SummaryBackground-Although the use of magnetic resonance imaging (MRI) for the diagnosis of acute stroke is increasing, this method has not proved more effective than computed tomography (CT) in the emergency setting. We aimed to prospectively compare CT and MRI for emergency diagnosis of acute stroke.

Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function 1, 2 . At present no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain novel insights into TBI pathogenesis, we developed a novel closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic receptor dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We additionally show that the skull bone is permeable to small molecular weight compounds and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results provide novel insights into the acute cellular response to TBI and a means to locally deliver therapeutic compounds to the site of injury.TBI encompasses injuries that range from mild to severe 1, 3 and occurs when the brain is exposed to external forces that induce focal and / or diffuse pathologies, including vascular damage, edema, axonal shearing, and neuronal cell death [4][5][6] . TBI is usually divided into two phases: the primary insult and ensuing secondary reaction. It is postulated that primary cell death cannot be prevented without avoiding the injury itself, but that secondary damage is amenable therapeutic intervention because it is driven by pathogenic parameters such as ROS 7,8 , calcium release 9 , glutamate toxicity 10, 11 , mitochondrial dysfunction 12 , inflammation 6 , etc. To date, animal models of TBI have been developed that reflect mild, Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. In humans, primary injury to the meninges and vasculature can be observed in the absence of conspicuous brain damage following minor head trauma. As part of an ongoing study of mild TBI, we evaluated research MRI with contrast from patients presenting to the emergency room within 48 hours of minor head injury. Over a period of 30 months, 142 patients were enrolled with a baseline Glasgow Coma Scale (GCS) of 15, reporting loss-ofconsciousness or post-traumatic amnesia, and a clinical computed tomography (CT) scan without evidence of injury to the parenchyma. Meningeal hemorrhag...

Packed erythrocytes are ideally suited as a model system for the study of water diffusion in biological tissue, because cell size, membrane permeability, and extracellular volume fraction can be varied independently. We used a pulsed-field-gradient spin echo NMR technique to measure the time-dependent diffusion coefficient D(t) in packed erythrocytes. The long-time diffusion constant, Deff, depends sensitively on the extracellular volume fraction. This may explain the drop in Ddf during the early stages of brain ischemia, where just minutes after an ischemic insult the extra-cellular volume in the affected region of the brain is significantly reduced.Using an effective medium formula, we estimate the erythrocyte membrane permeability, in good agreement with measurements on isolated cells. From the short-time behavior of D(t), we determine the surface-to-volume ratio of the cells, -(0.72 ,um)-l.Diffusive transport of water in the presence of permeable membranes is of fundamental biological importance (1). The measured diffusion coefficient, D(t), depends on observation time and is a sensitive function of several physical parameters: membrane permeability, K; the volume fraction of connected extracellular fluid, 4; and local water concentrations. The geometrical arrangement of the membranes is important in determining D(t), and 4 is a parameter that characterizes this arrangement. Samples of erythrocytes (RBCs) are ideally suited for the study of such effects since cell size, K, and 4 can all be independently controlled. The pulsed-field-gradient (PFG) NMR technique (2) has been used to determine the membrane permeability of biological membranes in packed RBCs and some types of tissue (3, 4). To derive K from the effective (long time) diffusion coefficient, Doff, these studies utilized the relation, noted by Crick (5), ample, the second term on the righthand side should be replaced by cl(Ka) if, in the space between membranes, other molecules such as proteins occupy a fractional concentration 1 -c. This effect is in addition to the change in the microscopic diffusion coefficient of water produced by the presence of the proteins.PFG NMR is an ideal tool for measuring the timedependent diffusion coefficient (2). The measurement is nondestructive and does not involve the introduction of chemical or isotopic tracers. The observation time can be varied over several orders of magnitude. The minimum observation time is determined by the minimum length of gradient pulses and the subsequent recovery of the apparatus from eddy current and magnetoacoustic effects and by signalto-noise considerations. The maximum time is determined by the spin-lattice and spin-spin relaxation times of the fluid.We used PFG NMR to study the effects of 4 and K on Doff.Using an effective medium theory (EMT), we calculate K from measured values of Deff. We also measured the time dependence of the diffusion coefficient at short times. Our data are consistent with recent work on porous media with solid grains (8,9) and demonstrate that the ...