ESA, iron therapy and new drugs: Are there new perspectives in the treatment of anaemia?

Anemia is a well-known consequence of chronic kidney disease (CKD); it is mainly due to a relative insufficiency of erythropoietin synthesis by the failing kidneys. Over the years, the combination of erythropoiesis stimulating agents (ESA) and iron has become the standard of care of anemia. All ESAs effectively increase hemoglobin (Hb) levels in a substantial percentage of patients. However, in the last decade, their use has been surrounded by safety issues in increased cardiovascular risk, especially when used at high doses in inflamed and hyporesponsive patients. This has led to the definition of a more cautious Hb target. Iron deficiency is very frequent in CKD patients, with a higher frequency in non-dialysis patients. Traditionally, iron supplementation is mostly used as supportive therapy for anemia control. However, the concept is growing that intravenous iron therapy per se could be beneficial in the presence of heart failure. A new class of drugs, prolyl hydroxylase domain (PHD) inhibitors (PHD inhibitors) is becoming available for the treatment of anemia in CKD patients. Theoretically, these agents have a number of advantages, the main ones being that of stimulating the synthesis of endogenous erythropoietin and increasing iron avail-ability. The impact of their future use in clinical practice is still to be defined. Another possible strategy could be targeting serum hepcidin and its related pathways. This possibility is fascinating from the scientific point of view, but at present its development phase is still far from clinical application

Limit analysis of conical and parabolic domes based on semi-analytical solution

The evaluation of limit loads of masonry domes has received increasing interest especially due to the importance of historical buildings where domes mainly are one of the most relevant structures. The limit design is used to obtain the safety assessment and the design guidance for restoration and transformation toward preservation and reuse of historical heritage. In the following paper, we present a formulation of the limit analysis based on the semi-analytical approach that starts on Melan's theorem. The self-equilibrated Melan's residual is obtained through the discretization of the analytical form of the equilibrium equation of the spherical dome. The procedure provides a finite-dimensional map of the eigenstress of the structure. Furthermore, the superimposition of the elastic solution to actual loads, obtained by finite element calculation, completes the admissible stress evaluation. Such amissible stress is introduced into the maximization algorithm, based on the lower bound theorem, which results in the collapse load. The same approach is used to get the safety assessment under prescribed load that allows checking the safety of prescribed load pattern and geometry

Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53 independent pathways

Most cancer cells use aerobic glycolysis to fuel their growth. The enzyme lactate dehydrogenase-A (LDH-A) is key to cancer’s glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD þ ) from reduced nicotinamide adenine dinucleotide (NADH) necessary to sustain glycolysis. As such, LDH-A is a promising target for anticancer therapy. Here we ask if the tumour suppressor p53, a major regulator of cellular metabolism, influences the response of cancer cells to LDH-A suppression. LDH-A knockdown by RNA interference (RNAi) induced cancer cell death in p53 wild-type, mutant and p53-null human cancer cell lines, indicating that endogenous LDH-A promotes cancer cell survival irrespective of cancer cell p53 status. Unexpectedly,however,weuncoveredanovelroleforp53intheregulationofcancercellNADþ anditsreducedformNADH.Thus, LDH-A silencing by RNAi, or its inhibition using a small-molecule inhibitor, resulted in a p53-dependent increase in the cancer cell ratioofNADH:NADþ.Thiseffectwasspecificforp53þ/þ cancercellsandcorrelatedwith(i)reducedactivityofNADþ-dependent deacetylase sirtuin 1 (SIRT1) and (ii) an increase in acetylated p53, a known target of SIRT1 deacetylation activity. In addition, activation of the redox-sensitive anticancer drug EO9 was enhanced selectively in p53 þ / þ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53þ/þ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADþ cellular redox status can be modulated in a cancer-specific, p53-dependent manner and we show that this can impact upon the activity of important NAD(H)-dependent enzymes. To summarise, this work indicates two distinct mechanisms by which suppressing LDH-A could potentially be used to kill cancer cells selectively, (i) through induction of apoptosis, irrespective of cancer cell p53 status and (ii) as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism

Thermal Kinetic Inductance Detectors for Millimeter-Wave Astrophysics

Thermal Kinetic Inductance Detectors (TKIDs) combine the excellent noise performance of traditional bolometers with a radio frequency (RF) multiplexing architecture that enables the large detector counts needed for the next generation of millimeter-wave instruments. Here we present dark prototype TKID pixels that demonstrate a noise equivalent power NEP = 2×10⁻¹⁷√W/Hz with a 1/f knee at 0.1 Hz, suitable for background-limited noise performance at 150 GHz from a ground-based site. We discuss the optimizations in the device design and fabrication techniques to realize optimal electrical performance and high quality factors at a bath temperature of 250 mK

Functionally graded plate fracture analysis using the field boundary element method

This paper describes the Field Boundary Element Method (FBEM) applied to the fracture analysis of a 2D rectangular plate made of Functionally Graded Material (FGM) to calculate Mode I Stress Intensity Factor (SIF). The case study of this Field Boundary Element Method is the transversely isotropic plane plate. Its material presents an exponential variation of the elasticity tensor depending on a scalar function of position, i.e., the elastic tensor results from multiplying a scalar function by a constant taken as a reference. Several examples using a parametric representation of the structural response show the suitability of the method that constitutes a Stress Intensity Factor evaluation of Functionally Graded Materials plane plates even in the case of more complex geometries

Localization Capability of Cooperative Anti-Intruder Radar Systems

System aspects of an anti-intruder multistatic radar based on impulse radio ultrawideband (UWB) technology are addressed. The investigated system is composed of one transmitting node and at least three receiving nodes, positioned in the surveillance area with the aim of detecting and locating a human intruder (target) that moves inside the area. Such systems, referred to also as UWB radar sensor networks, must satisfy severe power constraints worldwide imposed by, for example, the Federal Communications Commission (FCC) and by the European Commission (EC) power spectral density masks. A single transmitter-receiver pair (bistatic radar) is considered at first. Given the available transmitted power and the capability of the receiving node to resolve the UWB pulses in the time domain, the surveillance area regions where the target is detectable, and those where it is not, are obtained. Moreover, the range estimation error for the transmitter-receiver pair is discussed. By employing this analysis, a multistatic system is then considered, composed of one transmitter and three or four cooperating receivers. For this multistatic system, the impact of the nodes location on area coverage, necessary transmitted power and localization uncertainty is studied, assuming a circular surveillance area. It is highlighted how area coverage and transmitted power, on one side, and localization uncertainty, on the other side, require opposite criteria of nodes placement. Consequently, the need for a system compromising between these factors is shown. Finally, a simple and effective criterion for placing the transmitter and the receivers is drawn

High cardiovascular risk in patients with Type 2 diabetic nephropathy: the predictive role of albuminuria and glomerular filtration rate. The NID-2 Prospective Cohort Study

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Thermal Kinetic Inductance Detectors for Millimeter-Wave Astrophysics

Thermal Kinetic Inductance Detectors (TKIDs) combine the excellent noise performance of traditional bolometers with a radio frequency (RF) multiplexing architecture that enables the large detector counts needed for the next generation of millimeter-wave instruments. Here we present dark prototype TKID pixels that demonstrate a noise equivalent power NEP = 2×10⁻¹⁷√W/Hz with a 1/f knee at 0.1 Hz, suitable for background-limited noise performance at 150 GHz from a ground-based site. We discuss the optimizations in the device design and fabrication techniques to realize optimal electrical performance and high quality factors at a bath temperature of 250 mK