. Reversal of cardiac iron loading and dysfunction in thalassemic mice by curcuminoids.

    Science.gov (United States)

    Thephinlap, C; Phisalaphong, C; Lailerd, N; Chattipakorn, N; Winichagoon, P; Vadolas, J; Fucharoen, S; Porter, J B; Srichairatanakool, S

    2011-01-01

    Non-transferrin bound iron (NTBI) is found in plasma of β-thalassemia patients and causes oxidative tissue damage. Cardiac siderosis and complications are the secondary cause of death in β-thalassemia major patients. Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising chelators used to get negative iron balance and improve life quality. DFP has been shown to remove myocardial iron effectively. Curcuminoids (CUR) can chelate plasma NTBI, inhibit lipid peroxidation and alleviate cardiac autonomic imbalance. Effects of CUR on cardiac iron deposition and function were investigated in iron-loaded mice. Wild type ((mu)β(+/+) WT) and heterozygous β-knockout ((mu)β(th-3/+) BKO) mice (C57BL/6) were fed with ferrocene-supplemented diet (Fe diet) and coincidently intervened with CUR and DFP for 2 months. Concentrations of plasma NTBI and malondialdehyde (MDA) were measured using HPLC techniques. Heart iron concentration was determined based on atomic absorption spectrophotometry and Perl's staining methods. Short-term electrocardiogram (ECG) was recorded with AD Instruments Power Lab, and heart rate variability (HRV) was evaluated using MATLAB 7.0 program. Fe diet increased levels of NTBI and MDA in plasma, nonheme iron and iron deposit in heart tissue significantly, and depressed the HRV, which the levels were higher in the BKO mice than the WT mice. CUR and DFP treatments lowered plasma NTBI as well as MDA concentrations (p <0.05), heart iron accumulation effectively, and also improved the HRV in the treated mice. The results imply that CUR would be effective in decreasing plasma NTBI and myocardial iron, alleviating lipid peroxidation and improving cardiac function in iron-loaded thalassemic mice.

  19. A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia.

    Science.gov (United States)

    Kennedy, Glen A; Morris, Kirk L; Subramonpillai, Elango; Curley, Cameron; Butler, Jason; Durrant, Simon

    2013-06-01

    This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid- and post- each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 μg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.

  20. Effect of iron deficiency on c-kit⁺ cardiac stem cells in vitro.

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    Dongqiang Song

    Full Text Available AIM: Iron deficiency is a common comorbidity in chronic heart failure (CHF which may exacerbate CHF. The c-kit⁺ cardiac stem cells (CSCs play a vital role in cardiac function repair. However, much is unknown regarding the role of iron deficiency in regulating c-kit⁺ CSCs function. In this study, we investigated whether iron deficiency regulates c-kit⁺ CSCs proliferation, migration, apoptosis, and differentiation in vitro. METHOD: All c-kit⁺ CSCs were isolated from adult C57BL/6 mice. The c-kit⁺ CSCs were cultured with deferoxamine (DFO, an iron chelator, mimosine (MIM, another iron chelator, or a complex of DFO and iron (Fe(III, respectively. Cell migration was assayed using a 48-well chamber system. Proliferation, cell cycle, and apoptosis of c-kit⁺ CSCs were analyzed with BrdU labeling, population doubling time assay, CCK-8 assay, and flow cytometry. Caspase-3 protein level and activity were examined with Western blotting and spectrophotometric detection. The changes in the expression of cardiac-specific proteins (GATA-4,TNI, and β-MHC and cell cycle-related proteins (cyclin D1, RB, and pRB were detected with Western blotting. RESULT: DFO and MIM suppressed c-kit⁺ CSCs proliferation and differentiation. They also modulated cell cycle and cardiac-specific protein expression. Iron chelators down-regulated the expression and phosphorylation of cell cycle-related proteins. Iron reversed those suppressive effects of DFO. DFO and MIM didn't affect c-kit⁺ CSCs migration and apoptosis. CONCLUSION: Iron deficiency suppressed proliferation and differentiation of c-kit⁺ CSCs. This may partly explain how iron deficiency affects CHF prognosis.

  1. Aortocaval Fistula in Rat: A Unique Model of Volume-Overload Congestive Heart Failure and Cardiac Hypertrophy

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    Zaid Abassi

    2011-01-01

    Full Text Available Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy developement. The aortocaval fistula (ACF model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long-term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience.

  2. Sustained improvements in myocardial T2* over 2 years in severely iron-overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine.

    Science.gov (United States)

    Pennell, Dudley J; Porter, John B; Piga, Antonio; Lai, Yong-Rong; El-Beshlawy, Amal; Elalfy, Mohsen; Yesilipek, Akif; Kilinç, Yurdanur; Habr, Dany; Musallam, Khaled M; Shen, Junwu; Aydinok, Yesim

    2015-02-01

    Long-term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion-dependent beta thalassemia patients. In a 1-year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [Gmean ] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long-term safety profile of deferasirox or DFO was consistent with previous reports; serious drug-related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron-overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938).

  3. Exogenous nerve growth factor supplementation elevates myocardial immunoreactivity and attenuates cardiac remodeling in pressure-overload rats

    Institute of Scientific and Technical Information of China (English)

    Bing He; and Yuming Li; Fan Ye; Xin Zhou; He Li; Xiaoqing Xun; Xiaoqing Ma; Xudong Liu; Zhihong Wang; Pengxiao Xu

    2012-01-01

    It is postulated that supplementation of exogenous nerve growth factor (NGF) might mediate improvement of the cardiac sympathetic nerve function in heart failure (HF).Local intramuscular injection of NGF near the cardiac sympathetic ganglia could influence the innervation pattern,norepinephrine transporter (NET) gene expression,and improve the cardiac remodeling in experimental HF animals.In this study,we injected NGF into the scalenus medius muscles of Sprague-Dawley rats with abdominal aortic constriction (AC).The nerve innervated pattern,left ventricular morphology,and function following injection in rats with AC were investigated respectively by immunohistochemistry and echocardiography.Levels of mRNA expression of NET,growth associated protein 43 (GAP 43),NGF and its receptors TrkA and p75NTR,and brain natriuretic peptide (BNP) were measured by realtime polymerase chain reaction.The results showed that myocardial NGF mRNA levels were comparable in rats with AC.Short-term supplementation of exogenous NGF raised the myocardial NGF immunoreactivity,but did not cause hyperinnervation and NET mRNA upregulation in the AC rats.Furthermore,myocardial TrkA mRNA was found to be remarkably decreased and p75NTR mRNA was increased.Myocardial TrkA downregulation may play a beneficial effect for avoiding the hyperinnervation,and it is reasonable to postulate that p75NTR can function as an NGF receptor in the absence of TrkA.Interestingly,local NGF administration into the neck muscles near the ganglia could attenuate cardiac remodeling and downregulate BNP mRNA.These results suggest that exogenous NGF can reach the target tissue along the axons anterogradely,and improve the cardiac remodeling.

  4. Quantification of myocardial iron deficiency in nonischemic heart failure by cardiac T2* magnetic resonance imaging.

    Science.gov (United States)

    Nagao, Michinobu; Matsuo, Yoshio; Kamitani, Takeshi; Yonezawa, Masato; Yamasaki, Yuzo; Kawanami, Satoshi; Abe, Kohtaro; Mukai, Yasushi; Higo, Taiki; Yabuuchi, Hidetake; Takemura, Atsushi; Yoshiura, Takashi; Sunagawa, Kenji; Honda, Hiroshi

    2014-03-15

    The aim of this study was to use T2* cardiac magnetic resonance (CMR) imaging to quantify myocardial iron content in patients with heart failure (HF) and to investigate the relation between iron content, cardiac function, and the cause of HF. CMR data were analyzed from 167 patients with nonischemic and 31 with ischemic HF and 50 patients with normal ventricular function. Short-axis T2* imaging was accomplished using 3-T scanner and multiecho gradient-echo sequence. Myocardial T2* value (M-T2*) was calculated by fitting the signal intensity data for the mid-left ventricular (LV) septum to a decay curve. Patients with nonischemic HF were categorized into patients with LV ejection fraction (LVEF) iron deficiency and nonischemic HF. M-T2* is a biomarker that can predict adverse cardiac function in patients with nonischemic HF.

  5. Oral iron chelators.

    Science.gov (United States)

    Kwiatkowski, Janet L

    2010-02-01

    Effective chelation therapy can prevent or reverse organ toxicity related to iron overload, yet cardiac complications and premature death continue to occur, largely related to difficulties with compliance in patients who receive parenteral therapy. The use of oral chelators may be able to overcome these difficulties and improve patient outcomes. A chelator's efficacy at cardiac and liver iron removal and side-effect profile should be considered when tailoring individual chelation regimens. Broader options for chelation therapy, including possible combination therapy, should improve clinical efficacy and enhance patient care.

  6. Five Years of Deferasirox Therapy for Cardiac Iron in β-Thalassemia Major.

    Science.gov (United States)

    Vlachaki, Efthymia; Agapidou, Alexandra; Spanos, Georgios; Klonizakis, Philippos; Vetsiou, Evaggelia; Mavroudi, Melahrini; Boura, Panagiota

    2015-01-01

    Myocardial siderosis in β-thalassemia major (β-TM) remains the leading cause of death. Deferasirox (DFX), a new iron chelation treatment, has proved to be effective in reducing or preventing cardiac iron burden in thalassemic patients according to clinical trials with maximum duration of up to 3 years except one that was recently published and lasted 5 years. The aim of this study was to evaluate the efficacy of DFX in reducing or preventing cardiac iron burden in 23 patients with β-TM after 5 years of therapy. All patients had a magnetic resonance imaging (MRI) T2* evaluation of their cardiac iron load before starting DFX therapy and after a period of 5 years. Ferritin levels and left ventricular ejection fraction (LVEF) were also evaluated at the same time. Deferasirox was administered in a starting dose of 30 mg/kg/day and never increased to more than 40 mg/kg/day. The MRI T2* cardiac iron load mean values before DFX was 32.82 ± 10.86 ms, and after 32.13 ± 7.74 ms, showing a stability in MRI T2* myocardial value but a significant improvement in two patients with an intermediate iron load (12 vs. 23 ms). The mean LVEF value was 68.43 ± 7.08% before treatment with DFX and 67.95 ± 5.94% after DFX therapy without significant change. Our results confirm previous studies that DFX is considered an effective chelating agent used as monotherapy for at least 5 years and is more efficacious in moderate to severe cardiac iron loaded thalassemic patients.

  7. The autocrine role of tryptase in pressure overload-induced mast cell activation, chymase release and cardiac fibrosis

    Directory of Open Access Journals (Sweden)

    Jianping Li

    2016-03-01

    Results and conclusion: The results indicate the presence of PAR-2 on MCs and that tryptase inhibition and nedocromil prevented TAC-induced fibrosis and increases in MC density, activation, and chymase release. Tryptase also significantly increased chymase concentration in ventricular slice culture media, which was prevented by the tryptase inhibitor. Hydroxyproline concentration in culture media was significantly increased with tryptase incubation as compared to the control group and the tryptase group incubated with nafamostat mesilate or chymostatin. We conclude that tryptase contributes to TAC-induced cardiac fibrosis primarily via activation of MCs and the amplified release of chymase.

  8. Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

    Institute of Scientific and Technical Information of China (English)

    Xue-Hui Wang; Xiao-Zhen Zhuo; Ya-Juan Ni; Min Gong; Ting-Zhong Wang; Qun Lu; Ai-Qun Ma

    2012-01-01

    Objective We performed experiments using Neuregulin-1β (NRG-1β) treatment to determine a mechanism for the protective role derived from its beneficial effects by remodeling gap junctions (GJs) during heart failure (HF). Methods Rat models of HF were established by aortocaval fistula. Forty-eight rats were divided randomly into the HF (HF, n = 16), NRG-1β treatment (NRG, n = 16), and sham operation (S, n = 16) group. The rats in the NRG group were administered NRG-1β (10 μg/kg per day) for 7 days via the tail vein, whereas the other groups were injected with the same doses of saline. Twelve weeks after operation, Connexin 43 (Cx43) expression in single myocytes obtained from the left ventricle was determined by immunocytochemistry. Total protein was extracted from frozen left ventricular tissues for immunoblotting assay, and the ultrastructure of myocytes was observed by transmission electron microscopy. Results Compared with the HF group, the cardiac function of rats in the NRG group was markedly improved, irregular distribution and deceased Cx43 expression were relieved. The ultrastructure of myocytes was seriously damaged in HF rats, and NRG-1β reduced these pathological damages. Conclusions Short-term NRG-1β treatment can rescue pump failure in experimental models of volume overload-induced HF, which is related to the recovery of GJs structure and the improvement of Cx43 expression.

  9. 铁超载与肝细胞癌关系的研究进展%Recent progress in relationship between iron overload and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    赵睿

    2011-01-01

    Hepatocellular carcinoma (HCC) is associated with many specific etiologies. Some epidemiological investigations has shown that dietary iron overload is associated with HCC in Africans. And subsequent studies found that many iron-loading diseases, such as hereditary hemochromatosis, chronic hepatitis C, nonalcoholic fatty liver disease etc, appeared to increase the risk of HCC with the development of these diseases. The carcinogenic potential of these iron-loading diseases is probably mainly associated with genetic mutation, abnormal expression of iron metabolism related proteins, oxidative stress reaction, immune disorder and so on. We summarized the recent findings concerning the correlation between iron-loading diseases and HCC.%肝细胞癌(HCC)的发生与多种因素有关.早期的流行病学研究显示非洲人群饮食中铁过量与HCC发生相关,继而研究发现许多与铁沉积相关的疾病如遗传性血色素沉积症(HH)、丙型病毒性肝炎、非酒精性脂肪性肝病(NAFLD)等在发展过程中均有发生HCC的可能性,提示铁超载可能在其中发挥着直接或间接的作用.现认为铁超载的发生与基因突变、铁代谢相关基因蛋白的异常表达、氧化应激反应、免疫紊乱、促进癌细胞生长等因素有关.本文就铁超载与HCC的相关研究现状作一综述.

  10. Brazilian Thalassemia Association protocol for iron chelation therapy in patients under regular transfusion

    Directory of Open Access Journals (Sweden)

    Monica Pinheiro de Almeida Verissimo

    2013-01-01

    Full Text Available In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA, presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams and the role of T2* magnetic resonance imaging (MRI to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions.

  11. Association of Right Ventricular Pressure and Volume Overload with Non-Ischemic Septal Fibrosis on Cardiac Magnetic Resonance.

    Directory of Open Access Journals (Sweden)

    Jiwon Kim

    Full Text Available Non-ischemic fibrosis (NIF on cardiac magnetic resonance (CMR has been linked to poor prognosis, but its association with adverse right ventricular (RV remodeling is unknown. This study examined a broad cohort of patients with RV dysfunction, so as to identify relationships between NIF and RV remodeling indices, including RV pressure load, volume and wall stress.The population comprised patients with RV dysfunction (EF 6-fold more common in the highest, vs. the lowest, common tertile of PASP and RV size (p<0.001.Among wall stress components, NIF was independently associated with RV chamber dilation and afterload, supporting the concept that NIF is linked to adverse RV chamber remodeling.

  12. Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study

    DEFF Research Database (Denmark)

    Gattermann, Norbert; Finelli, Carlo; Porta, Matteo Della;

    2010-01-01

    patients were chelation-naïve or previously chelated; changes were dependent on dose adjustments and ongoing iron intake. Sustained reductions in labile plasma iron were observed. Discontinuation rate (48.7%) and adverse event profile were consistent with previously reported deferasirox data in MDS...

  13. Effect of Yiqi Huoxue Recipe(益气活血方)on Cardiac Function and Ultrastructure in Regression of Pressure Overload-induced Myocardial Hypertrophy in Rats

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective:To investigate the effect of Yiqi Huoxue Recipe(YHR,益气活血方)on the cardiac function and ultrastructure during the regression of myocardial hypertrophy induced by pressure overload in rats.Methods:The model of myocardial hypertrophy was established by abdominal aortic banding.Eighty male Wistar rats were divided into six groups,the normal control group Ⅰ(n=20),the normal control group Ⅱ(n=12),the hypertension model group [(n=12),the hypertension model group Ⅱ(n=12),the YHR group(n=12)and the Captopril group(n=12).The observation was carried out in the normal control group Ⅰ and the hypertension model group Ⅰ after 4weeks of modeling,and the other four groups were observed after 16 weeks of modeling(12 weeks of administration).The cardiac function was measured with a multichannel biological signal analysis system,and the myocardium ultrastructure was observed by a transmission electron microscope.Results:(1)Compared with the normal control group Ⅰ,the systolic blood pressure and cardiac coefficient(left ventricular weight/body weight)in the model Ⅰ group was higher(P<0.05,P<0.01).(2)In the YHR group,cardiac coefficient and -dp/dtmax were lower,left ventricular systolic pressure and +dp/dtmin were higher when compared with the model group Ⅱ and the Captopril group(P<0.05or P<0.01).In the Captopril group,only cardiac coefficient was lower when compared with the mode group Ⅱ(P<0.05).(3)Compared with the normal control group Ⅱ,+dp/dtrmax was higher(P<0.01),-dp/dtnmax and isovolumetric contraction time(ICT)was lower(P<0.05,P<0.01)in both the YHR group and the Captopril group.(4)Results of the myocardium ultrastructure showed edema under myocardium plasmalemma,enlarged sarcoplasmic reticulum and T tube,and significantly enlarged intercalated disc of the cardiac muscle in the model groups.In the Captopril group,the extension of sarcoplasmic reticulum and T tube as well as the pathological changes of intercalated disc

  14. 铁过载对骨髓增生异常综合征患者不良危害若干问题的认识%Current Understanding of Iron Overload Hazard in Patients with Myelodysplastic Syndrome-Review

    Institute of Scientific and Technical Information of China (English)

    宋陆茜; 苏基滢; 张征; 常春康

    2013-01-01

    骨髓增生异常综合征(myelodysplastic syndromes,MDS)患者自然病程中会出现输血依赖并发展为输血相关的铁过载,同时由于MDS红细胞无效造血,肠道加强膳食铁的吸收而加重铁过载.铁过载与MDS并发症、降低MDS生存期密切相关.因此,本文将阐述MDS输血依赖及铁过载的认识,特别关注作为不稳定铁的氧化还原活性存在形式的作用机制、铁过载通过氧化应激对MDS造血机能影响的机制及对MDS生存期及白血病转化风险的影响等问题.%Patients with myelodysplastic syndromes (MDS) become dependent on blood transfusions and develop into transfusional iron overload, which is exacerbated by increased absorption of dietary iron in response to ineffective erythropoiesis. However, it is uncertain whether there is an association among iron accumulation, clinical complications, and decreased likelihood of survival in MDS patients. Thereby our current understanding of the effects of transfusion dependency and iron overload in MDS are discussed. Particular emphasis should be placed on further characterizing the role of redox-active forms of labile iron and oxidative stress in iron overload, decreased life expectancy and increased risk of leukemic transformation in MDS patients with iron overload.

  15. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state.

    Science.gov (United States)

    Waldmeier, Felix; Bruin, Gerard J; Glaenzel, Ulrike; Hazell, Katharine; Sechaud, Romain; Warrington, Steve; Porter, John B

    2010-05-01

    Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult beta-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (approximately 20 mg/kg) of [14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5'-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).

  16. Risks of iron overload for patients with myelodysplastic syndrome and the efficacy of deferasirox%铁过载对骨髓增生异常综合征患者的危害及地拉罗司祛铁疗效探讨

    Institute of Scientific and Technical Information of China (English)

    刘容容

    2012-01-01

    长期规律输血是骨髓增生异常综合征(M DS)最为重要的支持疗法,然而长期输血带来的铁过载会导致器官损害,严重影响患者的生存预后.祛铁治疗对于改善MDS患者造血机能、减少心脏事件、延长生存起着重要作用.地拉罗司是一种新型的口服铁螯合剂,能有效改善MDS患者的造血机能、促进血液学缓解并改善脏器功能,是MDS患者祛铁治疗的一线药物.本文就铁过载对MDS患者的危害、MDS祛铁治疗指南及地拉罗司在MDS铁过载治疗中的应用做一综述.%Long-term regular transfusion is the most important supportive treatment for patients with myelodysplastic syndrome (MDS). However, iron overload caused by long-term transfusion could lead to organ dysfunction, and remarkably shorten patients' survival. Iron chelation treatment (ICT) plays a significant role in improving hematopoiesis of MDS patients, decreasing cardiac events and increasing their survival. Deferasirox is a new type of oral iron chelators, which effectively improves hematopoietic response and organ functions of MDS patients. Also, deferasirox is recommended as the first-line chelator for MDS patients in most of MDS treatment guidelines. This review summarized the risks of iron overload for MDS patients, ICT guideline for MDS patients and efficacy of deferasirox in MDS patients.

  17. 铁过载巨噬细胞体外模型的建立及氧化应激对铁过载巨噬细胞的损伤作用%Establishment of macrophage model of iron overload in vitro and the injury induced by oxidative stress on macrophage with iron overload

    Institute of Scientific and Technical Information of China (English)

    曹小立; 赵明峰; 李德冠; 邢艺; 张宇辰; 陈洁; 贺小圆; 崔蕊; 孟娟霞

    2016-01-01

    Objective To establish macrophage iron overload model in vitro by co-culture macrophages with iron,and to explore the effect of iron overload on cell reactive oxygen species (ROS) and the impact of ROS on macrophages.Method Iron overload group were treated with different concentrations (0,5,10,20,40,80 μmol/L respectively) of ferric ammonium citrate (FAC).The control group was the group of macrophages without FAC treatment.We detected the number and state of cells,metabolic activity,the change of phagocytosis,the levels of ROS and reactive nitrogen,and changes of related oxidative stress signaling pathways in different groups.Changes in the above indexes were detected after application of deferasirox (DFX) to remove iron and the antioxidant N-acetylcysteine (NAC) to clear excess oxidative stress.Results (1) The levels of labile iron pool (LIP) in macrophages co-cultivated with iron was increased with the increase of iron concentration in a dose-dependent manner.The LIP levels was the highest in the macrophages treated with 80 μmol/L.(2)The increase of FAC concentration,the metabolic activity of macrophages in the 5 FAC-treated groups decreased to 51.58%,40.98%,16.23%,3.46%,and 0.05% of the activity level of the control group (all P < 0.05).The group with the metabolic activity decreased to 16.23% (20 μmol/L) was selected as the iron overload group for the following experiments.(3) Compared with the control group,the number of macrophages in the iron overload group reduced to 32.80% (P < 0.05),and the state of cells changed from adherence to partial suspension.The phagocytosis of macrophages in the iron overload group reduced to 20.40% of the control group (P < 0.05).(4) Our further experiment showed that the levels of ROS and the activity nitrogen in the iron overload group increased by 7.71-and 1.45-fold compared with the control group (both P < 0.05).The RT-PCR showed up-regulated mRNA expression of genes related with ROS production

  18. A novel germline PIGA mutation in Ferro-Cerebro-Cutaneous syndrome: a neurodegenerative X-linked epileptic encephalopathy with systemic iron-overload.

    Science.gov (United States)

    Swoboda, Kathryn J; Margraf, Rebecca L; Carey, John C; Zhou, Holly; Newcomb, Tara M; Coonrod, Emily; Durtschi, Jacob; Mallempati, Kalyan; Kumanovics, Attila; Katz, Ben E; Voelkerding, Karl V; Opitz, John M

    2014-01-01

    Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism.

  19. THERAPEUTIC VALUE OF COMBINED THERAPY WITH DEFERASIROX AND SILYMARIN ON IRON OVERLOAD IN CHILDREN WITH BETA THALASSEMIA

    Directory of Open Access Journals (Sweden)

    adel abd elhaleim hagag

    2013-11-01

    Patients and Methods: This study was conducted on 40 children with beta thalassemia major under follow-up at Hematology Unit, Pediatric Department, Tanta University Hospital having serum ferritin level more than 1000 ng/ml and was divided in two groups. Group IA: Received oral Deferasirox (Exjade and silymarin for 6 months. Group IB: Received oral Deferasirox (Exjade and placebo for 6 months and 20 healthy children serving as a control group in the period between April 2011 and August 2012 and was performed after approval from research ethical committee center in Tanta University Hospital and obtaining an informed written parental consent from all participants in this research. Results: Serum ferritin levels were markedly decreased in group IA cases compared with group IB (P= 0.001. Conclusion: From this study we concluded that, silymarin in combination with Exjade can be safely used in treatment of iron-loaded thalassemic patients as it showed good iron chelation with no sign of toxicity. Recommendations: Extensive multicenter studies in large number of patients with longer duration of follow up and more advanced methods of assessment of iron status is recommended to clarify the exact role of silymarin in reduction of iron over load in children with beta thalassemia.

  20. Role of ferritin in the rice tolerance to iron overload Papel da ferritina na tolerância de arroz ao excesso de ferro

    Directory of Open Access Journals (Sweden)

    Vivian Chagas da Silveira

    2009-08-01

    Full Text Available Plants ordinarily face iron (Fe deficiency, since this mineral is poorly available in soils under aerobic conditions. Nonetheless, wetland and irrigated rice plants can be exposed to excess, highly toxic Fe. Ferritin is a ubiquitous Fe-storage protein, important for iron homeostasis. Increased ferritin accumulation resulting from higher Fe availability was shown in some plant species. However, the role of ferritin in tolerance mechanisms to Fe overload in rice is yet to be established. In this study, recombinant rice ferritin was expressed in Escherichia coli, producing an anti-rice ferritin polyclonal antibody which was used to evaluate ferritin accumulation in two rice (Oryza sativa L. cultivars, either susceptible (BR-IRGA 409 or tolerant (EPAGRI 108 to Fe toxicity. Increased ferritin mRNA and protein levels resulting from excess Fe treatment were detected in both cultivars, with higher ferritin protein accumulation in EPAGRI 108 plants, which also reached lower shoot Fe concentrations when submitted to iron overload. The tolerance mechanism to excess Fe in EPAGRI 108 seems to include both restricted Fe translocation and increased ferritin accumulation. This is the first work that shows higher accumulation of the ferritin protein in an iron-excess tolerant Oryza sativa cultivar, providing evidence of a possible role of this protein in iron tolerance mechanisms.Deficiência de ferro (Fe ocorre freqüentemente em plantas, uma vez que este mineral é pouco disponível em condições aeróbicas. Plantas de arroz cultivadas sob alagamento, no entanto, estão sujeitas ao excesso de Fe, que pode ser extremamente tóxico. Alguns cultivares de arroz são resistentes a altas concentrações de ferro, mas os mecanismos fisiológicos responsáveis por essa resistência são pouco conhecidos. A ferritina é uma proteína de ampla distribuição e capaz de armazenar ferro, sendo considerada importante para a homeostase deste metal. Acúmulo de ferritina em

  1. 不同铁螯合剂治疗输血依赖性铁过载的对比研究%A comparative study of different iron chela-tion therapy transfusion dependent iron over-load

    Institute of Scientific and Technical Information of China (English)

    李仙松; 杜娟; 李伟平

    2014-01-01

    目的:对比不同铁螯合剂对贫血患者长期输血治疗后铁过载的驱铁作用及安全性。方法:将24例反复输血的患者在血清铁蛋白(SF)水平相同条件下随机均分为三组,采用不同铁螯合剂去铁治疗,分别检测其在治疗后1个月、2个月、3个月的铁蛋白(SF)水平,并观察其治疗相关不良反应。结果:地拉罗司组在治疗后SF下降最明显,且不良反应最少。结论:地拉罗司治疗输血依赖性铁过载的效果最好,安全性较高,不良反应最少。%AIM:To compare the effects and safety of iron over-load of patients with anemia who received different iron chelators treatment after long-term transfusion.METHODS:Dividing the 24 patients who transfused blood repeatedly into three groups un-der the same condition of serum ferritin (SF)level for iron remov-al treatment with different iron chelators.Then we detected the se-rum ferritin (SF)level after treatment of 1 month,2 months and 3 months respectively,and observed the adverse reactions relative-ly.RESULTS:The group with Deferasirox that the SF level de-creased at most and had minimal adverse reactions after treat-ment.CONCLUSION:The best therapeutic efficacy for iron o-verload of transfusion dependency is Deferasirox which has high safety and minimal adverse reactions.

  2. A Phase 1/2, Dose-Escalation Trial of Deferasirox for the Treatment of Iron Overload in HFE-Related Hereditary Hemochromatosis

    Science.gov (United States)

    Phatak, Pradyumna; Brissot, Pierre; Wurster, Mark; Adams, Paul C; Bonkovsky, Herbert L; Gross, John; Malfertheiner, Peter; McLaren, Gordon D; Niederau, Claus; Piperno, Alberto; Powell, Lawrie W; Russo, Mark W; Stoelzel, Ulrich; Stremmel, Wolfgang; Griffel, Louis; Lynch, Nicola; Zhang, Yiyun; Pietrangelo, Antonello

    2010-01-01

    Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase >3× baseline and greater than the upper limit of normal range, and eight patients had serum creatinine >33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to <250 ng/mL. Conclusion: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population. (Hepatology

  3. Pentosan polysulfate decreases myocardial expression of the extracellular matrix enzyme ADAMTS4 and improves cardiac function in vivo in rats subjected to pressure overload by aortic banding.

    Directory of Open Access Journals (Sweden)

    Maria Vistnes

    Full Text Available BACKGROUND: We hypothesized that cleavage of the extracellular matrix (ECM proteoglycans versican and aggrecan by ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs proteases, which contributes to stress-induced ECM-reorganization in atherogenesis and osteoarthritis, also play a role in heart failure development. OBJECTIVES: The primary objective was to identify alterations in expression of ADAMTS versicanases and aggrecanases during development of heart failure, while evaluation of the effects of in vivo modulation of relevant changes in ADAMTS activity constituted the secondary objective. METHODS: Myocardial levels of versican, aggrecan, and their ADAMTS cleaving proteases were examined in Wistar rats six weeks after aortic banding (AB, and versican and selected ADAMTS versicanases were further analyzed in neonatal cardiomyocytes (NCM and cardiac fibroblasts (NFB after stimulation by inflammatory mediators. Based on the initial findings, ADAMTS4 was selected the most promising therapeutic target. Thus, rats with AB were treated with pentosan polysulfate (PPS, a polysaccharide with known ADAMTS4-inhibitory properties, and effects on versican fragmentation, left ventricular function and geometry were evaluated. RESULTS: We discovered that myocardial mRNA and protein levels of ADAMTS1 and -4, and mRNA levels of versican, aggrecan, and ADAMTS8 increased after AB, and TNF-α and IL-1β synergistically increased mRNA of versican and ADAMTS4 in NCM and NFB and secretion of ADAMTS4 from NCM. Furthermore, PPS-treatment improved systolic function, demonstrated by an improved fractional shortening (vehicle 48±3% versus PPS 60±1%, p<0.01 after AB. Following PPS-treatment, we observed an ∼80% reduction in myocardial ADAMTS4 mRNA (p = 0.03, and ∼50% reduction in the extracellular amount of the p150 versican fragments (p = 0.05, suggesting reduced versicanase activity. CONCLUSIONS: Our findings suggest that AB induces an

  4. Physiology and pathophysiology of iron cardiomyopathy in thalassemia.

    Science.gov (United States)

    Wood, John C; Enriquez, Cathleen; Ghugre, Nilesh; Otto-Duessel, Maya; Aguilar, Michelle; Nelson, Marvin D; Moats, Rex; Coates, Thomas D

    2005-01-01

    Iron cardiomyopathy remains the leading cause of death in patients with thalassemia major. Magnetic resonance imaging (MRI) is ideally suited for monitoring thalassemia patients because it can detect cardiac and liver iron burdens as well as accurately measure left ventricular dimensions and function. However, patients with thalassemia have unique physiology that alters their normative data. In this article, we review the physiology and pathophysiology of thalassemic heart disease as well as the use of MRI to monitor it. Despite regular transfusions, thalassemia major patients have larger ventricular volumes, higher cardiac outputs, and lower total vascular resistances than published data for healthy control subjects; these hemodynamic findings are consistent with chronic anemia. Cardiac iron overload increases the relative risk of further dilation, arrhythmias, and decreased systolic function. However, many patients are asymptomatic despite heavy cardiac burdens. We explore possible mechanisms behind cardiac iron-function relationships and relate these mechanisms to clinical observations.

  5. Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence in β-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial

    Directory of Open Access Journals (Sweden)

    John Porter

    2012-01-01

    Full Text Available Treatment of iron overload using deferoxamine (DFO is associated with significant deficits in patients' health-related quality of life (HRQOL and low treatment satisfaction. The current article presents patient-reported HRQOL, satisfaction, adherence, and persistence data from β-thalassemia (n=274 and myelodysplastic syndrome (MDS patients (n=168 patients participating in the Evaluation of Patients' Iron Chelation with Exjade (EPIC study (NCT00171821; a large-scale 1-year, phase IIIb study investigating the efficacy and safety of the once-daily oral iron chelator, deferasirox. HRQOL and satisfaction, adherence, and persistence to iron chelation therapy (ICT data were collected at baseline and end of study using the Medical Outcomes Short-Form 36-item Health Survey (SF-36v2 and the Satisfaction with ICT Questionnaire (SICT. Compared to age-matched norms, β-thalassemia and MDS patients reported lower SF-36 domain scores at baseline. Low levels of treatment satisfaction, adherence, and persistence were also observed. HRQOL improved following treatment with deferasirox, particularly among β-thalassemia patients. Furthermore, patients reported high levels of satisfaction with deferasirox at end of study and greater ICT adherence, and persistence. Findings suggest deferasirox improves HRQOL, treatment satisfaction, adherence, and persistence with ICT in β-thalassemia and MDS patients. Improving such outcomes is an important long-term goal for patients with iron overload.

  6. Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence in β-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial

    Science.gov (United States)

    Porter, John; Bowden, Donald K.; Economou, Marina; Troncy, Jacques; Ganser, Arnold; Habr, Dany; Martin, Nicolas; Gater, Adam; Rofail, Diana; Abetz-Webb, Linda; Lau, Helen; Cappellini, Maria Domenica

    2012-01-01

    Treatment of iron overload using deferoxamine (DFO) is associated with significant deficits in patients' health-related quality of life (HRQOL) and low treatment satisfaction. The current article presents patient-reported HRQOL, satisfaction, adherence, and persistence data from β-thalassemia (n = 274) and myelodysplastic syndrome (MDS) patients (n = 168) patients participating in the Evaluation of Patients' Iron Chelation with Exjade (EPIC) study (NCT00171821); a large-scale 1-year, phase IIIb study investigating the efficacy and safety of the once-daily oral iron chelator, deferasirox. HRQOL and satisfaction, adherence, and persistence to iron chelation therapy (ICT) data were collected at baseline and end of study using the Medical Outcomes Short-Form 36-item Health Survey (SF-36v2) and the Satisfaction with ICT Questionnaire (SICT). Compared to age-matched norms, β-thalassemia and MDS patients reported lower SF-36 domain scores at baseline. Low levels of treatment satisfaction, adherence, and persistence were also observed. HRQOL improved following treatment with deferasirox, particularly among β-thalassemia patients. Furthermore, patients reported high levels of satisfaction with deferasirox at end of study and greater ICT adherence, and persistence. Findings suggest deferasirox improves HRQOL, treatment satisfaction, adherence, and persistence with ICT in β-thalassemia and MDS patients. Improving such outcomes is an important long-term goal for patients with iron overload. PMID:22924125

  7. Non-invasive diagnosis and follow-up of right ventricular overload

    NARCIS (Netherlands)

    Henkens, Ivo Reinier

    2008-01-01

    Right ventricular overload covers a spectrum ranging from volume overload to pressure overload, and often is a combination of these, compromising cardiac function. Part I focuses on right ventricular volume overload in adults with Fallot’s tetralogy corrected in early childhood. We determined whic

  8. Response of iron overload to deferasirox in rare transfusion-dependent anaemias: equivalent effects on serum ferritin and labile plasma iron for haemolytic or production anaemias

    Science.gov (United States)

    Porter, John B; Lin, Kai-Hsin; Beris, Photis; Forni, Gian Luca; Taher, Ali; Habr, Dany; Domokos, Gabor; Roubert, Bernard; Thein, Swee Lay

    2011-01-01

    Objectives It is widely assumed that, at matched transfusional iron-loading rates, responses to chelation therapy are similar, irrespective of the underlying condition. However, data are limited for rare transfusion-dependent anaemias, and it remains to be elucidated if response differs, depending on whether the anaemia has a primary haemolytic or production mechanism. Methods The efficacy and safety of deferasirox (Exjade®) in rare transfusion-dependent anaemias were evaluated over 1 yr, with change in serum ferritin as the primary efficacy endpoint. Initial deferasirox doses were 10–30 mg/kg/d, depending on transfusion requirements; 34 patients had production anaemias, and 23 had haemolytic anaemias. Results Patients with production anaemias or haemolytic anaemias had comparable transfusional iron-loading rates (0.31 vs. 0.30 mL red blood cells/kg/d), mean deferasirox dosing (19.3 vs. 19.0 mg/kg/d) and baseline median serum ferritin (2926 vs. 2682 ng/mL). Baseline labile plasma iron (LPI) levels correlated significantly with the transfusional iron-loading rates and with serum ferritin levels in both cohorts. Reductions in median serum ferritin levels were initially faster in the production than the haemolytic anaemias, but at 1 yr, similar significant reductions of 940 and 617 ng/mL were attained, respectively (−26.0% overall). Mean LPI decreased significantly in patients with production (P < 0.0001) and haemolytic (P = 0.037) anaemias after the first dose and was maintained at normal mean levels (<0.4 μm) subsequently. The most common drug-related, investigator-assessed adverse events were diarrhoea (n = 16) and nausea (n = 12). Conclusions At matched transfusional iron-loading rates, the responses of rare transfusion-dependent anaemias to deferasirox are similar at 1 yr, irrespective of the underlying pathogenic mechanism. PMID:21649735

  9. Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in Sao Miguel Island Population (Azores, Portugal.

    Directory of Open Access Journals (Sweden)

    Claudia C Branco

    Full Text Available Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal, six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations- c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family's HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3% patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40-2.94, pG;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association.

  10. Information overload and data overload in lexicography

    DEFF Research Database (Denmark)

    Tarp, Sven; Gouws, Rufus H.

    2017-01-01

    the often uncritical inclusion of too much data. This paper discusses the general term information overload and its lexicographical counterpart data overload. Different types of data overload are identified and the problems users have when retrieving the necessary information from dictionary articles...

  11. Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.

    Science.gov (United States)

    Cotter, P D; May, A; Li, L; Al-Sabah, A I; Fitzsimons, E J; Cazzola, M; Bishop, D F

    1999-03-01

    X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband's maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH) HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance of HFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

  12. SQUID biosusceptometry in the measurement of hepatic iron

    Energy Technology Data Exchange (ETDEWEB)

    Sheth, Sujit [Department of Pediatrics, Columbia University College of Physicians and Surgeons, Harkness Pavilion, Room HP570, 180 Fort Washington Avenue, NY 10032, New York (United States)

    2003-06-01

    Individuals with primary or secondary abnormalities of iron metabolism, such as hereditary hemochromatosis and transfusional iron loading, may develop potentially lethal systemic iron overload. Over time, this excess iron is progressively deposited in the liver, heart, pancreas, and other organs, resulting in cirrhosis, heart disease, diabetes and other disorders. Unless treated, death usually results from cardiac failure. The amount of iron in the liver is the best indicator of the amount of iron in the whole body. At present, the only sure way to measure the amount of iron in the liver is to remove a sample of the liver by biopsy. Iron stored in the liver can be magnetized to a small degree when placed in a magnetic field. The amount of magnetization is measured by our instrument, called a superconducting quantum interference device (SQUID) susceptometer. In patients with iron overload, our previous studies have shown that magnetic measurements of liver iron in patients with iron overload are quantitatively equivalent to biochemical determinations on tissue obtained by biopsy. The safety, ease, rapidity, and comfort of magnetic measurements make frequent, serial studies technically feasible and practically acceptable to patients. (orig.)

  13. Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.

    Science.gov (United States)

    Pronicka, Ewa; Węglewska-Jurkiewicz, Anna; Taybert, Joanna; Pronicki, Maciej; Szymańska-Dębińska, Tamara; Karkucińska-Więckowska, Agnieszka; Jakóbkiewicz-Banecka, Joanna; Kowalski, Paweł; Piekutowska-Abramczuk, Dorota; Pajdowska, Magdalena; Socha, Piotr; Sykut-Cegielska, Jolanta; Węgrzyn, Grzegorz

    2011-02-01

    ) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.

  14. 铁过载对骨髓损伤小鼠造血功能的作用及机制研究%Effects and mechanism of iron overload on hematopoiesis in mice with bone marrow injury

    Institute of Scientific and Technical Information of China (English)

    柴笑; 赵明峰; 李德冠; 张宇辰; 卢文艺; 曹小立; 孟娟霞; 游权; 孟爱民

    2014-01-01

    Objective To explore effects of iron overload on hematopoiesis in mice with bone marrow injury and its possible mechanism(s).Methods C57BL/6 mice were divided into control,iron,irradiation,irradiation+iron groups.The iron-overloaded model of bone marrow injury was set up after mice were exposed to the dose of 4 Gy total body irradiation and (or) were injected iron dextran intraperitoneally.Iron overload was confirmed by observing iron deposits in mice and bone marrow labile iron pool.Additionally,the number of peripheral blood and bone marrow mononuclear cells and the frequency of erythroid cells and myeloid cells were counted and hematopoietic function was assessed.Results ①Iron overload occurred by bone marrow biopsy and flow cytometry analysis.②Compared with control group,the number ofplatelets [(801.9±81.2) × 109/L vs (926.0±28.2) × 109/L] and BMMNC and the frequency of erythroid cells and myeloid cells decreased.Moreover,hematopoietic colony forming units and single-cell cloning counts decreased significantly in irradiation group (P < 0.05).③Compared with irradiation group,the number of platelets [(619.0±60.9) × 109/L vs (801.9±81.2) × 109/L] and the frequency of erythroid cells and myeloid cells decreased; moreover,hematopoietic colony forming units and singlecell cloning counts decreased significantly in irradiation + iron group (P<0.05).④Compared with irradiation group,ROS level increased by 1.94 fold in BMMNC,1.93 fold in erythroid cells and 2.70 fold in myeloid cells,respectively (P < 0.05).Conclusions The dose of 4 Gy total body irradiation caused bone marrow damage and iron overload based on this injury model,which could damage bone marrow hematopoietic function aggravatingly.And further study found that iron overload was closely related to increased ROS level in BMMNC.The findings would be helpful to further study the injury mechanism of iron overload on the hematopoiesis of bone marrow.%目的 探讨铁过载对骨髓损伤小

  15. Determination of iron-overload in thalassemia by hepatic MRI and ferritin Determinação da sobrecarga de ferro na talassemia pela IRM hepática e ferritina

    Directory of Open Access Journals (Sweden)

    Ivan L. Angulo

    2008-12-01

    Full Text Available Accumulation of iron in thalassemia causes organ damage and reduces patient survival due to heart lesions in the second decade of life. Iron deposits are monitored by direct (biopsy and indirect methods (ferritin with sequential data being better than isolated measurements. This paper compares two indirect measurements of iron overload; a single hepatic iron concentration (HIC by magnetic resonance and mean ferritin levels over four years. A retrospective study of 25 patients from the Centro Regional de Hemoterapia in Ribeirão Preto, Brazil was carried out. High HIC (above 7 mg per gram of dry weight was found in 20 patients and high mean serum ferritin (above 2500 μg/L in 10 patients. Stratification into three levels (low, moderate and high of iron overload gave similar results in both tests. Many other factors influence de degree of iron overload in thalassemia. No correlation was found using a non-parametric statistical test between HIC and mean serum ferritin. Both methods provide better planning of chelation therapy.O acúmulo de ferro na talassemia causa lesões orgânicas e reduz a sobrevida do paciente por lesão cardíaca na segunda década da vida, e tem sido avaliado por medidas diretas (biópsia e indiretas (ferritina. As medidas isoladas carecem de valor, sendo preferidas as sequenciais. Este trabalho pretende comparar medidas indiretas de sobrecarga de ferro, uma medida da concentração de ferro hepático por ressonância magnética, e a ferritina sérica média dos últimos quatro anos. Trata-se de estudo retrospectivo de 25 pacientes do Centro Regional de Hemoterapia, em Ribeirão Preto, Brasil. Encontrou-se em vinte pacientes ferro hepático acima de 7 mg/g peso seco e ferritina média elevada acima de 2.500 ug/l em dez. Estratificação em três níveis de sobrecarga (leve, moderada e grave produziu resultados semelhantes em ambos os testes. Vários outros fatores influenciam o grau de sobrecarga de ferro na talassemia. N

  16. 携带式微量注射泵在血液病中治疗铁过载的护理%Nursing of Portable Syringe Pump Iron Overload in the Treatment of Blood Diseases

    Institute of Scientific and Technical Information of China (English)

    陈为

    2014-01-01

    Objective: using portable micro pump subcutaneous deferoxamine to nursing iron overload of iron treatment, in order to improve the clinical treatment ef ect. Methods:I Division in 2011 January--2013 year in August a total of 31 cases of patients with clinical diagnosis of iron overload, the portable micro pump subcutaneous deferoxamine to iron therapy. Results: Patients with iron overload use portable micro injection pump to iron treatment ef icacy. Conclusion: to increase the safety coef icient and the ef ective concentration of the medication of the patients, improve the therapeutic ef ect, is beneficial to the recovery of patients. Simple operation, easy to use, reduces the burden of nurses, improve the quality of medical care, clinical curative ef ect, is a kind of new technique worthy of popularization and application.%目的:采用携带式微量泵皮下注射去铁胺去铁治疗铁过载的护理,以提高临床治疗效果。方法选择我科于2011年1月~2013年8月共有31例血液病患者符合铁过载的临床诊断,采用携带式微量泵皮下注射去铁胺去铁治疗。结果铁过载患者使用携带式微量注射泵去铁治疗效果肯定。结论增加患者用药安全系数和有效浓度,提高治疗效果,有利于患者早日康复。操作简单,使用方便,减轻了护士负担,提高了医疗护理质量,临床疗效确切,是值得推广应用的一种新技术。

  17. Iron deficiency and cardiovascular disease.

    Science.gov (United States)

    von Haehling, Stephan; Jankowska, Ewa A; van Veldhuisen, Dirk J; Ponikowski, Piotr; Anker, Stefan D

    2015-11-01

    Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.

  18. Prevention of Cardiomyopathy in Transfusion-Dependent Homozygous Thalassaemia Today and the Role of Cardiac Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Athanassios Aessopos

    2009-01-01

    Full Text Available Transfusion and iron chelation therapy revolutionised survival and reduced morbidity in patients with transfusion-dependent beta thalassaemia major. Despite these improvements, cardiac disease remained the most common cause of death in those patients. Recently the ability to determine the degree of cardiac iron overload, through cardiac magnetic resonance imaging (CMR has allowed more logical approaches to iron removal, particularly from the heart. The availability of two oral chelators, deferiprone and deferasirox has reduced the need for the injectable chelator deferrioxamine and an additional benefit has been that deferiprone has been shown to be more cardioprotective than deferrioxamine. This review on the prevention of cardiac disease makes recommendations on the chelation regime that would be desirable for patients according to their cardiac iron status as determined by CMR determined by CMR. It also discusses approaches to chelation management should CMR not be available.

  19. Establishment of Iron Overloaded Bone Marrow Model In Vitro and Its Impact on Hematopoiesis%铁过载骨髓造血细胞体外模型的建立及其对造血的影响

    Institute of Scientific and Technical Information of China (English)

    谢芳; 赵明峰; 朱海波; 肖霞; 徐新女; 穆娟; 李玉明

    2011-01-01

    This study was to establish an iron overload bone marrow (BM) model by co-culturing the mononuclear cells from BM with iron, and investigate its hematopoiesis changes. The iron overload model was set up by adding different concentration of ferric citrate (FAC) into the mononuclear cells from BM and culturing for different time, and the model was confirmed by detecting labile iron pool (LLP). Then the apoptosis of hematopoietic cells, ability of hematopoietic colony forming (CFU-E, BFU-E, CFU-GM and CFU-mix) and percentage of the CD34 + cells of the BM cells all were determined. The changes of these indexes were tested after the iron-overloaded BM was treated with deferasirox (DFO). The results showed that after BM cells were cultured with FAC at different concentrations for different time, the LLP increased in time-and concentration-dependent manners. The intracellular LIP reached maximum level when cultured at 400 μmol/L of FAC for 24 hours. The detection of BM cell hematopoietic function found that the apoptotic rate of the FAC-treated cells (24.8 ± 2.99% ) increased significantly, as compared with normal control ( 8.9 ±0.96%) (p <0.01 ). The ability of hematopoietic colony forming in FAC-treated cells decreased markedly, as compared with normal control (p < 0.05 ). The percentage of CD34 + cells of FAC-treated cells (0.39 ± 0.07 % ) also decreased significantly, as compared with normal control (0.91 ±0. 12% ) (p <0.01 ). And these changes could be alleviated by adding DFO. It is concluded that the iron-overloaded model has been set by adding iron into the mononuclear cells from BM in vitro, and the hematopoietic funtion of iron-overloaded BM is deficient. These changes can be alleviated by removing the excess iron from the BM cells through treating with DFO. These findings would be helpful to further study the mechanism of iron-overload on the hematopoiesis of BM and also useful to fmd the way to treat iron-overload patients with hematopoietic

  20. 磁共振成像技术定量检测铁过载的临床意义%Significance of magnetic resonance imaging in the detection of iron overload

    Institute of Scientific and Technical Information of China (English)

    张倩; 侯波; 王璐; 王晓英; 冯逢; 江滨; 石红霞; 马一盖; 刘辉

    2013-01-01

    Objective To evaluate the significance of magnetic resonance imaging (MRI) T2* value analysis in patients with iron overload and compare it with other clinical parameters.Methods A total of 53 patients with suspected iron overload were recruited from four Beijing hospitals from December 2010 to December 2012.Their liver and heart T2 * values were calculated and their serum ferritin (SF),transferin saturation,blood transfusion volume and other clinical parameters were recorded and analyzed.Results There were 37 males and 16 females with a medium age of 50 years(15-72 years).Their etiologies included myelodysplastic syndromes (MDS,n =25),aplastic anemia (AA,n =16),myelofibrosis (n =5),hemachromatosis (n =2) and β thalassaemia (n =2),and 3 patients with high SF values were found on regular health examinations.Among them,there were transfusion history (n =45),SF > 1000 μg/L (n =49),sign of iron overload (n =10),abnormal liver function (n =38) and hyperglycemia (n =32).T2* value analysis showed that 10 patients had no evidence of iron overload,43 patients had liver iron overload (14 mild,22 moderate and 7 severe) and 2 patients had heart iron overload (1 MDS with heavy transfusion history and 1 AA with heart failure).No relations existed between T2 * value and SF (P =0.050),T2 * value and transfusion volume (P =0.820),and liver T2 * value and heart T2 * value (P =0.129).Conclusions MRI T2* value is an accurate way of quantitative detection of iron overload.It provides a comprehensive understanding of patients with iron overload in conjunctions with MRI T2 * value and other clinical parameters.%目的 研究磁共振成像(MRI)技术定量检测铁过载的情况并与传统方法进行比较.方法 选取2010年12月至2012年12月北京4家医院临床上怀疑有铁过载而在北京协和医院进行MRI定量检测的患者53例,应用MRI T2* mapping的方法测定患者肝脏及心脏T2*值,依照MRI T2*值判断铁过载情况并与同期检测的血清铁蛋

  1. 地拉罗司治疗重型β-地中海贫血铁过载患儿临床疗效及安全性研究%Curative effects and safety of deferasirox in treatment of iron overload in children with β-thalassemia major

    Institute of Scientific and Technical Information of China (English)

    高红英; 李其; 陈娟娟; 陈光福; 李长钢

    2011-01-01

    Objective To study the effectiveness and safety of deferasirox (DFX) in the treatment of iron overload in children with β-thalassemia major. Methods Twenty-four β-thalassemia major children with iron overload who received regular blood transfusion were randomly enrolled. The serum feritin ( SF) levels were measured in the patients after different doses of DFX treatment. The DFX treatment-related adverse events were observed. The values of cardiac MRI T2 * and liver MRI T2 * were compared between the patients receiving DFX treatment for 5 years and the patients treated with deferoxamine and deferiprone. Results The patients with iron overload did not respond to DFX at the initial dose of 20-30 mg/kg · d. However, the SF level decreased significantly after the dose of DFX increased to 30-40 mg/kg · d ( U = 58, P < 0. 01 ). Serum liver transaminase elevation was the most common adverse effect, followed by non-progressive elevation in serum creatinine level. The mean SF level was significantly lower ( 1748±481 ng/mL vs 3462 t 1744 ng/mL; P < 0.05 ), in contrast, the liver MRI T2 * value was significantly higher ( 8.5 ± 2.9 ms vs 2.7 ± 1.9 ms; P < 0. 01 ) in patients receiving DFX treatment for 5 years than in the controls. There were no significant differences in the cardiac MRI T2 * value between the two groups. Conclusions DFX can reduce SF levels in a dose-dependent manner in children with β-thalassemia major. It can significantly lower liver iron overload but not cardiac overload. Serum liver transaminase elevation and non-progressive elevation in serum creatinine level are major adverse effects in DFX treatment.%目的 探讨铁鳌合剂地拉罗司(deferasirox,DFX)治疗重型β-地中海贫血(β-thalassemia major,β-TM)铁过载患儿的疗效及安全性.方法 随机选择24例规律输血的β-TM铁过载患儿,参加DFX不同服药剂量的临床研究,调查血清铁蛋白(SF)的变化及不良反应.并将持续服用DFX 5年患儿与间期

  2. Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

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    Elena Gammella

    2015-01-01

    Full Text Available The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies.

  3. Iron deposition following chronic myocardial infarction as a substrate for cardiac electrical anomalies: initial findings in a canine model.

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    Ivan Cokic

    Full Text Available PURPOSE: Iron deposition has been shown to occur following myocardial infarction (MI. We investigated whether such focal iron deposition within chronic MI lead to electrical anomalies. METHODS: Two groups of dogs (ex-vivo (n = 12 and in-vivo (n = 10 were studied at 16 weeks post MI. Hearts of animals from ex-vivo group were explanted and sectioned into infarcted and non-infarcted segments. Impedance spectroscopy was used to derive electrical permittivity ([Formula: see text] and conductivity ([Formula: see text]. Mass spectrometry was used to classify and characterize tissue sections with (IRON+ and without (IRON- iron. Animals from in-vivo group underwent cardiac magnetic resonance imaging (CMR for estimation of scar volume (late-gadolinium enhancement, LGE and iron deposition (T2* relative to left-ventricular volume. 24-hour electrocardiogram recordings were obtained and used to examine Heart Rate (HR, QT interval (QT, QT corrected for HR (QTc and QTc dispersion (QTcd. In a fraction of these animals (n = 5, ultra-high resolution electroanatomical mapping (EAM was performed, co-registered with LGE and T2* CMR and were used to characterize the spatial locations of isolated late potentials (ILPs. RESULTS: Compared to IRON- sections, IRON+ sections had higher[Formula: see text], but no difference in[Formula: see text]. A linear relationship was found between iron content and [Formula: see text] (p1.5% with similar scar volumes (7.28% ± 1.02% (Iron (1.5%, p = 0.51 but markedly different iron volumes (1.12% ± 0.64% (Iron (1.5%, p = 0.02, QT and QTc were elevated and QTcd was decreased in the group with the higher iron volume during the day, night and 24-hour period (p<0.05. EAMs co-registered with CMR images showed a greater tendency for ILPs to emerge from scar regions with iron versus without iron. CONCLUSION: The electrical behavior of infarcted hearts with iron appears to be different from those without iron. Iron within infarcted zones may

  4. HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Tongyi [Department of Cardiothoracic Surgery, No. 401 Hospital of PLA, Qingdao (China); Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Zhang, Ben [Centre of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Region, Guangzhou (China); Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Yang, Fan; Cai, Chengliang; Wang, Guokun [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Han, Qingqi, E-mail: handoctor@gmail.com [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Zou, Liangjian, E-mail: zouliangjiansh@gmail.com [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2015-05-08

    Pathological cardiac hypertrophy, often accompanied by hypertension, aortic stenosis and valvular defects, is typically associated with myocyte remodeling and cardiac dysfunction. Exercise preconditioning (EP) has been proven to enhance the tolerance of the myocardium to cardiac ischemia-reperfusion injury. However, the effects of EP in pathological cardiac hypertrophy are rarely reported. 10-wk-old male Sprague–Dawley rats (n = 80) were randomly divided into four groups: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and the EP + TAC and TAC groups were followed by TAC operations. The sham and EP + sham groups underwent the same operation without aortic constriction. Eight weeks after the surgery, we evaluated the effects of EP by echocardiography, morphology, and histology and observed the expressions of the associated proteins. Compared with the respective control groups, hypertrophy-related indicators were significantly increased in the TAC and EP + TAC groups (p < 0.05). However, between the TAC and EP + TAC groups, all of these changes were effectively inhibited by EP treatment (p < 0.05). Furthermore, EP treatment upregulated the expression of HSF1 and HSP70, increased the HSF1 levels in the nuclear fraction, inhibited the expression of the NF-κB p65 subunit, decreased the NF-κB p65 subunit levels in the nuclear fraction, and reduced the IL2 levels in the myocardia of rats. EP could effectively reduce the cardiac hypertrophic responses induced by TAC and may play a protective role by upregulating the expressions of HSF1 and HSP70, activating HSF1 and then inhibiting the expression of NF-κB p65 and nuclear translocation. - Highlights: • EP could effectively reduce the cardiac hypertrophic responses induced by TAC. • EP may play a protective role by upregulating the expressions of HSF1 and HSP70 and then activating HSF1. • EP may play a protective role by inhibiting the expression

  5. The Association between Myocardial Iron Load and Ventricular Repolarization Parameters in Asymptomatic Beta-Thalassemia Patients

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    Mehmet Kayrak

    2012-01-01

    Full Text Available Previous studies have demonstrated impaired ventricular repolarization in patients with β-TM. However, the effect of iron overload with cardiac T2* magnetic resonance imaging (MRI on cardiac repolarization remains unclear yet. We aimed to examine relationship between repolarization parameters and iron loading using cardiac T2* MRI in asymptomatic β-TM patients. Twenty-two β-TM patients and 22 age- and gender-matched healthy controls were enrolled to the study. From the 12-lead surface electrocardiography, regional and transmyocardial repolarization parameters were evaluated manually by two experienced cardiologists. All patients were also undergone MRI for cardiac T2* evaluation. Cardiac T2* score <20 msec was considered as iron overload status. Of the QT parameters, QT duration, corrected QT interval, and QT peak duration were significantly longer in the β-TM group compared to the healthy controls. Tp−Te and Tp−Te dispersions were also significantly prolonged in β-TM group compared to healthy controls. (Tp-Te/QT was similar between groups. There was no correlation between repolarization parameters and cardiac T2* MRI values. In conclusion, although repolarization parameters were prolonged in asymptomatic β-TM patients compared with control, we could not find any relation between ECG findings and cardiac iron load.

  6. Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6.

    Science.gov (United States)

    Truksa, Jaroslav; Gelbart, Terri; Peng, Hongfan; Beutler, Ernest; Beutler, Bruce; Lee, Pauline

    2009-11-01

    Hepcidin, the master regulator of enteric iron absorption, is controlled by the opposing effects of pathways activated in response to iron excess or iron attenuation. Iron excess is regulated through a pathway involving the cell surface receptor hemojuvelin (HFE2) that stimulates expression of the hepcidin encoding gene (HAMP). Iron attenuation is countered through a pathway involving the hepatocyte-specific plasma membrane protease matriptase-2 encoded by TMPRSS6, leading to suppression of HAMP expression. The non-redundant function of hemojuvelin and matriptase-2 has been deduced from the phenotype imparted by mutations of HFE2 and TMPRSS6, which cause iron excess and iron deficiency respectively. Hemojuvelin is positioned to be the ideal substrate for matriptase-2. To examine the relationship between hemojuvelin and matriptase-2 in vivo, we crossed mice lacking the protease domain of matriptase-2 with mice lacking hemojuvelin. Mice lacking functional matriptase-2 and hemojuvelin exhibited low Hamp (Hamp1) expression, high serum and liver iron, and high transferrin saturation. Surprisingly, the double mutant mice also exhibited lower levels of iron in the heart compared to hemojuvelin-deficient mice, demonstrating a possible cardioprotective effect resulting from the loss of matriptase-2. This phenotype is consistent with hemojuvelin being a major substrate for matriptase-2/TMPRSS6 protease activity.

  7. 黄芪多糖对压力超负荷诱导的大鼠心肌肥大的影响%Effect of Astragalus polysaccharides on cardiac hypertrophy induced by pressure overload in rat

    Institute of Scientific and Technical Information of China (English)

    李素娟; 吴伟平; 李杰锋; 张贵平; 魏毅; 宜全; 罗健东; 刘英华

    2012-01-01

    目的:探讨黄芪多糖(astragalus polysaccharides,APS)对压力超负荷所致大鼠心肌肥大的抑制作用.方法:SD大鼠随机分为5组:假手术手组、模型组、APS低剂量组(AP1)、APS高剂量组(AP2)和卡托普利组.给药8周后,分别进行心脏超声和HE染色检测心脏肥大指数及形态学改变.结果:超声检测发现,与假手术组相比,模型组左右心室质量比明显增加,舒张期左心室容量、左心室射血分数和左心室短轴缩短速率均明显降低;AP2组与模型组相比,以上指标均有显著性改善,而AP1组和模型组比较无明显差异.HE染色显示,模型组肌细胞排列疏松、肥大,AP1组和AP2组细胞排列整齐,有少量肥大细胞夹杂.结论:高剂量APS对压力超负荷大鼠的心肌肥大有明显保护作用.%Objective To investigate the inhibition of the astragalus polysaccharides (APS) on cardiac hypertrophy induced by pressure overload in rat. Methods 60 SD rats were randomly divided into 5 groups:Sham, Model, Captopril, low-dose APS and high-dose APS group. All these drugs were administrated for 8 weeks respectively. Echocardiography and cardiac hypertrophy index were detected respectively for the heart function, HE staining was detected to observe the cardiac morphology. Results Echocardiography showed that compared with the sham group, left and right ventricular mass ratio (LVM/RVM) of the model group significantly increased, diastolic left ventricular volume (LV Vol, d), left ventricular ejection fraction (EF) and left ventricular fractional shortening rate (FS) of the model group decreased significantly. While comparing with the model group, the indexes of the above in APS group significantly improved. HE staining showed that myocardial cells became hypertrophic and arranged loosely in model group, while the myocardial cells in AP2 group arranged in order, and the hypertrophy cells obviously decreased. But there was no significant difference between the API and

  8. METABOLISM OF IRON STORES

    OpenAIRE

    Saito, Hiroshi

    2014-01-01

    ABSTRACT Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis. Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since th...

  9. Reducing the iron burden and improving survival in transfusion-dependent thalassemia patients: current perspectives

    Directory of Open Access Journals (Sweden)

    Bayanzay K

    2016-08-01

    Full Text Available Karim Bayanzay, Lama Alzoebie Department of Hematology, Gulf Medical University, Ajman, United Arab Emirates Abstract: Hypertransfusion regimens for thalassemic patients revolutionized the management of severe thalassemia; transforming a disease which previously led to early infant death into a chronic condition. The devastating effect of the accrued iron from chronic blood transfusions necessitates a more finely tuned approach to limit the complications of the disease, as well as its treatment. A comprehensive approach including carefully tailored transfusion protocol, continuous monitoring and assessment of total body iron levels, and iron chelation are currently the mainstay in treating iron overload. There are also indications for ancillary treatments, such as splenectomy and fetal hemoglobin induction. The main cause of death in iron overload continues to be related to cardiac complications. However, since the widespread use of iron chelation started in the 1970s, there has been a general improvement in survival in these patients. Keywords: hematology, chelators, deferoxamine, deferiserox, deferiprone, liver iron concentration, iron overload, serum ferritin concentration, hepatic iron storage, iron chelation therapy

  10. Comparison of cardiac dysfunction in thalassemia major patients using deferoxamine or deferiprone as an iron-chelating agent

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    Rosalina Josep

    2012-09-01

    Full Text Available Background In Thalassemia major (TM patients, major mortality is due to cardiac hemosiderosis. Several types of iron chelating agent available recently are given to overcome this problem Objective To compare cardiac dysfunction in thalassemia major patients who used subcutaneous deferoxamine (DFO to those who used oral deferiprone (DFP as an iron-chelating agent Methods This cross-sectional study was held at the Thalassemia Center, Departemen of Child Health-Cipto Mangunkusumo Hospital (DCH-CMH, Jakarta. We included TM patients aged 10-18 years with a mean pre-transfused hemoglobin level of >7g/dL in the prior year, and who had used DFO or DFP for at least 1 year with good compliance, at astandard dose of DFO at 40-60 mg/kg/day for 5 days a week or DFP at 50-100 mg/kg/day We excluded TM patients with congenital heart disease or overt heart failure. Trans-thoracal echocardiography was performed at the Integrated Cardiac Service, CMH by a pediatric cardiologist using the conventional method and tissue Doppler imaging (TDI consecutively, and within 2 weeks of the subject’s receiving a packed red blood cell (PRBC transfusion. The 57 TM subjects consisted of 19 DFO users and 38 DFP users. Results In our subjects, diastolic dysfunction was more commonly seen than systolic dysfunction, especially moderate diastolic dysfunction. In the DFO group, diastolic dysfunction only was detected in 3/19 subjects, systolic dysfuntion only in 1/19 subjects, and both diastolic and systolic dysfuntion in 15-19 subjects. None of the DFO users had normal cardiac function. In the DFP group, diastolic dysfunction only was seen in 6/38 subjects, and both diastolic and systolic dysfunction in 30/38 subjrcts, while 2/38 subjects had normal cardiac function. Conclusion Diastolic and/or systolic dysfunction was detected in the majority of subjects, but with preserved global cardiac function. We found that cardiac dysfunction was not significantly different in the two iron

  11. Hepcidin Plays a Key Role in 6-OHDA Induced Iron Overload and Apoptotic Cell Death in a Cell Culture Model of Parkinson’s Disease

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    Qi Xu

    2016-01-01

    Full Text Available Background. Elevated brain iron levels have been implicated in the pathogenesis of Parkinson’s disease (PD. However, the precise mechanism underlying abnormal iron accumulation in PD is not clear. Hepcidin, a hormone primarily produced by hepatocytes, acts as a key regulator in both systemic and cellular iron homeostasis. Objective. We investigated the role of hepcidin in 6-hydroxydopamine (6-OHDA induced apoptosis in a cell culture model of PD. Methods. We downregulated hepcidin using siRNA interference in N27 dopaminergic neuronal cells and made a comparison with control siRNA transfected cells to investigate the role of hepcidin in 6-OHDA induced neurodegeneration. Results. Hepcidin knockdown (32.3%, P<0.0001 upregulated ferroportin 1 expression and significantly (P<0.05 decreased intracellular iron by 25%. Hepcidin knockdown also reduced 6-OHDA induced caspase-3 activity by 42% (P<0.05 and DNA fragmentation by 29% (P=0.086 and increased cell viability by 22% (P<0.05. In addition, hepcidin knockdown significantly attenuated 6-OHDA induced protein carbonyls by 52% (P<0.05 and intracellular iron by 28% (P<0.01, indicating the role of hepcidin in oxidative stress. Conclusions. Our results demonstrate that hepcidin knockdown protected N27 cells from 6-OHDA induced apoptosis and that hepcidin plays a major role in reducing cellular iron burden and oxidative damage by possibly regulating cellular iron export mediated by ferroportin 1.

  12. Fluorescent magnetic iron oxide nanoparticles for cardiac precursor cell selection from stromal vascular fraction and optimization for magnetic resonance imaging

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    Verma VK

    2015-01-01

    Full Text Available Vinod Kumar Verma,1 Suguna Ratnakar Kamaraju,1 Ravindranath Kancherla,1 Lakshmi K Kona,1 Syed Sultan Beevi,1 Tanya Debnath,1 Shalini P Usha,1 Rammohan Vadapalli,2 Ali Syed Arbab,3 Lakshmi Kiran Chelluri11Department of Transplant Biology, Immunology and Stem Cell Laboratory, Global Hospitals, 2Department of Imageology, Vijaya Radiology Centre, Hyderabad, India; 3Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, USAAbstract: Fluorescent magnetic iron oxide nanoparticles have been used to label cells for imaging as well as for therapeutic purposes. The purpose of this study was to modify the approach to develop a nanoprobe for cell selection and imaging with a direct therapeutic translational focus. The approach involves physical coincubation and adsorption of superparamagnetic iron oxide nanoparticle-polyethylene glycol (SPION-PEG complexes with a monoclonal antibody (mAb or a set of antibodies. Flow cytometry, confocal laser scanning microscopy, transmission electron microscopy, iron staining, and magnetic resonance imaging were used to assess cell viability, function, and labeling efficiency. This process has been validated by selecting adipose tissue-derived cardiac progenitor cells from the stromal vascular fraction using signal regulatory protein alpha (SIRPA/kinase domain receptor (KDR mAbs. These markers were chosen because of their sustained expression during cardiomyocyte differentiation. Sorting of cells positive for SIRPA and KDR allowed the enrichment of cardiac progenitors with 90% troponin-I positivity in differentiation cultures. SPION labeled cardiac progenitor cells (1×105 cells was mixed with gel and used for 3T magnetic resonance imaging at a concentration, as low as 12.5 µg of iron. The toxicity assays, at cellular and molecular levels, did not show any detrimental effects of SPION. Our study has the potential to achieve moderate to high specific cell selection for the dual purpose of

  13. Information overload and data overload in lexicography

    DEFF Research Database (Denmark)

    Tarp, Sven; Gouws, Rufus H.

    2016-01-01

    Too often online dictionaries still display too many features determined by the restrictions that applied to printed dictionaries. Data overload in dictionary articles can be regarded as one such relic from the past. However, the idea that online dictionaries have unlimited space has furthered th...

  14. Combination therapies in iron chelation

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    Raffaella Origa

    2014-12-01

    Full Text Available The availability of oral iron chelators and new non-invasive methods for early detection and treatment of iron overload, have significantly improved the life expectancy and quality of life of patients with b thalassemia major. However, monotherapy is not effective in all patients for a variety of reasons. We analyzed the most relevant reports recently published on alternating or combined chelation therapies in thalassemia major with special attention to safety aspects and to their effects in terms of reduction of iron overload in different organs, improvement of complications, and survival. When adverse effects, such as gastrointestinal upset with deferasirox or infusional site reactions with deferoxamine are not tolerable and organ iron is in an acceptable range, alternating use of two chelators (drugs taken sequentially on different days, but not taken on the same day together may be a winning choice. The association deferiprone and deferoxamine should be the first choice in case of heart failure and when dangerously high levels of cardiac iron exist. Further research regarding the safety and efficacy of the most appealing combination treatment, deferiprone and deferasirox, is needed before recommendations for routine clinical practice can be made.

  15. Upregulation of the kappa opioidergic system in left ventricular rat myocardium in response to volume overload: Adaptive changes of the cardiac kappa opioid system in heart failure.

    Science.gov (United States)

    Treskatsch, Sascha; Shaqura, Mohammed; Dehe, Lukas; Feldheiser, Aarne; Roepke, Torsten K; Shakibaei, Mehdi; Spies, Claudia D; Schäfer, Michael; Mousa, Shaaban A

    2015-12-01

    Opioids have long been known for their analgesic effects and are therefore widely used in anesthesia and intensive care medicine. However, in the last decade research has focused on the opioidergic influence on cardiovascular function. This project thus aimed to detect the precise cellular localization of kappa opioid receptors (KOR) in left ventricular cardiomyocytes and to investigate putative changes in KOR and its endogenous ligand precursor peptide prodynorphin (PDYN) in response to heart failure. After IRB approval, heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. All rats of the control and ACF group were characterized by their morphometrics and hemodynamics. In addition, the existence and localization as well as adaptive changes of KOR and PDYN were investigated using radioligand binding, double immunofluorescence confocal analysis, RT-PCR and Western blot. Similar to the brain and spinal cord, [(3)H]U-69593 KOR selective binding sites were detected the left ventricle (LV). KOR colocalized with Cav1.2 of the outer plasma membrane and invaginated T-tubules and intracellular with the ryanodine receptor of the sarcoplasmatic reticulum. Interestingly, KOR could also be detected in mitochondria of rat LV cardiomyocytes. As a consequence of heart failure, KOR and PDYN were up-regulated on the mRNA and protein level in the LV. These findings suggest that the cardiac kappa opioidergic system might modulate rat cardiomyocyte function during heart failure.

  16. Deferasirox treatment of iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes in medical practice: results from the observational studies eXtend and eXjange

    Science.gov (United States)

    Gattermann, Norbert; Jarisch, Andrea; Schlag, Rudolf; Blumenstengel, Klaus; Goebeler, Mariele; Groschek, Matthias; Losem, Christoph; Procaccianti, Maria; Junkes, Alexia; Leismann, Oliver; Germing, Ulrich

    2012-01-01

    EXtend and eXjange were prospective, 1-yr, non-interventional, observational, multicentre studies that investigated deferasirox, a once-daily oral iron chelator, in iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes (MDS), respectively, treated in the daily-routine setting of office-based physicians. No inclusion or exclusion criteria or additional monitoring procedures were applied. Deferasirox was administered as recommended in the European Summary of Product Characteristics. Haematological parameters and adverse events (AEs) were collected at two-monthly intervals. Data from 123 chelation-naïve patients with MDS (mean age 70.4 yrs) with median baseline serum ferritin level of 2679 (range 184–16 500) ng/mL, and 44 prechelated patients with MDS (mean age 69.6 yrs) with median baseline serum ferritin level of 2442 (range 521–8565) ng/mL, were assessed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. Treatment with deferasirox produced a significant reduction in median serum ferritin levels in chelation-naïve patients with MDS from 2679 to 2000 ng/mL (P = 0.0002) and a pronounced decrease in prechelated patients with MDS from 2442 to 2077 ng/mL (P = 0.06). The most common drug-related AEs were gastrointestinal, increased serum creatinine levels and rash. These studies demonstrate that deferasirox used in physicians’ medical practices is effective in managing iron burden in transfusion-dependent patients with MDS. PMID:22023452

  17. Deferasirox treatment of iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes in medical practice: results from the observational studies eXtend and eXjange.

    Science.gov (United States)

    Gattermann, Norbert; Jarisch, Andrea; Schlag, Rudolf; Blumenstengel, Klaus; Goebeler, Mariele; Groschek, Matthias; Losem, Christoph; Procaccianti, Maria; Junkes, Alexia; Leismann, Oliver; Germing, Ulrich

    2012-03-01

    EXtend and eXjange were prospective, 1-yr, non-interventional, observational, multicentre studies that investigated deferasirox, a once-daily oral iron chelator, in iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes (MDS), respectively, treated in the daily-routine setting of office-based physicians. No inclusion or exclusion criteria or additional monitoring procedures were applied. Deferasirox was administered as recommended in the European Summary of Product Characteristics. Haematological parameters and adverse events (AEs) were collected at two-monthly intervals. Data from 123 chelation-naïve patients with MDS (mean age 70.4 yrs) with median baseline serum ferritin level of 2679 (range 184-16,500) ng/mL, and 44 prechelated patients with MDS (mean age 69.6 yrs) with median baseline serum ferritin level of 2442 (range 521-8565) ng/mL, were assessed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. Treatment with deferasirox produced a significant reduction in median serum ferritin levels in chelation-naïve patients with MDS from 2679 to 2000 ng/mL (P = 0.0002) and a pronounced decrease in prechelated patients with MDS from 2442 to 2077 ng/mL (P = 0.06). The most common drug-related AEs were gastrointestinal, increased serum creatinine levels and rash. These studies demonstrate that deferasirox used in physicians' medical practices is effective in managing iron burden in transfusion-dependent patients with MDS.

  18. 活性氧在铁过载影响成骨细胞生物活性中的作用%Function of reactive species in effect of iron overload on the biological activity of osteoblasts

    Institute of Scientific and Technical Information of China (English)

    何银锋; 高超; 赵国阳; 张林林; 张增利; 林华; 徐又佳

    2013-01-01

    Objective To observe the effect of iron overload on the biological activity of human osteoblasts (hFOB1. 19) in vitro, and to observe the function of reactive species in this progress. Methods Osteoblasts were cultured in vitro and divided into 4 groups. One group was treated with 200 μmol/L ferric ammonium citrate ( FAC) ; one group was treated with 2.5 mmol/L antioxidant N-acetyl cysteine (NAC) ; one group was pretreated with NAC for lh and then treated with the same concentration of FAC intervention ; and the last group was normal control group. After 48 - hour culturing, the levels of reactive oxygen species ( ROS) in each group were detected using flow cytometry. Cell viability was detected using CCK -8 assay. The expression of OPG, BGP, and COL1 mRNA was detected using RT-PCR. Alkaline phosphatase (ALP) activity was detected using ALP viability kit. Results The levels of reactive oxygen species among different groups were significantly different ( P < 0. 05). The level in FAC group was higher than that in control group, and the level in FAC + NAC group was significantly lower than that in FAC group, but higher than that in NAC group. The content of active oxygen in each group was negatively correlated with osteoblast activity, the optical density ratio of OPG, BGP, and COL1mRNA expression, and alkaline phosphatase activity ( P < 0. 05 ). Conclusion The effect of iron overload on reducing the biological activity of osteoblasts may be associated with increased reactive oxygen species caused by iron overload.%目的 观察铁过载对人成骨细胞(hFOB1.19)生物活性的影响,同时观察活性氧在这一实验变化过程中的作用.方法 体外培养成骨细胞,一组运用200 μmol/L枸橼酸铁铵(FAC)干预,一组运用2.5 mmol/L抗氧化剂N-乙酰半胱氨酸(NAC)干预,一组NAC预处理1 h后运用相同浓度FAC干预,一组为正常对照;细胞培养48 h后,流式细胞仪检测各组细胞内活性氧(ROS)的水平;CCK-8法检测各组

  19. Iron nanoparticles increase 7-ketocholesterol-induced cell death, inflammation, and oxidation on murine cardiac HL1-NB cells

    Directory of Open Access Journals (Sweden)

    Edmond Kahn

    2010-03-01

    Full Text Available Edmond Kahn1, Mauhamad Baarine2, Sophie Pelloux3, Jean-Marc Riedinger4, Frédérique Frouin1, Yves Tourneur3, Gérard Lizard21INSE RM U678/UMR – S UPMC, IFR 14, CH U Pitié-Salpêtrière, 75634 Paris Cedex 13, France; 2Centre de Recherche INSE RM U866, Equipe Biochimie Métabolique et Nutritionnelle – Université de Bourgogne, Faculté des Sciences Gabriel, 6 Bd Gabriel, 21000 Dijon, France; 3Centre Commun de Quantimétrie, Université Lyon 1; Université de Lyon, Lyon, France; 4Département de Biologie et de Pathologie des Tumeurs, Centre Georges François-Leclerc, 21000 Dijon, FranceObjective: To evaluate the cytotoxicity of iron nanoparticles on cardiac cells and to determine whether they can modulate the biological activity of 7-ketocholesterol (7KC involved in the development of cardiovascular diseases. Nanoparticles of iron labeled with Texas Red are introduced in cultures of nonbeating mouse cardiac cells (HL1-NB with or without 7-ketocholesterol 7KC, and their ability to induce cell death, pro-inflammatory and oxidative effects are analyzed simultaneously.Study design: Flow cytometry (FCM, confocal laser scanning microscopy (CLSM, and subsequent factor analysis image processing (FAMIS are used to characterize the action of iron nanoparticles and to define their cytotoxicity which is evaluated by enhanced permeability to SYTOX Green, and release of lactate deshydrogenase (LDH. Pro-inflammatory effects are estimated by ELISA in order to quantify IL-8 and MCP-1 secretions. Pro-oxidative effects are measured with hydroethydine (HE.Results: Iron Texas Red nanoparticles accumulate at the cytoplasmic membrane level. They induce a slight LDH release, and have no inflammatory or oxidative effects. However, they enhance the cytotoxic, pro-inflammatory and oxidative effects of 7KC. The accumulation dynamics of SYTOX Green in cells is measured by CLSM to characterize the toxicity of nanoparticles. The emission spectra of SYTOX Green and

  20. Deferasirox effectively decreases iron burden in patients with double heterozygous HbS/β-thalassemia.

    Science.gov (United States)

    Voskaridou, Ersi; Plata, Eleni; Douskou, Marousa; Sioni, Anastasia; Mpoutou, Efrosini; Christoulas, Dimitrios; Dimopoulou, Maria; Terpos, Evangelos

    2011-01-01

    Iron overload is present in several cases of double heterozygous sickle-cell/beta-thalassemia (HbS/β-thal). Deferasirox is an orally administered iron chelator which is effective on iron overloaded patients with transfusion-dependent anemia. The aim of this study was to investigate the efficacy and safety of deferasirox on HbS/β-thal patients with iron overload. We evaluated 31 adult patients with HbS/β-thal (14M/17F; median age 41 years) who had serum ferritin levels >1,000 ng/mL and who were sporadically transfused. Total iron burden was monitored by measuring serum ferritin levels before and monthly after starting deferasirox, while liver iron concentration and cardiac iron burden were measured by magnetic resonance imaging (MRI) T2 and T2* parameters at baseline and 12 months after deferasirox treatment. Deferasirox managed to reduce the mean serum ferritin levels after 12 months of treatment from 1,989 ± 923 to 1,008 ± 776 ng/mL (P deferasirox provided effective control of iron levels (mainly of the liver) in minimally transfused patients with HbS/β-thal, without significant adverse events, at similar doses to those studied widely for the treatment of patients with thalassemia syndromes.

  1. Long-term safety and efficacy of deferasirox (Exjade) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease.

    Science.gov (United States)

    Vichinsky, Elliott; Bernaudin, Françoise; Forni, Gian Luca; Gardner, Renee; Hassell, Kathryn; Heeney, Matthew M; Inusa, Baba; Kutlar, Abdullah; Lane, Peter; Mathias, Liesl; Porter, John; Tebbi, Cameron; Wilson, Felicia; Griffel, Louis; Deng, Wei; Giannone, Vanessa; Coates, Thomas

    2011-08-01

    To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 μg/l (95% confidence intervals, -1411, -280 μg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.

  2. Long-term safety and efficacy of deferasirox (Exjade®) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease

    Science.gov (United States)

    Vichinsky, Elliott; Bernaudin, Françoise; Forni, Gian Luca; Gardner, Renee; Hassell, Kathryn; Heeney, Matthew M; Inusa, Baba; Kutlar, Abdullah; Lane, Peter; Mathias, Liesl; Porter, John; Tebbi, Cameron; Wilson, Felicia; Griffel, Louis; Deng, Wei; Giannone, Vanessa; Coates, Thomas

    2011-01-01

    To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥4 years deferasirox exposure significantly decreased by −591 μg/l (95% confidence intervals, −1411, −280 μg/l; P=0·027; n=67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years. PMID:21592110

  3. Efficacy and safety of deferasirox doses of >30 mg/kg per d in patients with transfusion-dependent anaemia and iron overload

    Science.gov (United States)

    Taher, Ali; Cappellini, Maria D; Vichinsky, Elliott; Galanello, Renzo; Piga, Antonio; Lawniczek, Tomasz; Clark, Joan; Habr, Dany; Porter, John B

    2009-01-01

    The highest approved dose of deferasirox is currently 30 mg/kg per d in many countries; however, some patients require escalation above 30 mg/kg per d to achieve their therapeutic goals. This retrospective analysis investigated the efficacy (based on change in serum ferritin levels) and safety of deferasirox >30 mg/kg per d in adult and paediatric patients with transfusion-dependent anaemias, including β-thalassaemia, sickle cell disease and the myelodysplastic syndromes. In total, 264 patients pooled from four clinical trials received doses of >30 mg/kg per d; median exposure to deferasirox >30 mg/kg per d was 36 weeks. In the overall population there was a statistically significant median decrease in serum ferritin of 440 μg/l (P30 mg/kg per d was consistent with previously published data. There was no worsening of renal or liver function following dose escalation. Deferasirox >30 mg/kg per d effectively reduced iron burden to levels lower than those achieved prior to dose escalation in patients with transfusion-dependent anaemias. This has important implications for patients who are heavily transfused and may require higher doses to reduce body iron burden. PMID:19764988

  4. Non cardiopatic and cardiopatic beta thalassaemic patients: quantitative and qualitative cardiac iron deposition evaluation with MRI; Pazienti {beta} talassemici non cardiopatici e cardiopatici: valutazione quantitativa e qualitativa del deposito di ferro cardiaco con RM

    Energy Technology Data Exchange (ETDEWEB)

    Macarini, Luca; Marini, Stefania; Scardapane, Arnaldo [Bari Univ., Bari (Italy). DIMIMP-Sezione di Diagnostica per Immagini; Pietrapertosa, Anna [Bari Univ., Bari (Italy). MIDIM-Cattedra di Ematologia II; Ettore, Giovanni Carlo [Foggia Univ., Foggia (Italy). Cattedra di Radiologia

    2005-02-01

    Purpose: Cardiomyopathy is one of the major complications of {beta} thalassaemia major as a result of transfusion iron overload. The aim of our study is to evaluate with MR if there is any difference of iron deposition signal intensity (SI) or distribution between non-cardiopatic and cardiopatic thalassaemic patients in order to establish if there is a relationship between cardiopathy and iron deposition. Materials and methods: We studied 20 patients affected by {beta} thalassaemia major, of whom 10 cardiopatic and 10 non-cardiopatic, and 10 healthy volunteers as control group. Serum ferritin and left ventricular ejection fraction were calculated in thalassaemic patients. All patients were examinated using a 1.5 MR unit with ECG-gated GE cine-MR T2*-weighted, SE T1-weighted and GE T2*-weighted sequences. In all cases, using an adequate ROI, the myocardial and skeletal muscle signal intensity (SI), the myocardial/skeletal muscle signal intensity radio (SIR) and the SI average of the myocardium and skeletal muscle were calculated for every study group. The qualitative evaluation of iron deposition distribution was independently performed by three radiologists who analysed the extension, the site and the morphology of iron deposition on the MR images and reported their observations on the basis of a four-level rating scale: 0 (absent), 1 (limited), 2 (partial), 3 (widespread deposition). The results of quantitative and qualitative evaluation were analysed with statistical tests. Results: Cardiac iron deposition was found in 8/10 non-cardiopatic thalassaemic patients and in all cardiopatic thalassaemic patients. We noticed a significant SI difference (p>0.05) between the healthy volunteer control group and the thalassaemic patients with iron deposition, but no significant SI difference in iron deposition between non-cardiopatic thalassaemic patients in the areas evaluated. The qualitative evaluation revealed a different distribution of iron deposition between the two

  5. Cardiac Failure after Liver Transplantation Requiring a Biventricular Assist Device

    Directory of Open Access Journals (Sweden)

    Rita Jermyn

    2014-01-01

    Full Text Available Increased hepatic iron load in extrahepatic organs of cirrhotic patients with and without hereditary hemochromatosis portends a poorer long term prognosis after liver transplant. Hepatic as well as nonhepatic iron overload is associated with increased infectious and postoperative complications, including cardiac dysfunction. In this case report, we describe a cirrhotic patient with alpha 1 antitrypsin deficiency and nonhereditary hemochromatosis (non-HFE that developed cardiogenic shock requiring mechanical circulatory support for twenty days after liver transplant. Upon further investigation, she was found to have significant iron deposition in both the liver and heart biopsies. Her heart regained complete and sustained recovery following ten days of mechanical biventricular support. This case highlights the importance of preoperatively recognizing extrahepatic iron deposition in patients referred for liver transplantation irrespective of etiology of liver disease as this may prevent postoperative complications.

  6. Iron

    Science.gov (United States)

    Iron is a mineral that our bodies need for many functions. For example, iron is part of hemoglobin, a protein which carries ... It helps our muscles store and use oxygen. Iron is also part of many other proteins and ...

  7. Iron

    Science.gov (United States)

    ... of iron stored in the body become low, iron deficiency anemia sets in. Red blood cells become smaller and ... from the lungs throughout the body. Symptoms of iron deficiency anemia include tiredness and lack of energy, GI upset, ...

  8. Novel therapies in cardiac pressure overload

    OpenAIRE

    Nordén, Einar Sjaastad

    2016-01-01

    Background/Introduction: Entresto (LCZ696) is a newly approved drug for the treatment of heart failure with reduced ejection fraction (HFrEF). It combines the effects of angiotensin receptor blockade and neprilysin inhibition. In a recent large clinical trial, LCZ969 was shown to yield a major reduction in mortality when compared to current standard therapy for HFrEF. However, it still remains unclear which mechanisms are responsible for the beneficial effects observed. Purpose: To investigat...

  9. Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice

    Science.gov (United States)

    Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses pre-established hypertrophic cardiomyopathy in the presence of pressure overload induced by ascending aor...

  10. Patient Involvement as Experts in the Development and Assessment of a Smartphone App as a Patient Education Tool for the Management of Thalassemia and Iron Overload Syndromes.

    Science.gov (United States)

    Ward, Richard; Taha, Karim M

    2016-09-01

    Our aim was to develop and assess the feasibility of an education tool to improve health outcomes of patients with thalassemia. Thirty-five patients attending a Canadian thalassemia clinic were enrolled. Acting in an expert role, they participated in a Delphi method to reach consensus as to what tools and information should be incorporated in the development of a self management Smartphone app. One- and 6-month usability and health impact feedback surveys were built-in. Sixty percent of responders were 18-34 years old, over 50.0% had a college degree. The Delphi method successfully generated a comprehensive list of features important to patients. The app has been downloaded 147 times globally. Between March 2015 and January 2016, 19 responses for the 1-month survey were collected and the trends described. Responders reported improved medication adherence. The personal adherence pledge feature supports gamification of health apps to individualize goals of therapy. The impact of tracking iron levels was highly favorable. The Delphi method was an effective way to introduce a patient education and empowerment tool to the thalassemia population. The long-term impact requires data maturation. Use of validated methodology is essential to ensure ehealth interventions are positively contributing to patient education and disease outcomes.

  11. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes

    Directory of Open Access Journals (Sweden)

    Kontoghiorghe CN

    2016-01-01

    Full Text Available Christina N Kontoghiorghe, George J Kontoghiorghes Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus Abstract: The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM. Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30–40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO, oral deferiprone (L1, and DFO–L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve

  12. Estudo das mutações C282Y, H63D e S65C do gene HFE em doentes brasileiros com sobrecarga de ferro Study of C282Y, H63D and S65C mutations in the HFE gene in Brazilian patients with iron overload

    Directory of Open Access Journals (Sweden)

    Rodolfo D. Cançado

    2007-12-01

    Full Text Available Hemocromatose é uma das doenças genéticas mais freqüentes no ser humano e uma das causas mais importantes de sobrecarga de ferro. Os objetivos deste estudo foram determinar a freqüência das mutações C282Y, H63D e S65C do gene HFE em doentes brasileiros com sobrecarga de ferro, verificar a coexistência de anemia hemolítica hereditária, hepatite C e consumo excessivo de bebida alcoólica nestes doentes e avaliar a influência destas variáveis sobre os depósitos de ferro do organismo. Saturação da transferrina, ferritina sérica e análise das mutações C282Y, H63D e S65C do gene HFE, pelo método da PCR, foram determinadas em cinqüenta doentes com sobrecarga de ferro atendidos no Hemocentro da Santa Casa de São Paulo entre janeiro de 2000 e maio de 2004. A freqüência de mutação do gene HFE nos doentes com sobrecarga de ferro foi de 76,0% (38/50. Saturação da transferrina e ferritina foram significativamente maiores nos doentes homozigotos para a mutação C282Y confirmando a correlação entre genótipo C282Y/C282Y e maior risco de sobrecarga de ferro. A coexistência de hepatite C, consumo excessivo de bebida alcoólica ou anemia hemolítica hereditária estão implicados em aumento dos estoques de ferro e constituem fator de risco adicional em pacientes com mutação do gene HFE para a condição de sobrecarga de ferro.Hemochromatosis is one of the most frequent genetic diseases in humans and one of the most important causes of iron overload. The aims of this study were to determine the frequency of C282Y, H63D and S65C mutations of the HFE gene in Brazilian patients with iron overload, to verify the coexistence of chronic hemolytic anemia, hepatitis C and excessive alcohol consumption and to evaluate the influence of these variables on body iron deposits. Transferrin saturation, serum ferritin and C282Y, H63D and S65C HFE gene mutations (by PCR method were determined in 50 patients with iron overload in the Hemocentro da

  13. 铁过载引发人肝细胞HH4 N-糖链表达差异研究%Study on differential expression of N-linked glycans in iron overload-induced human hepatocytes HH4

    Institute of Scientific and Technical Information of China (English)

    李士伟; 关锋; 李想

    2015-01-01

    Hepatic iron overload is common in patients undergoing hematopoietic cell transplantation and may be associated with hepatic injury. Here iron overload model of HH4 cells induced by FAC (ferric ammonium citrate) was established. The total proteins of HH4 cells treated with or without FAC were extracted, and total glycopeptides were isolated by an ultrafiltration unit. The glycopeptides were enzymatically hydrolyzed by Peptide-N-glycosidase F (PNGase F) and the released N-linked glycans were desalinated using Sepharose 4B. The structures of the purified N-glycans were identified by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS). Furthermore, the comparative expression of N-glycans was analyzed by lectin immunohistochemistry. The result indicated that 16 N-glycans were differentially expressed in HH4 cells treated with or without FAC. The levels of high-mannose-type N-glycans were decreased significantly, while the expression of hybrid type, complex type, bisecting type, fucosylation and sialylation of glycans were enhanced markedly in FAC-treated HH4 cells. Consistent with MS analysis, lectin immunohistochemistry study showed that the binding affinity to lectin ConA was reduced in FAC-treated HH4 cells, but the binding affinities to 4 lectins PHA-E, AAL, LCA and MAL-II were significantly increased. The present research provides the fundamental observations for further understanding functional roles of differential expression of N-linked glycans in iron-overload HH4 cells.%肝脏铁过载是血液系统疾病患者进行骨髓移植后的典型并发症之一,长期铁过载可引发肝脏细胞凋亡和器官损坏,然而铁过载的分子调控机理迄今仍不清楚。以培养的枸橼酸铁铵过载人肝细胞HH4和正常人肝细胞HH4为研究对象,细胞裂解提取总蛋白,分子筛超滤管分离获得总糖肽,PNGase F酶解释放出N-糖链,Sepharose 4B除盐纯化N-糖链,再利用基质

  14. Transfusion associated circulatory overload

    Directory of Open Access Journals (Sweden)

    Naveen Agnihotri

    2014-01-01

    Full Text Available Transfusion associated circulatory overload (TACO is an established, but grossly under diagnosed and underreported complication of blood transfusion. We present the case of a 46-year-old diabetic and hypertensive patient admitted to our hospital for recurrent episodes of urinary retention. Over initial 3 days of the admission, the patient received multiple units of packed red blood cells (RBC and fresh frozen plasma, uneventfully. However, the patient developed signs and symptoms suggestive of TACO with only small amount of the 4 th unit of RBC. The patient had to be shifted to the Intensive Care Unit for further management of this complication. Etiology of TACO is more complex than a mere circulatory overload and is still not completely understood. TACO leads to a prolonged hospital stay and morbidity in the patients developing this complication. TACO thus needs to be suspected in patients at risk for this complication.

  15. A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload

    Directory of Open Access Journals (Sweden)

    Lacerda Rosa

    2006-03-01

    (p = 0.0009. Conclusion The present study provides evidence supporting an inextricable link between extended HLA haplotypes, CD8+ T-lymphocyte numbers and severity of iron overload in hereditary hemochromatosis(HH. It gives additional information to better define a candidate region involved in the regulation of CD8+ T-lymphocyte numbers. A new evolutionary hypothesis concerning the inheritance of the phenotype of low CD8+ T-lymphocyte numbers associated with particular ancestral HLA haplotypes carrying the C282Y mutation and its implication on the clinical heterogeneity of HH is discussed.

  16. Iron overload and genotype 3 are associated with liver steatosis in chronic hepatitis C Sobrecarga de hierro y genotipo 3 se asocian a la presencia de esteatosis en la hepatitis C

    Directory of Open Access Journals (Sweden)

    L. I. Fernández Salazar

    2004-12-01

    Full Text Available Objective: to determine epidemiological, biochemical, virological, and histological factors associated with liver steatosis in chronic hepatitis C. Subjects: the medical histories of 53 patients biopsied for chronic hepatitis C diagnosis between June 2000 and December 2002 were retrospectively studied. Epidemiological, biochemical, and virological data were collected. Patients with hepatitis B virus or human immunodeficiency virus coinfection were excluded. Liver biopsy specimens were reviewed and scored by one pathologist. Weight and height were measured at liver biopsy time. The statistic association between qualitative and quantitative variables and the presence of liver steatosis was studied. Results: steatosis was identified in 52% of biopsies. There was no statistic association with age, sex, method of transmission, duration of infection, alcohol consumption, other diseases, body mass index, glucose, triglycerides, cholesterol, AST, ALT, GGT, alkaline phosphatase, bilirubin, or viral load. Liver steatosis was associated with serum iron, transferrin saturation, and ferritin. Genotype 3 was also associated with steatosis. Piecemeal necrosis, hepatocellular injury, Kupffer cell hyperplasia, liver iron, and portal fibrosis were also associated with steatosis. A multivariate analysis showed that genotype 3, Kupffer cell hyperplasia, and liver iron were associated with the presence of steatosis. Conclusions: liver steatosis in chronic hepatitis C associates with genotype 3, Kupffer cell hyperplasia, and iron overload. Hepatic steatosis also associates with greater inflammation and fibrosis, and must be considered to contribute to disease progression.Objetivo: determinar los factores epidemiológicos, analíticos, virológicos e histológicos a los que se asocia la esteatosis en la hepatitis C. Pacientes: se revisaron de forma retrospectiva 53 historias clínicas de pacientes biopsiados consecutivamente desde junio de 2000 a dicembre de 2002. Se

  17. Iron

    DEFF Research Database (Denmark)

    Hansen, Jakob Bondo; Moen, I W; Mandrup-Poulsen, T

    2014-01-01

    The interest in the role of ferrous iron in diabetes pathophysiology has been revived by recent evidence of iron as an important determinant of pancreatic islet inflammation and as a biomarker of diabetes risk and mortality. The iron metabolism in the β-cell is complex. Excess free iron is toxic......, but at the same time, iron is required for normal β-cell function and thereby glucose homeostasis. In the pathogenesis of diabetes, iron generates reactive oxygen species (ROS) by participating in the Fenton chemistry, which can induce oxidative damage and apoptosis. The aim of this review is to present...... and discuss recent evidence, suggesting that iron is a key pathogenic factor in both type 1 and type 2 diabetes with a focus on inflammatory pathways. Pro-inflammatory cytokine-induced β-cell death is not fully understood, but may include iron-induced ROS formation resulting in dedifferentiation by activation...

  18. Iron mobilization using chelation and phlebotomy

    DEFF Research Database (Denmark)

    Flaten, T. P.; Aaseth, J.; Andersen, Ole;

    2012-01-01

    Knowledge of the basic mechanisms involved in iron metabolism has increased greatly in recent years, improving our ability to deal with the huge global public health problems of iron deficiency and overload. Several million people worldwide suffer iron overload with serious clinical implications....

  19. Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy

    Directory of Open Access Journals (Sweden)

    Walker LeeAnn

    2002-01-01

    Full Text Available Abstract Background Iron deficiency (ID results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1 intravenous norepinephrine would alter heart rate (HR and contractility, 2 abdominal aorta would be larger and more distensible, and 3 the beta-blocker propanolol would reduce hypertrophy. Methods 1 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2 Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3 An additional 10 rats (5 ID, 5 control were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed. Results Enhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio. Conclusions ID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission.

  20. Parameters influencing in-hospital mortality in patients hospitalized in intensive cardiac care unit: is there an influence of anemia and iron deficiency?

    Science.gov (United States)

    Uscinska, Ewa; Sobkowicz, Bozena; Sawicki, Robert; Kiluk, Izabela; Baranicz, Malgorzata; Stepek, Tomasz; Dabrowska, Milena; Szmitkowski, Maciej; Musial, Wlodzimierz J; Tycinska, Agnieszka M

    2015-04-01

    We investigated the incidence and prognostic value of anemia as well as of the iron status in non-selected patients admitted to an intensive cardiac care unit (ICCU). 392 patients (mean age 70 ± 13.8 years, 43% women), 168 with acute coronary syndromes (ACS), 122 with acute decompensated heart failure, and 102 with other acute cardiac disorders were consecutively, prospectively assessed. The biomarkers of iron status-serum iron concentration (SIC), total iron binding capacity (TIBC), and transferrin saturation (TSAT) together with standard clinical, biochemical and echocardiographic variables-were analyzed. In-hospital mortality was 3.8% (15 patients). The prevalences of anemia (according to WHO criteria), and iron deficiency (ID) were 64 and 63%, respectively. The level of biomarkers of iron status, but not anemia, was lower in patients who died (p < 0.05). Anemia was less frequent in patients with ACS as compared to the remaining ICCU population (p = 0.019). The analysis by logistic regression indicated the highest risk of death for age [odds ratio (OD) 1.38, 95% CI 1.27-1.55], SIC (OR 0.85, 95% CI 0.78-0.94), TIBC (OR 0.95, 95% CI 0.91-0.98), left ventricle ejection fraction (OR 0.85, 95% CI 0.77-0.93), as well as hospitalization for non-ACS (OR 0.25, 95% CI 0.14-0.46), (p < 0.05). The risk of death during hospitalization tended to increase with decreasing levels of TIBC (p = 0.49), as well as with the absence of ACS (p = 0.54). The incidence of anemia and ID in heterogeneous ICCU patients is high. Parameters of the iron status, but not anemia per se, independently influence in-hospital mortality. The prevalence of anemia is higher in non-ACS patients, and tends to worsen the prognosis.

  1. Iron chelation with deferasirox for the treatment of secondary hemosiderosis in pediatric oncology patients: a single-center experience.

    Science.gov (United States)

    Ktena, Yiouli P; Athanasiadou, Anastasia; Lambrou, George; Adamaki, Maria; Moschovi, Maria

    2013-08-01

    Pediatric oncology patients are often iron overloaded, due to the multiple blood transfusions necessary during the course of chemotherapy. Our aim is to report the efficacy and safety of deferasirox, an oral iron chelator, in this patient group. Deferasirox was administered to 13 children with malignancies in remission and iron overload. Ferritin, blood urea nitrogen, creatinine, transaminases, and bilirubin were recorded at 4- to 8-week intervals, and hepatic and cardiac iron overload were assessed with magnetic resonance imaging before initiation of treatment. Deferasirox was administered for an average of 6 months (SD=4.5; range, 0.3 to 18.2). Two children presented with skin rash, 1 with gastrointestinal disturbances, and 1 with fully reversible acute renal failure. The mean monthly rate of change in ferritin levels was -10.8 μg/L before initiation of treatment (95% confidence interval [CI], -19.8 to -1.8; P=0.02) and -93.6 μg/L during deferasirox treatment (95% CI, -118.1 to -69.1; PDeferasirox was effective in reducing the iron burden. The adverse effects were easily monitored and managed. Further studies are warranted to investigate the effect of deferasirox on mortality and morbidity in this population.

  2. Isolation of Related Genes of Cardiac Hypertrophy in Pressure overloaded Rat Models with Subtractive Hybridization%压力负荷型心肌肥厚大鼠心肌组织相关基因的分离

    Institute of Scientific and Technical Information of China (English)

    田靫; 潘德思; 陈兰英

    2000-01-01

    Cardiac hypertrophy is intensively related with the morbidity of heart failure,atherosclerosis and stroke. The rat models of left ventricular hypertrophy caused by abdominal aorta constriction and the method of subtractive hybridization to isolate genes expressing differently were used during cardiac hypertrophy. 24 cDNA segments were isolated and identified by colony and dot hybridization. Sequence homogenous comparison showed that some of them were very similar to known genes or segments, others were limitedly homogenous and the rest were not found to be significantly homogenous.

  3. Death by information overload.

    Science.gov (United States)

    Hemp, Paul

    2009-09-01

    The value of information in the knowledge economy is indisputable, but so is its capacity to overwhelm consumers of it. HBR contributing editor Hemp reports on practical ways for individuals and organizations to avoid getting too much of a good thing. Ready access to useful information comes at a cost: As the volume increases, the line between the worthwhile and the distracting starts to blur. And ready access to you--via e-mail, social networking, and so on--exacerbates the situation: On average, Intel executives get 300 e-mails a day, and Microsoft workers need 24 minutes to return to work after each e-mail interruption. Clearly, productivity is taking a hit. Technological aids can help, such as e-mail management software for you, a message-volume regulation system for your organization, or even more-sophisticated solutions being developed by Microsoft, IBM, and others. Yet, battling technological interruptions on their own turf only goes so far. You also need to change your mind-set, perhaps by seeking help from personal-productivity experts or by simply accepting that you can't respond to every distraction that flits across your screen. Similarly, organizations must change their cultures, for instance by establishing clear e-communication protocols. In the end, only a multipronged approach will help you and your organization subdue the multiheaded monster of information overload. The secret is to manage the beast while still respecting it for the beautiful creature it is.

  4. Effects of High Dietary HEME Iron and Radiation on Cardiovascular Function

    Science.gov (United States)

    Westby, Christian M.; Brown, A. K.; Platts, S. H.

    2012-01-01

    The radiation related health risks to astronauts is of particular concern to NASA. Data support that exposure to radiation is associated with a number of disorders including a heightened risk for cardiovascular diseases. Independent of radiation, altered nutrient status (e.g. high dietary iron) also increases ones risk for cardiovascular disease. However, it is unknown whether exposure to radiation in combination with high dietary iron further increases ones cardiovascular risk. The intent of our proposal is to generate compulsory data examining the combined effect of radiation exposure and iron overload on sensitivity to radiation injury to address HRP risks: 1) Risk Factor of Inadequate Nutrition; 2) Risk of Cardiac Rhythm Problems; and 3) Risk of Degenerative Tissue or other Health Effects from Space Radiation. Towards our goal we propose two distinct pilot studies using the following specific aims: Vascular Aim 1: To determine the short-term consequences of the independent and combined effects of exposure to gamma radiation and elevated body iron stores on measures of endothelial function and cell viability and integrity. We hypothesize that animals that have high body iron stores and are exposed to gamma radiation will show a greater reduction in endothelial dependent nitric oxid production and larger pathological changes in endothelial integrity than animals that have only 1 of those treatments (either high iron stores or exposure to gamma radiation). Vascular Aim 2: Identify and compare the effects of gamma radiation and elevated body iron stores on the genetic and epigenetic regulation of proteins associated with endothelial cell function. We hypothesize that modifications of epigenetic control and posttranslational expression of proteins associated with endothelial cell function will be differentially altered in rats with high body iron stores and exposed to gamma radiation compared to rats with only 1 type of treatment. Cardiac Aim 1: To determine the

  5. Echocardiographic evaluation of pressure overload-induced cardiac remodeling in mice using different ultrasound machines%小动物超声仪与临床用超声仪评价小鼠心脏重构的对比分析

    Institute of Scientific and Technical Information of China (English)

    赵静; 曾智; 颜亮; 纪丽景; 罗滔; 宾建平; 廖禹林

    2011-01-01

    目的 比较不同类型超声仪对小鼠压力负荷下心脏重构的评价结果.方法 C57 BL/6小鼠18只,随机分为假手术(sham)组和主动脉弓缩窄(TAC)组,每组9只.手术8周后,首先应用连接15L8高频探头的临床用西门子超声仪测定TAC组小鼠心功能,并比较清醒和麻醉状态下的差异.然后比较西门子超声仪和小动物用高分辨超声仪(Vevo770)对心功能评价的影响.结果 与清醒状态相比,异氟烷吸入麻醉小鼠的心率和左室短轴缩短率显著降低(P<0.001),而左室内径显著增加(P<0.05).但与相应的sham组比较,两种仪器都可以较敏感地反映TAC组的心脏重构.与西门子超声仪相比,小动物超声仪的分辨率明显增高,并可通过二尖瓣血流频谱图评价左室舒张功能,但暂不能在小鼠清醒状态下评价心功能.结论 麻醉本身会降低心功能,但在反映干预手段对心脏重构的影响程度上与清醒状态下有可比性.高分辨小动物超声仪在评价左室舒张功能方面优于西门子超声仪.%To compare the results of echocardiographic evaluation of pressure overload-induced cardiac remodeling in mice using different ultrasound machines. Methods Eighteen C57 BL/6 mice were randomly divided into the sham-operated and the transverse aortic constriction (TAC) groups (n=9). Eight weeks after the operation, the cardiac function of TAC group was evaluated using Siemens ultrasonic instrument with 15L8 probe and the differences between the awake and anesthetized states were compared. The heart rate, left ventricular (LV) dimensions, systolic and diastolic functions were measured in both sham-operated and TAC groups using the Siemens ultrasonic instrument and a high-resolution ultrasonic imaging system for small animals (Vevo 770). Results Compared with the mice in wakefulness, the anesthetized mice showed significantly decreased heart rate and LV fractional shortening (P<0.001) and markedly increased LV end

  6. 磁共振-R2*值无创评估铁过载肝脏铁含量的初步研究%The Experiment Study of MRI R2 * Value for Noninvasive Measurement of Liver Iron Content in Iron Overload Rabbit

    Institute of Scientific and Technical Information of China (English)

    胡粟; 胡春洪; 张京刚; 张敏鸽; 王芳芳; 邢建明; 陈剑华; 高茜; 刘运练

    2012-01-01

    Objective To study the feasibility of MRI R2* for measurement of liver iron content ( LIC) in iron overload rabbit compared with the pathological findings and laboratory data, and explore the relationship between R2* and LIC. Materials and Methods 32 adult healthy New Zealand rabbits were randomly divided into four groups, group A(n =8), group B (n = 8 ) , group C ( n = 8 ) and control group ( n = 8 ). Three iron overload groups received intravenous injection of i-ron sucrose of different dose every one week for four weeks. All experimental animals underwent liver Bean with 2D MFGRE sequence by using GE Signa HDx 3. 0 T MR. The R2 * value were measured on R2 * Map with small region of interest (RO1) methods by one observer who had been trained to use the technology proficiently. The liver of experimental animals were sent for LIC assessment immediately after MR scan. SPSS 13.0 for Windows statistical software was used to compare the relationship between R2*value with small ROI methods and LIC. Results (l)The LIC increased with the increased in total dose of iron. (2)There was a significant exponent curve association between the R2 * value and LIC. Curve regression equation of the R2 ' value and LIC was Y = EXP( 1.950 + 16. 200X) ,R =0.894. A weak correlation (R = 0. 186) was displayed in animals with high LJC( above 20.0 mg/g dw). Conclusion R2 * value can accurately predict LIC with a significant exponent curve association, the correlation become weak with increased LIC (above 20.0 mg/g dw).%目的 以病理学结果为对照,研究磁共振R2*成像定量评估铁过载家兔模型肝脏铁含量的可行性及R2*值与肝脏铁含量(LIC)之间的关系.材料与方法 成年健康新西兰大白兔32只,随机分成4组,每组各8只(n=8).A、B、C组每周注射一次铁剂,注射剂量分别为5、10、25 mg/kg体重,共4周.D组不予任何处理.应用MR扫描仪行肝脏的R2 StarMap成像,经后处理生成R2*图,由一名经R2*Map成像后处理技术

  7. Pregnancy as a cardiac stress model

    OpenAIRE

    2014-01-01

    Cardiac hypertrophy occurs during pregnancy as a consequence of both volume overload and hormonal changes. Both pregnancy- and exercise-induced cardiac hypertrophy are generally thought to be similar and physiological. Despite the fact that there are shared transcriptional responses in both forms of cardiac adaptation, pregnancy results in a distinct signature of gene expression in the heart. In some cases, however, pregnancy can induce adverse cardiac events in previously healthy women witho...

  8. 芪苈强心胶囊通过抑制血管紧张素Ⅱ改善压力超负荷致小鼠心肌肥厚%Qiliqiangxin Capsules Ameliorate Pressure Overload-Induced Cardiac Hypertrophy in Mice Via Reducing the Expression of Angiotensin Ⅱ

    Institute of Scientific and Technical Information of China (English)

    叶勇; 邹云增; 李磊; 蒋国良; 吴剑; 周宁; 马宏; 关爱丽; 龚惠; 葛均波

    2011-01-01

    目的 探讨探讨芪苈强心胶囊是否通过抑制血管紧张素Ⅱ(AngⅡ)表达改善压力超负荷下小鼠心肌肥厚.方法 小鼠行升主动脉缩窄手术(TAC)建立心肌肥厚模型,8-10周龄野生型雄性小鼠(WT)和雄性血管紧张素原基因敲除小鼠(ATG-)随机分为假手术组,生理盐水组、芪苈强心胶囊三组,TAC组小鼠给予生理盐水或1.0mg/(kg.d)药物灌胃处理,术后2周行心超及血流动力学检查,同时分析心肌组织学指标以及肥厚相关基因表达,酶联免疫吸附法(ELISA)检测血浆和心肌组织AngⅡ浓度,蛋白印迹法检测磷酸化细胞外信号调节激酶(p-ERK)及血管紧张素Ⅱ-Ⅰ型(AT1)受体表达.结果 WT和ATG-小鼠TAC后2周,主动脉血压及左室收缩末期压显著升高,芪苈强心胶囊对其均正影响.WT小鼠中,此药显著抑制TAC介导AngⅡ的升高(P<0.05),抑制TAC介导的左室前壁,左室后壁增厚以及心肌细胞横截面积 (CSA)和纤维化面积增大,同时抑制肥厚相关基因,AT1受体和p-ERK表达上调(P<0.05),ATG-小鼠中,在AngⅡ缺失的情况下,TAC两组间左室前后壁、CSA、纤维化面积以及肥厚相关基因、AT1、受体和p-ERK表达无明显差异(P>0.05).结论 芪苈强心胶囊改善压力超负荷致小鼠心肌肥厚是通过抑制AngⅡ表达来减弱AT1受体激活,非直接抑制压力超负荷机械刺激引起AT1,受体的激活.%Objective To investigate whether downregulation of Angiotensin U was involved in ihe mechanism by which Qiliqianipan Capsules inhibits (he pressure overload-induced cardiac hypertrophy in mice. Methods Pressure-overload model was eslablished in (I-10 weeks old wild lype (WT) und angiotensmogen-deficifnl {AT(? ) (lacking endogenous Ang 11) male mice performed with Transverse Anna Constricting (TAC) surgery for 2 weeks. All the miee were treated with Sham or TAC operation, and all TAC mice was administered with salme or Qiliqiang*inCapsuks(l.l)mg*g.d) through

  9. Comparison of deferasirox and deferoxamine treatment in iron-overloaded patients: liver iron concentration determined by quantitative MRI-R2%MRI-R2*定量评价肝铁超负荷患者去铁治疗疗效的研究

    Institute of Scientific and Technical Information of China (English)

    彭鹏; 龙莉玲; 黄仲奎; 张灵; 李小会; 冯潇; 杨高辉

    2013-01-01

    目的 探讨MRI-R2*定量评价肝铁超负荷患者去铁治疗疗效的价值.方法 采用完全随机均衡设计法将24例铁超负荷患者分成2组,地拉罗司组和去铁胺组各12例.地拉罗司组和去铁胺组的剂量分别为40和50 mg·kg-1·d-1,所有患者分别在治疗前及治疗后6和12个月行3次肝脏MR检查并测量R2*值.采用配对设计秩和检验分别比较2种药物治疗6及12个月后肝脏R2*值与治疗前的差异,并采用完全随机设计两样本秩和检验分别比较2组患者治疗6、12个月的肝脏R2*变化率(△R2*)及SF变化率(△SF).结果 地拉罗司组治疗前及治疗后6、12个月肝脏R2*值中位数分别为1081、889和712 Hz,去铁胺组分别为1042、838和488 Hz,治疗前2组患者肝脏R2*值间差异无统计学意义(Z=-0.029,P >0.05).地拉罗司治疗12个月的△R2*为-32%,去铁胺组为-58%,差异有统计学意义(Z=-3.060,P<0.01).△SF地拉罗司治疗12个月为-15%,去铁胺组为-55%,差异有统计学意义(Z=-2.945,P <0.01).结论 MRI-R2*技术能检测去铁疗效,去铁胺和地拉罗司都能有效去除肝铁,且去铁胺的去铁效能优于地拉罗司.%Objective To explore the value of MRI-R2 * and to compare clinical effect of two iron chelators(deferasirox and deferoxamine) in iron-overloaded patients.Methods By completely randomized balanced design,24 iron-overloaded patients were randomly divided into 2 groups,which consisted of 12 patients treated with deferasirox and 12 patients treated with deferoxamine.The planned deferasirox dose was 40 mg· kg-1 · d-1,and the deferoxamine dose was no less than 50 mg · kg-1 · d-1 All patients underwent quantitative MRI at the time points of the primary screening,6 months and 12 months.Pair Wilcoxon rank sum test was used to compare the differences of liver R2 * values of the 2 groups at various time points respectively.Wilcoxon rank sum test was used to compare the differences of change rate of liver R2

  10. OVERLOAD ANALYSIS OF MARKOVIAN MODELS

    Institute of Scientific and Technical Information of China (English)

    Yiqiang Q. ZHAO

    1999-01-01

    A new procedure for computing stationary probabilities for an overloaded Markovian model is proposed interms of the rotated Markov chain.There are two advantages to use this procedure:i) This procedure allows us to approximate an overloaded finite model by using a stable infinite Markov chain. This will makethe study easier when the infinite model has a simpler solution.ii) Numerically, this procedure often significantly reduces the number of computations and the requirement of computer memory. By using different examples,we specifically demonstratethe process of implementing this rotating procedure.

  11. Iron excess in recreational marathon runners

    NARCIS (Netherlands)

    Mettler, S.; Zimmermann, M.B.

    2010-01-01

    Background/Objectives: Iron deficiency and anemia may impair athletic performance, and iron supplements are commonly consumed by athletes. However, iron overload should be avoided because of the possible long-term adverse health effects. Methods: We investigated the iron status of 170 male and femal

  12. In vitro effect of iron overload on bone marrow cell function by inducing the reactive oxygen species%铁过载诱导活性氧物质生成对骨髓造血功能影响的体外实验研究

    Institute of Scientific and Technical Information of China (English)

    谢芳; 吕海蓉; 赵明峰; 李玉明; 朱海波; 江燕; 徐新女; 肖霞; 穆娟; 刘鹏江

    2011-01-01

    Objective To investigate the in vitro effect of iron overload on the generation of reactive oxygen species (ROS) and of bone marrow (BM) cell function. Methods BM mononuclear cells (BMMNCs) were cultured with ferric citrate(FAC) at different concentrations and for different time to create iron overload and confirmed by the detection of cellular labile iron pool (LIP). The changes of ROS, apoptosis, hematopoietic colony formation ( CFU-E, BFU-E, CFU-GM and CFU-mix) and the percentage of the CD34 + cells percentage were analyzed. The differences of these index were tested after the iron overload treated with deferasirox (DFO) or antioxidants ( N-acetyl-L-cysteine, NAC). Results ①When BMMNCs were cultured with FAC, the LIP was found to increase in a time and concentration dependent manner. The intra cellular LIP reached maximum at 400 μmol/L of FAC for 24 hours. ② The ROS of total cells, leukocytes and erythrocytes increased to 1.77, 1.75 and 2.12 fold respectively compared with that of normal control when cells were cultured at 400 μmol/L of FAC for 24 hours . DFO and NAC could reduce the ROS efficiently (P < 0.05 ). ③ The apoptotic rates of the FAC treated cells[( 24.80 ± 2.99 ) %]increased significantly compared with that of normal control[(8.90 ± 0. 96) %]. The capacity of hematopoietic colony formation in FAC treated cells decreased markedly compared with that of normal control ( P < 0.05 ). The percentage of CD34 + cells of FAC treated cells[(0.39 ± 0.07 )%]also decreased significantly compared with that of nor mal control[(0.91 ±0. 12)%]. And these changes could be recovered by addition of NAC or DFO. Condusion Iron overload can affect the hematopoiesis by inducing the generation of ROS and this damage could be corrected by removing the excess iron and ROS of the BM cells. These findings might improve the treatment of dyshematopoiesis in patients with iron overload.%目的 建立体外铁过载骨髓造血细胞模型,检验铁过载

  13. Iron load

    Directory of Open Access Journals (Sweden)

    Filippo Cassarà

    2013-03-01

    Full Text Available Recent research addressed the main role of hepcidin in the regulation of iron metabolism. However, while this mechanism could be relevant in causing iron load in Thalassemia Intermedia and Sickle-Cell Anemia, its role in Thalassemia Major (TM is marginal. This is mainly due to the high impact of transfusional requirement into the severe increase of body iron. Moreover, the damage of iron load may be worsened by infections, as HCV hepatitis, or liver and endocrinological damage. One of the most relevant associations was found between splenectomy and increase of risk for mortality due,probably, to more severe iron load. These issues suggest as morbidity and mortality of this group of patients they do not depend only by our ability in controlling heart damage but even in preventing or treating particular infections and complications. This finding is supported by the impairment of survival curves in patients with complications different from heart damage. However, because, during recent years different direct and indirect methods to detect iron overload in patients affected by secondary hemochromatosis have been implemented, our ability to maintain under control iron load is significantly improved. Anyway, the future in iron load management remains to be able to have an iron load map of our body for targeting chelation and other medical treatment according to the single organ damage.

  14. Cardiac complications and diabetes in thalassaemia major: a large historical multicentre study.

    Science.gov (United States)

    Pepe, Alessia; Meloni, Antonella; Rossi, Giuseppe; Caruso, Vincenzo; Cuccia, Liana; Spasiano, Anna; Gerardi, Calogera; Zuccarelli, Angelo; D'Ascola, Domenico G; Grimaldi, Salvatore; Santodirocco, Michele; Campisi, Saveria; Lai, Maria E; Piraino, Basilia; Chiodi, Elisabetta; Ascioti, Claudio; Gulino, Letizia; Positano, Vincenzo; Lombardi, Massimo; Gamberini, Maria R

    2013-11-01

    The relationship between diabetes mellitus (DM) and cardiac complications has never been systematically studied in thalassaemia major (TM). We evaluated a large retrospective historical cohort of TM to determine whether DM is associated with a higher risk of heart complications. We compared 86 TM patients affected by DM with 709 TM patients without DM consecutively included in the Myocardial Iron Overload in Thalassaemia database where clinical/instrumental data are recorded from birth to the first cardiovascular magnetic resonance (CMR) exam. All of the cardiac events considered were developed after the DM diagnosis. In DM patients versus non-DM patients we found a significantly higher frequency of cardiac complications (46.5% vs. 16.9%, P < 0.0001), heart failure (HF) (30.2% vs. 11.7%, P < 0.0001), hyperkinetic arrhythmias (18.6% vs. 5.5%, P < 0.0001) and myocardial fibrosis assessed by late gadolinium enhancement (29.9% vs. 18.4%, P = 0.008). TM patients with DM had a significantly higher risk of cardiac complications [odds ratio (OR) 2.84, P < 0.0001], HF (OR 2.32, P = 0.003), hyperkinetic arrhythmias (OR 2.21, P = 0.023) and myocardial fibrosis (OR 1.91, P = 0.021), also adjusting for the absence of myocardial iron overload assessed by T2* CMR and for the covariates (age and/or endocrine co-morbidity). In conclusion, DM significantly increases the risk for cardiac complications, HF, hyperkinetic arrhythmias and myocardial fibrosis in TM patients.

  15. Extracellular Matrix Remodeling During the Progression of Volume Overload-Induced Heart Failure

    Science.gov (United States)

    Hutchinson, Kirk R.; Stewart, James A.; Lucchesi, Pamela A.

    2009-01-01

    Volume overload-induced heart failure results in progressive left ventricular remodeling characterized by chamber dilation, eccentric cardiac myocyte hypertrophy and changes in extracellular matrix (ECM) remodeling changes. The ECM matrix scaffold is an important determinant of the structural integrity of the myocardium and actively participates in force transmission across the LV wall. In response to this hemodynamic overload, the ECM undergoes a distinct pattern of remodeling that differs from pressure overload. Once thought to be a static entity, the ECM is now regarded to be a highly adaptive structure that is dynamically regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress, that result in alterations in collagen and other matrix components and a net change in matrix metalloproteinase (MMP) expression and activation. These changes dictate overall ECM turnover during volume overload hear failure progression. This review will discuss the cellular and molecular mechanisms that dictate the temporal patterns of ECM remodeling during heart disease progression. PMID:19524591

  16. Relationship between myocardial T2* values and cardiac volumetric and functional parameters in β-thalassemia patients evaluated by cardiac magnetic resonance in association with serum ferritin levels

    Energy Technology Data Exchange (ETDEWEB)

    Liguori, Carlo, E-mail: c.liguori@unicampus.it [Department of Diagnostic Imaging, Campus Bio Medico University, via Alvaro del Portillo 200, 00128 Rome (Italy); Pitocco, Francesca, E-mail: f.pitocco@unicampus.it [Department of Diagnostic Imaging, Campus Bio Medico University, via Alvaro del Portillo 200, 00128 Rome (Italy); Di Giampietro, Ilenia, E-mail: i.digiampietro@unicampus.it [Department of Diagnostic Imaging, Campus Bio Medico University, via Alvaro del Portillo 200, 00128 Rome (Italy); Vivo, Aldo Eros de, E-mail: devivoeros@gmail.com [Department of Diagnostic Imaging, Campus Bio Medico University, via Alvaro del Portillo 200, 00128 Rome (Italy); Schena, Emiliano, E-mail: e.schena@unicampus.it [Unit of Measurements and Biomedical Instrumentation, Campus Bio Medico University, via Alvaro del Portillo 200, 00128 Rome (Italy); Cianciulli, Paolo, E-mail: CIANCIULLI.PAOLO@aslrmc.it [Thalassemia Unit, Ospedale Sant Eugenio, Piazzale dell’Umanesimo 10, 00143 Rome (Italy); Zobel, Bruno Beomonte, E-mail: b.zobel@unicampus.it [Department of Diagnostic Imaging, Campus Bio Medico University, via Alvaro del Portillo 200, 00128 Rome (Italy)

    2013-09-15

    Purpose: Myocardial T2* cardiovascular magnetic resonance provides a rapid and reproducible assessment of cardiac iron load in thalassemia patients. Although cardiac involvement is mainly characterized by left ventricular dysfunction caused by iron overload, little is known about right ventricular function. The aim of this study was to assess the relationship between T2* value in myocardium and left–right ventricular volumetric and functional parameters and to evaluate the existing associations between left–right ventricles volumetric and functional parameter, myocardial T2* values and blood ferritin levels. Materials and methods: A retrospective analysis of 208 patients with β-thalassemia major and thalassemia intermedia was performed (109 males and 99 females; mean age 37.7 ± 13 years; 143 thalassemia major, 65 thalassemia intermedia). Myocardial iron load was assessed by T2* measurements, and volumetric functions were analyzed using the steady state free precession sequence. Results: A significant correlation was observed between EFLV and T2* (p = 0.0001), EFRV and T2* (p = 0.0279). An inverse correlation was present between DVLV and T2* (p = 0.0468), SVLV and T2* (p = 0.0003), SVRV and T2* (p = 0.0001). There was no significant correlation between cardiac T2* and LV–RV mass indices. A significant correlation was observed between T2* and serum ferritin levels (p < 0.001) and between EFLV and serum ferritin (p < 0.05). Conclusion: Myocardial iron load assessed by T2* cardiac magnetic resonance is associated with deterioration in left–right ventricular function; this is more evident when T2* values fall below 14 ms. CMR appears to be a promising approach for cardiac risk evaluation in TM patients.

  17. Rotigaptide (ZP123) improves atrial conduction slowing in chronic volume overload-induced dilated atria.

    Science.gov (United States)

    Haugan, Ketil; Miyamoto, Takuya; Takeishi, Yasuchika; Kubota, Isao; Nakayama, Jun; Shimojo, Hisashi; Hirose, Masamichi

    2006-07-01

    Chronic atrial dilation is associated with atrial conduction velocity slowing and an increased risk of developing atrial tachyarrhythmias. Rotigaptide (ZP123) is a selective gap junction modifier that increases cardiac gap junctional intercellular communication. We hypothesised that rotigaptide treatment would increase atrial conduction velocity and reduce the inducibility to atrial tachyarrhythmias in a model of chronic volume overload induced chronic atrial dilatation characterized by atrial conduction velocity slowing. Chronic volume overload was created in Japanese white rabbits by arterio-venous shunt formation. Atrial conduction velocity and atrial tachyarrhythmias inducibility were examined in Langendorff-perfused chronic volume overload hearts (n=12) using high-resolution optical mapping before and after treatment with rotigaptide. Moreover, expression levels of atrial gap junction proteins (connexin40 and connexin43) were examined in chronic volume overload hearts (n=6) and compared to sham-operated controls (n=6). Rotigaptide treatment significantly increased atrial conduction velocity in chronic volume overload hearts, however, rotigaptide did not decrease susceptibility to the induction of atrial tachyarrhythmias. Protein expressions of Cx40 and Cx43 were decreased by 32% and 72% (P<0.01), respectively, in chromic volume overload atria compared to control. To conclude, rotigaptide increased atrial conduction velocity in a rabbit model of chromic volume overload induced atrial conduction velocity slowing. The demonstrated effect of rotigaptide on atrial conduction velocity did not prevent atrial tachyarrhythmias inducibility. Whether rotigaptide may possess antiarrhythmic efficacy in other models of atrial fibrillation remains to be determined.

  18. ANG II is required for optimal overload-induced skeletal muscle hypertrophy

    Science.gov (United States)

    Gordon, S. E.; Davis, B. S.; Carlson, C. J.; Booth, F. W.

    2001-01-01

    ANG II mediates the hypertrophic response of overloaded cardiac muscle, likely via the ANG II type 1 (AT(1)) receptor. To examine the potential role of ANG II in overload-induced skeletal muscle hypertrophy, plantaris and/or soleus muscle overload was produced in female Sprague-Dawley rats (225-250 g) by the bilateral surgical ablation of either the synergistic gastrocnemius muscle (experiment 1) or both the gastrocnemius and plantaris muscles (experiment 2). In experiment 1 (n = 10/group), inhibiting endogenous ANG II production by oral administration of an angiotensin-converting enzyme (ACE) inhibitor during a 28-day overloading protocol attenuated plantaris and soleus muscle hypertrophy by 57 and 96%, respectively (as measured by total muscle protein content). ACE inhibition had no effect on nonoverloaded (sham-operated) muscles. With the use of new animals (experiment 2; n = 8/group), locally perfusing overloaded soleus muscles with exogenous ANG II (via osmotic pump) rescued the lost hypertrophic response in ACE-inhibited animals by 71%. Furthermore, orally administering an AT(1) receptor antagonist instead of an ACE inhibitor produced a 48% attenuation of overload-induced hypertrophy that could not be rescued by ANG II perfusion. Thus ANG II may be necessary for optimal overload-induced skeletal muscle hypertrophy, acting at least in part via an AT(1) receptor-dependent pathway.

  19. Myelodysplastic Syndromes and Iron Chelation Therapy

    Science.gov (United States)

    Angelucci, Emanuele; Urru, Silvana Anna Maria; Pilo, Federica; Piperno, Alberto

    2017-01-01

    Over recent decades we have been fortunate to witness the advent of new technologies and of an expanded knowledge and application of chelation therapies to the benefit of patients with iron overload. However, extrapolation of learnings from thalassemia to the myelodysplastic syndromes (MDS) has resulted in a fragmented and uncoordinated clinical evidence base. We’re therefore forced to change our understanding of MDS, looking with other eyes to observational studies that inform us about the relationship between iron and tissue damage in these subjects. The available evidence suggests that iron accumulation is prognostically significant in MDS, but levels of accumulation historically associated with organ damage (based on data generated in the thalassemias) are infrequent. Emerging experimental data have provided some insight into this paradox, as our understanding of iron-induced tissue damage has evolved from a process of progressive bulking of organs through high-volumes iron deposition, to one of ‘toxic’ damage inflicted through multiple cellular pathways. Damage from iron may, therefore, occur prior to reaching reference thresholds, and similarly, chelation may be of benefit before overt iron overload is seen. In this review, we revisit the scientific and clinical evidence for iron overload in MDS to better characterize the iron overload phenotype in these patients, which differs from the classical transfusional and non-transfusional iron overload syndrome. We hope this will provide a conceptual framework to better understand the complex associations between anemia, iron and clinical outcomes, to accelerate progress in this area. PMID:28293409

  20. Clinical Analysis of Magnetic Resonance Imaging T2* Tests on Iron Overload in Children With β-Thalassemia Major%重型β-地中海贫血患儿体内铁负荷磁共振成像T2*检测的临床分析

    Institute of Scientific and Technical Information of China (English)

    许吕宏; 方建培; 张亚停; 徐宏贵; 翁文骏; 刘勇; 吴佳凯

    2011-01-01

    Objective To investigate the clinical significance of magnetic resonance imaging T2-star (MRI T2 # ) tests on iron overload in children with β-thalassemia major. Methods Nineteen children with |3-thalassemia major were recruited in this study during January to December 2010. Retrospective analytical study on the history of blood transfusion and chelation therapy were recorded. Sera were obtained from the patients and were tested for serum ferritin. MRI T2* tests on iron overload of liver, heart, pancreas and pituitary in these children were performed in Queen Mary Hospital, Hong Kong. The results were evaluated, and the relationships between different values of iron overload were analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Sun Yat-sen Memorial Hospital, Sun Yat-sen University. Informed consent was obtained from the parents of each participating child. Results All the patients received irregular blood transfusion and chelation therapy. The value of serum ferritin ranged from 3114 μg/L to 14 550μg/L. The organs of the patients showed different degrees of iron overload by MRI T2* detection. Levels of serum ferritin were negatively correlated with liver MRI T2* , left ventricular ejection fraction, and pancreas MRI T2* O= - 0.569, P = 0. Oil ;r= -0. 633, P = 0. 004 ;r=- 0.592, P = 0. 008). In addition, there were positive correlation between heart MRI T2* and pancreas MRI T2* 0 = 0. 696, P = 0. 001), between pancreas MRI T2* and pituitary MRI T2* 0=0. 491, P=0. 033) as well. Conclusion MRI T2* tests show clinical significance for evaluating iron overload in children with β-thalassemia major.%目的 探讨磁共振成像T2*(MRI T2*)技术检测β-地中海贫血患儿体内铁负荷的应用价值.方法 2010年1月至12月本院儿科共收治19例重型β-地中海贫血患儿,采用回顾性分析方法 记录患儿输血及去铁治疗情况.分离患儿血清,检测血清铁蛋白含量.入组患儿

  1. Mitochondrial calcium overload is a key determinant in heart failure.

    Science.gov (United States)

    Santulli, Gaetano; Xie, Wenjun; Reiken, Steven R; Marks, Andrew R

    2015-09-08

    Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial for excitation-contraction (E-C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca2+ is essential for optimal function of these organelles. However, Ca2+ accumulation can impair mitochondrial function, leading to reduced ATP production and increased release of reactive oxygen species (ROS). Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca2+ plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca2+ release channels on cardiac SR: type 2 ryanodine receptors (RyR2s) and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial Ca2+ overload, dysmorphology, and malfunction. In contrast, cardiac-specific deletion of IP3R2 had no major effect on mitochondrial fitness in HF. Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of RyR2 macromolecular complex. Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca2+ overload and dysfunction in HF.

  2. Changes and Significance of Matrix Metalloproteinase and Its Tissue Inhibitor in Plasma and Cardiac Muscle of Rats with Chronic Cardiac Failure Induced by Volume Overload%基质金属蛋白酶及其抑制物在容量过负荷致慢性心力衰竭大鼠血浆及心肌组织中的变化及意义

    Institute of Scientific and Technical Information of China (English)

    张超英; 李晓惠; 伏瑾; 崔小岱

    2011-01-01

    目的 观察容量过负荷致慢性心力衰竭大鼠血浆及心肌组织基质金属蛋白酶-8(MMP-8)及其抑制物-1(TIMP-1)的表达变化,探讨其在慢性心力衰竭发病中的病理生理作用.方法 雄性SD大鼠17只,随机分为分流组(n=9)和对照组(n=8).分流组通过腹主动脉下腔静脉穿刺术建立容量过负荷致慢性充血性心力衰竭动物模型,对照组大鼠除不做穿刺外,余操作过程同分流组.分别测定2组大鼠心功能及血流动力学指标,检测血浆MMP-8及TIMP-1水平,实时荧光定量PCR测定大鼠左心室、右心室MMP-8 mRNA、TIMP-1 mRNA的表达.结果 术后8周,分流组大鼠左心室收缩压、左心室舒张压、左心室内压差、左心室内压最大上升速率及最大下降速率较对照组明显降低(Pa<0.05,0.01);左心室舒张末压较对照组明显升高(P<0.05).分流组大鼠血浆MMP-8、TIMP-1水平均较对照组明显升高(Pa<0.05).与对照组相比,分流组大鼠左心室心肌组织MMP-8 mRNA及左、右心室心肌组织TIMP-1 mRNA水平均有升高趋势,右心室MMP-8 mRNA水平有下降趋势,但2组比较差异均无统计学意义(Pa>0.05);左心室和右心室心肌组织中MMP-8/TIMP-1明显降低,右心室较左心室下降更明显.结论 MMP-8与TIMP-1通过影响胶原代谢,参与容量过负荷致慢性充血性心力衰竭的病理生理过程.%Objective To observe the changes of matrix metalloproteinase - 8 ( MMP - 8 ) and its tissue inhibitors of metallopreteinase -1 ( TIMP - 1 ) in plasma and cardiac muscle of rats with chronic cardiac failure induced by volume overload, and to explore those roles in physiology of chronic cardiac failure. Methods Seventeen male SD rats were randomly divided into 2 groups as follows:9 shunt rat models were established by abdominal aorta and inferior vena cava shunt operation and 8 rats after sham operation served as controls. Hemodynamic and echocardiographic measurements were obtained 8 weeks

  3. 番茄红素对铁负荷大鼠抗氧化功能影响%Protective effects of lycopene on oxidative stress in iron overload rats

    Institute of Scientific and Technical Information of China (English)

    王瑞; 张红; 吴博; 冯彦红; 刘重斌

    2012-01-01

    Objective To examine protective effects of lycopene on oxidative stress. Methods Thirty-six SD rats were randomly divided into control, iron, lycopene, iron + high lycopene, iron + medium lycopene, and iron + low lycopene group(6 rats in each group) and fed for 6 weeks. The iron concentration and total iron-binding capacity(TIBC) in serum and liver,kidney, spleen,heart,and colon tissue of the rats were determined. At the same time, the levels of ma-londialdehyde(MDA),total superoxide dismutase(T-SOD) ,catalase(CAT) ,and glutathione S-transferase( GST) were measured. Results In iron + high lycopene group,iorn concentrations of serum and liver,spleen,heart,and colon tissue were 19.06 ±2. 1 μmol/L,25. 67 ±2. 7,38. 30 ±4. 8,and 12.08 ±2.9 μg/g. In the high lycopene group,the serum iron decreased significantly;the serum TIBC increased significantly;the content of MDA decreased significantly;the activity of T-SOD increased significantly;and the activities of CAT and GST in serum,heart,liver and colon increased significantly compared to those of the iron load group( P <0. 05 for all). Conclusion The results suggest that lycopene prevents iron-induced oxidative stress with its potent free radical scavenging and antioxidant properties.%目的 探讨番茄红素对铁负荷大鼠抗氧化功能保护作用.方法 36只SD大鼠按体重随机分为空白对照、铁负荷、番茄红素、番茄红素高、中、低剂量干预6组,每组6只,持续饲喂6周后,取血和肝、肾、脾、心和结肠组织测定铁含量,总铁结合力;测定血清和组织中丙二醛( MDA)、总超氧化物歧化酶(T-SOD)、过氧化氢酶(CAT)及谷胱甘肽-S转移酶(GST)活性.结果 高剂量番茄红素干预组大鼠血清、肝、脾、心脏和结肠组织中铁含量分别为(19.06 ±2.1)μmol/L、(25.67±2.7)μg/g、(38.30±4.8)μg/g、(17.30±2.6) μg/g和(12.08±2.9)μg/g,与铁负荷组比较,高剂量番茄红素干预组大鼠组织中铁含量明显下降,血清

  4. 新型铁螯合剂地拉罗司治疗骨髓增生异常综合征铁过载的临床研究%Efficacy of deferasirox in iron overload patients secondary to myelodysplastic syndrome

    Institute of Scientific and Technical Information of China (English)

    金香淑; 徐绎涵; 靖彧; 韩晓蘋; 李红华; 姚子龙; 于力; 朱海燕

    2016-01-01

    Objective To analyze the efficacy of a new iron chelator , deferasirox, in treatment of iron overload secondary to myelo-dysplastic syndrome ( MDS) and investigate its adverse reactions .Methods Clinical data of all the iron overload patients secondary to MDS who receiving deferasirox therapy in our hospital from January 2012 to April 2014 were collected and retrospectively analyzed . Their serum ferritin ( SF) level, amount of red blood cell transfusion , and hemoglobin level were measured and recorded before and after treatment, and adverse reactions were observed .Results There were totally 8 cases of MDS secondary iron overload enrolled in this study.They were 7 males and 1 female, and at a median age of 52 (ranging from 38 to 71) years.After 3 months’ treatment, complete response (CR) was obtained in 3 cases, minor response (MiR) in 3 cases, and stable iron load (SIL) in 2 cases.The overall response rate was 75.0%(6/8), and the median amount of red blood cell transfusion was 2 (1-3) u/month.In 1 year after treatment, SF level was significantly decreased [(871.0 ±584.2) vs (2164.9 ±1233.6) ng/ml], while that of hemoglobin was obviously increased[(101.5 ±34.59) vs (65.37 ±21.35) g/L], with statistical differences (P <0.05).At this time point, 5 patients were out of red blood cell transfusion , and the amount of red blood cell transfusion was 0.5, 1.5 and 2.0 u/month respectively, for the other 3 patients.After 1 year treatment, only 1 patient died, 3 patients experienced nausea and vomiting, and 1 patient diarrhea .Conclusion Deferasirox therapy is safe and effective for MDS secondary iron overload patients .%目的:分析新型铁螯合剂地拉罗司治疗骨髓增生异常综合征( MDS )继发性铁过载的临床疗效及不良反应。方法回顾性分析了解放军总医院2012年1月至2014年4月期间应用新型铁螯合剂地拉罗司治疗MDS继发性铁过载患者的临床资料,观察治疗前后血清铁蛋白( SF)、红细

  5. Efficacy and safety of Iranian made Deferasirox (Osveral®) in Iranian major thalassemic patients with transfusional iron overload: A one year prospective multicentric open-label non-comparative study

    Science.gov (United States)

    Eshghi, P.; Farahmandinia, Z.; Molavi, M.; Naderi, M.; Jafroodi, M.; Hoorfar, H.; Davari, K.; Azarkeivan, A.; Keikhaie, B.; Ansari, S.; Arasteh, M.

    2011-01-01

    Purpose of the study to determine the efficacy, adverse effects and safety of a new Iranian generic product of deferasirox (Osveral®) in Iranian transfusion dependent major thalassemic (TD-MT) patients. Methods In 9 main thalassemia treatment centers, all of TD-MT patients (aged ≥2 yrs) with serum ferritin (SF) levels≥1000 ng/ml, or >100 ml/kg of RBC transfusion,who could not tolerate parental iron chelating were recruited regardless of their previous iron chelation therapy. Periodical clinical and laboratory evaluations were conducted for adverse effects (AEs). Primary efficacy end point was Mean of Relative Change of Serum Ferritin (MRC-SF) from the baseline level during one year. Analysis of variance (ANOVA), t test, chi-square or Fisher exact test were used for statistic analysis appropriately (P values 5 time increase in transaminases (24;5.89%).The causes of discontinuation of treatment were non-satisfactory treatment ( 24; 5.8%), poor or non-compliance of patients (21;5.1%), and adverse effects (13; 3.1%) Conclusion A detailed comparison with similar studies on deferasirox (Exjade®) shows a promising efficacy and safety for its Iranian generic product (Osveral ®). PMID:22615664

  6. Multi-center transferability of a breath-hold T2 technique for myocardial iron assessment

    Directory of Open Access Journals (Sweden)

    Chan Godfrey CF

    2008-02-01

    Full Text Available Abstract Background Cardiac iron overload is the leading cause of death in thalassemia major and is usually assessed using myocardial T2* measurements. Recently a cardiovascular magnetic resonance (CMR breath-hold T2 sequence has been developed as a possible alternative. This cardiac T2 technique has good interstudy reproducibility, but its transferability to different centres has not yet been investigated. Methods and Results The breath-hold black blood spin echo T2 sequence was installed and validated on 1.5T Siemens MR scanners at 4 different centres across the world. Using this sequence, 5–10 thalassemia patients from each centre were scanned twice locally within a week for local interstudy reproducibility (n = 34 and all were rescanned within one month at the standardization centre in London (intersite reproducibility. The local interstudy reproducibility (coefficient of variance and mean difference were 4.4% and -0.06 ms. The intersite reproducibility and mean difference between scanners were 5.2% and -0.07 ms. Conclusion The breath-hold myocardial T2 technique is transferable between Siemens scanners with good intersite and local interstudy reproducibility. This technique may have value in the diagnosis and management of patients with iron overload conditions such as thalassemia.

  7. [Iron function and carcinogenesis].

    Science.gov (United States)

    Akatsuka, Shinya; Toyokuni, Shinya

    2016-07-01

    Though iron is an essential micronutrient for humans, the excess state is acknowledged to be associated with oncogenesis. For example, iron overload in the liver of the patients with hereditary hemocromatosis highly increases the risk of hepatocellular carcinoma. Also, as to asbestos-related mesothelioma, such kinds of asbestos with a higher iron content are considered to be more carcinogenic. Iron is a useful element, which enables fundamental functions for life such as oxygen carrying and electron transport. However, in the situation where organisms are unable to have good control of it, iron turns into a dangerous element which catalyzes generation of reactive oxygen. In this review, I first outline the relationships between iron and cancer in general, then give an explanation about iron-related animal carcinogenesis models.

  8. 地拉罗司治疗重型β-地中海贫血铁过载的三年临床试验研究%A 3-year clinical trial of deferasirox in heavily iron-overloaded patients with Beta-thalassemia major

    Institute of Scientific and Technical Information of China (English)

    刘容容; 赖永榕; 马劼; 张新华; 罗建明; 李辉萍; 梁金清; 李喆; 王明月; 苏鹏

    2010-01-01

    Objective To evaluate the efficacy and safety of deferasirox in heavily iron-overloaded patients with beta-thalassemia major. Methods A single arm, open-label clinical trial was conducted to evaluate the efficacy and safety of deferasirox in the treatment for 23 patients with beta-thalassemia major and heavily iron-overloaded in 3 years follow-up. Results The 23 patients never received regular chelation before enrolling this trial [the mean baseline of serum ferritin was (5433.96 ± 2873.90) μg/L]. In this trial, a deferasirox dose of 20 mg·kg-1·d-1 could stabilize serum ferritin levles,while of ≥30mg·d-1 reduced the levels and achieved negative iron balance. There were no serious adverse events related to the drug.Most common adverse events were mild increases of liver enzyme and serum creatinine levels. Overall, 23 patients could tolerate the drug on schedule and all completed the trial. Conclusion As a new oral iron chelator, deferasirox has a significant efficacy for the treatment of iron overload. The effectiveness is dependent on the courses of treatment and the dose of deferasirox. The single-dose used is safe and tolerated, so deferasirox can remarkably improve life quality of patients.%目的 评价新型口服铁螯合剂--地拉罗司治疗重型β-地中海贫血(β-地贫)患者铁过载的疗效及安全性.方法 采用单组、开放试验设计,观察23例重型β-地贫铁过载患者3年随访中地拉罗司的疗效及安全性.结果 入组的23例重型β-地贫患者治疗前均未规则使用铁螫合剂,铁过载状况严重[血清铁蛋白平均基线值为(5433.96±2873.90)μg/L].20 mg·kg-1·d-1的地拉罗司能维持患者铁过载处于平衡状态,治疗前后血清铁蛋白水平无显著性变化;随治疗时间的延长,服药剂量的增加,≥30 mg·kg-1·d-1的地拉罗司能使患者铁过载达到负平衡状态,治疗前后比较血清铁蛋白水平差异具有统计学意义(P<0.01).3年随访中未出现地拉罗

  9. Attenuation of mitochondrial, but not cytosolic, Ca2+ overload reduces myocardial injury induced by ischemia and reperfusion

    Institute of Scientific and Technical Information of China (English)

    Chun-mei CAO; Wing-yee YAN; Jing LIU; Kenneth WL KAM; Shi-zhong ZHAN; James SK SHAM; Tak-ming WONG

    2006-01-01

    Aim: Attenuation of mitochondrial Ca2+ ([Ca2+]m, but not cytosolic Ca2+ ([Ca2+]c), overload improves contractile recovery. We hypothesized that attenuation of [Ca2+]m, but not [Ca2+]c, overload confers cardioprotection against ischemia/ reperfusion-induced injury. Methods: Infarct size from isolated perfused rat heart, cell viability, and electrically-induced Ca2+ transient in isolated rat ventricular myocytes were measured. We determined the effects of BAPTA-AM, a Ca2+ chelator, at concentrations that abolish the overload of both [Ca2+]c and [Ca2+]m, and ruthenium red, an inhibitor of mitochondrial uniporter of Ca2+ transport, at concentrations that abolish the overload of [Ca2+]m, but not [Ca2+]c, on cardiac injury induced by ischemia/reperfusion. Results: Attenuation of both [Ca2+]m and [Ca2+]c by BAPTA-AM, and attenuation of [Ca2+]m, but not [Ca2+]c, overload by ruthenium red, reduced the cardiac injury observations, indicating the importance of [Ca2+]m in cardioprotection and contractile recovery in response to ischemia/reperfusion. Conclusion: The study has provided unequivocal evidence using a cause-effect approach that attenuation of [Ca2+]m, but not [Ca2+]c, overload is responsible for cardioprotection against ischemia/reperfusion-induced injury. We also confirmed the previous observation that attenuation of [Ca2+]m, but not [Ca2+]c, by ruthenium red improves contractile recovery following ischemia/ reperfusion.

  10. Intelligent Overload Control for Composite Web Services

    NARCIS (Netherlands)

    Meulenhoff, P.J.; Ostendorf, D.R.; Zivkovic, M.; Meeuwissen, H.B.; Gijsen, B.M.M.

    2009-01-01

    In this paper, we analyze overload control for composite web services in service oriented architectures by an orchestrating broker, and propose two practical access control rules which effectively mitigate the effects of severe overloads at some web services in the composite service. These two rules

  11. Intelligent overload control for composite web services

    NARCIS (Netherlands)

    Meulenhoff, P.J.; Ostendorf, D.R.; Živković, M.; Meeuwissen, H.B.; Gijsen, B.M.M.

    2009-01-01

    In this paper, we analyze overload control for composite web services in service oriented architectures by an orchestrating broker, and propose two practical access control rules which effectively mitigate the effects of severe overloads at some web services in the composite service. These two rules

  12. [Iron chelate treatment of hereditary sideroblastic anemia complicated by hemochromatosis].

    Science.gov (United States)

    Kremp, L; Girot, R; Alliot, S; Najean, Y; Douchain, F; Hongre, J F

    1983-01-01

    In a child with sideroblastic anemia complicated with hemochromatosis, iron overload was successfully treated with slow subcutaneous perfusion of deferoxamine. A 28 month-treatment resulted in the inversion of iron balance, which became negative, and the normalization of serum ferritin and abdominal CT scan. These results indicate that deferoxamine perfusion 12/24 hrs is able to restrict or even to remove the iron overload, previously responsible for hemochromatosis, a factor of mortality in this disease.

  13. Efficacy and safety of Iranian made Deferasirox (Osveral®in Iranian major thalassemic patients with transfusional iron overload: A one year prospective multicentric open-label non-comparative study

    Directory of Open Access Journals (Sweden)

    P Eshghi

    2011-07-01

    Full Text Available       Purpose of the study:to determine the efficacy, adverse effects and safety of a new Iranian generic product of deferasirox (Osveral® in Iranian transfusion dependent major thalassemic (TD-MT patients. Methods:In 9 main thalassemia treatment centers, all of TD-MT patients (aged ≥2 yrs with serum ferritin (SF levels≥1000 ng/ml, or >100 ml/kg of RBC transfusion ,who could not tolerate parental iron chelating were recruited regardless of their previous iron chelation therapy. Periodical clinical and laboratory evaluations were conducted for adverse effects (AEs. Primary efficacy end point was Mean of Relative Change of Serum Ferritin (MRC-SF from the baseline level during one year. Analysis of variance (ANOVA, t test, chi-square or Fisher exact test were used for statistic analysis appropriately (P values <0.05 were considered as statistical significant. Results:In 407 cases the male/female ratio was 0.98. Mean age was 11.5±7.4 (2-58 years. The mean of initiating dose of Osveral® and mean usage dose during the study was 23.5±4.9 mg/kg and 24.9 ± 4.9 mg/kg respectively. MRC-SF was -11.44% ±38.92 and it showed significant decline in SF (P value<0.001 one hundred and forty eight patients out of 407 patients experienced at least one. AE, the most common of them were transient increase in serum creatinin (97;24.1% and > 5 time increase in transaminases (24;5.89%.The causes of discontinuation of treatment were non-satisfactory treatment ( 24; 5.8%, poor or non-compliance of patients (21;5.1%, and adverse effects (13; 3.1% . Conclusion:A detailed comparison with similar studies on deferasirox (Exjade® shows a promising efficacy and safety for its Iranian generic product (Osveral ®.

  14. Iron homeostasis: new players, newer insights.

    Science.gov (United States)

    Edison, Eunice S; Bajel, Ashish; Chandy, Mammen

    2008-12-01

    Although iron is a relatively abundant element in the universe, it is estimated that more than 2 billion people worldwide suffer from iron deficiency anemia. Iron deficiency results in impaired production of iron-containing proteins, the most prominent of which is hemoglobin. Cellular iron deficiency inhibits cell growth and subsequently leads to cell death. Hemochromatosis, an inherited disorder results in disproportionate absorption of iron and the extra iron builds up in tissues resulting in organ damage. As both iron deficiency and iron overload have adverse effects, cellular and systemic iron homeostasis is critically important. Recent advances in the field of iron metabolism have led to newer understanding of the pathways involved in iron homeostasis and the diseases which arise from alteration in the regulators. Although insight into this complex regulation of the proteins involved in iron homeostasis has been obtained mainly through animal studies, it is most likely that this knowledge can be directly extrapolated to humans.

  15. Intestinal Iron Homeostasis and Colon Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Yatrik M. Shah

    2013-06-01

    Full Text Available Colorectal cancer (CRC is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations or excess dietary iron uptake has been identified as a risk factor for CRC. Intestinal iron is tightly controlled by iron transporters that are responsible for iron uptake, distribution, and export. Dysregulation of intestinal iron transporters are observed in CRC and lead to iron accumulation in tumors. Intratumoral iron results in oxidative stress, lipid peroxidation, protein modification and DNA damage with consequent promotion of oncogene activation. In addition, excess iron in intestinal tumors may lead to increase in tumor-elicited inflammation and tumor growth. Limiting intratumoral iron through specifically chelating excess intestinal iron or modulating activities of iron transporter may be an attractive therapeutic target for CRC.

  16. Iron deficiency anemia in heart failure.

    Science.gov (United States)

    Arora, Natasha P; Ghali, Jalal K

    2013-07-01

    Anemia and iron deficiency are quite prevalent in patients with heart failure (HF) and may overlap. Both anemia and iron deficiency are associated with worse symptoms and adverse clinical outcomes. In the past few years, there has been an enormous interest in the subject of iron deficiency and its management in patients with HF. In this review, the etiology and relevance of iron deficiency, iron metabolism in the setting of HF, studies on iron supplementation in patients with HF and potential cardiovascular effects of subclinical iron overload are discussed.

  17. Iron metabolism in mynah birds (Gracula religiosa) resembles human hereditary haemochromatosis

    NARCIS (Netherlands)

    Mete, A; Hendriks, HG; Klaren, PHM; Dorrestein, GM; van Dijk, JE; Marx, JJM

    2003-01-01

    Iron overload is a very frequent finding in several animal species and a genetic predisposition is suggested. In one of the most commonly reported species with susceptibility for iron overload ( mynah bird), it was recently shown that the cause of this pathophysiology is high uptake and retention of

  18. Secondary Hemochromatosis due to Chronic Oral Iron Supplementation

    Science.gov (United States)

    Isang, Emmanuel

    2017-01-01

    Iron may accumulate in excess due to a mutation in the HFE gene that upregulates absorption or when it is ingested or infused at levels that exceed the body's ability to clear it. Excess iron deposition in parenchymal tissue causes injury and ultimately organ dysfunction. Diabetes mellitus and hepatic cirrhosis due to pancreas and liver damage are just two examples of diseases that result from iron overload. Despite the rapid growth of information regarding iron metabolism and iron overload states, the most effective treatment is still serial phlebotomies. We present a patient who developed iron overload due to chronic ingestion of oral ferrous sulfate. This case illustrates the importance of querying geriatric patients regarding their use of nonprescription iron products without a medical indication. PMID:28133557

  19. Thermal Characterization of the Overload Carbon Resistors

    Directory of Open Access Journals (Sweden)

    Ivana Kostić

    2013-01-01

    Full Text Available In many applications, the electronic component is not continuously but only intermittently overloaded (e.g., inrush current, short circuit, or discharging interference. With this paper, we provide insight into carbon resistors that have to hold out a rarely occurring transient overload. Using simple electrical circuit, the resistor is overheating with higher current than declared, and dissipation is observed by a thermal camera.

  20. Deferasirox protects against iron-induced hepatic injury in Mongolian gerbil.

    Science.gov (United States)

    Al-Rousan, Rabaa M; Rice, Kevin M; Katta, Anjaiah; Laurino, Joseph; Walker, Ernest M; Wu, Miaozong; Triest, William E; Blough, Eric R

    2011-06-01

    Iron overload is associated with an increased risk of liver complications including fibrosis, cirrhosis, and hepatocellular carcinoma. Deferasirox is a new oral chelator with high iron-binding potency and selectivity. Here we investigate the ability of deferasirox to remove excessive hepatic iron and prevent iron-induced hepatic injury. Adult male Mongolian gerbils were divided into 3 groups (n=5/group)-control, iron overload (100 mg iron-dextran/kg body weight/5 days; intraperitoneal for 10 weeks), and iron overload followed by deferasirox treatment (100 mg deferasirox/kg body weight/d; pulse oral for 1 or 3 months). Compared with the nontreated iron overload group, deferasirox reduced hepatic iron concentration by 44% after 3 months of treatment (Pdeferasirox treatment, and no evidence of lipid accumulation was observed. Immunoblotting demonstrated that iron overload caused approximately 2-fold increase in hepatic ferritin expression (Pdeferasirox treatment (PDeferasirox treatment also was associated with reduced hepatic protein oxidation, superoxide abundance, and cell death. The percentage of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells in the deferasirox-treated livers was 41% lower than that of iron overloaded group (Pdeferasirox treatment. These findings suggest that deferasirox may confer protection against iron-induced hepatic toxicity.

  1. Expression of Rho/Rho kinase of cardiac myocyte of heart failure model of pressure overload rats and intervention of fasudil%压力负荷心力衰竭大鼠心肌细胞内Rho/Rho激酶的表达及药物干预

    Institute of Scientific and Technical Information of China (English)

    张曼; 曾定尹

    2005-01-01

    目的探讨升主动脉缩窄压力超负荷心力衰竭大鼠心肌细胞内Rho/Rho激酶的表达及法舒地尔(fasudil)--Rho/Rho激酶拮抗剂对心力衰竭的影响.方法制备升主动脉缩窄大鼠心力衰竭及假手术组(S组)模型.将升主动脉缩窄术后Wistar雌性大鼠随机分为2组,一组为心力衰竭组(H组),给予生理盐水0.1ml,腹腔注射,每日2次;一组为fasudil治疗组(F组),治疗组给予fasudil 5 mg/Kg,腹腔注射,每日2次;治疗4周.H组、F组及S组每组各10只大鼠.观察各组大鼠各项指标变化.结果H组鼠心肌细胞RhoA,Rho激酶mRNA表达显著增高,F组心肌细胞RhoA mRNA,Rho激酶mRNA表达下降.结论心肌细胞RhoA、Rho激酶表达与充血性心力衰竭密切相关,法舒地尔可有效降低心肌细胞内RhoA mRNA,Rho激酶mRNA表达,缓解心力衰竭症状,可能为一种新的、有效的治疗心力衰竭的血管扩张剂.%Objective: To study the expression of Rho/Rho kinase of cardiac myocyte of heart failure pressure overload rat models subsequent to coarctation of ascending aorta and the effects of fasudil on heart failure. Methods:A model of heart failure induced by coarctation of ascending aorta was used in this study. 20 female wistar operation rats were divided randomly into two groups (n =10). Heart failure (Natrii chloridi, 0.1 ml), fasudil (5 mg/Kg), Bid i.p,20 weeks after coarctation of ascending aorta operation, 10 agematched sham operation group as control. Treatment time was 4 weeks. Hemodynamics, ratio of LV weight to body weight, expression of RhoA and Rho kinase mRNA were investigated in the two groups and sham operation group. Results: RhoA, Rho kinase mRNA level were higher in heart failure when compared with sham. Fasudil could change the expression of RhoA, Rho kinase mRNA level.Conclusion: These results indicate that heart failure is probably related to activating of RhoA, Rho kinase. Fasudil may contribute to the observed beneficial effects on heart

  2. C-Myc regulates substrate oxidation patterns during early pressure-overload hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Ledee, Dolena R. [Seattle Children' s Research Inst., Seattle, WA (United States); Smith, Lincoln [Seattle Children' s Hospital, Seattle, WA (United States); Kajimoto, Masaki [Seattle Children' s Research Inst., Seattle, WA (United States); Bruce, Margaret [Seattle Children' s Research Inst., Seattle, WA (United States); Isern, Nancy G. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL); Xu, Chun [Seattle Children' s Research Inst., Seattle, WA (United States); Portman, Michael A. [Seattle Children' s Research Inst., Seattle, WA (United States); Olson, Aaron [Seattle Children' s Research Inst., Seattle, WA (United States)

    2013-11-26

    Pressure overload cardiac hypertrophy alters substrate metabolism. Prior work showed that myocardial inactivation of c-Myc (Myc) attenuated hypertrophy and decreased expression of glycolytic genes after aortic constriction. Accordingly, we hypothesize that Myc regulates substrate preferences for the citric acid cycle during pressure overload hypertrophy from transverse aortic constriction (TAC) and that these metabolic changes impact cardiac function and growth. To test this hypothesis, we subjected FVB mice with cardiac specific, inducible Myc inactivation (MycKO-TAC) and non-transgenic littermates (Cont-TAC) to transverse aortic constriction (n=7/group). A separate group underwent sham surgery (Sham, n=5). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketones and unlabeled glucose and insulin. Western blots were used to evaluate metabolic enzymes. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. Compared to Sham, Cont-TAC had increased free fatty acid fractional contribution with a concurrent decrease in unlabeled (presumably glucose) contribution. Myc inactivation (MycKO-TAC) inhibited these metabolic changes. Hypertrophy in general increased protein levels of PKM2; however this change was not linked to Myc status. Protein post-translation modification by O-GlcNAc was significantly greater in Cont-TAC versus both Sham and MycKO-TAC. In conclusion, Myc regulates substrate utilization during early pressure overload hypertrophy. Our results show that the metabolic switch during hypertrophy is not necessary to maintain cardiac function, but it may be important mechanism to promote cardiomyocyte growth. Myc also regulates protein O-GlcNAcylation during hypertrophy.

  3. Liver iron concentration quantification by MRI: are recommended protocols accurate enough for clinical practice?

    Energy Technology Data Exchange (ETDEWEB)

    Castiella, Agustin; Zapata, Eva M. [Mendaro Hospital, Gastroenterology Service, Mendaro (Spain); Alustiza, Jose M. [Osatek Donostia, Radiology Service, Donostia (Spain); Emparanza, Jose I. [Donostia Hospital CASPe, CIBER-ESP, Clinical Epidemiology Unit, Donostia (Spain); Costero, Belen [Principe de Asturias Hospital, Gastroenterology Service, Alcala de Henares (Spain); Diez, Maria I. [Principe de Asturias Hospital, Radiology Service, Alcala de Henares (Spain)

    2011-01-15

    To assess the accuracy of quantification of liver iron concentration (LIC) by MRI using the Rennes University (URennes) algorithm. In the overall study period 1999-2006 the LIC in 171 patients was calculated with the URennes model and the results were compared with LIC measured by liver biopsy. The biopsy showed that 107 patients had no overload, 38 moderate overload and 26 high overload. The correlation between MRI and biopsy was r = 0.86. MRI correctly classified 105 patients according to the various levels of LIC. Diagnostic accuracy was 61.4%, with a tendency to overestimate overload: 43% of patients with no overload were diagnosed as having overload, and 44.7% of patients with moderate overload were diagnosed as having high overload. The sensitivity of the URennes method for high overload was 92.3%, and the specificity for the absence of overload was 57.0%. MRI values greater than 170 {mu}mol Fe/g revealed a positive predictive value (PPV) for haemochromatosis of 100% (n = 18); concentrations below 60 {mu}mol Fe/g had a negative predictive value (NPV) of 100% for haemochromatosis (n = 101). The diagnosis in 44 patients with intermediate values remained uncertain. The assessment of LIC with the URennes method was useful in 74.3% of the patients to rule out or to diagnose high iron overload. The method has a tendency to overestimate overload, which limits its diagnostic performance. (orig.)

  4. [Involvement and role of iron in nonalcoholic steatohepatitis].

    Science.gov (United States)

    Cojocariu, Camelia; Trifan, Anca; Stanciu, C

    2008-01-01

    Nonalcoholic steatohepatitis (NASH) was described by Ludwig mainly in obese, middle-aged women, often associated with diabetes mellitus and hyperlipidemia. In the recent years, NASH was found to be associated with male, nonobese, nondiabetic patients and with liver iron overload, which led to the hypothesis of iron playing a role in NASH pathogenesis. Increased ferritin with normal transferrin saturation is frequently found in fatty liver patients, but it reflects iron overload only in those patients in which it persists despite an appropriate diet. Insulin resistance hepatic iron overload (IR-HIO) is a new condition of hepatic iron overload, characterized by hyperferritinemia with normal or slightly increased transferrin saturation in the absence of hemochromatotic gene mutations. Although patients with IR-HIO have a high prevalence of insulin resistance-related metabolic disorders, the relationship of IR-HIO and NASH is unclear. Two characteristics allow differentiation of IR-HIO from genetic haemochromatosis: iron overload is heterogeneous from one hepatocyte to another in the periportal area, and sinusoidal iron is distributed throughout the lobule. In IR-HIO, fibrosis develops at a much lower hepatic iron burden than in genetic haemochromatosis, and sinusoidal iron, steatosis and inflammation could represent the histological mark of activity and progression of liver disease in IR-HIO.

  5. Low coronary perfusion pressure is associated with endocardial fibrosis in a rat model of volume overload cardiac hypertrophy A redução da pressão de perfusão coronariana está associada com a fibrose endocárdica no modelo de hipertrofia por sobrecarga de volume em ratos

    Directory of Open Access Journals (Sweden)

    Maria Carolina Guido

    2004-01-01

    Full Text Available Left ventricular hypertrophy following volume overload is regarded as an example of cardiac remodeling without increased fibrosis accumulation. However, infarction is associated with increased fibrosis within the noninfarcted, hypertrophied myocardium, particularly in the subendocardial regions. It is conceivable to suppose that, as also occurs postinfarction, low coronary driving pressure may also interfere with accumulation of myocardial fibrosis following aortocaval fistula. PURPOSE: To investigate the role of acute hemodynamic changes in subsequent deposition of cardiac fibrosis in response to aortocaval fistula. METHOD: Aortocaval fistula were created in 4 groups of Wistar rats that were followed over 4 and 8 weeks: aortocaval fistula 4 and aortocaval fistula 8 (10 rats each and their respective controls (sham-operated controls - Sh, Sh4 and Sh8 (8 rats each. Hemodynamic measurements were performed 1 week after surgery. Hypertrophy and fibrosis were quantified by myocyte diameter and collagen volume fraction at the end of follow up. RESULT: Compared with Sh4 and Sh8, pulse pressure, left ventricular end-diastolic pressure, and +dP/dt were higher in aortocaval fistula 4 and aortocaval fistula 8, but -dP/dt was similar. Coronary driving pressure (mm Hg, used as an estimate of perfusion pressure, was lower in aortocaval fistula 8 (52.6 ± 4.1 than in Sh8 (100.8 ± 1.3, but comparable between aortocaval fistula 4 (50.0 ± 8.9 and Sh4 (84.8 ± 2.3. Myocyte diameter was greater in aortocaval fistula 8, whereas interstitial and subendocardial fibrosis were greater in aortocaval fistula 4 and aortocaval fistula 8. Coronary driving pressure correlated inversely and independently with subendocardial fibrosis (r² = .86, P No remodelamento que se segue às sobrecargas de volume não é descrito o aumento de fibrose miocárdica. Após o infarto, entretanto, há hipertrofia do miocárdio remoto com acúmulo de fibrose, particularmente no subendoc

  6. Maternal Cardiovascular Function in Normal Pregnancy: Evidence of Maladaptation to Chronic Volume Overload.

    Science.gov (United States)

    Melchiorre, Karen; Sharma, Rajan; Khalil, Asma; Thilaganathan, Baskaran

    2016-04-01

    The aim of this study was to investigate cardiac functional status in pregnancy using a comprehensive approach taking into account the simultaneous changes in loading and geometry, as well as maternal age and anthropometric indices. This was a prospective cross-sectional study of 559 nulliparous pregnant women assessed at 4 time points during pregnancy and at 1 year postpartum. All women underwent conventional echocardiography and tissue Doppler velocities and strain rate analysis at multiple cardiac sites. Mean arterial pressure and total vascular resistance index significantly decreased (both Ppregnancy and increased thereafter. Stroke volume index and cardiac index showed the opposite trend compared with mean arterial pressure and total vascular resistance index (both Ppregnancy, significant chamber diastolic dysfunction and impaired myocardial relaxation was evident in 17.9% and 28.4% of women, respectively, whereas myocardial contractility was preserved. There was full recovery of cardiac function at 1 year postpartum. Cardiovascular changes during pregnancy are thought to represent a physiological adaptation to volume overload. The findings of a drop in stroke volume index, impaired myocardial relaxation with diastolic dysfunction, and a tendency toward eccentric remodeling in a significant proportion of cases at term are suggestive of cardiovascular maladaptation to the volume-overloaded state in some apparently normal pregnancies. These unexpected cardiovascular findings have important implications for the management of both normal and pathological pregnancy states.

  7. Iron in haemoglobinopathies and rare anaemias

    Directory of Open Access Journals (Sweden)

    John Porter

    2014-12-01

    Full Text Available Iron overload in haemoglobinopathies and rare anaemias may develop from increased iron absorption secondary to hepcidin suppression, and/or from repeated blood transfusions. While the accumulation of body iron load from blood transfusion is inevitable and predictable from the variable rates of transfusion in the different conditions, there are some important differences in the distribution of iron overload and its consequences between these. Transfusion-dependent thalassaemia (TDT is the best described condition in which transfusional overload occurs. Initially iron loads into macrophages, subsquently hepatocytes, and then the endocrine system including the anterior pituiatry and finally the myocardium. The propensity to extrahepatic iron spread increases with rapid transfusion and with inadequate chelation therapy but there is considerable interpatient and interpopulation variability in this tendency. The conduits though which iron is delivered to tissues is through non transferrin iron species (NTBI which are taken into liver, endocrine tissues and myocardium through L-type calcium channells and possibly through other channells. Recent work by the MSCIO group1 suggests that levels of NTBI are determined by three mechanisms: i increasing with iron overload; ii increasing with ineffective erythropoieis; iii and decreasing when level of transferrin iron utilisation is high. In TDT all three mechanisms increase NTBI levels because transferrin iron utilisation is suppressed by hypertransfusion. It is hypothesized that the transfusion regimen and target mean Hb may have a key impact on NTBI levels because high transfusion regimes may suppress the ‘sink’ effect of the erythron though decreased clearance of transferrin iron. In sickle cell disease (SCD without blood transfusion the anaemia results mainly from haemolysis rather than from ineffective erythropoiesis.2 Thus there is a tendency to iron depletion because of urinary iron loss from

  8. The Study on Intramyocardial Calcium Overload and Apoptosis Induced by Cosackievirus B3

    Institute of Scientific and Technical Information of China (English)

    HU; Xiufen; WANG; Hongwei; LU; Weiwei; DONG; Yongsui; CHENG; Peixuan

    2001-01-01

    The isolated cardiac myocytes of rats were immediately infected by cosackievirus B3(CVB3) to investigate the effects of such procedure on the cell cycle, apoptosis and intracellular ionized calcium (Ca2+ i) of cardiac myocytes. Newborn Balb/c murine cardiac myocytes were cultivated,then infected by CVB3. Intracellular Ca2+ i was measured by flow cytometer. The calcium in the medium for culturing cardiac myocytes was detected by using atom absorb spectrum test. It was found that CVB3 could markedly inhibit the differentiation and proliferation of the infected cardiac myocytes and induce the apoptosis. The intracellular Ca2+ i level in the infected group was significantly higher than in the control group (P<0. 01). The calcium concentration in the medium for culturing cardiac myocytes in the infected group was significantly lower than in the control group (P<0.05). It was suggested that the apoptosis and intracellular calcium overload of the CVB3-affected cardiac myocytes are likely to play an important role in the pathogenesis of viral myocarditis.

  9. Transcriptional profiling of Helicobacter pylori Fur- and iron-regulated gene expression

    NARCIS (Netherlands)

    F.D.J. Ernst (Florian); S. Bereswill (Stefan); B. Waidner (Barbara); J. Stoof (Jeroen); U. Mader; J.G. Kusters (Johannes); E.J. Kuipers (Ernst); M. Kist (Manfred); A.H.M. van Vliet (Arnoud); G. Homuth (Georg)

    2005-01-01

    textabstractIntracellular iron homeostasis is a necessity for almost all living organisms, since both iron restriction and iron overload can result in cell death. The ferric uptake regulator protein, Fur, controls iron homeostasis in most Gram-negative bacteria. In the human gastri

  10. Mössbauer Spectra of Mouse Hearts reveal age-dependent changes in mitochondrial and ferritin iron levels.

    Science.gov (United States)

    Wofford, Joshua D; Chakrabarti, Mrinmoy; Lindahl, Paul Alan

    2017-02-15

    Cardiac function requires continuous high levels of energy, and so iron, a critical player in mitochondrial respiration, is an important component of the heart. Hearts from (57)Fe-enriched mice were evaluated by Mossbauer spectroscopy. Spectra consisted of a sextet and two quadrupole doublets. One doublet was due to residual blood while the other was due to [Fe4S4](2+) clusters and Fe(II) hemes, most of which were associated with mitochondrial respiration. The sextet was due to ferritin; there was no evidence of hemosiderin, a ferritin decomposition product. Iron from ferritin was nearly absent in young hearts, but increased steadily with age. EPR spectra exhibited signals similar to those of brain, liver, and human cells. No age-dependent EPR trends were apparent. Hearts from HFE(-/-) mice with hemochromatosis contained slightly more iron overall than controls, including more ferritin and less mitochondrial iron; these differences typify slightly older hearts, perhaps reflecting the burden due to this disease. HFE(-/-) livers were overloaded with ferritin but had low mitochondrial iron levels. IRP2(-/-) hearts contained less ferritin than controls but normal levels of mitochondrial iron. Hearts of young mice born to an iron-deficient mother contained normal levels of mitochondrial iron and no ferritin; the mothers heart contained low ferritin and normal levels of mitochondrial iron. High-spin Fe(II) ions were nearly undetectable in heart samples; these were evident in brains, livers, and human cells. Previous Mossbauer spectra of unenriched diseased human hearts lacked mitochondrial and blood doublets, and included hemosiderin features. This suggests degradation of iron-containing species during sample preparation.

  11. Ferritin iron minerals are chelator targets, antioxidants, and coated, dietary iron.

    Science.gov (United States)

    Theil, Elizabeth C

    2010-08-01

    Cellular ferritin is central for iron balance during transfusions therapies; serum ferritin is a small fraction of body ferritin, albeit a convenient reporter. Iron overload induces extra ferritin protein synthesis but the protein is overfilled with the extra iron that damages ferritin, with conversion to toxic hemosiderin. Three new approaches that manipulate ferritin to address excess iron, hemosiderin, and associated oxidative damage in Cooley's Anemia and other iron overload conditions are faster removal of ferritin iron with chelators guided to ferritin gated pores by peptides; more ferritin protein synthesis using ferritin mRNA activators, by metal complexes that target mRNA 3D structures; and determining if endocytotic absorption of iron from legumes, which is mostly ferritin, is regulated during iron overload to prevent excess iron entry while providing protein. More of a focus on ferritin features, including protein cage structure, iron mineral, regulatable mRNA, and specific gut absorption properties, will achieve the three novel experimental goals for managing iron homeostasis with transfusion therapies.

  12. Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity.

    Science.gov (United States)

    Shizukuda, Yukitaka; Tripodi, Dorothy J; Zalos, Gloria; Bolan, Charles D; Yau, Yu-Ying; Leitman, Susan F; Waclawiw, Myron A; Rosing, Douglas R

    2012-03-15

    It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation.

  13. Iron inhibits respiratory burst of peritoneal phagocytes in vitro

    DEFF Research Database (Denmark)

    Gotfryd, Kamil; Jurek, Aleksandra; Kubit, Piotr

    2011-01-01

    Objective. This study examines the effects of iron ions Fe(3+) on the respiratory burst of phagocytes isolated from peritoneal effluents of continuous ambulatory peritoneal dialysis (CAPD) patients, as an in vitro model of iron overload in end-stage renal disease (ESRD). Material and Methods....... Respiratory burst of peritoneal phagocytes was measured by chemiluminescence method. Results. At the highest used concentration of iron ions Fe(3+) (100 µM), free radicals production by peritoneal phagocytes was reduced by 90% compared to control. Conclusions. Iron overload may increase the risk of infectious...

  14. Control over Permissible Short Emergency Overloads in Power Transformers

    Directory of Open Access Journals (Sweden)

    V. A. Anischenko

    2010-01-01

    Full Text Available The paper proposes a method for determination a permissible duration of short intermittent overloads of power transformers that permits to avoid non-permissible over-heating of winding insulation and fully utilize overloading transformer ability.

  15. On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure

    Directory of Open Access Journals (Sweden)

    Carpenter JP

    2011-09-01

    Full Text Available Abstract Background Trials of iron chelator regimens have increased the treatment options for cardiac siderosis in beta-thalassemia major (TM patients. Treatment effects with improved left ventricular (LV ejection fraction (EF have been observed in patients without overt heart failure, but it is unclear whether these changes are clinically meaningful. Methods This retrospective study of a UK database of TM patients modelled the change in EF between serial scans measured by cardiovascular magnetic resonance (CMR to the relative risk (RR of future development of heart failure over 1 year. Patients were divided into 2 strata by baseline LVEF of 56-62% (below normal for TM and 63-70% (lower half of the normal range for TM. Results A total of 315 patients with 754 CMR scans were analyzed. A 1% absolute increase in EF from baseline was associated with a statistically significant reduction in the risk of future development of heart failure for both the lower EF stratum (EF 56-62%, RR 0.818, p Conclusion These data show that during treatment with iron chelators for cardiac siderosis, small increases in LVEF in TM patients are associated with a significantly reduced risk of the development of heart failure. Thus the iron chelator induced improvements in LVEF of 2.6% to 3.1% that have been observed in randomized controlled trials, are associated with risk reductions of 25.5% to 46.4% for the development of heart failure over 12 months, which is clinically meaningful. In cardiac iron overload, heart mitochondrial dysfunction and its relief by iron chelation may underlie the changes in LV function.

  16. Overload-protector/fault-indicator circuit

    Science.gov (United States)

    Paluka, J. R.; Moore, S. F.

    1977-01-01

    Circuit incorporates three-terminal current limiter (78M24) to increase overall reliability and to eliminate transistor burnouts resulting from shorted interconnection lines and other overloads. Fact-acting light emitting diodes across the limiters show status of transistor output circuits.

  17. Aggradation in rivers due to overloading

    NARCIS (Netherlands)

    Ribberink, J.S.; Van der Sande, J.T.M.

    1984-01-01

    The problem of aggradation in a river due to overloading is tackled with a mathematical model consisting of a set of one-dimensional (in space) basic equations in which the water motion is assumed to be quasi-steady and the sediment transport is determined by local conditions. Analytical solutions a

  18. 30 CFR 56.12001 - Circuit overload protection.

    Science.gov (United States)

    2010-07-01

    ... § 56.12001 Circuit overload protection. Circuits shall be protected against excessive overload by fuses or circuit breakers of the correct type and capacity. ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Circuit overload protection. 56.12001...

  19. 30 CFR 57.12001 - Circuit overload protection.

    Science.gov (United States)

    2010-07-01

    ... Electricity Surface and Underground § 57.12001 Circuit overload protection. Circuits shall be protected against excessive overloads by fuses or circuit breakers of the correct type and capacity. ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Circuit overload protection. 57.12001...

  20. Measurement of Liver Iron Concentration by MRI Is Reproducible

    Directory of Open Access Journals (Sweden)

    José María Alústiza

    2015-01-01

    Full Text Available Purpose. The objectives were (i construction of a phantom to reproduce the behavior of iron overload in the liver by MRI and (ii assessment of the variability of a previously validated method to quantify liver iron concentration between different MRI devices using the phantom and patients. Materials and Methods. A phantom reproducing the liver/muscle ratios of two patients with intermediate and high iron overload. Nine patients with different levels of iron overload were studied in 4 multivendor devices and 8 of them were studied twice in the machine where the model was developed. The phantom was analysed in the same equipment and 14 times in the reference machine. Results. FeCl3 solutions containing 0.3, 0.5, 0.6, and 1.2 mg Fe/mL were chosen to generate the phantom. The average of the intramachine variability for patients was 10% and for the intermachines 8%. For the phantom the intramachine coefficient of variation was always below 0.1 and the average of intermachine variability was 10% for moderate and 5% for high iron overload. Conclusion. The phantom reproduces the behavior of patients with moderate or high iron overload. The proposed method of calculating liver iron concentration is reproducible in several different 1.5 T systems.

  1. Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

    Directory of Open Access Journals (Sweden)

    Qifeng Zhou

    2015-01-01

    Full Text Available Mutations in the giant sarcomeric protein titin (TTN are a major cause for inherited forms of dilated cardiomyopathy (DCM. We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygous Ttn knock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC in heterozygous (Het Ttn knock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction (p<0.05, while wild-type (WT TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure.

  2. Noninvasive assessment of filling pressure and left atrial pressure overload in severe aortic valve stenosis: relation to ventricular remodeling and clinical outcome after aortic valve replacement

    DEFF Research Database (Denmark)

    Dahl, Jordi S; Videbæk, Lars; Poulsen, Mikael K

    2011-01-01

    One of the hemodynamic consequences of aortic valve stenosis is pressure overload leading to left atrial dilatation. Left atrial size is a known risk factor providing prognostic information in several cardiac conditions. It is not known if this is also the case in patients with aortic valve...

  3. Hepcidin: regulation of the master iron regulator

    Science.gov (United States)

    Rishi, Gautam; Wallace, Daniel F.; Subramaniam, V. Nathan

    2015-01-01

    Iron, an essential nutrient, is required for many diverse biological processes. The absence of a defined pathway to excrete excess iron makes it essential for the body to regulate the amount of iron absorbed; a deficiency could lead to iron deficiency and an excess to iron overload and associated disorders such as anaemia and haemochromatosis respectively. This regulation is mediated by the iron-regulatory hormone hepcidin. Hepcidin binds to the only known iron export protein, ferroportin (FPN), inducing its internalization and degradation, thus limiting the amount of iron released into the blood. The major factors that are implicated in hepcidin regulation include iron stores, hypoxia, inflammation and erythropoiesis. The present review summarizes our present knowledge about the molecular mechanisms and signalling pathways contributing to hepcidin regulation by these factors. PMID:26182354

  4. New developments and controversies in iron metabolism and iron chelation therapy.

    Science.gov (United States)

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-03-26

    Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic

  5. Pregnancy as a cardiac stress model.

    Science.gov (United States)

    Chung, Eunhee; Leinwand, Leslie A

    2014-03-15

    Cardiac hypertrophy occurs during pregnancy as a consequence of both volume overload and hormonal changes. Both pregnancy- and exercise-induced cardiac hypertrophy are generally thought to be similar and physiological. Despite the fact that there are shared transcriptional responses in both forms of cardiac adaptation, pregnancy results in a distinct signature of gene expression in the heart. In some cases, however, pregnancy can induce adverse cardiac events in previously healthy women without any known cardiovascular disease. Peripartum cardiomyopathy is the leading cause of non-obstetric mortality during pregnancy. To understand how pregnancy can cause heart disease, it is first important to understand cardiac adaptation during normal pregnancy. This review provides an overview of the cardiac consequences of pregnancy, including haemodynamic, functional, structural, and morphological adaptations, as well as molecular phenotypes. In addition, this review describes the signalling pathways responsible for pregnancy-induced cardiac hypertrophy and angiogenesis. We also compare and contrast cardiac adaptation in response to disease, exercise, and pregnancy. The comparisons of these settings of cardiac hypertrophy provide insight into pregnancy-associated cardiac adaptation.

  6. Liver iron content determination by magnetic resonance imaging

    Institute of Scientific and Technical Information of China (English)

    Konstantinos; Tziomalos; Vassilios; Perifanis

    2010-01-01

    Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately re? ects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potenti...

  7. Monoubiquitin-dependent endocytosis of the IRON-REGULATED TRANSPORTER 1 (IRT1) transporter controls iron uptake in plants

    OpenAIRE

    Barberon, Marie; Zelazny, Enric; Robert, Stéphanie; Conejero, Geneviève; Curie, Catherine; Friml, Jìrí; Vert, Grégory

    2011-01-01

    Plants take up iron from the soil using the IRON-REGULATED TRANSPORTER 1 (IRT1) high-affinity iron transporter at the root surface. Sophisticated regulatory mechanisms allow plants to tightly control the levels of IRT1, ensuring optimal absorption of essential but toxic iron. Here, we demonstrate that overexpression of Arabidopsis thaliana IRT1 leads to constitutive IRT1 protein accumulation, metal overload, and oxidative stress. IRT1 is unexpectedly found in trans-Golgi network/early endosom...

  8. Hydroxyurea could be a good clinically relevant iron chelator.

    Directory of Open Access Journals (Sweden)

    Khushnooma Italia

    Full Text Available Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.

  9. CQ Switch Analysis under Traffic Overload

    Directory of Open Access Journals (Sweden)

    I. Maljević

    2011-06-01

    Full Text Available An analysis of 2x2 crossbar packet switch with buffers at crosspoints and round robin scheduling algorithm is presented in this paper. The analysis is performed for a non-admissible traffic pattern, where output ports are overloaded. The case of full offered load is observed and output ports are loaded with packets that have different arrival probabilities. In addition to the parameters that are commonly observed in such an analysis (throughput and average packet delay, memory requirements for the implementation of the buffer, as well as fair representation when servicing the buffer - the so-called fairness are also analyzed. The results show that even for a switch with a small number of ports very large buffers should be implemented, if we want to achieve satisfactory performance under traffic overload.

  10. The Regulation of Iron Absorption and Homeostasis

    Science.gov (United States)

    Wallace, Daniel F

    2016-01-01

    Iron is an essential element in biology, required for numerous cellular processes. Either too much or too little iron can be detrimental, and organisms have developed mechanisms for balancing iron within safe limits. In mammals there are no controlled mechanisms for the excretion of excess iron, hence body iron homeostasis is regulated at the sites of absorption, utilisation and recycling. This review will discuss the discoveries that have been made in the past 20 years into advancing our understanding of iron homeostasis and its regulation. The study of iron-associated disorders, such as the iron overload condition hereditary haemochromatosis and various forms of anaemia have been instrumental in increasing our knowledge in this area, as have cellular and animal model studies. The liver has emerged as the major site of systemic iron regulation, being the location where the iron regulatory hormone hepcidin is produced. Hepcidin is a negative regulator of iron absorption and recycling, achieving this by binding to the only known cellular iron exporter ferroportin and causing its internalisation and degradation, thereby reducing iron efflux from target cells and reducing serum iron levels. Much of the research in the iron metabolism field has focussed on the regulation of hepcidin and its interaction with ferroportin. The advances in this area have greatly increased our knowledge of iron metabolism and its regulation and have led to the development of novel diagnostics and therapeutics for iron-associated disorders.

  11. Valgus Extension Overload in Baseball Players.

    Science.gov (United States)

    Paulino, Franklin E; Villacis, Diego C; Ahmad, Christopher S

    2016-01-01

    Repetitive throwing, such as in baseball pitching, applies massive stress on the elbow. This can often lead to a predictable constellation of elbow injuries, such as valgus extension overload syndrome (VEO). The following review of VEO provides an understanding of relevant anatomy, explanation of pathomechanics, key aspects to clinical evaluation, effective treatment options, and indications for surgery. In addition, we provide the senior author's (CSA) preferred arthroscopic technique for cases of VEO refractory to conservative management.

  12. Significance of assess the iron reserves of severe renal anemia patients before and after blood transfusion

    Institute of Scientific and Technical Information of China (English)

    Gui-Fen Zhang

    2015-01-01

    Objective:To study the significance of evaluating hemoglobin and iron reserves in the severe renal anemia patient before and after blood transfusion, to guide clinical treatment.Methods:Simple randomly selected 120 patients in phase 5 of chronic renal failure from the department of nephrology, who are regular dialysis with severe renal anemia, according to the situation of iron reserves before blood transfusion, patients will be divided into its reserves of iron deficiency and iron overload group and normal group, and the three groups were divided into 1 U and 2 U group. Comparing the change of different unit quantity of hemoglobin, serum iron, iron, protein and total iron binding force before and after blood transfusion and variation is compared between groups.Results: Three groups of patients with 1U blood transfusion ,Hemoglobin, serum iron and ferritin, total iron binding force, transferrin saturation are higher before a blood transfusion,The differences were statistically significant; before and after blood transfusion hemoglobin, serum iron and ferritin, total iron binding force, transferrin saturation change in 1 U group normal iron reserves compared with Insufficient iron reserves 1 U group has no statistically significant difference, iron overload 1 U group before and after blood transfusion hemoglobin, serum iron and ferritin, total iron binding force, transferrin saturation change significantly greater than Insufficient iron reserves 1 U group and 1U with normal iron reserves group, the differences were statistically significant; Three groups of patients blood transfusion after 2 U, hemoglobin, serum iron and ferritin, total iron binding force, transferrin saturation were higher before a blood transfusion, differences were statistically significant; iron overload 2 U group before and after blood transfusion hemoglobin, serum iron and ferritin, total iron binding force, transferrin saturation change significantly greater than Insufficient iron reserves 2

  13. Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions

    Directory of Open Access Journals (Sweden)

    Saliba AN

    2015-06-01

    Full Text Available Antoine N Saliba, Afif R Harb, Ali T Taher Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut, Beirut, Lebanon Abstract: Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence. Keywords: thalassemia, transfusion-dependent thalassemia, iron overload, iron chelation therapy, transfusion

  14. Iron metabolism and ineffective erythropoiesis in beta-thalassemia mouse models.

    Science.gov (United States)

    Ramos, Pedro; Melchiori, Luca; Gardenghi, Sara; Van-Roijen, Nico; Grady, Robert W; Ginzburg, Yelena; Rivella, Stefano

    2010-08-01

    beta-thalassemia is a disease associated with decreased beta-globin production leading to anemia, ineffective erythropoiesis, and iron overload. New mechanisms associated with modulation of erythropoiesis and iron metabolism have recently been discovered in thalassemic mice, improving our understanding of the pathophysiology of this disease. These discoveries have the potential to be translated into clinically-relevant therapeutic options to reduce ineffective erythropoiesis and iron overload. A new generation of therapies based on limiting ineffective erythropoiesis, iron absorption, and the correction of iron maldistribution could be on the way, possibly complementing and improving the current standard of patient care.

  15. Iron metabolism and ineffective erythropoiesis in β-thalassemia mouse models

    Science.gov (United States)

    Ramos, Pedro; Melchiori, Luca; Gardenghi, Sara; Van-Roijen, Nico; Grady, Robert W.; Ginzburg, Yelena; Rivella, Stefano

    2013-01-01

    β-thalassemia is a disease associated with decreased β-globin production leading to anemia, ineffective erythropoiesis, and iron overload. New mechanisms associated with modulation of erythropoiesis and iron metabolism have recently been discovered in thalassemic mice, improving our understanding of the pathophysiology of this disease. These discoveries have the potential to be translated into clinically-relevant therapeutic options to reduce ineffective erythropoiesis and iron overload. A new generation of therapies based on limiting ineffective erythropoiesis, iron absorption, and the correction of iron maldistribution could be on the way, possibly complementing and improving the current standard of patient care. PMID:20712768

  16. The role of iron in patients after bone marrow transplantation.

    NARCIS (Netherlands)

    Witte, T.J.M. de

    2008-01-01

    Haemopoietic stem cell transplantation (HSCT) is an important intervention for malignant and non-malignant blood diseases. However, HSCT is also associated with considerable morbidity and mortality, some of which may be related to iron overload. Levels of serum iron are elevated in patients undergoi

  17. 地拉罗司对伴有铁过载的再生障碍性贫血患者的祛铁疗效及安全性--一项单臂、多中心、前瞻性临床研究%Efficacy and safety of deferasirox in aplastic anemia patients with iron overload:a single arm, multi-center, prospective study in China

    Institute of Scientific and Technical Information of China (English)

    施均; 全日成; 郑春梅; 肖海燕; 胡明辉; 胡令彦; 刘锋; 周永明; 郑以州; 张凤奎; 常红; 张莉; 邵英起; 聂能; 张静; 黄金波; 张丽; 唐旭东

    2016-01-01

    Objective To explore the efficacy and safety of deferasirox in aplastic anemia(AA) patients with iron overload. Methods A single arm, multi-center, prospective, open-label study was conducted to evaluate absolute change in serum ferritin(SF)from baseline to 12 months of deferasirox administration, initially at a dose of 20 mg · kg-1 · d-1, and the safety in 64 AA patients with iron overload. Results All patients started their deferasirox treatment with a daily dose of 20 mg · kg-1 · d-1. The mean actual dose was(18.6 ± 3.60)mg · kg-1 · d-1. The median SF decreased from 4 924(2 718-6 765)μg/L at baseline (n=64) to 3 036(1 474-5 551)μg/L at 12 months (n=23) with the percentage change from baseline as 38%. A median SF decrease of 651(126-2 125)μg/L was observed at the end of study in 23 patients who completed 12 months’treatment, the median SF level decreased by 1 167(580-4 806)μg/L[5 271(3 420-8 278)μg/L at baseline;3 036(1 474-5 551)μg/L after 12 months’treatment;the percentage change from baseline as 42%]after 12 months of deferasirox treatment. The most common adverse events (AEs)were increased serum creatinine levels(40.98%), gastrointestinal discomfort(40.98%), elevated liver transaminase(ALT:21.31%;AST:13.11%)and proteinuria(24.59%). The increased serum creatinine levels were reversible and non-progressive. Of 38 patients with concomitant cyclosporine use, 12(31.8%) patients had two consecutive values>ULN, 10(26.3%)patients had two consecutive values>1.33 baseline values, but only 1(2.6%)patient’s serum creatinine increased more than 1.33 baseline values and exceeded ULN. For both AST and ALT, no patients experienced two post-baseline values >5 × ULN or >10 × ULN during the whole study. In AA patients with low baseline PLT count(less than 50 × 109/L), there was no decrease for median PLT level during 12 months’treatment period. Conclusions AA patients with iron overload could achieve satisfactory efficacy of iron chelation by deferasirox

  18. Novel Protective Role of Endogenous Cardiac Myocyte P2X4 Receptors in Heart Failure

    Science.gov (United States)

    Yang, Tiehong; Shen, Jian-bing; Yang, Ronghua; Redden, John; Dodge-Kafka, Kimberly; Grady, James; Jacobson, Kenneth A.; Liang, Bruce T.

    2014-01-01

    Background Heart failure (HF), despite continuing progress, remains a leading cause of mortality and morbidity. P2X4 receptors (P2X4R) have emerged as potentially important molecules in regulating cardiac function and as potential targets for HF therapy. Transgenic P2X4R overexpression can protect against HF, but this does not explain the role of native cardiac P2X4R. Our goal is to define the physiological role of endogenous cardiac myocyte P2X4R under basal conditions and during HF induced by myocardial infarction or pressure overload. Methods and Results Mice established with conditional cardiac-specific P2X4R knockout were subjected to left anterior descending coronary artery ligation–induced postinfarct or transverse aorta constriction–induced pressure overload HF. Knockout cardiac myocytes did not show P2X4R by immunoblotting or by any response to the P2X4R-specific allosteric enhancer ivermectin. Knockout hearts showed normal basal cardiac function but depressed contractile performance in postinfarct and pressure overload models of HF by in vivo echocardiography and ex vivo isolated working heart parameters. P2X4R coimmunoprecipitated and colocalized with nitric oxide synthase 3 (eNOS) in wild-type cardiac myocytes. Mice with cardiac-specific P2X4R overexpression had increased S-nitrosylation, cyclic GMP, NO formation, and were protected from postinfarct and pressure overload HF. Inhibitor of eNOS, L-N5-(1-iminoethyl)ornithine hydrochloride, blocked the salutary effect of cardiac P2X4R overexpression in postinfarct and pressure overload HF as did eNOS knockout. Conclusions This study establishes a new protective role for endogenous cardiac myocyte P2X4R in HF and is the first to demonstrate a physical interaction between the myocyte receptor and eNOS, a mediator of HF protection. PMID:24622244

  19. Cardiac arrest

    Science.gov (United States)

    ... Article.jsp. Accessed June 16, 2014. Myerburg RJ, Castellanos A. Approach to cardiac arrest and life-threatening ... PA: Elsevier Saunders; 2011:chap 63. Myerburg RJ, Castellanos A. Cardiac arrest and audden aardiac death. In: ...

  20. Role of alcohol in the regulation of iron metabolism

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis,an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.

  1. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    NARCIS (Netherlands)

    Benyamin, Beben; Esko, Tonu; Ried, Janina S.; Radhakrishnan, Aparna; Vermeulen, Sita H.; Traglia, Michela; Goegele, Martin; Anderson, Denise; Broer, Linda; Podmore, Clara; Luan, Jian'an; Kutalik, Zoltan; Sanna, Serena; van der Meer, Peter; Tanaka, Toshiko; Wang, Fudi; Westra, Harm-Jan; Franke, Lude; Mihailov, Evelin; Milani, Lili; Haeldin, Jonas; Winkelmann, Juliane; Meitinger, Thomas; Thiery, Joachim; Peters, Annette; Waldenberger, Melanie; Rendon, Augusto; Jolley, Jennifer; Sambrook, Jennifer; Kiemeney, Lambertus A.; Sweep, Fred C.; Sala, Cinzia F.; Schwienbacher, Christine; Pichler, Irene; Hui, Jennie; Demirkan, Ayse; Isaacs, Aaron; Amin, Najaf; Steri, Maristella; Waeber, Gerard; Verweij, Niek; Powell, Joseph E.; Nyholt, Dale R.; Heath, Andrew C.; Madden, Pamela A. F.; Visscher, Peter M.; Wright, Margaret J.; Montgomery, Grant W.; Martin, Nicholas G.; Hernandez, Dena; Bandinelli, Stefania; van der Harst, Pim; Uda, Manuela; Vollenweider, Peter; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.; van Duijn, Cornelia; Beilby, John; Pramstaller, Peter P.; Hicks, Andrew A.; Ouwehand, Willem H.; Oexle, Konrad; Gieger, Christian; Metspalu, Andres; Camaschella, Clara; Toniolo, Daniela; Swinkels, Dorine W.; Whitfield, John B.

    2014-01-01

    Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find

  2. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    NARCIS (Netherlands)

    B. Benyamin (Beben); T. Esko (Tõnu); J.S. Ried (Janina); A. Radhakrishnan (Aparna); S.H.H.M. Vermeulen (Sita); M. Traglia (Michela); M. Gögele (Martin); D. Anderson (David); L. Broer (Linda); C. Podmore (Clara); J. Luan; Z. Kutalik (Zoltán); S. Sanna (Serena); P. van der Meer (Peter); T. Tanaka (Toshiko); F. Wang (Fudi); H.J. Westra (Harm-Jan); L. Franke (Lude); E. Mihailov (Evelin); L. Milani (Lili); J. Häldin (Jonas); B. Winkelmann; T. Meitinger (Thomas); J. Thiery (Joachim); A. Peters (Annette); M. Waldenberger (Melanie); A. Rendon (Augusto); G.J. Jolley (Jason); J.G. Sambrook (Jennifer); L.A.L.M. Kiemeney (Bart); F.C. Sweep (Fred); C. Sala (Cinzia); C. Schwienbacher (Christine); I. Pichler (Irene); J. Hui (Jennie); A. Demirkan (Ayşe); A. Isaacs (Aaron); N. Amin (Najaf); M. Steri (Maristella); G. Waeber (Gérard); N. Verweij (Niek); J.E. Powell (Joseph); A.S. Dimas (Antigone); A.C. Heath (Andrew); P.A. Madden (Pamela); P.M. Visscher (Peter); M.J. Wright (Margaret); G.W. Montgomery (Grant); N.G. Martin (Nicholas); D.G. Hernandez (Dena); S. Bandinelli (Stefania); P. van der Harst (Pim); M. Uda (Manuela); P. Vollenweider (Peter); R.A. Scott (Robert); C. Langenberg (Claudia); N.J. Wareham (Nick); C.M. van Duijn (Cock); J. Beilby (John); P.P. Pramstaller (Peter Paul); A.A. Hicks (Andrew); W.H. Ouwehand (Willem); K. Oexle (Konrad); C. Gieger (Christian); A. Metspalu (Andres); C. Camaschella (Clara); D. Toniolo (Daniela); D.W. Swinkels (Dorine); J. Whitfield (John)

    2014-01-01

    textabstractVariation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subject

  3. Nutritional Status and Cardiac Autophagy

    Directory of Open Access Journals (Sweden)

    Jihyun Ahn

    2013-02-01

    Full Text Available Autophagy is necessary for the degradation of long-lasting proteins and nonfunctional organelles, and is activated to promote cellular survival. However, overactivation of autophagy may deplete essential molecules and organelles responsible for cellular survival. Lifelong calorie restriction by 40% has been shown to increase the cardiac expression of autophagic markers, which suggests that it may have a cardioprotective effect by decreasing oxidative damage brought on by aging and cardiovascular diseases. Although cardiac autophagy is critical to regulating protein quality and maintaining cellular function and survival, increased or excessive autophagy may have deleterious effects on the heart under some circumstances, including pressure overload-induced heart failure. The importance of autophagy has been shown in nutrient supply and preservation of energy in times of limitation, such as ischemia. Some studies have suggested that a transition from obesity to metabolic syndrome may involve progressive changes in myocardial inflammation, mitochondrial dysfunction, fibrosis, apoptosis, and myocardial autophagy.

  4. 地拉罗司治疗2~6岁重型β-地中海贫血铁过载一年安全性观察%Therapy iron overload with deferasiroX in 2 ~ 6 years old patients with β - thalassemia major:observe the safety in a year

    Institute of Scientific and Technical Information of China (English)

    杨潍嘉; 黄开明; 申琰军; 匡小风

    2014-01-01

    Objective To assess the safety of deferasirox used in 2 to < 6 years old patients with β - thalassemia major in a year. Meth-ods The single group,open - label study design were used. 26 cases of patients took deferasirox,and monthly followed up the presence of gastro-intestinal reaction(nausea,vomiting,etc. ),detected serum ferritin(SF),alanine aminotransferase(ALT),alanine aminotransferase(AST) and alkaline phosphatase(ALP),serum creatinine(SCr). Before the patients entering the group,the qualitative results of urine protein were de-tected,12 lead electrocardiogram(ECG)was performed. According to the left wrist X - ray results to calculate bone age,detect distant vision. Transient evoked otoacoustic emission(TEOAE)was used to check the hearing. Results When finished 1 year of observation,we found no urine protein is positive,increase in creatinine,visual impairment. Deferasirox has no effect on bone age. Gastrointestinal tract reaction is mild,nausea in 2 cases(7. 7% ),4 cases were abdominal pain(15. 4% ). Many cases have a transient increase of ALT and AST,increased more than five times of the ULN found in 3 patients(11. 5% ). Transient hearing impaired in 4 cases(15. 4% ). And 1 case was diagnosed as ear cochlear dam-age. Conclusion Therapy iron overload with deferasirox can be used for 2 ~ 6 years old patients with β - thalassemia major. The total clinical safety is good,gastrointestinal reaction is slight,liver transaminase transient increase was observed in most cases. ALT and AST increased more than 5 times. After a short time of discontinue medication,the abnormality will not continue to rise when take the medication again,and no effect on kidney and bone age,which should be paid close attention to the influence to hearing. These indexes should be checked every 3 months.%目的:对一组年龄在2~6岁的重型β-地中海贫血患者应用地拉罗司治疗铁过载1年的安全性进行评估。方法采用单组、开放性实验设计,对26例受

  5. Effects of 17-methoxyl-7-hydroxy-benzfuranchalcon on Intracellular Calcium Overload in Cultured Cardiac Myocytes of Neonatal Rats Injured by H2O2 and L-type Calcium Current in Isolated Ventricular Myocytes of Mice%17-甲氧基-7-羟基-苯并呋喃查尔酮对心肌细胞内游离钙浓度及L-型钙电流的影响

    Institute of Scientific and Technical Information of China (English)

    李映新; 黄媛恒; 覃斐章; 林兴; 黄仁彬

    2013-01-01

    Objective:To investigate the effects of 17-methoxyl-7-hydroxy-benzfuranchalcon (YLSC) on intracellular calcium overload in cultured cardiac myocytes of neonatal rats injured by H2O2 and L-type calcium current (ICa-L) in isolated ventricular myocytes.Method:The cells of primary cultured cardiac myocytes of neonatal rats were divided into groups:①control group; ② model group:administrated with 0.3 mmol · L-1 H2O2; ③YLSC treated groups:incubation respectively with 100,200,400 μmol ·L-1 YLSC for 24 h,and add 0.3 mmol · L-1 H2O2.Laser confocal microscopy was used with Fluo-3/Am as indicator to detect changes of [Ca2+]i immediately and 15 mintues after H2O2 intervention.Single ventricular cell was obtained enzymatically by Langendorff perfusion apparatus.The wholecell patch clamp was used to record the ICa-L.Result:①The average fluorescence intensity values of the model group treated by H2O2 higher significantly than control group and the fluorescence enhancement ratio was 60.43 % ± 7.75%.The YLSC could decline the intensity values in a does-dependent manner manner,the fluorescence enhancement ratios of low,middle and high does respectively were 38.39% ±13.87%,14.49% ±2.94%,-28.1% ± 1.52%,and all of them were much lower compared with H2O2 group (P < 0.01).②YLSC can up-shifted the current-voltage (Ⅰ-Ⅴ) curves and markedly shifted the steady state activation and inactivation curve of ICa-L to the left.Conclusion:YLSC inhibited the L-type calcium channel,it can significantly reduce the myocardial intracellular Ca2+ overload induced by H2O2.%目的:研究17-甲氧基-7-羟基-苯并呋喃查尔酮(YLSC)对H2O2诱导的心肌细胞内钙超载的拮抗作用及对L型钙电流(ICa-L)的影响.方法:采用SD大鼠乳鼠进行心肌细胞培养,实验分为①正常对照组;②H2O2组:上机前加入终浓度为0.3 mmol·L-1的H2O2;③预先给予低、中、高不同终浓度YLSC药物处理组:分别给予100,200,400 μmol·L-1YLSC

  6. The Role of Iron in the Skin & Cutaneous Wound Healing

    Directory of Open Access Journals (Sweden)

    Josephine Anne Wright

    2014-07-01

    Full Text Available In this review article we discuss current knowledge about iron in the skin and the cutaneous wound healing process. Iron plays a key role in both oxidative stress and photo-induced skin damage. The main causes of oxidative stress in the skin include reactive oxygen species (ROS generated in the skin by ultraviolet (UVA 320-400 nm portion of the ultraviolet spectrum and biologically available iron. We also discuss the relationships between iron deficiency, anaemia and cutaneous wound healing. Studies looking at this fall into two distinct groups. Early studies investigated the effect of anaemia on wound healing using a variety of experimental methodology to establish anaemia or iron deficiency and focused on wound-strength rather than effect on macroscopic healing or re-epithelialisation. More recent animal studies have investigated novel treatments aimed at correcting the effects of systemic iron deficiency and localised iron overload. Iron overload is associated with local cutaneous iron deposition, which has numerous deleterious effects in chronic venous disease and hereditary haemochromatosis. Iron plays a key role in chronic ulceration and conditions such as Rheumatoid Arthritis (RA and Lupus Erythematosus are associated with both anaemia of chronic disease and dysregulation of local cutaneous iron haemostasis. Iron is a potential therapeutic target in the skin by application of topical iron chelators and novel pharmacological agents, and in delayed cutaneous wound healing by treatment of iron deficiency or underlying systemic inflammation.

  7. Cardiac failure in β-thalassemia: diagnosis, prevention and management

    Directory of Open Access Journals (Sweden)

    A. Aessopos

    2011-12-01

    Full Text Available Heart failure always represented and still remains the leading cause of mortality in β (β-thalassemia, despite the therapeutic advances and the considerable amelioration of prognosis accomplished over the last decades. High cardiac output due to chronic anemia and myocardial iron overload due to repetitive blood transfusions are the two main pathogenetic mechanisms causing heart failure in β-thalassemia. In regularly treated thalassemia major patients, left ventricular dysfunction, resulting mainly from myocardial siderosis, is considered to be the primary cause of heart failure and thus the prevention, early recognition and effective management of iron overload is of key importance. However, the spectrum of cardiovascular complications that may ultimately lead to heart is wide and should be individually investigated in each one of the patients. Echocardiography is the main modality used for the regular follow-up and screening of asymptomatic patients and for the evaluation of patients with cardiac symptoms, while the T2* relaxation time provided by magnetic resonance imaging allows the accurate identification and quantification of myocardial iron burden and thus the proper guidance of iron chelation therapy. 近几十年来,尽管治疗方法取得进步和预断方法得到显著改进,但是心脏衰竭仍是引起β地中海贫血症患者死亡的主要原因。 慢性贫血导致的高心输出量和反复输血导致的心脏铁过载,是导致β地中海贫血患者心脏衰竭的两大发病机制。 在常规治疗的重型地中海贫血患者中,心脏铁质沉着病引起的可逆性左心室功能障碍,被认为是心脏衰竭的主要原因。因此,预防、早期确诊和有效控制铁过载至关重要。 然而,最终导致心脏衰竭的心血管并发症的症状繁多,应对每个患者单独进行检查。 超声心动图仪是用于无症状患者定期随访、筛查和诊断有心脏病症状患

  8. Dietary Fat Overload Reprograms Brown Fat Mitochondria

    Directory of Open Access Journals (Sweden)

    DANIELE eLETTIERI BARBATO

    2015-09-01

    Full Text Available Chronic nutrient overload accelerates the onset of several aging-related diseases reducing life expectancy. Although the mechanisms by which overnutrition affects metabolic processes in many tissues are known, its role on BAT physiology is still unclear. Herein, we investigated the mitochondrial responses in BAT of female mice exposed to high fat diet (HFD at different steps of life. Although adult mice showed an unchanged mitochondrial amount, both respiration and OxPHOS subunits were strongly affected. Differently, offspring pups exposed to HFD during pregnancy and lactation displayed reduced mitochondrial mass but high oxidative efficiency that, however, resulted in increased bioenergetics state of BAT rather than augmented uncoupling respiration. Interestingly, the metabolic responses triggered by HFD were accompanied by changes in mitochondrial dynamics characterized by decreased content of the fragmentation marker Drp1 both in mothers and offspring pups. HFD-induced inactivation of the FoxO1 transcription factor seemed to be the up-stream modulator of Drp1 levels in brown fat cells. Furthermore, HFD offspring pups weaned with normal diet only partially reverted the mitochondrial dysfunctions caused by HFD. Finally these mice failed in activating the thermogenic program upon cold exposure. Collectively our findings suggest that maternal dietary fat overload irreversibly commits BAT unresponsiveness to physiological stimuli such as cool temperature and this dysfunction in the early stage of life might negatively modulates health and lifespan.

  9. [Chronic nicotinamide overload and type 2 diabetes].

    Science.gov (United States)

    Zhou, Shi-Sheng; Li, Da; Zhou, Yi-Ming; Sun, Wu-Ping; Liu, Xing-Xing; Lun, Yong-Zhi

    2010-02-25

    Type 2 diabetes is a major global health problem. It is generally accepted that type 2 diabetes is the result of gene-environmental interaction. However, the mechanism underlying the interaction is unclear. Diet change is known to play an important role in type 2 diabetes. The fact that the global high prevalence of type 2 diabetes has occurred following the spread of food fortification worldwide suggests a possible involvement of excess niacin intake. Our recent study found that nicotinamide overload and low nicotinamide detoxification may induce oxidative stress associated with insulin resistance. Based on the relevant facts, this review briefly summarized the relationship between the prevalence of type 2 diabetes and the nicotinamide metabolism changes induced by excess niacin intake, aldehyde oxidase inhibitors, liver diseases and functional defects of skin. We speculate that the gene-environmental interaction in type 2 diabetes may be a reflection of the outcome of the association of chronic nicotinamide overload-induced toxicity and the relatively low detoxification/excretion capacity of the body. Reducing the content of niacin in foods may be a promising strategy for the control of type 2 diabetes.

  10. Urinary iron excretion induced by intravenous infusion of deferoxamine in ß-thalassemia homozygous patients

    Directory of Open Access Journals (Sweden)

    Boturão-Neto E.

    2002-01-01

    Full Text Available The purpose of the present study was to identify noninvasive methods to evaluate the severity of iron overload in transfusion-dependent ß-thalassemia and the efficiency of intensive intravenous therapy as an additional tool for the treatment of iron-overloaded patients. Iron overload was evaluated for 26 ß-thalassemia homozygous patients, and 14 of them were submitted to intensive chelation therapy with high doses of intravenous deferoxamine (DF. Patients were classified into six groups of increasing clinical severity and were divided into compliant and non-compliant patients depending on their adherence to chronic chelation treatment. Several methods were used as indicators of iron overload. Total gain of transfusion iron, plasma ferritin, and urinary iron excretion in response to 20 to 60 mg/day subcutaneous DF for 8 to 12 h daily are useful to identify iron overload; however, urinary iron excretion in response to 9 g intravenous DF over 24 h and the increase of urinary iron excretion induced by high doses of the chelator are more reliable to identify different degrees of iron overload because of their correlation with the clinical grades of secondary hemochromatosis and the significant differences observed between the groups of compliant and non-compliant patients. Finally, the use of 3-9 g intravenous DF for 6-12 days led to a urinary iron excretion corresponding to 4.1 to 22.4% of the annual transfusion iron gain. Therefore, continuous intravenous DF at high doses may be an additional treatment for these patients, as a complement to the regular subcutaneous infusion at home, but requires individual planning and close monitoring of adverse reactions.

  11. The 'iron salute' in haemochromatosis.

    Science.gov (United States)

    Romas, Evange

    2009-03-01

    The presentation of haemochromatosis is typified by abdominal pain, arthralgia and fatigue or weakness. Arthropathy may be the major presenting feature. The detection of an osteoarthritis-like process involving the metacarpophalangeal (MCP) and wrist joints in middle aged men should signal the possibility of under lying haemochromatosis. Other joints such as the shoulder, hip,knee or ankle may be affected. However, the preferential involvement of the second and third MCP joints is striking and may provide the opportunity for early identification of iron overload disease. The "iron salut" can be an efficient screening tool for this MCP joint arthropathy but it is not well known by clinicians.

  12. Cardiomyocyte Overexpression of FABP4 Aggravates Pressure Overload-Induced Heart Hypertrophy.

    Directory of Open Access Journals (Sweden)

    Ji Zhang

    Full Text Available Fatty acid binding protein 4 (FABP4 is a member of the intracellular lipid-binding protein family, responsible for the transportation of fatty acids. It is considered to express mainly in adipose tissues, and be strongly associated with inflammation, obesity, diabetes and cardiovasculardiseases. Here we report that FABP4 is also expressed in cardiomyocytes and plays an important role in regulating heart function under pressure overload. We generated heart-specific transgenic FABP4 (FABP4-TG mice using α myosin-heavy chain (α-MHC promoter and human FABP4 sequence, resulting in over-expression of FABP4 in cardiomyocytes. The FABP4-TG mice displayed normal cardiac morphology and contractile function. When they were subjected to the transverse aorta constriction (TAC procedure, the FABP4-TG mice developed more cardiac hypertrophy correlated with significantly increased ERK phosphorylation, compared with wild type controls. FABP4 over-expression in cardiomyocytes activated phosphor-ERK signal and up-regulate the expression of cardiac hypertrophic marker genes. Conversely, FABP4 induced phosphor-ERK signal and hypertrophic gene expressions can be markedly inhibited by an ERK inhibitor PD098059 as well as the FABP4 inhibitor BMS309403. These results suggest that FABP4 over-expression in cardiomyocytes can aggravate the development of cardiac hypertrophy through the activation of ERK signal pathway.

  13. Retinal iron homeostasis in health and disease

    Directory of Open Access Journals (Sweden)

    Delu eSong

    2013-06-01

    Full Text Available Iron is essential for life, but excess iron can be toxic. As a potent free radical creator, iron generates hydroxyl radicals leading to significant oxidative stress. Since iron is not excreted from the body, it accumulates with age in tissues, including the retina, predisposing to age-related oxidative insult. Both hereditary and acquired retinal diseases are associated with increased iron levels. For example, retinal degenerations have been found in hereditary iron overload disorders, like aceruloplasminemia, Friedreich’s ataxia, and pantothenate kinase-associated neurodegeneration. Similarly, mice with targeted mutation of the iron exporter ceruloplasmin and its homolog hephaestin showed age-related retinal iron accumulation and retinal degeneration with features resembling human age-related macular degeneration (AMD. Post mortem AMD eyes have increased levels of iron in retina compared to age-matched healthy donors. Iron accumulation in AMD is likely to result, in part, from inflammation, hypoxia, and oxidative stress, all of which can cause iron dysregulation. Fortunately, it has been demonstrated by in vitro and in vivo studies that iron in the retinal pigment epithelium and retina is chelatable. Iron chelation protects photoreceptors and retinal pigment epithelial cells (RPE in a variety of mouse models. This has therapeutic potential for diminishing iron-induced oxidative damage to prevent or treat AMD.

  14. POST-OPERATIVE VENTRICULAR TACHYCARDIA LEADING TO CARDIAC ARREST IN AN ASAG- I PATIENT OF CHOLECYSTECTOMY: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Pradip

    2014-03-01

    Full Text Available We here present our experience with ventricular tachycardia (VT leading to cardiac arrest in a patient with American Society of Anesthesiologists grade-I (ASA-I 11 hours after cholecystectomy. Excessive fluid overload and hypoxemia due to lung congestion may lead to cardiac arrest in this case. Immediate diagnosis and appropriate intervention saved the life of the patient.

  15. Cardiac Sarcoidosis.

    Science.gov (United States)

    Birnie, David; Ha, Andrew C T; Gula, Lorne J; Chakrabarti, Santabhanu; Beanlands, Rob S B; Nery, Pablo

    2015-12-01

    Studies suggest clinically manifest cardiac involvement occurs in 5% of patients with pulmonary/systemic sarcoidosis. The principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. Data indicate that an 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic (clinically silent) cardiac involvement. An international guideline for the diagnosis and management of CS recommends that patients be screened for cardiac involvement. Most studies suggest a benign prognosis for patients with clinically silent CS. Immunosuppression therapy is advocated for clinically manifest CS. Device therapy, with implantable cardioverter defibrillators, is recommended for some patients.

  16. Identification of genes regulated during mechanical load-induced cardiac hypertrophy

    Science.gov (United States)

    Johnatty, S. E.; Dyck, J. R.; Michael, L. H.; Olson, E. N.; Abdellatif, M.; Schneider, M. (Principal Investigator)

    2000-01-01

    Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth. Copyright 2000 Academic Press.

  17. Self-* overload control for distributed web systems

    CERN Document Server

    Bartolini, Novella; Silvestri, Simone

    2008-01-01

    Unexpected increases in demand and most of all flash crowds are considered the bane of every web application as they may cause intolerable delays or even service unavailability. Proper quality of service policies must guarantee rapid reactivity and responsiveness even in such critical situations. Previous solutions fail to meet common performance requirements when the system has to face sudden and unpredictable surges of traffic. Indeed they often rely on a proper setting of key parameters which requires laborious manual tuning, preventing a fast adaptation of the control policies. We contribute an original Self-* Overload Control (SOC) policy. This allows the system to self-configure a dynamic constraint on the rate of admitted sessions in order to respect service level agreements and maximize the resource utilization at the same time. Our policy does not require any prior information on the incoming traffic or manual configuration of key parameters. We ran extensive simulations under a wide range of operati...

  18. Avoiding Program-Induced Cumulative Overload (PICO).

    Science.gov (United States)

    Orr, Robin; Knapik, Joseph J; Pope, Rodney

    2016-01-01

    This article defines the concept of program-induced cumulative overload (PICO), provides examples, and advises ways to mitigate the adverse effects. PICO is the excessive cumulative physical workload that can be imparted to military personnel by a military training program with an embedded physical training component. PICO can be acute (accumulating within a single day) or chronic (accumulating across the entirety of the program) and results in adverse outcomes for affected personnel, including detrimental fatigue, performance degradation, injuries, or illness. Strategies to mitigate PICO include focusing administration and logistic practices during the development and ongoing management of a trainee program and implementing known musculoskeletal injury prevention strategies. More training is not always better, and trainers need to consider the total amount of physical activity that military personnel experience across both operational training and physical training if PICO is to be mitigated.

  19. Evaluation of thermal overload in boiler operators.

    Science.gov (United States)

    Braga, Camila Soares; Rodrigues, Valéria Antônia Justino; Campos, Julio César Costa; de Souza, Amaury Paulo; Minette, Luciano José; de Moraes, Angêlo Casali; Sensato, Guilherme Luciano

    2012-01-01

    The Brazilians educational institutions need a large energy demand for the operation of laundries, restaurants and accommodation of students. Much of that energy comes from steam generated in boilers with wood fuel. The laboral activity in boiler may present problems for the operator's health due to exposure to excessive heat, and its operation has a high degree of risk. This paper describes an analysis made the conditions of thermal environment in the operation of a B category boiler, located at a Higher Education Institution, located in the Zona da Mata Mineira The equipments used to collect data were Meter WBGT of the Heat Index; Meter of Wet Bulb Index and Globe Thermometer (WBGT); Politeste Instruments, an anemometer and an Infrared Thermometer. By the application of questionnaires, the second phase consisted of collecting data on environmental factors (temperature natural environment, globe temperature, relative humidity and air velocity). The study concluded that during the period evaluated, the activity had thermal overload.

  20. Bioimpedance can solve problems of fluid overload.

    Science.gov (United States)

    Abbas, Samer R; Zhu, Fansan; Levin, Nathan W

    2015-03-01

    Bioimpedance (BI) techniques for measuring normal hydration status (NHS) can be generally classified as (1) by frequency as single frequency at 50 kHz, BI analysis, and multifrequency BI spectroscopy and (2) by method as whole body (wrist to ankle) measurement and calf BI spectroscopy. The aim of this article was to review current BI methods for clinical practice in patients with end-stage of kidney disease. BI vector analysis using whole-body single-frequency BI at 50 kHz may be useful for population studies to indicate a range of degree of fluid loading and of nutritional status. Whole body multifrequency BI spectroscopy is used to estimate extracellular (ECV), intracellular fluid volume, and total body water in dialysis patients. The whole-body BI model is used in the body composition monitor (BCM). The whole-body BI model is established with ECV, intracellular fluid volume, and body weight based on parameters from regression analysis in healthy subjects to calculate fluid overload in dialysis patients. Calf BI methods have been developed to measure NHS by 2 ways: (1) continuous measurement of the intradialytic resistance curve until flattening occurs; (2) calf normalized resistivity in the range of healthy subjects (18.5 × 10(-2) Ω m(3)/kg in male and 19.1 × 10(-2) Ω m(3)/kg in female). In general, for population studies, BI vector analysis or ECV/total body water may be useful; BCM is a commercially available device that can certainly guide volume reduction safely over time. For more exact measure of fluid overload, calf BI methods appear to be most accurate, but these are at present research tools. BI techniques are not only useful in assessing NHS but also in the study of nutrition and body composition.

  1. Plasma protein haptoglobin modulates renal iron loading

    DEFF Research Database (Denmark)

    Fagoonee, Sharmila; Gburek, Jakub; Hirsch, Emilio

    2005-01-01

    Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. The strength of hemoglobin binding and the existence of a specific receptor for the haptoglobin-hemoglobin complex in the monocyte/macrophage system clearly suggest that haptoglobin may have a crucial role in heme...... distribution of hemoglobin in haptoglobin-deficient mice resulted in abnormal iron deposits in proximal tubules during aging. Moreover, iron also accumulated in proximal tubules after renal ischemia-reperfusion injury or after an acute plasma heme-protein overload caused by muscle injury, without affecting...... morphological and functional parameters of renal damage. These data demonstrate that haptoglobin crucially prevents glomerular filtration of hemoglobin and, consequently, renal iron loading during aging and following acute plasma heme-protein overload....

  2. Targeting at SUR2B/Kir6.1 subtype of ATP-sensitive potassium channel opener natakalim improves pressure overload-induced heart failure

    Institute of Scientific and Technical Information of China (English)

    TANG Yuan; LONG Chao-liang; WANG Hai

    2008-01-01

    Objective To explore the new stratigies targeting at SUR2B/Kir6.1 subtype against pressure overload-induced heart failure. Methods Pressure overload-induced heart failure was induced in Wistar rat by abdominal aortic banding (AAB) .The effects of natakalim (1,3, 9 mg·kg-1·d-1, 10 weeks) were assessed on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression. Isolated working heart and isolated tail artery helical strips were used to examine the influence of natakalim on heart and resistant vessels. Results Ten weeks after the onset of pressure overload, natakalim therapy potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim inhibited the changes of left ventricular haemodynamic parameters, reversed the increase of heart mass index, left ventricular weight index and lung weight index remarkably. Histological examination demonstrated that there were no significant hypertrophy and fibrosis in hearts of pressure overload rat treated with natakalim. Ultrastructural examination of heart revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in natakalim group rats. The content of serum NO and plasma PGI2 was increased, while that of plasma ET-1 and cardiac tissue hydroxyproline, ANP and BNP mRNA was down-regulated in natakalim-treated rats. Natakalim at concentrations ranging from 0.01-100 μM had no effects on isolated working heart derived from Wistar rats; however, natakalim had endothelium-dependent vasodilation effects on the isolated tail artery helical strips precontracted with NE. Conclusions These results indicate that natakalim improves heart failure due to pressure overload by activating KATP channel SUR2B/Kir6.1 subtype and reversing endothelial dysfunction.

  3. Ferritin and iron studies in anaemia and chronic disease.

    Science.gov (United States)

    Peng, Ying Y; Uprichard, James

    2017-01-01

    Anaemia is a condition in which the number of red cells necessary to meet the body's physiological requirements is insufficient. Iron deficiency anaemia and the anaemia of chronic disease are the two most common causes of anaemia worldwide;(1) iron homeostasis plays a pivotal role in the pathogenesis of both diseases. An understanding of how iron studies can be used to distinguish between these diseases is therefore essential not only for diagnosis but also in guiding management. This review will primarily focus on iron deficiency anaemia and anaemia of chronic disease; however, iron overload in anaemia will also be briefly discussed.

  4. Effects of iron salts and haemosiderin from a thalassaemia patient on oxygen radical damage as measured in the comet assay

    NARCIS (Netherlands)

    Anderson, D.; Yardley-Jones, A.; Hambly, R.J.; Vives-Bauza, C.; Smykatz-Kloss, V.; Chua-anusorn, W.; Webb, J.

    2000-01-01

    Thalassaemia is a group of genetic diseases where haemoglobin synthesis is impaired. This chronic anaemia leads to increased dietary iron absorption, which develops into iron overload pathology. Treatment through regular transfusions increases oxygen capacity but also provides iron through the red c

  5. Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers.

    Science.gov (United States)

    Roy, C N; Andrews, N C

    2001-10-01

    The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. Identification of HFE, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as TFR2, that are important in non-HFE-associated iron overload. There are clearly several other, unidentified, iron overload disease genes yet to be found. In parallel, our understanding of iron transport has expanded through identification of Fpn1/Ireg1/MTP1, Sfxn1 and DCYTB: Ongoing studies of Friedreich's ataxia, sideroblastic anemia, aceruloplasminemia and neurodegeneration with brain-iron accumulation are clarifying the role for iron in the nervous system. Finally, as the number of known iron metabolic genes increases and their respective functions are ascertained, new opportunities have arisen to identify genetic modifiers of iron homeostasis.