Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions

Non-transfusion-dependent thalassaemias (NTDT) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with β thalassaemia intermedia (n = 95), haemoglobin (Hb) E/β thalassaemia (n = 49) and Hb H syndromes (n = 22). Liver iron concentration (LIC), serum ferritin (SF), transferrin saturation (TfSat) and non-transferrin-bound iron (NTBI) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR), labile plasma iron (LPI) and nucleated red blood cells (NRBCs), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI, TfSat, NRBCs and SF relative to LIC, than non-splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR, growth differentiation factor-15, NRBCs) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI, LPI and NRBCs. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra-hepatic iron distribution are more likely in previously transfused, splenectomised and iron-overloaded NTDT patients with TfSat >70%

Displaced Tokyo

LAUREA MAGISTRALEThe phenomenon of urbanization has become, in the past decades, a major issue in the global economy. Huge masses of people have been moving at a high rate to the urbanized areas. Cities, in order to satisfy the demand for spaces, are in constant evolution and expansion. This phenomenon demands architects and urban planners great caution and understanding of it. The purpose of this thesis is to analyze the condition of modern metropolises, by taking as test subject the city of Tokyo, probably Today’s biggest and most advanced urban agglomerate in the World. The work hereby proposed, is an investigation on a specific thematic that affects most of the urban territories: the relation between spaces and their uses. In this research, Photography has been used as added investigative device. In particular, the thesis is focused on the distinction between the designed use of a space, meaning the use expected by architects and planners, and the actual use of it, meaning the use that people, living the city, do of it. Tokyo represents, in this sense, an extremely interesting case study for different reasons: first, the contradiction between the absence of an urban plan, as the city grows like an organism, spontaneously, and the design of specific spaces of the city, extremely normed and defined, not leaving any space to spontaneity in their use. Second, the absence of public spaces as Western culture defines them, due to an extremely privatized society, as Japanese society is. The structure of the work is based on two distinct moments of it: a theoretical part, with both an objective description of the city and a subjective one, based on the months I spent living there; and the photographic corpus. The photographic research is structured into five ‘chapters’; each chapter represents a dimension of the city, meaning a peculiar characteristic that can be recognized in most of the big cities of the World. It is an experiment of re-construction of the image of a personal city, a reflection of the idea that in order to survive in such a metropolitan jungle, the inhabitants have to build their own cities in the city, with spaces they specifically design, even though not physically, for themselves, according to their needs and will, cutting them out from the material city

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

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

Effects of combined deferiprone with deferoxamine on right ventricular function in thalassaemia major

BACKGROUND: Combination therapy with deferoxamine and oral deferiprone is superior to deferoxamine alone in removing cardiac iron and improving left ventricular ejection fraction (LVEF). The right ventricle (RV) is also affected by the toxic effects of iron and may cause additional cardiovascular perturbation. We assessed the effects of combination therapy on the RV in thalassaemia major (TM) using cardiovascular magnetic resonance (CMR). METHODS: We retrieved imaging data from 2 treatment trials and re-analyzed the data for the RV responses: Trial 1 was a randomized controlled trial (RCT) of 65 TM patients with mild-moderate cardiac siderosis receiving combination therapy or deferoxamine with placebo; Trial 2 was an open label longitudinal trial assessing combination therapy in 15 TM patients with severe iron loading. RESULTS: In the RCT, combination therapy with deferoxamine and deferiprone was superior to deferoxamine alone for improving RVEF (3.6 vs 0.7%, p = 0.02). The increase in RVEF was greater with lower baseline T2* 8-12 ms (4.7 vs 0.5%, p = 0.01) than with T2* 12-20 ms (2.2 vs 0.8%, p = 0.47). In patients with severe cardiac siderosis, substantial improvement in RVEF was seen with open-label combination therapy (10.5% ± 5.6%, p < 0.01). CONCLUSIONS: In the RCT of mild to moderate cardiac iron loading, combination treatment improved RV function significantly more than deferoxamine alone. Combination treatment also improved RV function in severe cardiac siderosis. Therefore adding deferiprone to deferoxamine has beneficial effects on both RV and LV function in TM patients with cardiac siderosis

Recent advances in β-thalassemias

β-thalassemias are heterogeneous hereditary anemias characterized by a reduced output of β-globin chains. The disease is most frequent in the temperate regions of the world, where it represents an important health problem. In the last decades, several programs, aimed at controlling the birth rate of thalassemia newborns by screening and prenatal diagnosis of populations with high risk of β-thalassemia, have been successful accomplished. Bone marrow transplantation has offered a definitive cure for the fraction of patients with available donors. In the same time, steady improvements were made in the traditional clinical management of β-thalassemia patients. The introduction of the oral iron chelators deferiprone that preferentially chelates hearth iron and the development of novel NMR diagnostic methods has led to reduced morbility, increased survival and improved quality of life. More recently, major advances have being made in the discovery of critical modifier genes, such as Myb and especially BCL11A (B cell lymphoma 11A), a master regulator of HbF (fetal hemoglobin) and hemoglobin switching. Polimorphysms of BCL11A, Myb and γ-globin genes account for most of the variability in the clinical phenotypes in β-thalassemia and sickle cell anemia patients. Finally, the year 2010 has brought in the first successful experiment of gene therapy in a β-thalassemia patient, opening up the perspective of a generalized cure for all β- thalassemia patients

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

The highest approved dose of deferasirox is currently 30 mg/kg per d in many countries; however, some patients require escalation above 30 mg/kg per d to achieve their therapeutic goals. This retrospective analysis investigated the efficacy (based on change in serum ferritin levels) and safety of deferasirox >30 mg/kg per d in adult and paediatric patients with transfusion-dependent anaemias, including β-thalassaemia, sickle cell disease and the myelodysplastic syndromes. In total, 264 patients pooled from four clinical trials received doses of >30 mg/kg per d; median exposure to deferasirox >30 mg/kg per d was 36 weeks. In the overall population there was a statistically significant median decrease in serum ferritin of 440 μg/l (P< 0·0001) from pre-dose-escalation to the time-of-analysis; significant decreases were also observed in adult and paediatric patients, as well as β-thalassaemia patients. The adverse event profile in patients who received deferasirox doses of >30 mg/kg per d was consistent with previously published data. There was no worsening of renal or liver function following dose escalation. Deferasirox >30 mg/kg per d effectively reduced iron burden to levels lower than those achieved prior to dose escalation in patients with transfusion-dependent anaemias. This has important implications for patients who are heavily transfused and may require higher doses to reduce body iron burden

Combined therapy with deferiprone and desferrioxamine in thalassemia major

Effective and convenient iron chelation remains one of the main targets of clinical management of thalassemia major. The combined treatment with desferrioxamine and deferiprone could have an increased chelation efficacy and sometimes allow drug doses and toxicity to be reduced and the number of days of desferrioxamine infusion to be decreased, improving compliance and quality of life