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The early detection of traumatic brain injuries can directly impact the prognosis and survival of patients. Preceding attempts to automate the detection and the assessment of the severity of traumatic brain injury continue to be based on clinical diagnostic methods, with limited tools for disease outcomes in large populations. Despite advances in machine and deep learning tools, current approaches still use simple trends of statistical analysis which lack generality. The effectiveness of deep learning to extract information from large subsets of data can be further emphasised through the use of more elaborate architectures. We therefore explore the use of a multiple input, convolutional neural network and long short-term memory (LSTM) integrated architecture in the context of traumatic injury detection through predicting the presence of brain injury in a murine preclinical model dataset. We investigated the effectiveness and validity of traumatic brain injury detection in the proposed model against various other machine learning algorithms such as the support vector machine, the random forest classifier and the feedforward neural network. Our dataset was acquired using a home cage automated (HCA) system to assess the individual behaviour of mice with traumatic brain injury or non-central nervous system (non-CNS) injured controls, whilst housed in their cages. Their distance travelled, body temperature, separation from other mice and movement were recorded every 15 minutes, for 72 hours weekly, for 5 weeks following intervention. The HCA behavioural data was used to train a deep learning model, which then predicts if the animals were subjected to a brain injury or just a sham intervention without brain damage. We also explored and evaluated different ways to handle the class imbalance present in the uninjured class of our training data. We then evaluated our models with leave-one-out cross validation. Our proposed deep learning model achieved the best performance and showed promise in its capability to detect the presence of brain trauma in mice.

Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders.

Traumatic brain injury (TBI) can cause major disability and increases the risk of neurodegeneration. Post-TBI, there is infiltration of peripheral myeloid and lymphoid cells; there is limited information on the peripheral immune response post-TBI in the immature brain—where injury may interfere with neurodevelopment. We carried out two injury types in juvenile mice: invasive TBI with a controlled cortical impact (CCI) and repetitive mild TBI (rmTBI) using weight drop injury and analysed the response at 5- and 35-days post-injury. In the two models, we detected the brain infiltration of immune cells (e.g., neutrophils, monocytes, dendritic cells, CD4+ T cells, and NK cells). There were increases in macrophages, neutrophils, and dendritic cells in the spleen, increases in dendritic cells in blood, and increases in CD8+ T cells and B cells in lymph nodes. These results indicate a complex peripheral immune response post-TBI in the immature brain, with differences between an invasive injury and a repetitive mild injury.

The early detection of traumatic brain injuries can directly impact the prognosis and survival of patients. Preceding attempts to automate the detection and the assessment of the severity of traumatic brain injury continue to be based on clinical diagnostic methods, with limited tools for disease outcomes in large populations. Despite advances in machine and deep learning tools, current approaches still use simple trends of statistical analysis which lack generality. The effectiveness of deep learning to extract information from large subsets of data can be further emphasised through the use of more elaborate architectures. We therefore explore the use of a multiple input, convolutional neural network and long short-term memory (LSTM) integrated architecture in the context of traumatic injury detection through predicting the presence of brain injury in a murine preclinical model dataset. We investigated the effectiveness and validity of traumatic brain injury detection in the proposed model against various other machine learning algorithms such as the support vector machine, the random forest classifier and the feedforward neural network. Our dataset was acquired using a home cage automated (HCA) system to assess the individual behaviour of mice with traumatic brain injury or non-central nervous system (non-CNS) injured controls, whilst housed in their cages. Their distance travelled, body temperature, separation from other mice and movement were recorded every 15 minutes, for 72 hours weekly, for 5 weeks following intervention. The HCA behavioural data was used to train a deep learning model, which then predicts if the animals were subjected to a brain injury or just a sham intervention without brain damage. We also explored and evaluated different ways to handle the class imbalance present in the uninjured class of our training data. We then evaluated our models with leave-one-out cross validation. Our proposed deep learning model achieved the best performance and showed promise in its capability to detect the presence of brain trauma in mice.

The targeted delivery of therapies to diseased tissues offers a safe opportunity to achieve optimal efficacy while limiting systemic exposure. These considerations apply to many disease indications but are especially relevant for rheumatoid arthritis (RA), as RA is a systemic autoimmune disease which affects multiple joints. We have identified an antibody that is specific to damaged arthritic cartilage (anti-ROS-CII) that can be used to deliver treatments specifically to arthritic joints, yielding augmented efficacy in experimental arthritis. In the current study, we demonstrate that scaffolds enriched with bioactive payloads can be delivered precisely to an inflamed joint and achieve superior efficacy outcomes consistent with the pharmacological properties of these payloads. As a scaffold, we have used extracellular vesicles (EVs) prepared from human neutrophils (PMNs), which possess intrinsic anti-inflammatory properties and the ability to penetrate inflamed arthritic cartilage. EV fortified with anti-ROS-CII (EV/anti-ROS-CII) retained anti-ROS-CII specificity and bound exclusively to the damaged cartilage. Following systemic administration, EV/anti-ROS-CII (a) exhibited the ability to localize specifically in the arthritic joint in vivo and (b) was able to specifically target single (viral IL-10 or anti-TNF) or combined (viral IL-10 and anti-TNF) anti-inflammatory treatments to the arthritic joint, which accelerated attenuation of clinical and synovial inflammation. Overall, this study demonstrates the attainability of targeting a pro-resolving biological scaffold to the arthritic joint. The potential of targeting scaffolds such as EV, nanoparticles, or a combination thereof alongside combined therapeutics is paramount for designing systemically administered broad-spectrum of anti-inflammatory treatments.

Cardiac dysfunction (CD) importantly contributes to mortality in trauma patients, who survive their initial injuries following successful hemostatic resuscitation. This poor outcome has been correlated with elevated biomarkers of myocardial injury, but the pathophysiology triggering this CD remains unknown. We investigated the pathophysiology of acute CD after trauma using a mouse model of trauma hemorrhage shock (THS)-induced CD with echocardiographic guidance of fluid resuscitation, to assess the THS impact on myocardial integrity and function. Mice were subjected to trauma (soft tissue and bone fracture) and different degrees of hemorrhage severity (pressure controlled ~MABP < 35 mmHg or

The precise flow characteristics that promote different atherosclerotic plaque types remain unclear. We previously developed a blood flow-modifying cuff for ApoE−/− mice that induces the development of advanced plaques with vulnerable and stable features upstream and downstream of the cuff, respectively. Herein, we sought to test the hypothesis that changes in flow magnitude promote formation of the upstream (vulnerable) plaque, whereas altered flow direction is important for development of the downstream (stable) plaque. We instrumented ApoE−/− mice (n = 7) with a cuff around the left carotid artery and imaged them with micro-CT (39.6 µm resolution) eight to nine weeks after cuff placement. Computational fluid dynamics was then performed to compute six metrics that describe different aspects of atherogenic flow in terms of wall shear stress magnitude and/or direction. In a subset of four imaged animals, we performed histology to confirm the presence of advanced plaques and measure plaque length in each segment. Relative to the control artery, the region upstream of the cuff exhibited changes in shear stress magnitude only (p

El 20 de Octubre del 2010 se publico la nueva Directiva Europea 2010/63/EU sobre la protección de los animales utilizados en procedimientos científicos. Dicha publicación en el Diario Oficial de la Unión Europea supone el inicio de su tramitación para su entrada en vigor como ley Europea. Los países miembros tienen ahora un periodo de dos años para implementar dicha directiva como documento legal asegurando su completa entrada en vigor para Enero del 2013. En este artículo se realiza un análisis comparativo de la nueva Directiva 2010/63/EU y la normativa actual vigente en el Reino Unido, referente mundial en el área de protección de animales de laboratorio. La nueva Directiva reconoce la importancia de la utilización de animales de experimentación en los avances científicos, pero reforzando la defensa y el respeto del valor intrínseco del ser animal. En este sentido la Directiva representa un importante avance para la protección del bienestar animal en todos los estados miembros, con el objetivo de armonizar la legislación vigente. Si bien varios países ya disponen de una legislación bastante progresiva, la implementación de la nueva directiva representa una excelente oportunidad para asentar y/o homogeneizar criterios de alto estándar de protección del bienestar animal en todos los países miembros, reforzando así el compromiso de la Unión Europea con la investigación científica y el respeto al bienestar de los animales de experimentación. On 20th October 2010 the new 2010/63/EU European directive on the protection of animals used in scientific procedures was published in the Official Journal of the European Union, entering into force as a European law. Member States now have a period of two years to implement the directive as a legal document ensuring its full legal binding by January 2013. This article undertakes a comparative analysis between the new directive 2010/63/EU and the current regulatory system in the UK, which is an international reference in the protection of laboratory animals. The new directive recognizes the importance of the use of animal experiments in scientific advances, but ensuring the defence and respect for the intrinsic values of the animals. In this regard the directive represents an important advance for the protection of animal welfare in all the Member States, with the aim of harmonizing such values in the EU current legislation. While several countries already have fairly progressive legislation, the implementation of the new directive represents an excellent opportunity to reinforce high criteria levels in the defence of animal welfare throughout all the Member States. This represents a good opportunity for the EU to reinforce its commitment with the scientific research and the welfare of experimental animals.

Noninvasive imaging methods are required to monitor the inflammatory content of atherosclerotic plaques. FEDAA1106 (N-(5-fluoro- 2-phenoxyphenyl)- N -(2-(2-fluoroethoxy)-5-methoxybenzyl) acetamide) is a selective ligand for TSPO-18kDa (also known as peripheral benzodiazepine receptor), which is expressed by activated macrophages. We compared 18 F-FEDAA1106 and 2-deoxy-2-[ 18 F]fluoro-D- glucose ( 18 F-FDG, a marker of glucose metabolism) for positron emission tomographic (PET) imaging of vascular inflammation. This was tested using a murine model in which focal inflammation was induced in the carotid artery via placement of a constrictive cuff. Immunostaining revealed CD68-positive cells (macrophages) at a disturbed flow site located downstream from the cuff. Dynamic PET imaging using 18 F-FEDAA1106 or 18 F-FDG was registered to anatomic data generated by computed tomographic (CT)/CT angiography. Standardized uptake values were significantly increased at cuffed compared to contralateral arteries using either 18 F-FEDAA1106 ( p < .01) or FDG ( p < .05). However, the 18 F-FEDAA1106 signal was significantly higher at the inflamed disturbed flow region compared to the noninflamed uniform flow regions, whereas differences in FDG uptake were less distinct. We conclude that 18 F-FEDAA1106 can be used in vivo for detection of vascular inflammation. Moreover, the signal pattern of 18 F-FEDAA1106 corresponded with vascular inflammation more specifically than FDG uptake.

C-type natriuretic peptide (CNP) is highly expressed in the central nervous system (CNS) and key to neuronal development; however, a broader role for CNP in the CNS remains unclear. To address this deficit, we investigated behavioral, sensory and motor abnormalities and blood-brain barrier (BBB) integrity in a unique mouse model with inducible, global deletion of CNP (gbCNP–/–). gbCNP–/– mice and wild-type littermates at 12 (young adult) and 65 (aged) weeks of age were investigated for changes in gait and motor coordination (CatWalk™ and rotarod tests), anxiety-like behavior (open field and elevated zero maze tests), and motor and sensory function (modified neurological severity score [mNSS] and primary SHIRPA screen). Vascular permeability was assessed in vivo (Miles assay) with complementary in vitro studies conducted in primary murine brain endothelial cells. Young adult gbCNP–/– mice had normal gait but reduced motor coordination, increased locomotor activity in the open field and elevated zero maze, and had a higher mNSS score. Aged gbCNP–/– animals developed recurrent spontaneous seizures and had impaired gait and wide-ranging motor and sensory dysfunction. Young adult and aged gbCNP–/– mice exhibited increased BBB permeability, which was partially restored in vitro by CNP administration. Cultured brain endothelial cells from gbCNP–/– mice had an abnormal ZO-1 protein distribution. These data suggest that lack of CNP in the CNS impairs tight junction protein arrangement and increases BBB permeability, which is associated with changes in locomotor activity, motor coordination and late-onset seizures.