Doxorubicin paradoxically protects cardiomyocytes against iron-mediated toxicity: role of reactive oxygen species and ferritin.

The cardiotoxicity induced by the anticancer anthracycline doxorubicin (DOX) is attributed to reactions between iron and reactive oxygen species (ROS) that lead to oxidative damage. We found that DOX forms ROS in H9c2 cardiomyocytes, as shown by dichlorodihydrofluorescein oxidation and the expression of stress-responsive genes such as catalase or aldose reductase. DOX also increased ferritin levels in these cells, particularly the H subunit. A considerable increase in ferritin mRNA levels showed that DOX acted at transcriptional level, but an additional potential mechanism was identified as the down-regulation of iron regulatory protein-2, post-transcriptional inhibitor of ferritin synthesis. Pretreatment with DOX protected H9c2 cells against the damage induced by subsequent exposure to ferric ammonium citrate, and experiments with 55Fe revealed that the protection was due to the deposition of iron in ferritin. Cytoprotection was also observed when DOX was replaced by glucose/glucose oxidase, a source of H2O2, thus suggesting that DOX increases ferritin synthesis through the action of ROS. This concept was supported by three more lines of evidence. (i) DOX-induced ferritin synthesis was blocked by N-acetylcysteine, a scavenger of ROS. (ii) Mitoxantrone, a ROS-forming analogue, similarly induced ferritin expression and protected the cells against iron toxicity. (iii) 5-Iminodaunorubicin, an analogue lacking ROS-forming activity, did not induce ferritin synthesis or protect the cells against iron toxicity. These results characterize a paradoxically beneficial link between anthracycline-derived ROS, increased ferritin synthesis, and resistance to iron-mediated damage. The role of iron and ROS in anthracycline-induced cardiotoxicity may, therefore, be more complex than previously believed

Three-dimensional easy morphological (3-DEMO) classification of scoliosis, part I

BACKGROUND: While scoliosis has, for a long time, been defined as a three-dimensional (3D) deformity, morphological classifications are confined to the two dimensions of radiographic assessments. The actually existing 3-D classification proposals have been developed in research laboratories and appear difficult to be understood by clinicians. AIM OF THE STUDY: The aim of this study was to use the results of a 3D evaluation to obtain a simple and clinically oriented morphological classification (3-DEMO) that might make it possible to distinguish among different populations of scoliotic patients. METHOD: We used a large database of evaluations obtained through an optoelectronic system (AUSCAN) that gives a 3D reconstruction of the spine. The horizontal view was used, with a spinal reference system (Top View). An expert clinician evaluated the morphological reconstruction of 149 pathological spines in order to find parameters that could be used for classificatory ends. These were verified in a mathematical way and through computer simulations: some parameters had to be excluded. Pathological data were compared with those of 20 normal volunteers. RESULTS: We found three classificatory parameters, which are fully described and discussed in this paper: Direction, the angle between spinal pathological and normal AP axis; Shift, the co-ordinates of the barycentre of the Top View ; Phase, the parameter describing the spatial evolution of the curve. Using these parameters it was possible to distinguish normal and pathological spines, to classify our population and to differentiate scoliotic patients with identical AP classification but different 3D behaviors. CONCLUSION: The 3-DEMO classification offers a new and simple way of viewing the spine through an auxiliary plane using a spinal reference system. Further studies are currently under way to compare this new system with the existing 3-D classifications, to obtain it using everyday clinical and x-rays data, and to develop a triage for clinical use

Wearable device for swim assessment: a new ecologic approach for communication and analysis

This paper describes a wearable system for the assessment of swim performance focusing on the description of the system and especially on the novel method for data transmission in water, and the algorithm used for extracting some parameters for the qualitative assessment of the performance. We placed a 3-axes Inertial Measurement Unit (IMU) on the athlete's back in a specific swimsuit, which also allows for recording 1-lead ECG. The system and the algorithm have been tested on 13 trials with 10 subjects comparing the results with data extracted from video recording. The system demonstrated able and reliable to measure time and kinematic parameters of swimming

Human Mitochondrial Ferritin Expressed in HeLa Cells Incorporates Iron and Affects Cellular Iron Metabolism

Mitochondrial ferritin (MtF) is a newly identified ferritin encoded by an intronless gene on chromosome 5q23.1. The mature recombinant MtF has a ferroxidase center and binds iron in vitro similarly to H-ferritin. To explore the structural and functional aspects of MtF, we expressed the following forms in HeLa cells: the MtF precursor (approximately 28 kDa), a mutant MtF precursor with a mutated ferroxidase center, a truncated MtF lacking the approximately 6-kDa mitochondrial leader sequence, and a chimeric H-ferritin with this leader sequence. The experiments show that all constructs with the leader sequence were processed into approximately 22-kDa subunits that assembled into multimeric shells electrophoretically distinct from the cytosolic ferritins. Mature MtF was found in the matrix of mitochondria, where it is a homopolymer. The wild type MtF and the mitochondrially targeted H-ferritin both incorporated the (55)Fe label in vivo. The mutant MtF with an inactivated ferroxidase center did not take up iron, nor did the truncated MtF expressed transiently in cytoplasm. Increased levels of MtF both in transient and in stable transfectants resulted in a greater retention of iron as MtF in mitochondria, a decrease in the levels of cytosolic ferritins, and up-regulation of transferrin receptor. Neither effect occurred with the mutant MtF with the inactivated ferroxidase center. Our results indicate that exogenous iron is as available to mitochondrial ferritin as it is to cytosolic ferritins and that the level of MtF expression may have profound consequences for cellular iron homeostasis

Spatial resource wars: A two region example

We develop a spatial resource model in continuous time in which two agents strategically exploit a mobile resource in a two-location setup. In order to contrast the overexploitation of the resource (the tragedy of commons) that occurs when the player are free to choose where to fish/hunt/extract/harvest, the regulator can establish a series of spatially structured policies. We compare the three situations in which the regulator: (a) leaves the player free to choose where to harvest; (b) establishes a natural reserve where nobody is allowed to harvest; (c) assigns to each player a specific exclusive location to hunt. We show that when preference parameters dictate a low harvesting intensity, the policies cannot mitigate the overexploitation and in addition they worsen the utilities of the players. Conversely, in a context of harsher harvesting intensity, the intervention can help to safeguard the resource, preventing the extinction and also improving the welfare of both players

Gait Analysis before and after Gastrocnemius Fascia Lengthening for Spastic Equinus Foot Deformity in a 10-Year-Old Diplegic Child

Purpose. This case study quantified kinematic and kinetic effects of gastrocnemius lengthening on gait in a Cerebral Palsy child with equinus foot. Methods. A 10-year-old diplegic child with Cerebral Palsy was evaluated with Gait Analysis (GA) before and after gastrocnemius fascia lengthening, investigating the lower limb joints kinematics and kinetics. Results. Kinematics improved at the level of distal joints, which are directly associated to gastrocnemius, and also at the proximal joint (like hip); improvements were found in ankle kinetics, too. Conclusions. This case study highlighted that GA was effective not only to quantify the results of the treatment but also to help preoperative decision making in dealing with CP child