Beta-Blockers and Ivabradine in Chronic Heart Failure: From Clinical Trials to Clinical Practice

Beta-blockers have become one of the cornerstones of treatment of patients with heart failure (HF) and depressed left ventricular function, but in clinical practice only 30–35 % of patients achieve the therapeutic target dose as established in randomized clinical trials. Moreover, high resting heart rate (HR) has emerged as a simple but relevant risk factor for cardiovascular events, including coronary artery disease and HF; also, it was found to have an independent prognostic value in patients with HF. Evidence that HR could be considered a good parameter to evaluate the quality of treatment in patients with HF has been suggested; of note, many patients maintain a resting HR ≥70 beats per minute despite optimal beta-blocker therapy. In recent years, a new drug able to reduce HR, ivabradine, has been introduced in clinical practice, and its use in the clinical setting of HF patients has been recommended by current European Society of Cardiology (ESC) guidelines. Here we review the evidence of the prognostic role of HR in systolic HF and the potential relationship between HR lowering and the beneficial effects of beta-blockers; we will also analyze the reasons why an appropriate use of these drugs is seldom achieved in clinical practice, and review the evidence for the use of ivabradine in systolic HF in the clinical setting.     

Pre-implantation genetic testing in ART: who will benefit and what is the evidence?

Pre-implantation genetic diagnosis for aneuploidy testing (PGD-A) is a tool to identify euploid embryos during IVF. The suggested populations of patients that can benefit from it are infertile women of advanced maternal age, with a history of recurrent miscarriages and/or IVF failures. However, a general consensus has not yet been reached.After the clinical failure of its first version based on cleavage stage biopsy and 9 chromosome-FISH analysis, PGD-A is currently performed by 24 chromosome screening techniques on trophectoderm (TE) biopsies. This approach has been clearly demonstrated to involve a higher clinical efficiency with respect to the standard care, in terms of sustained pregnancy rate per transfer and lower miscarriage rate. However, data about PGD-A efficacy calculated on a per intention-to-treat basis, as well as an analysis of its cost-effectiveness, are still missing.TE biopsy is a safe and extensively validated approach with low biological and technical margin of error. Firstly, the prevalence of mosaic diploid/aneuploid blastocysts is estimated to be between 0 and 16 %, thus largely tolerable. Secondly, all the comprehensive chromosome screening (CCS) technologies adapted to, or designed to conduct PGD-A are highly concordant, and qPCR in particular has been proven to show the lowest false positive error rate (0.5 %) and a clinically recognizable error rate per blastocyst of just 0.21 %.In conclusion, there is a sufficient body of evidence to support the clinical application of CCS-based PGD-A on TE biopsies. The main limiting factor is the need for a high-standard laboratory to conduct blastocyst culture, biopsy and vitrification without impacting embryo viability.     

Laser-induced osteoblast proliferation is mediated by ROS production

Low-level laser therapy (LLLT) is widely used in regenerative medicine and in dental therapy by virtue of its beneficial effects in a plethora of pathological conditions. In this study, the effect of a 980 nm diode laser on pre-osteoblasts proliferation has been evaluated, along with reactive oxygen species (ROS) production. We hypothesized that ROS were a key factor in LLLT-induced pre-osteoblasts proliferation, as it is known that ROS can induce the activation of many biological pathways, leading to cell proliferation, differentiation or apoptosis. Murine pre-osteoblasts MC3T3 cells were irradiated with different energy outputs (1–50 J) in the absence or presence of the antioxidant N-Acetyl-L-cysteine (NAC). Laser treatment, in the absence of NAC, was able to induce a fluence-dependent statistically significant increase in ROS generation, while the presence of NAC strongly inhibited it. Cell proliferation, measured after laser stimulation, was significantly increased both at low and higher energy, with a peak at 10 J in the absence of the antioxidant. On the contrary, in the presence of NAC, laser irradiation was not able to induce any cell proliferation, suggesting a crucial role of ROS in this laser-induced cell effect. These results suggest that LLLT may be a useful tool for bone regeneration therapy and an effective range of fluences to be used is indicated.     

Three-dimensional finite-element analysis of a central lower incisor under labial and lingual loads

IntroductionThe aim was to evaluate the differences between labial and lingual application of an orthodontic force. This was achieved using a three-dimensional CAD design software model of a real lower incisor surrounded by a prismatic representation of the mandibular bone. This model was subjected to various loading conditions, with finite-element analysis.Materials and methodsCone-beam computed tomography scanning was used to create a three-dimensional geometric model of a lower incisor, together with its simulated periodontal ligament. This model was then meshed and analysed with commercial finite-element code. Various single and combined forces and moments were applied to each side of the simulated lower incisor at the centre of the clinical crown. To evaluate the effects of the various forces considered, the instantaneous displacement and stress generated in the bone and the periodontal ligament were measured, as a comparison of the labial and lingual loading sites.ResultsDental movement was only influenced by the side of the force application when an intrusive component was present. The simulations showed larger displacement when a vertical force was present at the lingual surface. In general, this movement was of the tipping type when the combined forces were applied, while there was greater intrusion upon application of combined forces and an anticlockwise moment to the labial surface.ConclusionsApplication of an intrusive lingual force to a lower incisor appears to generate bodily movement, while the same intrusive labial force appears to lead to labial tipping. Subject to further study, this should be taken into consideration when devising treatment plans for fixed appliances.     

The Role of Computational Models of the Immune System in Designing Vaccination Strategies

Mathematical and computational models are designed to improve our understanding of biological phenomena, to confirm/reject hypotheses, and to find points of intervention by altering the behavior of the studied systems. Here we describe the role of mathematical/computational models of the immune system. In particular, we analyze some examples of how mathematical modeling can contribute to finding optimal vaccination strategies. Indeed, computational modeling offers an intriguing opportunity from the theoretical point of view, and it will be of interest for clinically oriented investigators who wish to find optimal therapeutic strategies and for pharmaceutical industries that want to produce effective and successful drugs.     

Granular Computing Techniques for Classification and Semantic Characterization of Structured Data

We propose a system able to synthesize automatically a classification model and a set of interpretable decision rules defined over a set of symbols, corresponding to frequent substructures of the input dataset. Given a preprocessing procedure which maps every input element into a fully labeled graph, the system solves the classification problem in the graph domain. The extracted rules are then able to characterize semantically the classes of the problem at hand. The structured data that we consider in this paper are images coming from classification datasets: they represent an effective proving ground for studying the ability of the system to extract interpretable classification rules. For this particular input domain, the preprocessing procedure is based on a flexible segmentation algorithm whose behavior is defined by a set of parameters. The core inference engine uses a parametric graph edit dissimilarity measure. A genetic algorithm is in charge of selecting suitable values for the parameters, in order to synthesize a classification model based on interpretable rules which maximize the generalization capability of the model. Decision rules are defined over a set of information granules in the graph domain, identified by a frequent substructures miner. We compare the system with two other state-of-the-art graph classifiers, evidencing both its main strengths and limits.     

The scavenger receptor MARCO mediates cytoskeleton rearrangements in dendritic cells and microglia

Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor expressed in peritoneal macrophages and in a subpopulation of macrophages in the marginal zone of the spleen and in the medullary cord of lymph nodes. By global gene expression analysis, it has been found that the MARCO mRNA was one of the most up-regulated in splenic dendritic cells (DCs) following lipopolysaccharide or bacterial activation and in granulocyte-macrophage colony-stimulating factor (GM-CSF)-treated microglial cells. Here we show that MARCO is expressed on splenic DCs at late time points after activation and that its expression correlates with profound changes in actin cytoskeleton organization in DCs and microglia. During maturation, DCs undergo profound rearrangements of actin cytoskeleton. Immature DCs are adherent with visible actin cables, while fully mature, MARCO-expressing, splenic DCs are nonadherent, round in shape, and have an actin cytoskeleton with a punctate distribution. The simple expression of MARCO was sufficient to induce these cytoskeleton modifications in DCs. MARCO-transfected immature DCs acquired a typical morphology of mature DCs and did not rearrange the actin cytoskeleton following activation. Moreover, DCs in which MARCO was knocked down did not reach the mature phenotype and maintained the typical morphology of transitional DCs. MARCO expression in DCs and microglial cells was also associated with a decrease of antigen internalization capacity. Thus, the MARCO receptor is important for actin cytoskeleton rearrangements and the down-regulation of antigen uptake function during DC and microglial cell maturation.