Neuroprotection in traumatic brain injury : mesenchymal stromal cells can potentially overcome some limitations of previous clinical trials

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In the last 30 years several neuroprotective agents, attenuating the downstream molecular and cellular damaging events triggered by TBI, have been extensively studied. Even though many drugs have shown promising results in the pre-clinical stage, all have failed in large clinical trials. Mesenchymal stromal cells (MSCs) may offer a promising new therapeutic intervention, with preclinical data showing protection of the injured brain. We selected three of the critical aspects identified as possible causes of clinical failure: the window of opportunity for drug administration, the double-edged contribution of mechanisms to damage and recovery, and the oft-neglected role of reparative mechanisms. For each aspect, we briefly summarized the limitations of previous trials and the potential advantages of a newer approach using MSCs

Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury

There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il-corpus callosum (CC: − 30%) and external capsule (EC: − 21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (− 17%) and EC (− 13%), corresponding to histopathological evidence of white matter loss (cl-CC: − 68%; cl-EC: − 30%) associated with ongoing microgliosis and astrogliosis. These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration

A novel organotypic cortical slice culture model for traumatic brain injury: molecular changes induced by injury and mesenchymal stromal cell secretome treatment

Traumatic brain injury (TBI) is a major worldwide neurological disorder with no neuroprotective treatment available. Three-dimensional (3D) in vitro models of brain contusion serving as a screening platform for drug testing are lacking. Here we developed a new in vitro model of brain contusion on organotypic cortical brain slices and tested its responsiveness to mesenchymal stromal cell (MSC) derived secretome. A focal TBI was induced on organotypic slices by an electromagnetic impactor. Compared to control condition, a temporal increase in cell death was observed after TBI by propidium iodide incorporation and lactate dehydrogenase release assays up to 48 h post-injury. TBI induced gross neuronal loss in the lesion core, with disruption of neuronal arborizations measured by microtubule-associated protein-2 (MAP-2) immunostaining and associated with MAP-2 gene down-regulation. Neuronal damage was confirmed by increased levels of neurofilament light chain (NfL), microtubule associated protein (Tau) and ubiquitin C-terminal hydrolase L1 (UCH-L1) released into the culture medium 48 h after TBI. We detected glial activation with microglia cells acquiring an amoeboid shape with less ramified morphology in the contusion core. MSC-secretome treatment, delivered 1 h post-injury, reduced cell death in the contusion core, decreased NfL release in the culture media, promoted neuronal reorganization and improved microglia survival/activation. Our 3D in vitro model of brain contusion recapitulates key features of TBI pathology. We showed protective effects of MSC-secretome, suggesting the model stands as a tractable medium/high throughput, ethically viable, and pathomimetic biological asset for testing new cell-based therapies

Site effect studies following the 2016 Mw 6.0 Amatrice Earthquake (Italy): the Emersito Task Force activities

On August 24, 2016, at 01:36 UTC a MW 6.0 earthquake struck an extensive area of the Central Apennines (Italy) be-tween the towns of Norcia and Amatrice. Due to the mainshock magnitude and the widespread damaging level of build-ings in the epicentral area, the Emersito task force has been mobilized by the Istituto Nazionale di Geofisica e Vulcanologia (INGV). The aim of Emersito is to carry out and coordinate the monitoring of local site effects, caused by geological and geomorphological settings. During the first days of the seismic emergency, Emersito installed a tempo-rary seismic network for site effect studies at 4 municipalities close to the epicentral area (Amandola, Civitella del Tronto, Montereale and Capitignano), using 22 stations equipped with both velocimetric and accelerometric sensors. The selection of the sites where stations have been installed was mainly driven by the proximity to the epicentral area (without interfere with the rescue operations) and by peculiar geologic and geomorphologic settings (topographic irregu-larities, fault zones, alluvial plains). Preliminary analyses performed on ambient noise and aftershocks signals show that directional amplification effects may have occurred at stations installed on the top of topographic irregularities. We also observed the lengthening and amplification of the seismograms and a variability of the peaked frequency across the sedi-mentary basin between Montereale and Capitignano, probably related to a different thickness of the deposits. Further analyses are necessary to assess the correlation with surface geology.Published4T. Sismologia, geofisica e geologia per l'ingegneria sismica1SR. TERREMOTI - Servizi e ricerca per la Società1IT. Reti di monitoraggioJCR Journa

Placenta-derived cells for acute brain injury

Acute brain injury resulting from ischemic/hemorrhagic or traumatic damage is one of the leading causes of mortality and disability worldwide and is a significant burden to society. Neuroprotective options to counteract brain damage are very limited in stroke and traumatic brain injury (TBI). Given the multifaceted nature of acute brain injury and damage progression, several therapeutic targets may need to be addressed simultaneously to interfere with the evolution of the injury and improve the patient’s outcome. Stem cells are ideal candidates since they act on various mechanisms of protection and repair, improving structural and functional outcomes after experimental stroke or TBI. Stem cells isolated from placenta offer advantages due to their early embryonic origin, ease of procurement, and ethical acceptance. We analyzed the evidence for the beneficial effects of placenta-derived stem cells in acute brain injury, with the focus on experimental studies of TBI and stroke, the engineering strategies pursued to foster cell potential, and characterization of the bioactive molecules secreted by placental cells, known as their secretome, as an alternative cell-free strategy. Results from the clinical application of placenta-derived stem cells for acute brain injury and ongoing clinical trials are summarily discussed

Induction of a transmissible tau pathology by traumatic brain injury.

Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans

Temporary dense seismic network during the 2016 Central Italy seismic emergency for microzonation studies

In August 2016, a magnitude 6.0 earthquake struck Central Italy, starting a devastating seismic sequence, aggravated by other two events of magnitude 5.9 and 6.5, respectively. After the first mainshock, four Italian institutions installed a dense temporary network of 50 seismic stations in an area of 260 km2. The network was registered in the International Federation of Digital Seismograph Networks with the code 3A and quoted with a Digital Object Identifier ( https://doi.org/10.13127/SD/ku7Xm12Yy9 ). Raw data were converted into the standard binary miniSEED format, and organized in a structured archive. Then, data quality and completeness were checked, and all the relevant information was used for creating the metadata volumes. Finally, the 99 Gb of continuous seismic data and metadata were uploaded into the INGV node of the European Integrated Data Archive repository. Their use was regulated by a Memorandum of Understanding between the institutions. After an embargo period, the data are now available for many different seismological studies.Publishedid 1825T. Sismologia, geofisica e geologia per l'ingegneria sismicaJCR Journa

The Contribution of Mesenchymal Stromal Cells in Traumatic Brain Injury

Traumatic brain injury (TBI) is the leading cause of mortality and disability among young people in high-income countries. No single-agent treatment has been successfully translated to the clinical setting, hence there is still the need to focus on strategies that simultaneously act on multiple injury mechanisms. Mesenchymal stem/stromal cells (MSCs) are ideal candidates since they act on multiple mechanisms of protection and repair, improving structural and functional outcome after experimental TBI. The magnitude of protection varies extremely in different studies. Besides conceptual issues and methodological differences between injury models and laboratories, heterogeneity of MSC populations also affects the outcomes. This chapter focuses on the biology of MSCs, on mechanisms of brain protection and repair and on open questions that need to be addressed in order to increase effectiveness, reduce variability and safely move from preclinical studies to clinical application

SITE CHARACTERIZATION DATABASE OF INGV ITALIAN SEISMIC NETWORK

A critical issue in the performance of a seismic network is the characterization of site response where stations are located. This information is essential to improve some aspects related to seismic surveillance and the publication of products in near-real time following an earthquake. A proper evaluation of the site effect is also necessary to improve the quality of recordings databases, facilitating their use for research purposes. The Italian National Seismic Network of the INGV (Rete Sismica Nazionale, RSN) consists of about 400 seismic stations equipped with a velocimeter and, for one-third of the sites, an accelerometer. They are connected in real time to the INGV data center in order to locate earthquakes for civil defense purposes and their records are distributed through the EIDA node (eida.rm.ingv.it/). Recently INGV has addressed the site characterization of RSN with an internal project (funded within the INGV research line T3 “Seismic hazard and contributions to the definition of risk”), as well as within the INGV-DPC Agreements (INGV-DPC Agreement 2016-17-18, Annex B2 Objective 1 - Task B “Characterization of accelerometric sites”, funded by the Civil Protection Department), with the purpose of characterizing the seismic response of all the stations acquired in real time by its data center. The basic goal is building a geographic relational database, integrated with the other INGV infrastructures, designed to archive homogeneous parameters through the seismic network useful for a complete site characterization, including housing, geological, seismological and geotechnical features as well as site and topographic class according to the European and Italian building codes. The system resides on a dedicated server and the data are organized in an internal storage based on PostgreSQL DBMS (acronym CRISP). It will be directly related to SeisNet, the INGV database used for the network management, but it is still possible to insert new sites not belonging to the RSN. The backend of the system includes several procedures that allow the information updating through web services created ad-hoc, such as those of the Institute for Environmental Protection and Research (ISPRA) for geological and lithological attributes and for visualization of geological maps and related legends. On the other hand, specific programming interface services – API- expose the shared information to allow the transfer to other strong-motion data providers (e.g. ITACA, http://itaca.mi.ingv.it, and ESM, http://esm.mi.ingv.it) in semi-automatic way. The collection of geological, morphological and seismological data followed a nationwide approach, aimed at obtaining homogeneous data for the RSN sites. We started from the revision of all available geological and geophysical data and the analysis of noise waveforms, storing the analysis results as images and searchable data. Thanks to the collaboration with the Geological Survey of Italy (ISPRA-SGI), a review of the geological map of Italy (at a scale of 1:100,000 and 1:50,000) and their relative explanatory notes, including also many other available published data (borehole logs, local geographical portal, etc.), allowed to develop a stratigraphic conceptual model under each site. As for the attribution to each site of a topographic class according to the Italian building code, a morphometric analysis using an automatic procedure has been carried out on two DEM datasets with resolution at 30 m and 10 m. Regarding the seismological parameters, noise velocimetric records at all the stations were homogeneously analyzed by using mostly continuous data, as follow: 1) estimation of data quality with annual and seasonal noise analysis; 2) selection of noise traces (day/night and seasonal), horizontal-to-vertical spectral ratio computation and determination of directionality of the amplification peaks; 3) in case of directionality, we proceeded with the polarization analysis of the signal to identify the preferred direction of the movement, slope and straightness. A preliminary statistical analysis highlights that only 26% of the RSN accelerometric stations do not have amplification peaks, while 29% show a polarization of the signal in a preferential direction. Finally, we are collecting all the available information about the station housing, to account for possible soil-structure interaction. The database includes also 15 sites that have been fully characterized by performing a geological survey followed by the 1:5,000 geological and lithotechnical maps, a geological cross section and report, the S-wave velocity profile inferred through seismic noise arrays and, for one site, downhole measurements. With the contribution of the Site-Characterization Team: S. Amoroso, R. Azzaro, R. Bianconi, M. Cattaneo, R. Cogliano, D. Di Naccio, C. Felicetta, A. Fodarella, S. Lovati, A. Mandiello, C. Marcocci, C. Mascandola, M. Massa, A. Mercuri, G. Milana, S. Pucillo, G. Riccio, G. Tusa, M. Vassallo, et al. (INGV); M. Amanti, G. Conte, C. Cipolloni, G. M. Monti, C. D’Ambrogi, M. D’Orefice, P. Di Manna, D. Fiorenza, R. M. Gafà, B. Roberto, M. Roma, L. Vita (ISPRA)PublishedLa Valletta-Malta5T. Sismologia, geofisica e geologia per l'ingegneria sismic