Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity.

PURPOSE Several recent studies have suggested that experimental myopia can be induced in mice. However, it is not clear what role the photopic visual input plays in this process and whether mouse myopia is similar to human myopia. The purpose of this study was to carry out an in vivo high-resolution analysis of changes in ocular components and refractive state of the eye upon induction of experimental myopia in mice. METHODS A high-resolution small animal 4.7T Bruker Avance MRI System and a high-resolution automated eccentric infrared photorefractor were used to analyze changes of the refractive state and ocular components in C57BL/6J mice associated with experimental myopia induced by diffusers and −25 D lenses under photopic conditions. RESULTS We found that both diffusers and −25 D lenses induce myopia in C57BL/6J mice under photopic conditions (continuous light, 200 ± 15 lux). The extent of myopic shift induced by −25 D lenses was greater compared to the shift induced by diffusers (−15.2 ± 0.7 D, lenses ; −12.0 ± 1.4 D, diffusers). Myopia in mice is attributed to an increase in size of the postequatorial segment of the eye. Experimental myopia in mice can be induced only during the susceptible period in postnatal development, which ends around P67. CONCLUSIONS Both diffusers and spectacle lenses induce myopia in mice under photopic conditions, during the susceptible period in postnatal development. Myopia in mice is associated with elongation of the vitreous chamber of the eye, as in humans and non-human primates.

EuII rivals GdIII in its ability to enhance contrast in magnetic resonance imaging; however, all reported EuII-based complexes have been studied in vitro largely because the tendency of EuII to oxidize to EuIII has been viewed as a major obstacle to in vivo imaging. Here, we present solid- and solution-phase characterization of a EuII-containing cryptate and first in vivo use of EuII to provide contrast enhancement. The results are indicative of a water-coordination number between one and two upon dissolution and are a demonstration of the ability to observe EuII-based contrast enhancement for hours in a mouse.

The current study used a rat model to investigate the underlying mechanisms of blast-induced tinnitus, hearing loss, and associated traumatic brain injury (TBI). Seven rats were used to evaluate behavioral evidence of tinnitus and hearing loss, and TBI using magnetic resonance imaging following a single 10-msec blast at 14 psi or 194 dB sound pressure level (SPL). The results demonstrated that the blast exposure induced early onset of tinnitus and central hearing impairment at a broad frequency range. The induced tinnitus and central hearing impairment tended to shift towards high frequencies over time. Hearing threshold measured with auditory brainstem responses also showed an immediate elevation followed by recovery on day 14, coinciding with behaviorally-measured results. Diffusion tensor magnetic resonance imaging results demonstrated significant damage and compensatory plastic changes to certain auditory brain regions, with the majority of changes occurring in the inferior colliculus and medial geniculate body. No significant microstructural changes found in the corpus callosum indicates that the currently adopted blast exposure mainly exerts effects through the auditory pathways rather than through direct impact onto the brain parenchyma. The results showed that this animal model is appropriate for investigation of the mechanisms underlying blast-induced tinnitus, hearing loss, and related TBI. Continued investigation along these lines will help identify pathology with injury/recovery patterns, aiding development of effective treatment strategies.

The +3 and +2 oxidation states of europium have drastically different magnetic and spectroscopic properties. Electrochemical measurements are often used to probe EuIII/II oxidation state changes, but a full suite of spectroscopic characterization is necessary to demonstrate conversion between these two oxidation states in solution. Here, we report the facile conversion of a EuIII tetraglycinate complex into its EuII analogue. We present electrochemical, luminescence, electron paramagnetic resonance, UV–visible, and NMR spectroscopic data demonstrating complete reversibility from the reduction and oxidation of the +3 and +2 oxidation states, respectively. The EuII-containing analogue has kinetic stability within the range of clinically approved GdIII-containing complexes using an acid-catalyzed dissociation experiment. Additionally, we demonstrate that the +3 and +2 oxidation states provide redox-responsive behavior through chemical exchange saturation transfer or proton relaxation, respectively. These results will be applicable to a wide range of redox-responsive contrast agents and Eu-containing complexes.

Purpose Studies of myopia in mice have been complicated by the difficulty in obtaining accurate measurements of small changes observed in the growing mouse eye in vivo and the lack of data on refractive eye development. The purpose of this study was to carry out an in vivo high-resolution analysis of mouse eye growth and refractive development. Methods A high-resolution small animal MRI and a high-resolution infrared photorefractor were used to analyze refractive development in P21-P89 C57BL/6J mice. Results The growth of the mouse eye decelerated after P40. The eye maintained a slightly prolate shape during growth. The anterior chamber growth exhibited similar pattern, while corneal radius of curvature (CRC) increased linearly. The growth rate of the lens remained constant until P89. The lens “overgrew” the eye at P40 resulting in a decline in vitreous chamber depth (VCD). Mice showed myopic refractive errors at younger age (−13.2 ± 2.0 D, mean ± SD, P21). The refractive errors stabilized around emmetropic values by P32 and remained emmetropic until P40. Mice became progressively hyperopic with age (+1.2 ± 1.7 D, P67; +3.6 ± 2.3 D, P89). Conclusions Development of ocular components in the mouse is similar to the tree shrew, but somewhat different from higher primates and humans. Main differences can be attributed to the age-related changes of the crystalline lens and CRC. In spite of these differences, mice appear to be able to achieve and maintain emmetropic refractive status at P32-P40.

Glatiramer acetate (GA) is a disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) with several putative mechanisms of action. Currently, there is paucity of in vivo human data linking the well-established peripheral immunologic effects of therapy with GA to its potential effects inside the central nervous system (CNS). Brain proton magnetic resonance spectroscopy (MRS) allows in vivo examination of axonal integrity by quantifying the resonance intensity of the neuronal marker N-acetylaspartate (NAA). In a pilot study to investigate the effect of GA on axonal injury, we performed combined brain magnetic resonance imaging (MRI) and MRS studies in 18 treatment naïve RRMS patients initiating therapy with GA at baseline and annually for two years on therapy. A small group of four treatment naïve RRMS patients, electing to remain untreated, served as controls. NAA/Cr was measured in a large central brain volume of interest (VOI) as well as the normal appearing white matter (NAWM) within the VOI. After two years, NAA/Cr in the GA-treated group increased significantly by 10.7% in the VOI (2.17 +/- 0.26 versus 1.96 +/- 0.24, P = 0.03) and by 71% in the NAWM (2.23 +/- 0.26 versus 2.08 +/- 0.31, P = 0.04). In the untreated group, NAA/Cr decreased by 8.9% at two years in the VOI (2.01 +/- 0.16 versus 1.83 +/- 0.21, P = 0.03) and 8.2% in the NAWM (2.07 +/- 0.24 versus 1.90 +/- 0.29, P = 0.03). Our data shows that treatment with GA leads to axonal metabolic recovery and protection from sub-lethal axonal injury. These results support an in situ effect of GA therapy inside the CNS and suggest potential neuroprotective effects of GA.

We treated traumatic brain injury (TBI) with human bone marrow stromal cells (hMSCs) and evaluated the effect of treatment on white matter reorganization using MRI. We subjected male Wistar rats (n = 17) to controlled cortical impact and either withheld treatment (controls; n = 9) or inserted collagen scaffolds containing hMSCs (n = 8). Six weeks later, the rats were sacrificed and MRI revealed selective migration of grafted neural progenitor cells towards the white matter reorganized boundary of the TBI-induced lesion. Histology confirmed that the white matter had been reorganized, associated with increased fractional anisotropy (FA; p <0.01) in the recovery regions relative to the injured core region in both treated and control groups. Treatment with hMSCs increased FA in the recovery regions, lowered T2 in the core region, decreased lesion volume and improved functional recovery relative to untreated controls. Immunoreactive staining showed axonal projections emanating from neurons and extruding from the corpus callosum into the ipsilateral cortex at the boundary of the lesion. Fiber tracking (FT) maps derived from diffusion tensor imaging confirmed the immunohistological data and provided information on axonal rewiring. The apparent kurtosis coefficient (AKC) detected additional axonal remodeling regions with crossing axons, confirmed by immunohistological staining, compared with FA. Our data demonstrate that AKC, FA, FTand T2 can be used to evaluate treatment-induced white matter recovery, which may facilitate restorative therapy in patients with TBI.