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1
Chua-anusorn, Wanida. "Iron oxide deposits in iron overload diseases." Thesis, Chua-anusorn, Wanida (1997) Iron oxide deposits in iron overload diseases. PhD thesis, Murdoch University, 1997. https://researchrepository.murdoch.edu.au/id/eprint/52151/.
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Iron overload diseases such as thalassaemia are a major public health problem in many parts of the world. Excess iron deposited in such tissues occurs in the form of ultrafine particles of iron oxyhydroxide. At low levels of iron loading, the iron(III) oxyhydroxide particles are mostly found in the iron storage protein, ferritin. At higher levels of loading, iron(III) oxyhydroxide particles are found in insoluble aggregates known as haemosiderin. Three different structures of these iron deposits are known: (i) ferrihydrite (5Fe203.9H20), (ii) poorly crystalline goethite (α-FeOOH), and (iii) non-crystalline hydrated iron(III) oxyhydroxide.
In this thesis, Mössbauer spectroscopy has been used to study the form of iron oxyhydroxide present in the tissues of thalassaemic patients who had undergone regular blood transfusion and chelation therapy as well as those receiving little, if any, such treatment. The data show a higher fraction of non-haem iron occurs as the goethite-like form in patients undergoing regular transfusion and chelation treatment. The poorly crystalline goethite form was not found in normal human tissues.
To define further some of the factors involved in the deposition of these different iron oxides, an iron-loaded rat system was established. Two routes of administration were chosen. The first involved regular administration of red blood cells injected intraperitoneally for up to one year. The second involved the oral administration of carbonyl-iron as a dietary supplement for nearly two years. Mössbauer spectra of livers and spleens at 78 K consisted of a relatively intense central doublet with spectral parameters indicative of paramagnetic or superparamagnetic high-spin iron(III). Many spectra obtained from parenterally iron-loaded spleens and dietary iron-loaded livers also showed a clear sextet at 78 K, which is indicative of the presence of the goethite-like form of iron oxyhydroxide. The relative intensity of this sextet spectral component in the livers from the dietary iron-loaded rats increased significantly with the age of rats. In order to distinguish iron present in the parenchymal versus non-parenchymal cells in the livers, an indirect quantitative assessment of the iron concentration was performed from liver histological sections using computer-assisted morphometric analysis. The goethite-like form increased significantly as the fraction of iron in non-parenchymal cells increased (r = 0.71, p < 0.005), suggesting that its formation may be associated with the nonparenchymal cells.
The ultrastructure of the iron oxide deposits and associated organic components was studied using a combination of scanning probe microscopy and transmission electron microscopy. Liver samples with ferrihydrite or goethite-like haemosiderin were studied as well as aggregated ferritin in the form of ferritin crystals, ferrihydrite-like form of haemosiderin shows topographies of iron aggregation similar to In contrast, liver with goethite-like form of Liver tissue with the that found in the ferritin crystals, haemosiderin showed a different topography.
Haemosiderin was isolated from a selection of tissues. Crude haemosiderin from patients who had undergone regular blood transfusion and chelation therapy showed a high fraction of goethite-like form of iron oxyhydroxide with a wide range of particle size. Infrared spectroscopy indicated that the iron oxyhydroxide in haemosiderins is associated with organic components. The availability of the different forms of iron oxyhydroxide present in different haemosiderins was assessed using the iron chelator desferrioxamine. The percentage of iron released showed a negative correlation (r = 0.82, p < 0.001) with the percentage of goethite-like iron oxyhydroxide present in these haemosiderins.
In summary, these studies indicate that the chemical forms of iron oxyhydroxide deposits are related to their deposition, toxicity and relative ease of removal. The study has implications for the clinical management of different groups of thalassaemic patients.
2
Baptista-Hon, Daniel Tomas. "Cellular substrates of iron overload cardiomyopathies." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/15878.
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Cardiomyopathies and arrhythmias are major causes of death in untreated hereditary haemochromatosis, acute iron poisoning and during secondary iron overload resulting from repeated blood transfusions in β-thalassaemia. Iron overload cardiomyopathies are associated with systolic and diastolic dysfunction, suggesting that Ca2+ homeostasis is impaired. However, the cellular mechanisms of these dysfunctions are unknown. The data presented in this thesis establishes for the first time iron effects on cardiomyocyte Ca2+ handling, as well as the potential cellular substrates responsible for this impairment during iron overload. Exposure of isolated rat ventricular cardiomyocytes to 200μM iron led to biphasic changes in systolic Ca2+ release. Phase 1: an initial reduction of systolic Ca2+ release followed by; Phase 2: increased Ca2+ release with arrhythmogenic spontaneous Ca2+ release, cell contracture and cell death. There is evidence that Fe2+ enters cardiomyocytes via L-type Ca2+ channels (LTCC) and reduces the Ca2+ trigger. The close apposition of LTCCs to cardiac ryanodine receptors (RyR2) suggests RyR2 may be a first target. Indeed RyR2 activity was drastically reduced on exposure to nanomolar [Fe2+] in single channel studies. Together with evidence that Fe2+ may reduce the Ca2+ trigger from LTCC, this is consistent with iron reducing sarcoplasmic reticulum (SR) Ca2+ release during Phase 1. In Phase 2, the presence of spontaneous Ca2+ release events is consistent with SR Ca2+ overload. Indeed, in single rat ventricular cardiomyocytes SR Ca2+ content was found to be increased by 27% during Phase 2. The cellular substrates responsible for this increased SR Ca2+ content were 2-fold: 1) through reduced extrusion via both the Na+ Ca2+ Exchanger (NCX) and Plasmalemmal Ca2+ ATPase (PMCA) and 2) through increased resequestration via the SR Ca2+ ATPase. Iron catalyses the production of reactive oxygen species (ROS) during the Fenton reaction. To investigate whether iron effects might be due to ROS, I used the cell permeant ROS scavenger Tempol. Tempol attenuated Phase 2 effects but Phase 1 effects were not affected. This is consistent with the hypothesis that Phase 1 effects were due to direct effects of Fe2+ affecting LTCC trigger and RyR2 function. The attenuation of Phase 2 effects suggests that ROS damage to key Ca2+ handling mechanisms, such as NCX and PMCA might account for a reduced Ca2+ extrusion and subsequent SR Ca2+ overload.
3
Sarmento, Carlos V. 1980. "Assessment of new iron chelating agents for treatment of iron-overload." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116063.
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Patients with acquired iron overload require chelation therapy using either Desferal or Exjade. Iron in excess may promote free radical formation in the Fenton reaction resulting in severe injuries of heart, liver and endocrine organs. Che1ators that bind ferric iron (Fe+3) in a 1:1 complex (Desferal) sequester it more efficiently than those che1ators that form 2:1 (Exjade) complexes. We initiated synthesis of new chelators derived from the tridentate chelator pyridoxal isonicotinoyl hydrazone (PIH) and its analogs. The aim of the synthesis was to generate chelators that bind iron in a 1:1 complex, which was confirmed for 8LK02, 10LK02, 11LK02 and 15LK03 by spectrophotometry. All novel chelators mobilized iron more efficiently compared to Desferal and Exjade from murine reticulocytes and human myeloid leukemia cells (K562). Additionally, aforementioned four chelators were also more efficient than PIH and were found to be less or equally toxic as Desferal and Exjade.
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Ward, Roberta J. "Tissue damage in iron overload and alcohol toxicity." Thesis, King's College London (University of London), 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304198.
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Mouralian, Cindy. "Evaluation of novel iron chelators for therapeutic use in secondary iron overload disorders." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33071.
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Pyridoxal isonicotinoyl hydrazone (PIH) has been described as an orally effective Fe chelator. It is both membrane permeable and plasma soluble, and has a high affinity for Fe, making it an ideal model on which to base future chelators. Ten novel ligands have been synthesized based on these attributes. Characterization experiments were performed to determine the ligands' selectivity and binding affinity for iron, their lipophilicity as both free and Fe-ligand complexes, and their stoichiometric relationship with iron. Efficacy of the chelators has been determined through their ability to effectively mobilize non-heme 59Fe from pre-labeled cells. Intracellular levels of chelator bound 59Fe were also determined. Concentration-dependence and time-dependence mobilization experiments were performed to determine the minimal concentrations of ligands required to elicit maximal 59Fe release. Toxicity experiments with various ligand concentrations were performed in order to determine the concentration which inhibits at least half of cellular growth as compared with control. (Abstract shortened by UMI.)
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Baffour, Richard. "The development of iron exchange system for the treatment of chronic iron overload /." Thesis, McGill University, 1985. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=63195.
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Kilbarger, Amy K. "The effect of iron overload on osteoblast function in cell culture." Greensboro, N.C. : University of North Carolina at Greensboro, 2007. http://libres.uncg.edu/ir/listing.aspx?styp=ti&id=146.
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Thesis (M.S.)--University of North Carolina at Greensboro, 2007.Title from PDF t.p. (viewed Feb. 29, 2008). Directed by Deborah Kipp; submitted to the School of Human Environmental Sciences. Embargoed until Dec. 20, 2008. Includes bibliographical references (p. 47-56).
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Hamilton, Jasmine La Juanie. "Innovative polymeric iron chelators with iron binding affinity and biocompatibility for the treatment of transfusional iron overload." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/52624.
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Desferrioxamine (Desferal®, DFO), deferiprone (Ferriprox®, L1) and desferasirox (Exjade®, ICL-670) are clinically approved iron chelators used to treat transfusion associated iron overload, a common condition in patients with severe hemoglobin disorders like β-thalassemia, sickle-cell disease and the myelodysplastic syndromes. The poor pharmacokinetics and inefficacy of iron chelators necessitate administration of almost maximum tolerated doses to achieve adequate iron removal. This causes toxicity ranging from neurological dysfunction in DFO users, agranulocytosis and neutropenia in L1 users, and severe kidney toxicity in ICL-670 treated patients. This also hinders the use of iron chelators during gestation. Thus, developing iron chelators with improved long-term efficacy and reduced toxicity is essential.
All currently approved iron chelators are of low molecular weight (MW) (< 600 Da) and the objectives reported for the “ideal” chelator of low MW is yet to be realized in practice. However, the limited attempts towards developing higher MW, long circulating iron chelators has shown tremendous promise. This thesis assesses the role of a new polymer, hyperbranched polyglycerol (HPG) in improving the properties of iron chelators.
High MW iron chelators were developed by conjugating DFO to HPG of various MWs, forming a library of HPG-DFO conjugates. Iron binding affinity of HPG-DFO was investigated using isothermal titration calorimetry, UV-visible spectroscopy and studying iron removal from ferritin. Biocompatibility and toxicity were investigated using coagulation assays in human blood and cell culture.
Since iron chelator toxicity during development remains an under-explored area, the second goal of this thesis was to expand knowledge of chelator toxicity during development. The toxicity of FDA-approved and HPG-DFO in developing embryos was investigated using zebrafish.
Studies indicate that HPG-DFOs are biocompatible, efficient chelators, capable of binding ferritin iron and preventing harmful redox reactions. Moreover, combining a low MW iron chelator with HPG-DFO enhances chelation. In vivo chemical screening indicated that while low MW chelators L1 and ICL-670 may interact with zebrafish embryos and cause toxicity, DFO and HPG-DFO did not have this effect. Results indicate that HPG-DFO is a new class of efficient, biocompatible iron chelator, potentially useful for development into clinical agents for the prevention of transfusion associated iron overload.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Stuart, Katherine Anne. "Iron overload in end-stage liver disease : mechanisms and pathophysiological significance /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18503.pdf.
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Liu, Zu Dong. "Design of orally active iron(II) chelators." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266259.
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Shah, Farrukh Tasnim. "The relationship between non transferrin bound iron and iron overload in thalassaemia and sickle syndromes." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444078/.
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Iron overload is a major cause of morbidity and subsequent mortality in patients with thalassaemia major, its effects in thalassaemia intermedia and sickle cell anaemia are however less well known. The presence of non transferrin bound iron is well described in adult thalassaemia patients but it is unclear as to when NTBI appears and what relationship it has to ineffective erythropoiesis and end organ damage. Data is presented on children with thalassaemia from a five-year prospective study showing that NTBI is present early in thalassaemia syndromes and this is probably due to ineffective erythropoiesis. In addition results from this study show that there is no relationship between markers of oxidative damage and NTBI in early childhood. Following this a comparison of adult patients with sickle cell anaemia and thalassaemia is undertaken looking at NTBI and cardiac iron burdens assessed by MRI. The thalassaemia patients at high liver iron burdens have a significant risk of cardiac iron loading and when patients with sickle cell anaemia and thalassaemia major are matched for liver iron it is seen that cardiac iron loading is not seen in sickle patients and this may be because NTBI is lower in this group. In the last chapter data is presented showing that serum pro-hepcidin is down regulated by NTBI, anaemia and erythropoietin in thalassaemia but not sickle syndromes. There is no clear relationship between pro-hepcidin and liver iron but hepcidin mRNA is down regulated by iron burden supporting the important role of this protein in iron regulation.
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Cardoso, Elsa Maria Pereira. "Lymphocytes in the liver and hepatic iron toxicity : human and animal models of iron overload." Doctoral thesis, Porto : Edição do Autor, 2000. http://hdl.handle.net/10216/64561.
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Cardoso, Elsa Maria Pereira. "Lymphocytes in the liver and hepatic iron toxicity : human and animal models of iron overload." Tese, Porto : Edição do Autor, 2000. http://catalogo.up.pt/F?func=find-b&local_base=UPB01&find_code=SYS&request=000087509.
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NAOE, TOMOKI, HISAO HAYASHI, HIDEAKI MAEDA, HARUHIKO OHASHI, AKIHIRO TOMITA, and HIROSHI SAITO. "DETERMINATION OF FERRITIN AND HEMOSIDERIN IRON IN PATIENTS WITH NORMAL IRON STORES AND IRON OVERLOAD BY SERUM FERRITIN KINETICS." Nagoya University School of Medicine, 2012. http://hdl.handle.net/2237/16021.
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Saghaie, Dehkordi Lotfollah. "Design of orally active pyridinone iron(III)-selective ligands." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362581.
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Patch, Christine. "Comparison of two screening strategies for haemochromatosis : a pilot study investigating uptake and acceptability, feasibility and cost." Thesis, University of Southampton, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289911.
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陈美翩 and Meipian Chen. "Effects of iron overload on apoptosis and titin proteolysis in cardiomyocytes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193425.
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Iron is one of the essential elements involved in various fundamental biological activities. However, excess iron may bypass the negative feedback regulatory systems, leading to the formation of iron overload. The increase of iron deposition generates cellular toxicity and subsequently damages vital organs. Primary and secondary iron overload are affecting patients worldwide. Iron overload cardiomyopathy is the primary cause of cardiac dysfunction and cardiovascular mortality in β-thalassaemia major patients. Current effective therapy includes chelation treatment with conventional and new iron chelators, while potential new therapies are currently under development.
The pathophysiology of iron overload cardiomyopathy remains unclear. Controversial findings on the mechanism of excessive iron entry into cardiomyocytes exist. Using novel real-time approach to trace iron entry into HL-1 cardiomyocytes, the only beating cardiac cell line with mature cardiac phenotype available currently, we visualized the patterns of iron entry following ferric iron incubation with and without ascorbate. Iron entry could be partly blocked by pretreatment with L-type calcium channel blockers but not T-type calcium channel blocker. Such blockage effect by L-type calcium channel blockers occurred in ferric iron overload. This finding suggested a role of L-type calcium channels for ferric iron uptake into cardiomyocytes under iron overload condition.
For the pathophysiology of iron cardiac toxicity, we assessed the iron overload induced apoptosis using both in vitro and in vivo approaches. The results demonstrated that iron-overloaded mouse HL-1 atrial cardiomyocytes and human embryonic stem cell derived ventricular cardiomyocytes underwent apoptosis via the mitochondria-mediated caspase-3 dependent pathway. Supportive data was found in iron-overloaded mouse myocardium by an increase in DNA fragmentation. However, despite the blockage of iron entry, L-type calcium channel blockers did not significantly prevent iron induced apoptosis in vitro.
The mechanism of cardiac contractile dysfunction caused by iron overload on cardiomyopathy has not yet been fully characterized. Given the central role of titin, the giant myofilament protein, as the main determinant in myocardial passive tension, stiffness, diastolic and systolic cardiac function, as well as myocardial twisting and untwisting motion, we investigated its expression in iron-overloaded cardiomyocytes in vitro and in vivo. Our results indicated that significant degradation of cardiomyocytes titin was induced by iron overload. This was associated with the cleavage at the elastic domain. Its potential upstream protease, calpain, was further identified to be activated under iron overload. The specific role of titin proteolysis in iron-overloaded cardiomyocytes merited further investigation.
The findings in this project provided new insights to the pathophysiology of iron overload cardiomyopathy, in terms of the route for iron entry, iron induced cardiac apoptosis, and titin proteolysis. Novel therapeutic approaches for prevention and treatment of iron overload cardiomyopathy can focus on inhibiting excessive iron uptake, as well as by targeting pathways involved in cardiac apoptosis and titin proteolysis.published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy
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Al-Refaie, Faris Nouraldin. "Oral iron chelation therapy with deferiprone (L(207))." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286321.
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Norin, Anneli. "Coordination Chemistry of Novel Drug Candidates for the Treatment of Iron Overload." Thesis, Mälardalen University, Department of Biology and Chemical Engineering, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-227.
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Iron overload is a serious clinical condition caused by excessive iron in the body, which can be largely prevented by the use of iron-specific chelating agents. At the moment there are only a few chelators in clinical use for the treatment of Fe overload. One of them, and so far the best working one, is desferrioxamine (DFO). This iron chelator has a major disadvantage of being orally inactive and is given by long and frequent subcutaneous infusions (12-24 hours/5-6 days/week) to patients. 1 Consequently, the design of an orally active, nontoxic, selective iron chelator has become a high priority. To design an iron chelator for clinical use, the important factors to consider are metal selectivity and affinity, ligand-metal complex stability, bioavailability and toxicity. The best iron chelator should be highly selective for iron(III) in order to minimize chelation of other biological essential metal ions which could lead to deficiency with prolonged usage. Favouring the Fe (III) oxidation state avoids Fenton chemistry and the production of toxic free radicals. This report deals with complexes of aroylpicolylhydrazines. Chemical and biological testing has established that these molecules function extremely well as iron chelators in vivo. The most effective candidates are more efficient at promoting iron efflux (release of iron) from cells than the existing drug DFO. Although the ligands discussed in this report, are selective for iron, there is no record of how they interact with other essential metal ions (Mn, Co, Ni, Cu and Zn) in our body and it is this that is the topic of this report. It was found that the complexes with H2PPH (N,N’-bis(α-picolinoyl)hydrazine) probably built polymeric complexes and therefore they were almost totally insoluble in all common solvents. The complexes of H2BPH (N-(benzoyl)-N’-(picolinoyl)hydrazine)) were also problematic in terms of insolubility. Another problem was decomposition of the complexes in solution, with resultant precipitation of the ligand and that happened with all of the ligands. The ligand H2TPH formed complexes with Ni and Co, [MII(HL)2] and [MIII(L)2]-, and crystals were grown suitable for x-ray structure studies. The cobalt complex is the first one reported of its kind. There was also crystals grown suitable for x-ray work of a protonated picolylhydrazide and that is also the first crystal structure reported.
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Human, Veronique. "Molecular analysis of genes involved in iron overload implicated in oesophageal cancer." Thesis, Link to the online version, 2007. http://hdl.handle.net/10019/391.
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SAITO, HIROSHI. "METABOLISM OF IRON STORES." Nagoya University School of Medicine, 2014. http://hdl.handle.net/2237/20543.
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Crowe, Sarah Lynn. "Cardioprotective effects of dihydropyridine antagonists in a murine model of chronic iron-overload." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2002. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ65615.pdf.
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SIGHINOLFI, SILVIA. "INTRACELLULAR IRON OVERLOAD AFFECTS HSC METABOLISM BY IMPAIRING MITOCHONDRIAL FITNESS IN β-THALASSEMIA." Doctoral thesis, Università Vita-Salute San Raffaele, 2023. https://hdl.handle.net/20.500.11768/137019.
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Mitochondrial activity and metabolism significantly control hematopoietic stem cell (HSC) function and fate. HSCs change the metabolic state in response to stress signals, such as reactive oxygen species (ROS), which drive HSC entry into cell cycle accompanied by increased mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. However, excessive accumulation of ROS results in oxidative damage of cellular organelles, including mitochondria. Iron is one of the sources of ROS and HSCs can uptake iron but little is known about the effects of iron on HSC metabolism.
Recently, we demonstrated an impaired function of HSCs in β-Thalassemia (BThal), a condition of systemic iron overload (IO). We also observed that IO reduces the hematopoietic supportive capacity of BThal BM mesenchymal stromal cells. However, there is no evidence of the direct effect of IO on HSCs in BThal. We hypothesized that IO and the resulting oxidative stress could alter HSC metabolism and function.
We found a positive enrichment of iron homeostasis genes in HSCs from thalassemic th3 mice, suggesting increased iron uptake and storage. Consistently, we detected high levels of free reactive iron in the cytoplasm and in mitochondria of th3 HSCs, correlating with high ROS levels. As a result, mitochondria are impaired, with low mass and activity. Interestingly, th3 multipotent progenitors inherited dysfunctional mitochondria since the rescue of mitochondrial activity occurred in the transition to more committed progenitors. In line with mitochondrial dysfunction, th3 HSCs had reduced OXPHOS-derived ATP and relied on glycolysis. In vivo reduction of mitochondrial ROS rescued mitochondrial activity and metabolism, and increased th3 HSC frequency and quiescence, thus indicating that oxidative stress is the cause of mitochondrial dysfunction and potentially HSC defects. Importantly, in vivo administration of iron dextran to wt mice generated intracellular IO and mitochondrial oxidative stress and decreased mitochondrial activity in HSCs, indicating that IO alone is sufficient to impair mitochondria.
Our study unveils that IO directly impacts on HSC metabolism by inducing oxidative stress and mitochondrial dysfunction. Alterations in mitochondrial activity and metabolic profile, in response to IO, are expected to alter HSC function. This research will add novel insight about the role of iron in regulating HSC metabolism and provide clues for improving clinical conditions associated to IO, such as BThal.L'attività e il metabolismo mitocondriali controllano in modo significativo la funzione e il destino delle cellule staminali ematopoietiche (HSC). Le HSC modificano lo stato metabolico in risposta a segnali di stress, come le specie reattive dell'ossigeno (ROS), che guidano l'ingresso delle HSC nel ciclo cellulare accompagnato da un aumento della fosforilazione ossidativa mitocondriale (OXPHOS) e della glicolisi. Tuttavia, l'eccessivo accumulo di ROS provoca il danno ossidativo degli organelli cellulari, compresi i mitocondri. Il ferro è una delle fonti di ROS e le HSC possono assorbire il ferro, ma si sa poco sugli effetti del ferro sul metabolismo delle HSC. Recentemente, abbiamo dimostrato una funzione alterata delle HSC nella β-talassemia (BThal), una condizione di sovraccarico sistemico di ferro (IO). Abbiamo anche osservato che l'eccesso di ferro riduce la capacità di supporto ematopoietica delle cellule stromali mesenchimali talassemiche. Tuttavia, non ci sono prove dell'effetto diretto del sovraccarico di ferro sulle HSC in BThal. Abbiamo ipotizzato che il sovraccarico di ferro e il conseguente stress ossidativo alterino il metabolismo e la funzione delle HSC. Abbiamo trovato un arricchimento positivo dei geni dell'omeostasi del ferro nelle HSC dei topi talassemici th3, suggerendo un aumento dell'assorbimento e dell'immagazzinamento del ferro. Coerentemente, abbiamo rilevato alti livelli di ferro reattivo libero nel citoplasma e nei mitocondri di th3 HSC, che correlano con alti livelli di ROS. Di conseguenza, i mitocondri sono alterati, con ridotta massa e attività. I progenitori multipotenti th3 hanno ereditato mitocondri disfunzionali poiché la correzione dell'attività mitocondriale si è verificata nella transizione verso progenitori più differenziati. In linea con la disfunzione mitocondriale, le HSC th3 hanno una ridotta produzione di ATP mediante OXPHOS e dipendono dalla glicolisi. La riduzione in vivo dei ROS mitocondriali ha ripristinato l'attività e il metabolismo mitocondriali e ha aumentato la frequenza e la quiescenza delle HSC th3, dimostrando così che lo stress ossidativo è la causa della disfunzione mitocondriale e dei potenziali difetti delle HSC. È importante sottolineare che la somministrazione in vivo di ferro destrano a topi wt ha generato eccesso di ferro intracellulare e stress ossidativo mitocondriale e una ridotta attività mitocondriale nelle HSC, indicando che il sovraccarico di ferro da solo è sufficiente per compromettere i mitocondri. Il nostro studio rivela che il sovraccarico di ferro ha un impatto diretto sul metabolismo delle HSC inducendo stress ossidativo e disfunzione mitocondriale. Le alterazioni dell'attività mitocondriale e del profilo metabolico, in risposta al sovraccarico di ferro, potrebbero alterare la funzione delle HSC. Questa ricerca aggiungerà nuove informazioni sul ruolo del ferro nella regolazione del metabolismo delle HSC e fornirà nuove conoscenze utili per migliorare le condizioni cliniche caratterizzate da sovraccarico di ferro, come BThal.
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Booley, Fadwah. "Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload in the South African population." Thesis, Stellenbosch : University of Stellenbosch, 2007. http://hdl.handle.net/10019.1/2220.
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Thesis (MSc (Genetics))—University of Stellenbosch, 2007.Hereditary haemochromatosis (HH), a common autosomal recessive disease, is characterized by increased iron absorption leading to progressive iron accumulation in organs such as the liver, heart and pancreas. In the South African population the disease is prevalent in individuals of Caucasian origin, with a carrier frequency of one in six for the C282Y mutation in the HFE gene. We investigated the role of genes implicated in iron metabolism, including the high-iron gene (HFE), haem oxgenase-1 gene (HMOX1), solute carrier family 40 (iron-regulated transporter) member 1 gene (SLC40A1), cytochrome b reductase gene (CYBRD1), hepcidin antimicrobial peptide gene (HAMP) and the hemojuvelin gene (HJV) in a patient cohort with non-HFE iron overload. DNA analysis was performed on samples from 36 unrelated South African Caucasian patients presenting with primary iron overload, who tested either negative or heterozygous for C282Y. In this study, mutation screening was performed by PCR amplification and HEX-SSCP analysis. Sixteen previously described and two novel variants were identified by semi-automated DNA sequencing. Common variants identified in the HFE gene included C282Y, H63D, IVS2+4T→C, IVS4-44T→C, IVS4+48G→A and IVS5-47G→A. The Q127H mutation in exon 3 of the HFE gene was identified in one patient, who tested negative for both C282Y and H63D. Mutation S65C was identified only in the population-matched controls and was absent in the patient group. Other previously described polymorphisms identified included the IVS5+51delTGGCTGTCTGACT deletion in HMOX1, I109 and V221 in SLC40A1, IVS1-4C→G, IVS2+8T→C and S266N, in the CYBRD1 gene and, S264 and A310G in the HJV gene. The novel variants, -89C→T, in the promoter region of the CYBRD1 gene, was detected in only one patient, while S333 in exon 4 of the HJV gene was present in three patients. These variants were not identified in any of the population-matched controls screened and could explain the non-HFE iron overload presented by these patients. This study clearly demonstrates the importance of modifier genes in patients with iron overload that cannot be explained by the common C282Y mutation. Studies on iron-related genes and the identification of mutations in these genes in non-HFE patients could lead to improved diagnosis and counselling of South African patients presenting with primary iron overload.
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Shirase, Tomoyuki. "Suppression of SLC11A2 expression is essential to maintain duodenal integrity during dietary iron overload." Kyoto University, 2012. http://hdl.handle.net/2433/152506.
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Lunova, Mariia [Verfasser]. "Hepcidin knockout mice as a model of iron-overload associated liver disease / Mariia Lunova." Ulm : Universität Ulm. Medizinische Fakultät, 2013. http://d-nb.info/1045278475/34.
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DEIDDA, Irene. "Retinal neurodegeneration and an innovative nanostructured approach in an iron overload in vivo model." Doctoral thesis, Università degli Studi di Palermo, 2020. http://hdl.handle.net/10447/426136.
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Visapää, Ilona. "Molecular genetics of the GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis and early death)." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/visapaa/.
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Guo, Feng. "Correlations of in vitro and in vivo metabolism and pharmacokinetics of a new iron chelator, APOCP363, in the normal and iron-overload rat." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ63749.pdf.
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Werner, Denise. "The Effect of Iron Overload on the Long-term Toxicological Effects of Fumonisin B1 in Rat Liver." Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-6138.
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Dee, Cathleen Michelle Ang, and 李明芳. "Sublethal iron overload can alter the morphology and function of dendritic cells which may predispose to gram-negative infection in beta-thalassemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208548.
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Antofiichuk, T. M. "Intensity of liver parenchym fibrosis in patients with alcoholic steatohepatitis depending on the presence of dysmetabolic iron overload syndrome." Thesis, БДМУ, 2022. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/19604.
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MACCHI, CHIARA. "DEVELOPMENT AND PATHOPHYSIOLOGICAL CHARACTERIZATION OF AN IN VIVO MODEL OF IRON OVERLOAD ASSOCIATED TO INSULIN RESISTANCE AND REPRODUCTIVE IMPAIRMENT." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/545620.
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Introduction. Iron is an essential micronutrient required for fundamental biochemical activities, such as oxygen and energy metabolism, mitochondrial function and brain development. However, it may catalyze the formation of highly reactive hydroxyl radicals, leading to oxidative stress, lipid peroxidation, and DNA damage with, finally, cell and tissue damages. Given its potential high toxicity, a condition of iron overload can promote multiple organ damages, associated to acute and chronic diseases. Among the several complications associated with iron overload syndromes, hypogonadism is the second most common endocrinopathy although the role of iron in its pathophysiology is still debated.
Aim. To explore in a dysmetabolic murine model, the molecular determinants of hypogonadism induced by iron overload, with a specific focus on hypothalamic derangement.
Material and methods. Male C57BL/6J mice fed standard iron concentration diet or iron-enriched diet (IED, 3% carbonyl-iron) and HFE-/- mice, these last resembling a murine model of human genetic hemochromatosis; cell-based models of gonadotropin-releasing hormone (GnRH) neurons (GN-11 and GT1-7 cell lines); radioimmunoassay (RIA); enzyme-linked immunosorbent assay (ELISA); histological analysis and immunostaining; image processing and quantitation; atomic absorption spectrometry; ATPliteTM 1step assay; Trypan Blue exclusion test; qRT-PCR; Boyden’s chamber assay; Western blot analysis.
Results. In vivo models. IED led to a hypogonadal phenotype as shown by micro- and macroscopic alterations at the testicular level. Iron accumulation in testes and pituitary significantly reduced serum levels of testosterone (-83%) and luteinizing hormone (-86%). Although, hypothalamic iron concentration did not differ in mice fed IED compared to controls, a significant increment in GnRH gene expression (+34%) and in intensity of GnRH-neuron innervation of the median eminence (+1.5-fold) were found; similar changes were obtained in HFE-/- mice. Hypothalamic gene expression of tumor necrosis factor α was increased in IED mice.
Moreover, a series of metabolic impairments, such as (i) increment in glycemia and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and (ii) reduction in body weight and fat as well as in plasma leptin was found upon IED.
In vitro models. Treatment of GN-11 and GT1-7 cells with ferric ammonium citrate, as a source of iron, significantly increased its intracellular concentration; as such, the genes involved in iron homeostasis were changed: transferrin receptor, -75%; ferritin H, +92%. Furthermore, GN-11 cell chemomigration was inhibited by iron overload with an apparent involvement of the extracellular signal-regulated kinase (ERK) 1/2 cell signaling pathway. Finally, iron overload induced oxidative stress in GN-11 cells.
Conclusions. In adult male mice, iron overload leads to a severe impairment of the hypothalamic-pituitary-gonadal axis possibly resulting in a hypogonadal condition, a feature possibly deriving from iron deposition in pituitary and/or gonads via extrahypothalamic mechanisms. This finding represents a further step in understanding how iron overload leads to this endocrinopathy. In this context, the use of in vitro GnRH neurons, which functions were impaired by iron accumulation, leaves open questions relative to the role of brain blood barrier in the protection of the central region (hypothalamus).
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Liljeholm, Maria. "Congenital Dyserythropoietic Anemia type III (CDA III) : diagnostics, genetics and morbidity." Doctoral thesis, Umeå universitet, Institutionen för strålningsvetenskaper, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-117454.
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The Congenital Dyserythropoietic Anemias (CDA) are rare hereditary hemolytic disorders with large bi- to multi-nucleated erythroblasts in the bone marrow. Hemolysis is negative in a direct antiglobulin test (DAT). Based on morphology and clinical picture, three major forms of CDAs, type I, II, and III have been defined. CDA III, dominantly inherited, constitutes the rarest type with a majority of cases belonging to a family in Västerbotten, Sweden. The genetic background of CDA I and CDA II has been linked to mutations in CDAN1 and SEC23B respectively. The mutation of CDA III has been linked to 15q22 in earlier studies. In this project we have defined the causative genetic lesion in two families with CDA III. The novel mutation KIF23 c.2747C>G (p.P916R) was shown to segregate with CDA III in the Swedish and American CDA III families and was absent in 356 healthy controls. KIF23 encodes mitotic kinesin-like protein 1 (MKLP1), which plays a central role in the last step of cytokinesis. RNAi-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, resulting in increasing number of bi-nuclear cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23, encoding MKLP1, a conserved mitotic kinesin crucial for cytokinesis. Flow cytometry with eosin-5´-maleimide (EMA), anti-CD55 and anti-CD59 is commonly used when investigating non-autoimmune hemolytic anemias. Reduced fluorescence of EMA, typically detected in hereditary spherocytosis, is also seen in CDA II, while reduction of CD55 and CD59 characterizes paroxysmal nocturnal hemoglobinuria (PNH). We studied the flow cytometric profile of EMA, CD55, and CD59 on erythrocytes in CDA III. We found no abnormality of the erythrocyte membrane in CDA III and concluded that standard flow cytometry cannot be used to discriminate between CDA III and normal controls. In CDA I and CDA II a majority of patients, including those who are not transfusion dependent, suffer from iron overload, which, according to earlier studies, is not the case in CDA III. We found that individuals of the Västerbotten CDA III family carry mutations in the hemochromatosis (HFE) gene. Three CDA III patients with heterozygous or compound HFE mutations need treatment with phlebotomy due to iron overload. One of them carries heterozygous H63D mutation, which is not reported to lead to iron overload by itself in otherwise healthy individuals. We propose that molecular genetic testing of the HFE gene is indicated in all patients with CDA, including CDA III.
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Muraca, Sergio. "Hepatic iron quantitation and liver biopsy in sickle cell disease and thalassemia major, impact on monitoring and preventing the progression of iron overload due to regular transfusion therapy." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ63151.pdf.
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Bartfay, Wally J. "Increased free radical generation, as measured by aldehyde-derived peroxidation products, is observed in the heart with chronic iron-overload." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0026/NQ49950.pdf.
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Panton, Nicola. "Mutation analysis of four genes implicated in iron homeostasis in porphyria cutanea tarda (PCT) patients." Thesis, Link to the online version, 2008. http://hdl.handle.net/10019/888.
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Pontre, Beau. "Measurement, modelling and potential clinical applications of spatial variations in magnetic resonance proton transverse relaxation rates in iron-loaded liver and heart tissue." University of Western Australia. School of Physics, 2006. http://theses.library.uwa.edu.au/adt-WU2006.0062.
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[Truncated abstract. Formulae and special characters in this field can only be approximated. See PDF version for accurate reproduction.] Magnetic resonance imaging (MRI) has been developed over the past two and a half decades to enable non-invasive assessment of soft tissues in the human body. MRI provides images of the tissues in the body with intensities weighted by nuclear magnetic relaxation properties of the tissue. Recent advances have utilised MRI as a quantitative tool with the nuclear magnetic relaxation rates in tissues being accurately quantified. One clinical application of quantitative MRI has been in the quantification of body iron stores in the management of iron overload diseases. MR images also contain information about the spatial variations of relaxation rates, which could be clinically useful. In the quantification of liver iron concentrations, proton transverse relaxation rate (R2) maps have been used not only to quantify iron concentrations but also to visualise the spatial variations. The work in this thesis addresses the use of spatial information from proton transverse relaxation rate maps in clinical practice. The quantitative spatial information contained in these maps is analysed in two clinically important settings, namely the non-invasive assessment of liver fibrosis and the assessment of magnetic susceptibility artefacts in cardiac proton transverse relaxometry. Spatial distributions of liver R2 maps were quantified using texture measures based on grey-tone spatial dependence (GTSD) matrices. Some of these measures gave a statistically significant distinction between patients with minimal or no fibrosis and those with fibrosis or cirrhosis. Distinction of fibrosis using this technique was enhanced in subjects with iron overload diseases, suggesting that iron is required as a contrast agent for sufficient sensitivity of image texture to fibrosis. In subjects with low tissue iron concentrations, tissue hydration was observed to also have an influence on R2. In patients with end stage liver disease, a model combining tissue iron concentration and tissue hydration gave a better prediction of R2 than iron concentration alone. A model combining several of the texture measures was developed using logistic regression and was found to improve distinction of high-grade fibrosis from low-grade fibrosis. For the distinction of F0 and F1 fibrosis stages (as assessed by the METAVIR system) from F2 and above the area under the receiver-operating characteristic (ROC) curve was 0.75. As this model was developed using a cohort of subjects with varying pathologies, the performance of the model is expected to improve if only iron-loaded subjects are considered.
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Hangel, Christoph [Verfasser], and Markus [Akademischer Betreuer] Hecker. "Leptin-mediated downregulation of glutathione peroxidase 4 and iron overload contributing to podocyte ferroptosis in diabetic nephropathy / Christoph Hangel ; Betreuer: Markus Hecker." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1199196096/34.
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Jereza, Noel Abique. "Investigations on potential digenic HAMP (hepcidin) and HFE haemochromatosis gene mutations in the development of iron overload in Irish patients with dilated cardiomyopathy." Thesis, University of the West of England, Bristol, 2016. http://eprints.uwe.ac.uk/25518/.
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Iron overload cardiomyopathy (IOC) has been recently described as a dilated cardiomyopathy, characterized by left ventricular (LV) remodelling with chamber dilatation and reduced LV ejection fraction (LVEF). However, primary haemochromatosis, a genetically determined condition leading to iron overload, is classically categorized as an infiltrative cause of cardiomyopathy. Moreover, secondary haemochromatosis may lead to severe diastolic LV dysfunction in the early stages of the disease, before LVEF is affected. In this study, we describe the forms, pathophysiology, and genotypic expressions of HFE and hepcidin (HAMP) gene mutations focusing on the possibility of digenic occurrence that could lead to potential development of iron overload cardiomyopathy among Irish patients and their direct family members. The prevalence of iron overload cardiomyopathy (IOC) in Irish population is increasing. The spectrum of symptoms of IOC varied. Early in the disease process, patients may be asymptomatic, whereas severely overloaded patients can have terminal heart failure complaints that are refractory to treatment. It has been shown that early recognition and intervention may alter outcomes. In this study the combination of cardiac biomarkers (troponin I and creatine kinase), iron studies (serum ferritin, serum hepcidin, and transferin saturation) level determinations and genotyping of the HFE (C282Y/H63D) and hepcidin HAMP (C70R) gene mutations were carried out and allele frequencies were correlated within the Irish population. The first finding of this study was a trend towards significant elevation of iron studies: serum ferritin level, percent transferin saturation and decreasing serum hepcidin observed in dilated cardiomyopathy patients and direct family members identified with HFE C282Y/H63D and HAMP C70R heterozygotes who were asymptomatic. This was not associated with age and suggests that there is a threshold level of iron studies above which symptoms occur. This discordance between the symptomatic and asymptomatic HFE C282Y/H63D and HAMP C70R heterozygous formed the basis of subsequent analyses. The second finding of this study was a trend towards significant elevation of the selected cardiac biochemical markers from the median level of serum troponin-I and creatine kinase observed in patients and direct family members with HFE C282Y/H63D and HAMP C70R heterozygous who were again asymptomatic. This was not associated with age and cardiac complaints or history and suggests that there is a threshold level of cardiac biochemical marker activities that triggers the condition and as predisposing factors to a potential development of iron overload cardiomyopathy. The genotypic expressions of HFE and HAMP were identified and showed that among the Irish patients diagnosed with dilated cardiomyopathy and their family members, a significant trend of digenic occurrence of both mutations. The heterozygous C282Y/H63D and C70R revealed in this study that it is a predisposing factors developed at certain age of life.
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Olivatto, Gabriela Marsola. "Caracterização sociodemográfica e clínica de pacientes com talassemia maior e diabetes mellitus de um centro de referência no interior de São Paulo." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/22/22132/tde-28112017-150253/.
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A maior expectativa de vida dos pacientes com talassemia maior, as repetidas transfusões de concentrado de hemácias como parte do tratamento, podem ocasionar maior deposição de ferro nos órgãos, e consequentemente, as comorbidades. Dessa forma, dentre as comorbidades endócrinas, temos o diabetes mellitus como uma das principais, sendo necessário conhecer o panorama em nossa realidade. O estudo tem como objetivos determinar a prevalência do diagnóstico de diabetes em pacientes com talassemia maior, caracterizar e comparar os pacientes com talassemia maior, e diabetes mellitus, segundo as variáveis sociodemográficas e clínicas.Trata-se de um estudo descritivo e transversal, realizado em um centro de referência no tratamento de talassemia do interior paulista. A amostra foi constituída por 31 pacientes com talassemia maior. Para a coleta de dados utilizou-se um instrumento subdividido em duas partes. Os dados sociodemográficos e clínicos foram obtidos por meio de entrevista dirigida e os resultados de exames laboratoriais pelo prontuário eletrônico do paciente, no período de junho a agosto de 2015. Os dados foram digitados e importados para o programa SPSS for Windows, versão 17.0 e submetidos à análise estatística descritiva. O projeto foi aprovado pelo Comitê de Ética em Pesquisa da Escola de Enfermagem de Ribeirão Preto da Universidade de São Paulo (CEP/EERP-USP), sob Protocolo nº 41912415.3.0000.5393. Dos 31 pacientes com talassemia maior, 5 (16,1%) tinham diabetes mellitus. Em relação as variáveis sociodemográficas, não houve diferenças na distribuição dos pacientes entre os sexos, a maioria eram solteiros e cursaram até o ensino médio completo. A idade variou de cinco a 48 anos, com média de 24,9 anos de idade, a maioria recebia até 10 salários mínimos, eram estudantes e possuíam carteira de trabalho assinada. No que tange às variáveis clínicas, temos que o tratamento utilizado predominante foi o quelante oral deferasirox, e naqueles pacientes com diabetes, além do deferasirox, a maioria utilizava a insulina. O esquema transfusional predominante foi o de 15 a 22 dias. O índice de massa corpórea foi classificado como eutrófico e a pressão arterial, considerada ótima para a maioria dos pacientes. Quanto aos achados dos exames laboratoriais, os pacientes com diabetes e talassemia apresentaram valores alterados de glicemia de jejum e transaminase, já os pacientes sem diabetes apresentaram valores alterados de ferritina sérica. No que se refere aos achados dos exames de imagem, nenhum paciente com diabetes e Talassemia maior apresentou massa óssea adequada, o que reforça a importância de seu monitoramento. Destaca-se o aumento de sobrecarga cardíaca para os pacientes com diabetes e talassemia. Para os pacientes com talassemia e sem diabetes, a maioria apresentou grave sobrecarga de ferro hepático na ressonância magnética do fígado, enquanto para a maioria dos pacientes com diabetes foi considerado normal. Dessa forma, conhecer as características clínicas dos pacientes com talassemia maior e diabetes permite subsidiar a assistência de enfermagem qualificada e contribuir com a saúde dos pacientes com condições crônicas. Contudo, os nossos achados corroboram com as taxas de prevalência de diabetes em pacientes com talassemia maior encontradas na literatura nacional e internacionalThe longer life expectancy of patients with thalassemia major, repeated red blood cell transfusions as part of the treatment, may lead to increased iron deposition in the organs, and consequently, comorbidities. Thus, among the endocrine comorbidities, we have diabetes mellitus as one of the main ones, being necessary to know the panorama in our reality. The aim of the study was to determine the prevalence of diabetes in patients with thalassemia major and to characterize and compare patients with thalassemia major, and diabetes mellitus, according to sociodemographic and clinical variables.This is a descriptive and cross-sectional study, carried out in a reference center in thalassemia treatment of São Paulo countryside. The sample consisted of 31 patients with thalassemia major. For data collection, an instrument was divided into two parts. Sociodemographic and clinical data were obtained by means of a directed interview and the laboratory tests results by the patient\'s electronic record, from June to August 2015. Data were loaded into SPSS for Windows software, version 17.0 and submitted to descriptive statistical analysis. The project was approved by the Research Ethics Committee of the University of São Paulo at Ribeirão Preto College of Nursing (CEP / EERP-USP) under Protocol No. 41912415.3.0000.5393. Of the 31 patients with thalassemia major, 5 (16,1%) had diabetes mellitus. Regarding the sociodemographic variables, there were no differences in the distribution of the patients between the sexes, most of them were single and enrolled in high school. The age ranged from five to 48 years, with a mean of 24,9 years of age, the majority received up to 10 minimum wages, were students and had a work contract. Regarding the clinical variables, we have that the predominant treatment was the oral chelator deferasirox, and in those patients with diabetes, in addition to deferasirox, the majority used insulin. The predominant transfusion regimen was 15 to 22 days. Body mass index was classified as eutrophic and blood pressure was considered optimal for most patients. Regarding the laboratory findings, patients with diabetes and thalassemia had altered values of fasting glycemia and transaminase, whereas patients without diabetes had altered values of serum ferritin. Regarding imaging exams findings, no patient with diabetes and major thalassemia presented adequate bone mass, which reinforces the importance of their monitoring. The increase in cardiac overload for patients with diabetes and thalassemia stands out. For patients with thalassemia and without diabetes, the majority had severe hepatic iron overload in the magnetic resonance imaging of the liver, while for most patients with diabetes it was considered normal. Thus, knowing the clinical characteristics of patients with thalassemia major and diabetes allows subsidizing qualified nursing care and contributing to the health of patients with chronic conditions. However, our findings corroborate the prevalence rates of diabetes in patients with thalassemia major found in the national and international literature
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Steffani, L. "MODELLI SPERIMENTALI DI SOVRACCARICO DIETETICO DI FERRO: EFFETTI CENTRALI E PERIFERICI SU METABOLISMO E FUNZIONE RIPRODUTTIVA." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/232404.
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Background and Aim. Iron is an essential micronutrient, which is involved as a cofactor in fundamental biochemical activities, and it is necessary for proper brain development in the fetal and early neonatal period. However, cellular iron overload produces toxic build-up in many organs, including brain, and, under aerobic conditions, catalyses the propagation of reactive oxygen species and the generation of highly reactive radicals through Fenton Chemistry. Association between metabolic and reproductive impairment has been proved in patients affected by dysmetabolic iron overload syndrome (DIOS). In particular, iron is the most important factor afflicting the hypothalamic-pituitary axis in a dose-dependent fashion leading to hypogonadotropic hypogonadism (HH). Our previous studies in a mouse model of DIOS showed the association between dietary iron overload, visceral adipose tissue insulin resistance and hypertriglyceridemia.
Aim of this thesis was to assess whether and how iron overload may affect (a) the reproductive axis (mainly at the hypothalamic-pituitary levels) in a mouse model of DIOS; (b) the migratory feature and GnRH secretory pattern in GN-11 and GT1-7 cells, in vitro models of immature/migratory and mature/GnRH-secreting neurons, respectively.
Results. In male mice, dietary-iron overload (IED) led to: a) an increment in testis iron content, b) a reduction in testicular weight and length, c) no changes in hypothalamic iron content c) no changes in mRNA levels of iron-responsive genes, transferrin receptor (TfR) and ferritin H (FtH), in testes and hypothalamus d) an up-regulation of hypothalamic GnRH mRNA levels, e) no changes in hypothalamic Kiss1 and GPR54 gene expression, e) a reduction in pituitary LHβ gene expression. Moreover, the hypothalamic increment of TNFα gene expression along with the phosphorylation/activation of AMPK protein suggested the presence of an inflammatory condition. Increased hypothalamic CHOP mRNA levels also confirmed the endoplasmic reticulum stress feature. IED mice gained less weight than controls showing a reduction in VAT mass and in serum leptin levels, whereas hypothalamic NPY mRNA levels were increased and POMC gene expression was reduced. Western blot analysis showed that the pAkt/Akt ratio was up-regulated in the hypothalamus of IED mice, whereas phosphorylation of ERK1/2 (pERK) protein resulted unchanged in both groups. As far as GN-11 and GT1-7 cells are concerned, a 24-hour treatment with 200 µM Ferric Ammonium Citrate (FAC, source of ferric iron) induced an increment in the intracellular specific iron content of both cell-based models without affecting the cell viability and morphology. Gene expression analysis showed that both cell lines express TfR and FtH, whose mRNA levels were modulated by iron overload. Exposure of GN-11 cells to FAC resulted in the dose (200–1000 µM FAC for 24 hours)- and time (24-72 hours with 200 µM FAC)-dependent inhibition of FBS-induced chemomigration, as assessed by Boyden chamber assay. Pre-treatment with 200 µM deferoxamine (DFO, a specific iron chelator) reverted the above reported iron-driven effect on cell migration. Time-course experiments showed that 200 μM FAC was associated with increased pERK1/2 and pAkt protein levels and with decreased pAMPK ones. Chemomigration assays carried out with the specific inhibitors of ERK1/2, Akt and AMPK highlighted that only Akt pathway seems involved in FAC-mediated inhibition of GN-11 cell migration. In GN-11 cells, iron treatment increased IL-6 gene expression in a dose-dependent mode, whereas NF-kB nuclear translocation and activation was not affected. Up-regulated SOD2 mRNA levels confirmed a condition of activated oxidative stress.
Conclusions. The present data show that dietary-iron overload impairs the reproductive axis, probably leading to HH, but further experiments are needed to understand the anatomic site mainly involved in iron-driven damage. Iron treatment negatively affects the migration of GN-11 neuronal cells by the activation of Akt signaling pathway. Hence, iron overload may impair the migration of GnRH neurons from the olfactory placode into forebrain and hypothalamus, where these neurons promote the reproductive competence.
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Silva, Ana Lúcia Bernardes da. "O papel das mutações do gene HFE e da sobrecarga de ferro na evolução da hepatite crônica pelo VHC." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5147/tde-08122009-181724/.
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Introdução: A infecção pelo VHC é uma epidemia de proporções globais, que se torna crônica em cerca de 85% dos indivíduos. Sobrecarga de ferro secundária a mutações HFE vem sendo proposta como fator agravante na evolução da hepatite crônica C. Objetivos: Avaliar se sobrecarga de ferro, mutações no gene HFE estão associadas a progressão da fibrose hepática e a carcinoma hepatocelular (CHC) em portadores crônicos VHC. Casuística e Métodos: De um banco de 2300 pacientes matriculados nos Ambulatórios de Hepatologia e de Transplante Hepático do HCFMUSP, selecionaram-se 320 portadores de hepatite crônica C. Os homens (55,6%) apresentaram 50,8 anos de idade em média e as mulheres 54,3. Obtiveram-se dados clínicos e laboratoriais da época da biópsia hepática, admissionais ou com pelo menos um ano de wash-out do tratamento antiviral. Considerou-se sobrecarga bioquímica níveis de ferro, saturação da transferrina e ferritina acima dos valores de referência. Sobrecarga de ferro tecidual foi identificada pela coloração de Perls graus 3-4. As mutações HFE C282Y e H63D foram pesquisadas pela técnica de PCR em tempo real, em DNA extraído de sangue total, após assinatura de TCLE aprovado pelo comitê de ética local. A fibrose hepática foi considerada avançada para graus 3-4 da classificação SBH/SBP e Metavir (n=167, 52,2%). CHC foi definido por biópsia ou por imagem típica por 2 métodos e AFP 400 mg/dL (n=45, 14,1%). Investigaram-se antecedentes de etilismo, diabetes mellitus, IMC e esteatose em biópsia hepática. A partir dos resultados de genotipagem HFE, constituiu-se um subgrupo caso-controle (n=182) com os portadores de mutações e pares de idade, sexo, etnia e IMC similares. Procederam-se análises de correlação bivariada e multivariada (IC=95%) nos grupos geral e caso-controle. Resultados: Quando se compararam casos com fibrose leve vs avançada, observaram-se níveis elevados de ferro em 17,7% vs 25,2% (p=0,019); saturação da transferrina em 24,3% vs 36,7% (p=0,001); ferritina em 25,8% vs 32,4% (p=0,040) e sobrecarga de ferro tecidual em 3,6% vs 1,4% (p=0,126). Quanto à mutação C282Y, observaram-se frequências alélicas de 0,9% vs 2,0% (p=0,110) e à H63D 5,0% vs 8,0% (p=0,033). No subgrupo casocontrole, as associações de C282Y e H63D com fibrose avançada ocorreram com significâncias de p=0,072 e 0,008, respectivamente. A análise multivariada, tendo fibrose como variável dependente nesse mesmo subgrupo, confirmou as associações com C282Y (OR=31,45; p=0,006) e H63D (OR=33,70; p=0,001). Neste mesmo subgrupo, a presença de pelo menos um alelo mutante esteve associada à ocorrência de CHC (p=0,015). Não se identificaram outros parâmetros associados a transformação carcinomatosa. Na análise multivariada, foram variáveis associadas a evolução da fibrose idade avançada (OR=2,36; p=0,000), etilismo (OR=2,18; p=0,007), saturação da transferrina (OR=2,11; p=0,010) e mutação H63D (OR=1,97; p=0,03). Discussão e Conclusões: Houve correlação de graus mais avançados de fibrose com níveis elevados de ferro, saturação da transferrina e ferritina; contudo, esses marcadores também podem estar igualmente elevados nos indivíduos com pouca fibrose. Ao contrário, em muitos casos, a sobrecarga bioquímica de ferro pode ser conseqüência da progressão da doença hepática, e não sua causa. As mutações H63D e C282Y ocorreram em associação com maiores graus de alteração arquitetural; mas, como não houve associação entre siderose tecidual e fibrose, é possível que seu papel na agressão hepática não ocorra diretamente por meio da sobrecarga de ferro. Os portadores de mutações HFE apresentam CHC com maior frequência que seus casos-controle.Introduction: HCV infection is an epidemic of global proportions, which becomes chronic in about 85% of individuals. Iron overload due to HFE mutations has been proposed as aggravating factor in the evolution of chronic hepatitis C. Objectives: To assess whether iron overload, mutations in the HFE gene are associated with progression of liver fibrosis and hepatocellular carcinoma (HCC) in chronic HCV. Patients and Methods: From a database of 2300 patients enrolled in the outpatient clinics of Hepatology and Liver Transplantation, HCFMUSP, 320 patients with chronic hepatitis C were selected. Men (55.6%) were 50.8 years old on average and women 54.3. Admissional clinical and laboratory data at the time of liver biopsy were obtained; when patient had been previously treated with antiviral drugs, the wash-out period required was of at least one year. Biochemical iron overload was defined as iron, ferritin and transferrin saturation above the reference values. Tissue iron overload was identified by Perls staining of grades 3-4. The HFE C282Y and H63D mutations were searched by real-time PCR technique in DNA extracted from whole blood, after signing of FICT approved by the local ethics committee. The liver fibrosis was considered advanced for grades 3-4 in the classification SBH/SBP and METAVIR(n = 167, 52.2%). HCC was defined by biopsy or by typical image by 2 methods and AFP 400 mg / dL (n = 45, 14.1%). Personal history of alcoholism, diabetes mellitus, BMI and steatosis in liver biopsy were obtained. A casecontrol group was constituted based on the results of HFE genotyping (n = 182), subjects were paired by age, gender, ethnicity and BMI. Bivariate correlation and multivariate analysis (CI = 95%) groups in general and case-control were carried-out. Results: When comparing patients with mild vs advanced fibrosis, biochemical high levels of iron were detected in 17.7% vs 25.2% (p = 0.019), transferrin saturation in 24.3% vs 36.7% (p = 0.001), ferritin in 25.8% vs 32.4% (p = 0.040) and tissue iron overload in 3.6% vs 1.4% (p = 0.126). Regarding to HFE mutations, the allelic frequencies of C282Y were 0.9% vs 2.0% (p = 0.110); and of H63D, 5.0% vs 8.0% (p = 0.033). In casecontrol group, associations of C282Y and H63D with advanced fibrosis occurred with significance of p=0.072 and 0.008, respectively. Multivariate analysis with fibrosis as the dependent variable in that group, confirmed the associations with C282Y (OR = 31.45, p = 0.006) and H63D (OR = 33.70, p = 0.001). In this same subgroup, the presence of at least one mutant allele was associated with occurrence of HCC (p = 0.015). There were not any other parameters found in association with carcinomatous transformation. The multivariate analysis using fibrosis as dependent variable showed association with age (OR = 2.36, p = 0.000), alcoholism (OR = 2.18, p = 0.007), transferrin saturation (OR = 2.11, p = 0.010) and H63D mutation (OR = 1.97, p = 0.03). Discussion and Conclusions: Advanced degrees of fibrosis were correlated with high levels of iron, transferrin saturation and ferritin; however, these markers can also be elevated in individuals with slight fibrosis. In contrary, in many cases, the biochemistry of iron overload may be a consequence of progression of liver disease. C282Y and H63D mutations occurred in association with more advanced fibrosis. However, as there was not any correlation between tissue siderosis and fibrosis, it might be possible that liver injury occurs not by the iron overload pathway. Finally, carriers of HFE mutations were found with HCC more frequently than their casecontrol.
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Veronese, Elisa. "Methods for segmentation and characterization of multiple sclerosis cortical lesions from MRI data." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422439.
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This thesis deals with the automatic analysis of magnetic resonance images of the brain, acquired from people affected by multiple sclerosis. In particular, the primary aim of the analysis is to obtain a quantitative measure of the cortical lesion burden due to the specific disease. Besides, we propose a technique for the characterization of the different lesion types, based on their inflammatory activity.
Multiple sclerosis is a chronic, inflammatory disease of the central nervous system, that causes a progressive demyelination of several areas of the brain and of the spinal cord. As far as diseases’ frequency is concerned, multiple
sclerosis represents the second neurologic disease in the young adult, and it is even the first inflammatory chronic disease. Besides, it can also be considered as a social burden, with heavy direct and indirect costs: multiple sclerosis prevents people from working as much as they could without the disease, and can lead to the impossibility to live autonomously. Last but not least, the cost of treatment and care can be very high.
Although the causes are still partly unclear, a lot has been achieved in the understanding of the different phases of the inflammatory process characterizing multiple sclerosis. Today it is possible to early diagnose the disease, thus allowing to limit symptoms by early therapies.
The lesions caused by multiple sclerosis can be visualized in vivo thanks to magnetic resonance (MR) imaging. In particular in the latest decades several MR sequences have been designed in order to highlight white matter lesions.
When studying gray matter lesions, instead, the available MR sequences are less numerous. This is partly due to the fact that the gray matter involvement in multiple sclerosis is a relatively recent finding.
It is important to verify both the evolution and the appearance of new lesions: in this way it is possible to monitor the disease progression, which is particularly tricky in the case of multiple sclerosis. This disease is characterized by acute relapses alternated with remitting periods of variable length.
For this reason patients are periodically examined acquiring MR images. The subsequent diagnosis made by the physician is based on the MR results.
So, it is fundamental for the neurologist to be well trained in order to be able to properly evaluate different magnetic resonance sequences. Besides, he/she has to pay close attention not only to detect new lesions, but also to recognize
those lesions that were already present in the previous examinations, and that might have changed their shape, their dimension or they activity. This process requires time and attention, but unfortunately, being human-based, it is strongly error prone. Unquestionably, the diagnose cannot prescind from
the neurologist’s evaluation. Nonetheless, the advent of techniques for the automatic analysis of magnetic resonance images and for the detection of multiple sclerosis lesions would represent a valid support for the physicians, who could provide accurate evaluations in faster timing.
In this thesis several MR techniques currently used for cortical lesions visualization will be described. Then a segmentation algorithm will be proposed, in order to find the region corresponding to gray matter. On this region a second algorithm will be presented, that detect multiple sclerosis cortical lesions.
Finally, a first attempt to characterize cortical lesions based on their inflammatory activity will be described.Questa tesi tratta l’analisi automatica di immagini di risonanza magnetica cerebrale in soggetti affetti da sclerosi multipla. In particolare, l’analisi è volta sia a una stima quantitativa del carico di lesioni corticali presenti a causa del decorso della malattia, sia a una caratterizzazione del tipo di lesioni presenti basata sul loro grado di infiammazione. La sclerosi multipla è una malattia infiammatoria a decorso cronico che colpisce il sistema nervoso centrale, provocandone una progressiva distruzione della mielina in più aree. Per frequenza, nel giovane adulto è la seconda malattia neurologica e la prima di tipo infiammatorio cronico. Inoltre, la sclerosi multipla può essere considerata anche come malattia sociale, con un’elevata ricaduta economica, sia diretta che indiretta: la diminuzione o la perdita dell’autonomia porta alla progressiva impossibilità di svolgere una qualsiasi attività lavorativa fino all’incapacità di condurre una vita indipendente. A questo si aggiungano il costo delle cure e dell’assistenza necessarie. Benché le cause siano ancora in parte sconosciute, molto è stato fatto nel chiarire le diverse fasi del processo infiammatorio che caratterizza tale patologia, permettendo così di arrivare a una diagnosi e a un trattamento precoce che consentono di ridurre gli effetti della malattia. Le lesioni causate dalla sclerosi multipla risultano visibili grazie a particolari tecniche di acquisizione di immagini basate sulla risonanza magnetica. In particolare negli ultimi decenni si sono studiate e messe a punto diverse sequenze di risonanza ottimizzate per la visualizzazione delle lesioni in materia bianca. Il quadro delle tecniche a disposizione qualora si vogliano studiare lesioni in materia grigia risulta invece meno completo, soprattutto a causa del fatto che la scoperta di un coinvolgimento della materia grigia nella malattia è molto più recente. La verifica dell’evoluzione e della comparsa di nuove lesioni è importante dal momento che consente di monitorare il progredire di una malattia caratterizzata da fasi acute intervallate a periodi di quiescenza più o meno lunghi. Per questo motivo i soggetti affetti da sclerosi multipla vengono periodicamente sottoposti a esami di risonanza magnetica. Ogni successiva valutazione da parte del medico neurologo dipenderà da quanto evidenziato dalle immagini acquisite. In questo senso è fondamentale che il medico sia ben allenato nella valutazione di immagini di risonanza, e che ponga particolare attenzione non solo nell’individuare la comparsa di nuove lesioni, ma anche nel riconoscere la presenza di lesioni già presenti in esami precedenti, che possono essere progredite nella forma, nelle dimensioni e nel grado di attività. La lettura di un esame di risonanza magnetica richiede tempo e attenzione, ed è inevitabilmente soggetta all’errore umano che caratterizza qualsiasi valutazione manuale. Per questo, benché sia impensabile prescindere dalla valutazione del medico, una tecnica di analisi automatica di immagini di risonanza magnetica cerebrale che sia in grado di evidenziare la presenza di lesioni da sclerosi multipla può rappresentare un valido aiuto alla refertazione, sia in termini di tempo che di accuratezza. In questa tesi si descriveranno le tecniche di risonanza magnetica a disposizione per una miglior visualizzazione delle lesioni corticali. Su queste si procederà alla segmentazione del tessuto di interesse, ossia del volume di materia grigia. In seguito verrà descritta la tecnica proposta per il riconoscimento delle regioni patologiche corticali. Infine sarà descritto un primo tentativo di caratterizzazione delle diverse lesioni corticali, basato sulla valutazione del grado di attività di ciascuna lesione.
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Cocato, Maria Lucia. "Sobrecarga moderada de ferro em ratos: interação com frutanos e/ou fitato no metabolismo hepático e ósseo." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/9/9132/tde-10112016-153854/.
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O excesso de Fe no organismo gera espécies reativas de oxigênio (ERO) que são potencialmente tóxicas. Entretanto, a magnitude dos efeitos da exposição à moderada sobrecarga de Fe e da sua interação com facilitadores e/ou inibidores da absorção mineral não é conhecida. O objetivo deste trabalho foi avaliar esses efeitos e a sua interação com fruta nos e/ou fitato (facilitadores e inibidores da absorção de Fe, respectivamente) nos índices séricos do estado nutricional em Fe, no perfil dos lipídeos séricos e em parâmetros do metabolismo hepático e ósseo. Para o experimento foram utilizados 34 ratos machos Wistar, pesando inicialmente 49,3 ± 3,9g, alojados individualmente em gaiolas de aço semimetabólicas por 92 dias. Uma dieta AIN-93G (Dieta 1: Grupo Controle) e quatro dietas AIN93G modificadas foram usadas para o estudo, com as seguintes características: Dieta 2: sobrecarga moderada de ferro com 550mgFe/kg de ração (Grupo SBC); Dieta 3: sobrecarga moderada de ferro + 18% de farinha de yacon (Grupo SBC+FY); Dieta 4: sobrecarga moderada de ferro + 0,6% de fitato (Grupo SBC+FIT); Dieta 5: sobrecarga moderada de ferro + 18% de farinha de yacon + 0,6 % de fitato (Grupo SBC+FY+FIT). Os resultados demonstraram que a moderada sobrecarga de Fe ou a sua interação com farinha de yacon e/ou fitato não alterou os índices séricos do estado nutricional em Fe. Ocorreu aumento na atividade sérica da AST apenas no grupo SBC (p=0,055). Nos grupos SBC e SBC+FY houve diminuição na concentração do colesterol sérico (p=0,002) e, apenas no grupo SBC+FY+FIT, diminuição da concentração sérica do VLDL. No fígado, houve aumento significativo (p=0,002) da concentração de Fe não-heme nos grupos IO (+83%) e SBC+FIT (+117%) e, em todos os grupos SBC, na atividade da enzima GPx (p=0,000). A atividade da CAT foi menor (p=0,036) apenas para o grupo SBC+FY+FIT. Em todos os grupos SBC ocorreu significativo aumento nos depósitos de hemossiderina em torno das células de Kupffer (p=0,000). Houve aumento na apoptose em todos os grupos SBC, com os grupos SBC+FY e SBC+FY +FIT apresentando o maior número de corpúsculos apoptóticos/área (+405% e +342%, respectivamente) (p=0,000). Não houve alteração nos parâmetros relacionados ao metabolismo ósseo. No grupo SBC+FY houve significativo aumento na absorção aparente de Ca (p<0,05). Conclusões: A moderada sobrecarga de Fe não alterou os índices séricos do estado nutricional em Fe, mas resultou em alterações no tecido hepático e no perfil dos lipídeos séricos. Com exceção do perfil de lipídeos séricos, no qual apenas o fitato pareceu exercer efeito protetor, nos demais parâmetros avaliados a interação com farinha de yacon rica em fruta nos e/ou fitato reverteu parcial ou totalmente as alterações induzidas pela moderada sobrecarga de Fe.Excess Fe in the organism generates potentially toxic reactive oxygen species (ROS). However, the magnitude of the effects of a moderate Fe overload and its interaction with factors which inhibit or facilitate mineral absorption is not known. The aim of the present work was to evaluate such effects and their interaction with fructans and/or phytate (compounds which facilitate and inhibit Fe absorption, respectively) on serum iron status indices, on the profile of serum lipids and on hepatic and bone metabolism parameters. In the experiment, thirty-four male Wistar rats initially weighing 49,3 ± 3,9g were used. The rats were housed in individual stainless-steel wire-mesh cages for 92 days. An AIN-93G diet (Diet 1: Control Group) and four modified AIN-93G diets were used in the study. The modified diets presented the following formulations: Diet 2: moderate Fe overload with 550mgFe/kg diet (IO Group); Diet 3: moderate Fe overload + 18% yacon flour (IO-YF Group); Diet 4: moderate Fe verload + 0.6% phytate (IO-Phy Group); Diet 5: moderate Fe overload + 18% yacon flour + 0.6% phytate (IO-YF-Phy Group). The results demonstrated that a moderate Fe overload or its interaction with yacon flour and/or phytate did not alter the serum iron status indices. An increase in the serum AST activity was observed only in the IO group (p=0,055). In the IO and IO-YF groups, there was a reduction in the serum cholesterol concentration (p=0,002) and a reduction in the serum VLDL concentration was observed only in the IO-YF-Phy group. In the liver, there was a significant increase (p=0,002) in non-heme Fe concentration in the IO (+83%) and IO-Phy (+117%) groups. Also, GPx activity was significantly increased (p=0,000) in all IO groups. CAT activity was lower (p=0,036) only in the IO-YF-Phy group. A significant increase in hemosiderin deposition around Kupffer cells was observed in all IO groups (p=0,000). Apoptosis was increased in all IO groups, whereas the IO-YF and IO-YF-Phy groups showed the largest number of apoptotic bodies/area (+405% and +342%, respectively) (p=0,000). There was no alteration in the parameters related to bone metabolism. In the IO-YF group, there was a significant increase in Ca apparent absorption (p<0,05).Conclusions: The moderate Fe overload did not alter the serum iron status índices, but led to alterations in the hepatic tissue and in the profile of serum lipids. Except for the profile of serum lipids where only phytate seemed to have a protective effect, in the other evaluated parameters the interaction with yacon flour rich in fructans and/or phytate partially or totally reversed the alterations induced by the moderate Fe overload.
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Holt, Randall William. "MRI susceptometry: Theory and robustness of an external phantom method for measuring bulk susceptibility from MRI field echo phase reconstruction maps applied to human liver iron overload." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1057155289.
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Jatob?, Carlos Andr? Nunes. "Avalia??o bioqu?mica e hostol?gica de f?gado de ratas wistar diab?ticas e tratadas com tamoxifeno." Universidade Federal do Rio Grande do Norte, 2007. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13111.
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Previous issue date: 2007-10-19Tamoxifen (TX), a drug used in the treatment of breast cancer, may cause hepatic changes in some patients. The consequences of its use on the liver tissues of rats with or without diabetes mellitus (DM) have not been fully explored. The purpose of this multidisciplinary study was to evaluate the correlation between plasma hepatic enzyme levels and the presence of iron overload in the hepatic tissue of female Wistar rats with or without streptozotocin-induced DM and using TX. Female rats were studied in control groups: C-0 (non-drug users), C-V (sorbitol vehicle only) and C-TX (using TX). DM (diabetic non-drug users) and DM-TX (diabetics using TX) were the test groups. Sixty days after induced DM, blood samples were collected for glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST) alkaline phosphatase (ALP) and bilirubin measures. Hepatic fragments were processed and stained with hematoxylin and eosin (H&E), Masson s trichrome, Perls. The hepatic iron content was quantified by atomic absorption spectrometry. AST, ALT and ALP levels were significantly elevated in the DM and DM-TX groups, with unchanged bilirubin levels. Liver iron overload using Perls stain and atomic absorption spectrometry were observed exclusively in groups C-TX and DM-TX. There was positive correlation between AST, ALT and ALP levels and microscopic hepatic siderosis intensity in group DM-TX. In conclusion, TX administration is associated with liver siderosis in diabetic and non-diabetic rats. In addition, TX induced liver iron overload with unaltered hepatic function in 2 non-diabetic rats and may be a useful tool for investigating the biological control of iron metabolism
O tamoxifeno? (TX), utilizado no tratamento do c?ncer de mama, pode causar altera??es hep?ticas. As conseq??ncias de seu uso em tecido hep?tico de ratos com ou sem diabetes mellitus (DM) n?o foram completamente investigadas. O estudo de car?ter multidisciplinar visou avaliar a correla??o entre n?veis de enzimas hep?ticas no plasma e a presen?a de sobrecarga de ferro em tecido hep?tico de ratas com ou sem DM induzido por estreptozotocina e em uso de TX. Ratas Wistar foram estudadas em grupos? controle: C-O (sem uso de droga), C-V (somente sorbitol) e C-TX (em uso de TX). DM (diab?ticos sem uso de droga) e DM-TX (diab?ticos em uso de TX) foram os grupos teste. Sessenta dias ap?s a indu??o do DM, amostras de sangue foram colhidas para a mensura??o de glicose, alanina aminotransferase (ALT), aspartato aminotransferase (AST) , fosfatase alcalina (ALP) e bilirrubina. Amostras hep?ticas foram coradas com hematoxilina e eosina, Tricr?mio de Masson e Perls. O conte?do hep?tico de ferro foi quantificado por espectrometria de absor??o at?mica. AST, ALT e ALP apresentaram-se significativamente elevados nos grupos DM e DM-TX, com bilirrubina n?o alterada. Siderose ? colora??o Perls e pela espectrometria de absor??o at?mica foram observados apenas nos grupos C-TX e DM-TX. Houve correla??o positiva entre os n?veis de AST, ALT e ALP e a intensidade da siderose hep?tica microsc?pica no grupo DM-TX. Em conclus?o, o uso de TX ? associada com siderose hep?tica em ratas diab?ticas ou n?o. O TX induziu sobrecarga hep?tica de ferro sem alterar a fun??o hep?tica em animais n?o diab?ticos e pode ser uma ferramenta ?til no estudo do metabolismo do ferro.A participa??o de pesquisadores em Patologia, Cirurgia Experimental, Farm?cia Cl?nica, Toxicologia, Nutri??o, Mastologia, Endocrinologia e Biologia Molecular do Centro de Ci?ncias da Sa?de (CCS) e o Departamento de Estat?stica do Centro de Ci?ncias Exatas e da Terra (CCET), de forma integrada e coordenada, foi fundamental para a execu??o do projeto proposto, de car?ter multidisciplinar
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Evangelista, Andréia Silva. "Caracterização fenotípica e genotipagem HFE em portadores de doença hepática crônica com sobrecarga de ferro." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5168/tde-01082013-134115/.
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A doença hepática associada a sobrecarga de ferro pode ocorrer devido a causas genéticas ou secundárias. Esse estudo avaliou pacientes com hepatopatia crônica com sobrecarga de ferro submetidos à pesquisa das mutações HFE no período de 2007-2009 e classificou como portadores de hemocromatose hereditária HFE (HH-HFE) aqueles que apresentavam as mutações C282Y/C282Y ou C282Y/H63D e como sobrecarga de ferro não HFE aqueles que apresentavam outras mutações no gene HFE como C282Y/-, H63D/- e H63D/H63D ou pacientes sem qualquer uma dessas mutações mencionadas. Os objetivos do estudo foram 1) analisar e correlacionar os aspectos fenotípicos e genotípicos de grupo de indivíduos com doença hepática crônica e sobrecarga de ferro; 2) caracterizar o quadro clínico, laboratorial e anatomopatológico, em busca de achados compatíveis com o fenótipo de hemocromatose; 3) Correlacionar o quadro clínico com as mutações no gene HFE. Foram analisados 108 indivíduos portadores de hepatopatia crônica selecionados a partir de saturação de transferrina (ST) > 45% e ferritina sérica > 350 ng/mL. Foram estudados e comparados 16 pacientes no grupo HH-HFE com 92 no grupo sobrecarga de ferro não HFE. Da casuística geral, a idade média ao diagnóstico da doença foi de 46,69 anos (16-77), com 70,73% constituída por indivíduos de cor branca, 77,57% do sexo masculino e 64,8% tinham cirrose hepática. A frequência de cirrose hepática não diferiu entre os grupos, entretanto, artropatia, carcinoma hepatocelular, diabetes e osteoporose foram mais frequentes no grupo HH- HFE (53,8% x 15,9%, 31,2% x 7,06%, 56,2% x 30%, 72,7% x 32,1%, respectivamente, p < 0,05). Os pacientes com mutações HFE diagnósticas de HH apresentaram maior chance de ter carcinoma hepatocelular (OR= 5,0, p= 0,032) quando comparados com os portadores de outros genótipos HFE e aqueles sem mutação. Os níveis de ST, ferro e ferritina também foram maiores naquele grupo, bem como os graus de siderose 3 e 4 (p= 0,026). A ST foi a variável que se correlacionou independentemente com o diagnóstico das mutações C282Y/C282Y e C282Y/H63D. A frequência de fatores de risco para sobrecarga de ferro não diferiu entre os grupos. Observou-se, entretanto, que no grupo HH-HFE havia maior número de pacientes sem qualquer fator de risco detectado (p= 0,019). Níveis de ST > 82% apresentaram maior valor preditivo negativo para o diagnóstico de HH-HFE do que os de ferritina, ferro, capacidade total de ligação de ferro e de transferrina. Concluímos que os portadores de HH-HFE têm maiores graus de sobrecarga de ferro quando comparados ao grupo de sobrecarga de ferro não-HFE; em indivíduos com doença hepática crônica. ST > 82% tem maior acurácia para diagnóstico de HH-HFE; portadores de mutações C282Y em homozigose ou em heterozigose composta com H63D têm maior chance de apresentar carcinoma hepatocelular do que os portadores de outras mutações no gene HFE e pacientes sem mutaçãoChronic liver disease related to iron overload may occur due to genetic or secondary causes. This study analyzed patients with chronic liver diseases and iron overload who were tested for HFE mutations from 2007 to 2009. Patients with C282Y/C282Y or C282Y/H63D mutations were diagnosed with HFE hereditary hemochromatosis (HFE-HH) and those with other HFE genotypes (C282Y/-, H63D/- or H63D/H63D) or individuals without HFE mutations (wild type) were designed as non-HFE iron overload. The aims of this study were: 1) to analyze and to establish correlations between phenotypic and genotypic aspects of individuals with chronic liver disease and with iron overload; 2) to charachterize the clinical manifestations, laboratory and histological findings consistent with the phenotype of hemochromatosis; 3) to verify associations between clinical manifestations and HFE mutations. One hundred and eight patients with chronic liver diseases and with iron overload, defined as transferrin saturation (TS) > 45% and serum ferritin levels > 350 ng/mL were included. Sixteen patients had HH-HFE and were compared with 92 patients with non-HFE iron overload group. The average of age at diagnosis was 46.69 years (16-77), 70.73% were Caucasians, 77.57% were male and 64.8% had hepatic cirrhosis. The proportion of hepatic cirrhosis was similar in both groups, nevertheless arthropathy, hepatocellular carcinoma, diabetes and osteoporosis were more frequent in the HFE-HH group (53,8% x 15,9%, 31,2% x 7,06%, 56,2% x 30%, 72,7% x 32,1%, respectively, p < 0,05). The HFE C282Y/C282Y or C282Y/ H63D genotypes had a higher chance to develop hepatocellular carcinoma (OR= 5.0, p= 0.032) when compared with the other HFE genotypes and with those wild type. The levels of TS, serum iron and ferritin were greater in HFE-HH group, as well as hepatic siderosis grade 3 and 4 (p= 0.026). TS was the biochemical marker of iron overload with the higher independent correlation with the presence of C282Y/C282Y and C282Y/H63D mutations. The frequency of risk factors for iron overload was not different between the groups, however, in HFE-HH group a greater number of patients without any risk factor was detected (p= 0.019). TS > 82% had a higher predictive negative value for diagnosing HFE-HH when compared to the levels of ferritin, serum iron, total iron binding capacity and transferrin. We concluded that the HFE-HH patients had a greater iron overload than patients with chronic liver diseases with non-HFE iron overload. TS > 82% had more accuracy to diagnose HFE-HH. The carriers of C282Y/C282Y or C282Y/H63D mutations had a higher probability to develop hepatocellular carcinoma, when compared to the patients with HFE genotypes and patients wild type
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Andrade, Lara Filipe Rocha. "Hereditary hemochromatosis: cellular response to oxidative stress." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/12495.
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Mestrado em Bioquímica - Bioquímica ClínicaIron is a key element for basic cellular functions. If iron homeostasis is not maintained it may lead to iron overload. Patients with Hereditary Hemochromatosis (HH) and with the C282Y HFE mutation have a progressive severe iron overload that, if it is not treated, may lead to tissue damage, that mostly culminate in hepatic cirrhosis and carcinoma. Having in mind that tissue damage in HH may be related with oxidative stress (OS) caused by iron toxicity, it is important to understand in what way the OS defense is acting in cells from HH patients with severe forms of iron overload. Few studies have been performed concerning the eventual prooxidant state in blood cells, which bear a major source of OS. Nevertheless, in a recent study it was shown that cultured lymphocytes (LY) from HH, when compared with cultured LY from controls and patients with secondary forms of hemochromatosis, have an increased protection against chromosome instability (CI) induced by 1,2:3,4 diepoxybutane (DEB) – an OS-related alkylating agent. This suggests an adaptive response of HH cells to the high level of OS. However, it is not known yet if the same response can be observed with other sources of iron toxicity, namely in the presence of bleomycin (BLM), that acts forming a complex with non-transferrin bound iron (NTBI). In order to better understand the oxidant status of HH blood cells and the putative adaptive response of HH cells to iron toxicity, a study was performed to characterize two selected OS parameters: evaluation of reduced glutathione (GSH) depletion and of lipid peroxidation (LPO). The study was performed in red blood cells (RBC) and lymphocytes (LY), either basal and after 36h in culture, with and without induction of OS. Induction of OS was performed with DEB and with BLM. A second objective of the present work was to test if the previously observed adaptive response of HH cells to DEB-induced OS can also be observed after induction with BLM. Characterization of the OS parameters was performed in RBC and LY from 5 HH patients with severe iron overload and 6 healthy donors (HD), at day 0 and after 36h of culture, non-treated and treated with DEB or BLM. Studies of CI were performed in BLM-induced LY from the same 5 HH patients and 6 HD. The results show that RBC from HH patients, compared with those from HD, have a larger GSH depletion and more LPO, either at day 0 and after 36h in culture medium. This suggests an increased level of OS in HH RBC. On the contrary, LY from HH patients present less GSH depletion after 36h of culture than LY from HD, being this effect more pronounced in DEB and BLM-treated cultures. Additionally, LPO levels were decreased in LY from HH patients after 36h of culture when compared with LY from HD. This result suggests that HH cultured LY, either non-treated or treated with DEB and BLM, have a still not completely understood mechanism of defense against OS. BLM-induced CI in cultured LY from HH patients was not different from the observed in cultured LY from HD. Therefore, we can postulate that toxicity induced by BLM did not increased CI in cells from HH patients with severe iron overload.
O ferro é um dos elementos chave para as funções celulares básicas. Se a sua homeostasia não for corretamente mantida, poderá ocorrer uma sobrecarga de ferro no organismo. Os doentes com Hemocromatose Hereditária (HH), com a mutação C282Y no gene HFE, possuem uma progressiva e severa sobrecarga de ferro que, se não for tratada, pode levar a dano nos tecidos, podendo mesmo culminar em cirrose hepática e carcinoma. Tendo em conta que o dano tecidular pode estar associado ao stress oxidativo (OS) causado pela sobrecarga de ferro, é importante perceber de que modo atua o sistema de defesa contra o OS nas células dos doentes HH com forma severa de sobrecarga de ferro. Poucos estudos foram realizados sobre o potencial estado oxidante nas células do sangue, onde se encontra uma das maiores fontes de reações oxidativas. Contudo, num estudo recente foi demonstrado que linfócitos de doentes com HH, quando comparados com linfócitos de controlos e pacientes com formas secundárias de hemocromatose, apresentam uma maior proteção relativamente à instabilidade cromossómica (CI) induzida por 1,2:3,4 diepoxibutano (DEB) – um agente alquilante que provoca OS. Este estudo sugere uma resposta adaptativa das células HH a níveis elevados de OS. No entanto, ainda não se sabe se esta mesma resposta pode ser observada com outras fontes de toxicidade do ferro, nomeadamente na presença de bleomicina (BLM) cuja atividade depende da formação de complexos com o ferro não ligado à transferrina (NTBI). Para compreender melhor o estado oxidante das células do sangue dos doentes HH e a suposta resposta adaptativa das células dos doentes de HH à toxicidade do ferro, foi feita a análise de dois parâmetros de OS selecionados: avaliação da depleção da glutationa reduzida (GSH) e da peroxidação lipídica (LPO). Esta análise foi efetuada em eritrócitos (RBC) e linfócitos (LY), tanto no tempo 0 como passadas 36h em cultura, com ou sem indução de OS. O segundo objetivo deste trabalho foi testar se a BLM promove uma resposta adaptativa à CI comparável à que foi observada com o DEB. Tanto a caracterização dos parâmetros de OS como os estudos de CI foram efetuados em células de 5 doentes com HH, com elevada sobrecarga de ferro, e em células de 6 dadores saudáveis (HD). Os resultados mostraram que os RBC dos doentes com HH, comparativamente com os dos HD, apresentam uma maior depleção de GSH e maior LPO, quer ao dia 0 quer após 36h em meio de cultura. Estes resultados sugerem um aumento de OS nos RBC dos doentes. Contrariamente, os LY dos doentes de HH apresentaram menor depleção de GSH após 36h de cultura, sendo esta mais notória nas culturas induzidas com DEB e BLM. Adicionalmente, os níveis de LPO são menores em LY dos doentes de HH, após 36h de cultura, comparativamente com os dos HD. Isto sugere que culturas de LY, quer não-tratadas quer tratadas com DEB ou BLM, têm um algum tipo de mecanismo de defesa contra o OS, ainda não compreendido. A frequência de CI induzida por BLM em LY de doentes com HH não é significativamente diferente da observada em LY de HD, não se observando assim uma diferença na capacidade de resposta à BLM, entre células de doentes e controlos. Pode-se então concluir que a toxicidade induzida por BLM não aumenta a CI em células de doentes com HH com forma severa de sobrecarga de ferro.
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Silva, Marcus Tolentino [UNIFESP]. "Boletim brasileiro de avaliação de tecnologias em saúde: deferasirox para o tratamento da sobrecarga de ferro." Universidade Federal de São Paulo (UNIFESP), 2011. http://repositorio.unifesp.br/handle/11600/9151.
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Publico-12515.pdf: 978359 bytes, checksum: 3be0798a82267f20204fe25244cbed7d (MD5)Objetivo: Avaliar a evidência de eficácia e segurança do deferasirox para o tratamento da sobrecarga de ferro relacionada à betatalassemia, doença falciforme e síndrome mielodisplásica, em comparação a outros quelantes de ferro disponíveis no Brasil (desferroxamina e deferiprona). Método: Para síntese da evidência foi realizada busca por relatórios de agências de avaliação de tecnologias em saúde e por revisões sistemáticas no Medline (março 2009). Adicionalmente, foi feita busca por ensaios clínicos para atualização da informação disponível. Das referências identificadas, foi selecionado o trabalho de McLeod (2009), por ser uma revisão sistemática e estudo de avaliação econômica elaborado por uma agência de avaliação de tecnologias em saúde de alta confiabilidade. Considerando o contexto econômico local e a disponibilidade dos medicamentos e insumos laboratoriais, a evidência foi adaptada e avaliada criticamente. Resultados: A evidência encontrada é baseada em três ensaios clínicos, de baixa qualidade metodológica, que avaliaram o uso do deferasirox em relação à desferroxamina. Não foram localizados estudos comparativos entre o deferasirox e a deferiprona. Nos ensaios clínicos identificados, a concentração hepática de ferro (exame não disponível no Brasil) foi considerada como desfecho primário, apesar de na prática clínica a quantidade de ferro ser monitorada pela concentração de ferritina sérica. As mudanças na ferritina sérica revelam-se mais favoráveis em pacientes com betatalassemia e doença falciforme (maior prevalência no Brasil) que receberam desferroxamina, do que aqueles que receberam deferasirox. As informações econômicas levantadas indicam que o deferasirox, em comparação a desferroxamina pode ser uma opção custo-efetiva. Conclusões: Como o deferasirox foi introduzido recentemente no mercado brasileiro e é considerado alternativa de tratamento no sistema público de saúde, informações de farmacovigilância precisam ser monitoradas, principalmente no que se refere ao risco de insuficiência renal, citopenias (agranulocitose e trombocitopenia), além de distúrbios gastrointestinais, hepáticos, renais e sanguíneos.
Objectives: to evaluate the evidence on efficacy and safety regarding deferasirox for treatment of iron overload relating to beta-thalassemia, sickle cell disease and myelodysplastic syndrome, in comparison with other iron chelators available in Brazil (deferoxamine and deferiprone). Methods: to produce a synthesis of the evidence, a search was conducted using reports from HTA agencies and systematic reviews in Medline (March 2009). Additionally, a search for clinical trials was conducted to update the information available. Among the references identified, the study by McLeod (2009) was selected because this was a systematic review and economic evaluation produced by a highly trustworthy HTA agency. Considering the local economic context and the availability of medications and laboratory supplies, the evidence was adapted and critically evaluated. Results: the evidence found was based on three clinical trials of low methodological quality that evaluated the use of deferasirox in relation to deferoxamine. No comparative studies between deferasirox and deferiprone were found. In the clinical trials identified, hepatic iron concentration (a test unavailable in Brazil) was taken to be the primary outcome, although in clinical practice, the iron levels were monitored by means of the serum ferritin concentration. The changes in serum ferritin concentration were more favorable among patients with beta thalassemia and sickle cell disease (highest prevalence in Brazil) who received deferoxamine than among those who received deferasirox. Previous economic evaluation suggests that deferasirox may be a cost-effective strategy. Conclusions: since deferasirox was only recently introduced onto the Brazilian market and is considered to be an alternative for treatment within the public healthcare system, drug surveillance information is required, particularly regarding the risks of kidney failure, cytopenia (agranulocytosis and thrombocytopenia) and gastrointestinal, hepatic, renal and blood disorders.
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