Understanding inflammation requires neuroscience

Inflammation and its resolution are processes subject to neural regulation (1). The best-characterized immune-regulating reflex is the “inflammatory reflex”, in which the efferent branch of the vagus nerve plays a central role in regulating cytokine-release in the periphery. This neural pathway is fundamental to maintaining host homeostasis and preventing potentially damaging inflammation (1–3) . Hence, this biology has already been exploited in several clinical trials regarding potentially new therapies for chronic inflammatory diseases (4–6). Of note, cardiovascular disease (CVD) represents the first cause of death worldwide, and its most common manifestation is atherosclerosis which is an inflammatory disease (7,8) . Little is known about the neural control of inflammation in this pathology. Atherosclerotic plaques are not innervated (9) , and neurotransmitter signaling in atherosclerosis has not been investigated. The 1998 Nobel Prize for “nitric oxide (NO) as a signaling molecule in the cardiovascular system” reveals the importance of the neurotransmitter acetylcholine (ACh) for regulation of vascular relaxation (10). ACh is also a key component of the inflammatory reflex, in which cholinergic signals regulate the course of inflammation. In the inflammatory reflex, ACh is produced by nerves and by acetyl-cholinesterase (ChAT)+ T cell under the control of the nervous system, and interacts with alpha 7 nicotinic acetylcholine receptor subunit (α7nAChR)-expressing macrophages (MΦ) (11) . Most of the current knowledge on the inflammatory reflex was obtained from numerous experiments performed in animals, mice in primis. Much is still unclear about the details of neural regulation of inflammation and its resolution, and understanding these mechanisms in detail will require further experimental studies. At the same time, it is also important to translate these findings to human pathophysiology, and investigate whether it may inform the design of therapeutic strategies for treatment of inflammatory diseases. This thesis addresses several aspects of this biology: In Project I, we discovered that human ChAT+ T cells participate in cholinergic regulation of vascular function and are found in blood collected from patients in circulatory distress. In Project II, we found components of neurotransmitter signaling in human atherosclerosis, observed an association between low glutamate-receptor expression and adverse clinical events, and found that glutamate signaling regulates smooth muscle cell phenotypic modulation. In Project III, we describe an effective and simple method to electrically stimulate the cervical vagus nerve in mice for the study of experimental inflammation. In Project IV, we provide evidence that electrical activation of the cervical vagus nerve accelerates inflammation resolution in mice through a cholinergic mechanism that involves synthesis of specialized pro-resolving mediators. Technological limitations in vagus nerve stimulation methods for mice has hampered mechanistic studies of peripheral nerve activation in chronic diseases. Hence, the understanding of mechanisms of vagus nerve regulation of inflammation in chronic diseases is yet incomplete. To solve this, in Project V we used a novel approach and developed noninvasive activation of peripheral nerves using temporally-interfering electrical fields. This technology attempts to address methodological shortcoming of “traditional” electrical vagus nerve stimulation (VNS) and enable studies of VNS in genetic mouse models of chronic inflammatory diseases and beyond. In summary, this thesis studies aspects of neural signaling in inflammation and reveal new details on glutamatergic and cholinergic signals in inflammation and vascular pathophysiology. The work also contributes new methodology which we postulate will be helpful in further understanding of the neural signals that regulate inflammation and for clinical translation of discoveries in this field

Theory and practice of Weigh in Motion (WIM) based on fibre Bragg gratings: lab tests for smart roads purposes

This paper is focused on ITS (Intelligent Transport Systems) for road transport, in particular, on the analysis and assessment of the effectiveness of one specific technology making highways and motorways more “perceptive” and “communicating”, i.e. “smart” using a fashion term, that is the dynamic weighing systems of vehicles, also recognised in literature as WIM (Weigh in motion). An application of the investigated technology has been developed at the Measurement Laboratory of the Politecnico di Torino (Italy) where a WIM based on fibre optical sensors has been arranged and tested. The aim has also been to evaluate its accuracy and the possibility of its practical use. The perspective goal is to make roads perceptive and alerting through ITS and the focus on optical fibre-based WIM, for pursuing smart road results, is interesting because fibre sensors are well suited to be employed in the monitoring of large infrastructures

Cable-Based Robotic Crane (CBRC): Design and Implementation of Overhead Traveling Cranes Based on Variable Radius Drums

In this paper, we present a new family of overhead traveling cranes based on variable radius drums (VRDs), called cable-based robotic cranes (CBRCs). A VRD is characterized by the variation of the spool radius along its profile. This kind of device is used, in this context, for the development of a cable-robot, which can support and move a load through a planar working area with just two degrees of freedom. First we present the kinematic analysis and the synthesis of the geometry of a VRD profile. Then, the schema of a bidimensional horizontal moving mechanism, based on the VRD theory, and an experimental prototype of a three-dimensional CBRC are presented. The features of this wire-based overhead crane and an analysis of cables tensions are discussed. Finally, the performance of this mechanism is evaluated, demonstrating a deviation between the end-effector and the nominal planar surface of less than 1% throughout the whole working area

Modeling the vibration of spatial flexible mechanisms through an equivalent rigid-link system/component mode synthesis approach

In this paper, a novel formulation for modeling the vibration of spatial flexible mechanisms and robots is introduced. The formulation is based on the concepts of equivalent rigid-link system (ERLS) that allows kinematic equations of motion for the ERLS decoupled from the compatibility equations of the displacement at the joint to be written. With respect to the available literature, in which the ERLS concept has been proposed together with a finite element method (FEM) approach (ERLS-FEM), the formulation is extended in this paper through a modal approach and, in particular, a component mode synthesis technique which allows a reduced-order system of dynamic equations to be maintained even when a fine discretization is needed. The model is validated numerically by comparing it with the results obtained from the Adams-Flex\u2122 software, which implements the well-known floating frame of reference approach for a benchmark L-shaped mechanism. A good agreement between the two models is shown

Supramolecular hydrogels based on custom-made poly(ether urethane)s and cyclodextrins as potential drug delivery vehicles: design and characterization

The design of supramolecular (SM) hydrogels based on host-guest complexes represents an effective strategy to develop drug delivery systems. In this work, we designed SM hydrogels based on α-cyclodextrin and high-molar mass amphiphilic poly(ether urethane)s (PEUs, ) based on Poloxamer® 407 and differing in their chain extender. The successful formation of poly(pseudo)rotaxanes and their supramolecular interactions were chemically demonstrated. Then, self-healing (80-100% mechanical recovery) supramolecular hydrogels were developed by mixing PEU and α-cyclodextrin solutions at different concentrations. Stability in physiological-like environment and mechanical properties improved with increasing α-cyclodextrin content (9-10% w/v), meanwhile gelation time decreased. A synergistic effect of poly(pseudo)rotaxanes crystals and PEU micellar structures on gel properties was observed: the first were predominant at low PEU concentrations (1-5% w/v), while the latter prevailed at high PEU concentrations (7-9% w/v). Increasing PEU concentration led to gels with increased dissolution rate, not-fully developed networks and slight cytotoxicity, meanwhile residence time in aqueous media improved (>7 d). At low PEU concentrations (1-5% w/v), cytocompatible gels (100% cell viability) were obtained, which maintained their shape in aqueous medium up to 5 d and completely dissolved within 7 d. PEU chemical composition affected PEU/α-cyclodextrin interactions, with longer gelation time and lower mechanical properties in gels based on PEU with pendant functionalities. Gels progressively released a model molecule (fluorescein isothiocyanate-dextran) within 3-4 days with no initial burst release. We thus demonstrated the suitability of custom-made PEUs as constituent of SM hydrogels with α-cyclodextrin and the high potential of the resulting systems for drug delivery applications

IN VIVO EVALUATION OF PERIODONTAL MICROCIRCULATORY CHANGES ASSOCIATED WITH ENDODONTIC TREATMENT

The purpose of this study was to investigate in vivo the gingival microcirculatory changes associated with endodontic treatment using the continuous wave of condensation technique. MATERIALS AND METHODS: Twenty necrotic one canal roots of 20 cooperative patients of both sexes, aged between 20 and 43 years, were selected. All patients were examined by capillaroscopy before, immediately after endodontic treatment, and after 7 days. The last examination was carried out by the same operator, and repeated twice for each examined area: masticatory, buccal and labial mucosa corresponding to the endodontically treated root. All canals were prepared using a simultaneous technique with Ni-Ti files (MTwo files). RESULTS: The images of the masticatory mucosa after root canal obturation showed evident micro-areas of extravasation, with significant bleeding and angio-morphological alterations due to heat. One hour after the endodontic treatment evident extravasation was observed, but a decrease of all altered parameters, was present. After seven days from treatment, in the periodontal tissues, a complete healing was observed. The in vivo evaluation of the vascular pattern during root canal obturation with System B showed that the high temperature in the canal determines visible effects on the vasculature of adjacent sites. It was found that microangiotectonic alterations decrease up to a complete healing after 7 days from treatment. CONCLUSION: All the changes in microcirculation, due to thermal shock of periodontal tissues, are reversible

Rapid direct analysis to discriminate geographic origin of extra virgin olive oils by flash gas chromatography electronic nose and chemometrics

At present, the geographical origin of extra virgin olive oils can be ensured by documented traceability, although chemical analysis may add information that is useful for possible confirmation. This preliminary study investigated the effectiveness of flash gas chromatography electronic nose and multivariate data analysis to perform rapid screening of commercial extra virgin olive oils characterized by a different geographical origin declared in the label. A comparison with solid phase micro extraction coupled to gas chromatography mass spectrometry was also performed. The new method is suitable to verify the geographic origin of extra virgin olive oils based on principal components analysis and discriminant analysis applied to the volatile profile of the headspace as a fingerprint. The selected variables were suitable in discriminating between ''100% Italian" and ''non-100% Italian" oils. Partial least squares discriminant analysis also allowed prediction of the degree of membership of unknown samples to the classes examined

Spinal cord injuries in the absence of post-traumatic radiographic anomalies (SCIWORA). The traumatic moment between patient anterior state and efficient/concurrent causes of injury

Background and aim: Spinal Cord Injury without Radiographic Abnormality (SCIWORA) represents acute traumatic myelopathy in the absence of instrumental evidence of fractures and/or dislocations of the cervical vertebrae. Methods: In this article we present 4 cases of SCIWORA that came to our observation and the medico-legal implications associated with them. Results: In defining the compensation in the context of a private accident policy for traumatic pathologies of the spinal cord, an in-depth medical-legal assessment is essential, based on an accurate examination of the health documentation including the instrumental investigations performed, the anamnesis and an accurate evaluation of the trauma dynamic. The paraphysiological deterioration of organ-tissue structures, identifiable in the concept of "natural variability of biological risk", should be included in the same definition of insured risk by age group, with the consequence that physical conditions that fall within the physiological or paraphysiological definitions, although potentially contributing to injury, do not necessarily exclude compensation. A different concept dominates the variability of the compensation according to a paraphysiological pre-existing condition. The two arguments therefore call for thorough consideration of both the paraphysiological contributing causes of injury and/or impairment as necessarily subject to a preliminary study, which through the clinical and instrumental investigation method, will define the perimeter of functionality

Rapid direct analysis to discriminate geographic origin of extra virgin olive oils by flash gas chromatography electronic nose and chemometrics

At present, the geographical origin of extra virgin olive oils can be ensured by documented traceability, although chemical analysis may add information that is useful for possible confirmation. This preliminary study investigated the effectiveness of flash gas chromatography electronic nose and multivariate data analysis to perform rapid screening of commercial extra virgin olive oils characterized by a different geographical origin declared in the label. A comparison with solid phase micro extraction coupled to gas chromatography mass spectrometry was also performed. The new method is suitable to verify the geographic origin of extra virgin olive oils based on principal components analysis and discriminant analysis applied to the volatile profile of the headspace as a fingerprint. The selected variables were suitable in discriminating between '100% Italian' and 'non-100% Italian' oils. Partial least squares discriminant analysis also allowed prediction of the degree of membership of unknown samples to the classes examined