Children and adolescents treated with neridronate for osteogenesis imperfecta show no evidence of any osteonecrosis of the jaw

Over recent years, several reports have been published on unusual cases of osteonecrosis of the jaw (ONJ) in adults using second- and third-generation nitrogen-containing bisphosphonates such as pamidronate, alendronate, risedronate and zoledronate, but no case has ever been reported either in children or in adult patients taking neridronate. Children and adolescents affected by osteogenesis imperfecta (OI) could belong to a high-risk group for ONJ because bone fragility in OI is associated with a connective tissue malfunction. The purpose of this study is to evaluate the incidence of ONJ in a pediatric population treated with neridronate for OI. A total of 102 pediatric patients with OI who received neridronate infusions for a mean of 6.81 years (SD \ub1 3.06 years) were clinically assessed for possible ONJ. Eligibility criteria for participation included patients between 1.2 and 24 years old who received cyclical neridronate infusions for at least 1 year. All the patients were reviewed to determine duration, dosage and cumulative dose of their bisphosphonate therapy and were examined clinically to assess their oral health status. We have not demonstrated any occurrence of ONJ in our patients. In conclusion, at the moment insufficient data are available to prove a greater risk of ONJ in children with OI than in children affected by other forms of bone fragility. However, cases may emerge in future because the risk of ONJ seems to be related to the cumulative dose and the duration of therap

A bilateral N2pc (N2pcb) component is elicited by search targets displayed on the vertical midline

The study of visually-elicited event-related potentials (ERPs) detected at posterior recording sites during visual search has enormously advanced our knowledge about how and when visuo-spatial attention locks onto one or more laterally presented target objects. The N2pc component to lateral targets has been pivotal to further our understanding of the mechanisms and time-course of target selection in visual search. However, the N2pc cannot track visuo-spatial attention deployment to targets displayed along the vertical midline. Here, we introduce a new ERP marker (N2pcb component) that is elicited during the selection of such midline targets. In line with retinal and callosal projections from striate to ventral extrastriate cortex, this component reflects an enhanced negativity elicited by midline targets over both posterior hemispheres. By comparing the attentional selection of lateral and midline targets in a singleton search condition and a feature search condition, we show that the N2pcb is triggered at the same time as the N2pc to lateral targets, and shows the same onset latency difference between singleton and feature search. We conclude that the N2pcb and N2pc components reflect the same attentional target selection processes in visual search

A novel background reduction strategy for high level triggers and processing in gamma-ray Cherenkov detectors

Gamma ray astronomy is now at the leading edge for studies related both to fundamental physics and astrophysics. The sensitivity of gamma detectors is limited by the huge amount of background, constituted by hadronic cosmic rays (typically two to three orders of magnitude more than the signal) and by the accidental background in the detectors. By using the information on the temporal evolution of the Cherenkov light, the background can be reduced. We will present here the results obtained within the MAGIC experiment using a new technique for the reduction of the background. Particle showers produced by gamma rays show a different temporal distribution with respect to showers produced by hadrons; the background due to accidental counts shows no dependence on time. Such novel strategy can increase the sensitivity of present instruments.Comment: 4 pages, 3 figures, Proc. of the 9th Int. Syposium "Frontiers of Fundamental and Computational Physics" (FFP9), (AIP, Melville, New York, 2008, in press

New Insights into the Molecular Mechanism of E-Cadherin-Mediated Cell Adhesion by Free Energy Calculations

Three-dimensional domain swapping is an important mode of protein association leading to the formation of stable dimers. Monomers associating via this mechanism mutually exchange a domain to form a homodimer. Classical cadherins, an increasingly important target for anticancer therapy, use domain swapping to mediate cell adhesion. However, despite its importance, the molecular mechanism of domain swapping is still debated. Here, we study the conformational changes that lead to activation and dimerization via domain swapping of E-cadherin. Using state-of-the-art enhanced sampling atomistic simulations, we reconstruct its conformational free energy landscape, obtaining the free energy profile connecting the inactive and active form. Our simulations predict that the E-cadherin monomer populates the open and closed forms almost equally, which is in agreement with the proposed “selected fit” mechanism in which monomers in an active conformational state bind to form a homodimer, analogous to the conformational selection mechanism often observed in ligand–target binding. Moreover, we find that the open state population is increased in the presence of calcium ions at the extracellular boundary, suggesting their possible role as allosteric activators of the conformational change