Path tracking control of a steerable catheter in transcatheter cardiology interventions.

PURPOSE: Intracardiac transcatheter interventions allow for reducing trauma and hospitalization stays as compared to standard surgery. In the treatment of mitral regurgitation, the most widely adopted transcatheter approach consists in deploying a clip on the mitral valve leaflets by means of a catheter that is run through veins from a peripheral access to the left atrium. However, precise manipulation of the catheter from outside the body while copying with the path constraints imposed by the vessels remains challenging. METHODS: We proposed a path tracking control framework that provides adequate motion commands to the robotic steerable catheter for autonomous navigation through vascular lumens. The proposed work implements a catheter kinematic model featuring nonholonomic constraints. Relying on the real-time measurements from an electromagnetic sensor and a fiber Bragg grating sensor, a two-level feedback controller was designed to control the catheter. RESULTS: The proposed method was tested in a patient-specific vessel phantom. A median position error between the center line of the vessel and the catheter tip trajectory was found to be below 2 mm, with a maximum error below 3 mm. Statistical testing confirmed that the performance of the proposed method exhibited no significant difference in both free space and the contact region. CONCLUSION: The preliminary in vitro studies presented in this paper showed promising accuracy in navigating the catheter within the vessel. The proposed approach enables autonomous control of a steerable catheter for transcatheter cardiology interventions without the request of calibrating the intuitive parameters or acquiring a training dataset.

Cnf1 Variants Endowed with the Ability to Cross the Blood-Brain Barrier: A New Potential Therapeutic Strategy for Glioblastoma.

Among gliomas, primary tumors originating from glial cells, glioblastoma (GBM) identified as WHO grade IV glioma, is the most common and aggressive malignant brain tumor. We have previously shown that the Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1) is remarkably effective as an anti-neoplastic agent in a mouse model of glioma, reducing the tumor volume, increasing survival, and maintaining the functional properties of peritumoral neurons. However, being unable to cross the blood-brain barrier (BBB), CNF1 requires injection directly into the brain, which is a very invasive administration route. Thus, to overcome this pitfall, we designed a CNF1 variant characterized by the presence of an N-terminal BBB-crossing tag. The variant was produced and we verified whether its activity was comparable to that of wild-type CNF1 in GBM cells. We investigated the signaling pathways engaged in the cell response to CNF1 variants to provide preliminary data to the subsequent studies in experimental animals. CNF1 may represent a novel avenue for GBM therapy, particularly because, besides blocking tumor growth, it also preserves the healthy surrounding tissue, maintaining its architecture and functionality. This renders CNF1 the most interesting candidate for the treatment of brain tumors, among other potentially effective bacterial toxins.

CNF1 Enhances Brain Energy Content and Counteracts Spontaneous Epileptiform Phenomena in Aged DBA/2J Mice.

Epilepsy, one of the most common conditions affecting the brain, is characterized by neuroplasticity and brain cell energy defects. In this work, we demonstrate the ability of the Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1) to counteract epileptiform phenomena in inbred DBA/2J mice, an animal model displaying genetic background with an high susceptibility to induced- and spontaneous seizures. Via modulation of the Rho GTPases, CNF1 regulates actin dynamics with a consequent increase in spine density and length in pyramidal neurons of rat visual cortex, and influences the mitochondrial homeostasis with remarkable changes in the mitochondrial network architecture. In addition, CNF1 improves cognitive performances and increases ATP brain content in mouse models of Rett syndrome and Alzheimer's disease. The results herein reported show that a single dose of CNF1 induces a remarkable amelioration of the seizure phenotype, with a significant augmentation in neuroplasticity markers and in cortex mitochondrial ATP content. This latter effect is accompanied by a decrease in the expression of mitochondrial fission proteins, suggesting a role of mitochondrial dynamics in the CNF1-induced beneficial effects on this epileptiform phenotype. Our results strongly support the crucial role of brain energy homeostasis in the pathogenesis of certain neurological diseases, and suggest that CNF1 could represent a putative new therapeutic tool for epilepsy.