Impact of nickel-titanium super-elastic material properties on the mechanical performance of self-expandable transcatheter aortic valves.

Self-expandable transcatheter aortic valves (TAVs) elastically resume their initial shape when implanted without the need for balloon inflation by virtue of the nickel-titanium (NiTi) frame super-elastic properties. Experimental findings suggest that NiTi mechanical properties can vary markedly because of a strong dependence on the chemical composition and processing operations. In this context, this study presents a computational framework to investigate the impact of the NiTi super-elastic material properties on the TAV mechanical performance. Finite element (FE) analyses of TAV implantation were performed considering two different TAV frames and three idealized aortic root anatomies, evaluating the device mechanical response in terms of pullout force magnitude exerted by the TAV frame and peak maximum principal stress within the aortic root. The widely adopted NiTi constitute model by Auricchio and Taylor (1997) was used. A multi-parametric sensitivity analysis and a multi-objective optimization of the TAV mechanical performance were conducted in relation to the parameters of the NiTi constitutive model. The results highlighted that: five NiTi material model parameters (EA, σtLS, σtUS, σtUE and σcLS) are significantly correlated with the FE outputs; the TAV frame geometry and aortic root anatomy have a marginal effect on the level of influence of each NiTi material parameter; NiTi alloy candidates with pareto-optimal characteristics in terms of TAV mechanical performance can be successfully identified. In conclusion, the proposed computational framework supports the TAV design phase, providing information on the relationship between the super-elastic behavior of the supplied NiTi alloys and the device mechanical response.

Targeting PSD95-nNOS interaction by Tat-N-dimer peptide during status epilepticus is neuroprotective in MAM-pilocarpine rat model.

Glutamate receptors play a crucial pathogenic role in brain damage induced by status epilepticus (SE). SE may initiate NMDAR-dependent excitotoxicity through the production of oxidative damage mediated by the activation of a ternary complex formed by the NMDA receptor, the post-synaptic density scaffolding protein 95 (PSD95) and the neuronal NO synthase (nNOS). The inhibition of the protein-protein-interaction (PPI) of the NMDAR-PSD95-nNOS complex is one of the most intriguing challenges recently developed to reduce neuronal death in both animal models and in patients with cerebral ischemia. We took advantage of this promising approach to verify whether early administration of a neuroprotective NMDAR-PSD95-nNOS PPI inhibitor preserves the brain from SE-induced damage in a model of acquired cortical dysplasia, the methylazoxymethanol (MAM)/pilocarpine rat. Pilocarpine-induced SE rapidly determined neurodegenerative changes mediated by a NMDAR-downstream neurotoxic pathway in MAM rats. We demonstrated that SE rapidly induces NMDAR activation, nNOS membrane translocation, PSD95-nNOS molecular interaction associated with neuronal and glial peroxynitrite accumulation in the neocortex of MAM-pilocarpine rats. These changes were paralleled by rapid c-fos overexpression and by progressive spectrin proteolysis, suggestive of calpain activity and irreversible cytoskeletal damage. Early administration of a cell-penetrating Tat-N-dimer peptide inhibitor of NMDAR-PSD95-nNOS PPI during SE significantly rescued the MAM-pilocarpine rats from SE-induced mortality, reduced the number of degenerating neurons, decreased neuronal c-fos activation, peroxynitrite formation and cytoskeletal degradation and prevented astrogliosis. Our findings suggest an overall neuroprotective effect of blocking PSD95-nNOS protein-protein-interaction against SE insult.

Continuous neurodegeneration and death pathway activation in neurons and glia in an experimental model of severe chronic epilepsy.

Whether seizures might determine the activation of cell death pathways and what could be the relevance of seizure-induced cell death in epilepsy are still highly debated issues. We recently developed an experimental model of acquired focal cortical dysplasia (the MAM-pilocarpine or MP rat) in which the occurrence of status epilepticus--SE--and subsequent seizures induced progressive cellular/molecular abnormalities and neocortical/hippocampal atrophy. Here, we exploited the same model to verify when, where, and how cell death occurred in neurons and glia during epilepsy course. We analyzed Fluoro Jade (FJ) staining and the activation of c-Jun- and caspase-3-dependent pathways during epilepsy, from few hours post-SE up to six months of spontaneous recurrent seizures. FJ staining revealed that cell injury in MP rats was not temporally restricted to SE, but extended throughout the different epileptic stages. The region-specific pattern of FJ staining changed during epilepsy, and FJ(+) neurons became more prominent in the dorsal and ventral hippocampal CA at chronic epilepsy stages. Phospho-c-Jun- and caspase-3-dependent pathways were selectively activated respectively in neurons and glia, at early but even more conspicuously at late chronic stages. Phospho-c-Jun activation was associated with increased cytochrome-c staining, particularly at chronic stages, and the staining pattern of cytochrome-c was suggestive of its release from the mitochondria. Taken together, these data support the content that at least in the MP rat model the recurrence of seizures can also sustain cell death mechanisms, thus continuously contributing to the pathologic process triggered by the occurrence of SE.