Improving survival with deferiprone treatment in patients with thalassemia major: A prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone–deferoxamine (DFP–DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP–DFO, or combined DFP–DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP–DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP–DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value <0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and ag

Spatiotemporal dynamics of nicotinic acetylcholine receptors and lipid platforms

Abstract: The relationships between neurotransmitter receptors and their membrane environment are complex, mutual (bidirectional) and physiologically important. Some of these relationships are established with subsets of the membrane lipid population, in the form of lipid platforms, lateral heterogeneities of the bilayer lipid having a dynamic chemical composition distinct from that of the bulk membrane. In addition to the equilibrium between the biosynthetic production, exocytic delivery and recycling of receptors on the one hand, and the endocytic internalization on the other, lateral diffusion, clustering and anchorage of receptors at the lipid platforms play key roles in determining the amount of active receptors at the synapse. Mobile receptors traffic between reservoir non-synaptic membranes and the synapse predominantly by thermally driven Brownian motion, and become immobilized at the perisynaptic region or the synapse proper by various mechanisms. These comprise: (a) clustering mediated by homotropic inter-molecular receptor-receptor associations; (b) heterotropic associations with non-receptor scaffolding proteins or the subjacent cytoskeletal meshwork, leading to diffusional “trapping”, and (c) protein-lipid interactions, particularly with the neutral lipid cholesterol. Preceded by a brief introduction on the currently used methods to study protein lateral mobility in membranes, this review assesses the contribution of some of these mechanisms to the supramolecular organization and dynamics of the paradigm neurotransmitter receptor of muscle and neuronal cells—the nicotinic acetylcholine receptor (nAChR). The translational mobility of nAChRs at these two cell surfaces differs in terms of diffusion coefficients and residence intervals at the synapse, which cover an ample range of time regimes. Neuronal α7 nAChRs exhibit diffusion coefficients similar to those of other neurotransmitter receptors and spend part of their lifetime confined to the perisynaptic region of glutamatergic (excitatory) and GABAergic (inhibitory) synapses; they may also be involved in the regulation of the dynamic equilibrium between excitation and inhibition in brain