The purpose of this study was to evaluate amino acid neurotransmitter dynamics in the reperfusion phase after transient cerebral ischemia. In vivo microdialysis was used to measure extracellular amino acid levels in a rabbit model of focal ischemia. During 30 min of transient ischemia (n = 5), small but significant (p < 0.05) increases in glutamate, aspartate, gamma-aminobutyric acid (GABA), and taurine were noted. These elevations rapidly returned to baseline levels upon recirculation and remained constant for up to 5.5 h of reperfusion. In rabbits subjected to 2 h of transient ischemia (n = 5), two phases of amino acid release were seen. During ischemia, large (5- to 50-fold) elevations in glutamate, aspartate, GABA, and taurine occurred, as expected. These elevations rapidly normalized upon unocclusion. However, significant (p < 0.05) secondary elevations in glutamate, aspartate, and GABA occurred after 2-4 h of reperfusion. Regression analysis demonstrated significant correlations between primary (ischemic) and secondary (reperfusion) efflux. In permanent ischemia (n = 5), amino acid levels remained elevated throughout the entire experiment. Secondary elevations in excitatory amino acids may further contribute to the excitotoxic cascade during reperfusion.

These data indicate that mice lacking eNOS expression show a greater degree of hemodynamic compromise after middle cerebral artery occlusion and suggest that a product of eNOS activity (eg. NO) may protect brain after focal cerebral ischemia, possibly by improving blood flow within the penumbral zone.

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Critical size defects in ovine tibiae, stabilised with intramedullary interlocking nails, were used to assess whether the addition of carboxymethylcellulose to the standard osteogenic protein-1 (OP-1/BMP-7) implant would affect the implant's efficacy for bone regeneration. The biomaterial carriers were a 'putty' carrier of carboxymethylcellulose and bovinederived type-I collagen (OPP) or the standard with collagen alone (OPC). These two treatments were also compared to "ungrafted" negative controls. Efficacy of regeneration was determined using radiological, biomechanical and histological evaluations after four months of healing. The defects, filled with OPP and OPC, demonstrated radiodense material spanning the defect after one month of healing, with radiographic evidence of recorticalisation and remodelling by two months. The OPP and OPC treatment groups had equivalent structural and material properties that were significantly greater than those in the ungrafted controls. The structural properties of the OPP-and OPC-treated limbs were equivalent to those of the contralateral untreated limb (p > 0.05), yet material properties were inferior (p < 0.05). Histopathology revealed no residual inflammatory response to the biomaterial carriers or OP-1. The OPP-and OPC-treated animals had 60% to 85% lamellar bone within the defect, and less than 25% of the regenerate was composed of fibrous tissue. The defects in the untreated control animals contained less than 40% lamellar bone and more than 60% was fibrous tissue, creating full cortical thickness defects. In our studies carboxymethylcellulose did not adversely affect the capacity of the standard OP-1 implant for regenerating bone.

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Summary: The aim of this study was to examine the quanti tative relationship between changes in apparent diffusion coefficient (ADC) and transverse relaxivity (f�Ri) measure ments of relative perfusion deficits within the gradients of a focal ischemic insult. Sixty minutes after permanent occlu sion of the middle cerebral artery, rats (n = 7) were subjected to spin echo diffusion-weighted scans followed by fast low angle shot (FLASH) perfusion-sensitive scans. Diffusion weighted images showed clear ischemic lesions in the af fected basal ganglia and cortex. Ischemic deficits were demonstrated as a decrease in first-pass transit of injected boluses of gadodiamide. ADC maps were generated and regions of interest (ROIs) were obtained to span the range of ADC reductions from the lesion center or core to the pe riphery or penumbra. Corresponding ROIs from the bolus injection images were used to calculate perfusion indexes Diffusion-weighted magnetic resonance imaging (DWI) can detect acute cerebral ischemia before le sions are apparent on conventional scans. DWI ap plies diffusion-sensitizing gradients that make the col lected MR signal sensitive to the incoherent motion of water protons (Le Bihan et aI., 1988). After isch emia, acute cell swelling and changes in cell mem brane permeability result in reduced water diffusion, thus increasing DWI signal intensity (Moseley et aI., 1990a; Minematsu et aI., 1992; Jiang et aI., 1993).Received March 11, 1996; final revision received August 7, 1996; accepted August 7, 1996.Address correspondence and reprint requests to Dr. E. OWl, diffusion-weighted magnetic resonance imaging; FLASH. fast low-angle shot; MCA. middle cerebral artery; MRI, magnetic resonance imaging; ROI. region of interest. 183relative to contralateral levels as ratios of t:.Ri integrals and ratios of t:.Ri peak values. In all animals, the degree of ADC reductions was related to the degree of t:.R; perfusion defi cits, ranging from severe ischemia in the core of the lesion to intermediate and moderate changes toward the lesion pe riphery. In the ischemic peri � hery, ADC reductions were linearly correlated with t:.R2 peak ratios. However, no significant correlation was found between ADC reductions and t:.R; integral ratios. These data suggest that magnetic resonance measurements of ADC and t:.R; peak ratios can be used to quantitatively assess the variable gradients in focal ischemia, including potentiallyn critical areas at risk in the ischemic periphery. Key Words: Diffusion-weighted imagnetic resonance imaging-Apparent diffusion coeffi cient-Perfusion-sensitive magnetic resonance imaging Focal cerebral ischemia-Penumbra.Alterations in water proton diffusion can be quantita tively monitored by calculating apparent diffusion coefficient (ADC) (Le Bihan et aI., 1988; Jiang et aI., 1993).Dynamic MRI can be used to track changes in first pass transit of injected contrast agent boluses through the brain. After ischemia, perfusion deficits can be observed as decreases in contrast bolus transit. The change ...

Summary: Recently, diffusion-weighted magnetic reso nance imaging (DWI) has been shown to visualize acute ischemic lesions in the brain before changes are observ able with conventional magnetic resonance imaging. However, the underlying mechanisms of these acute DWI changes are unclear and may include both reversible and irreversible damage. In this study, we demonstrate that acute DWI lesions may be reversed with MK801 therapy postischemia. Sprague-Dawley rats (n = 12) were sub jected to middle cerebral artery occlusion and DWI scans were obtained beginning 60 min postocclusion. Distinct regions of hyperintensity wgre observed in the basal gan glia and cortex, corresponding with the expected distri bution of ischemia in this model. After the first scan, animals were treated with MK801 (0.5 mg/kg i.v.) or nor- Magnetic resonance imaging (MRI) has beenshown to be a sensitive method for detecting stroke noninvasively (Matthews et aI. , 1992 Abbreviations used: ANOV A, analysis of variance; DWI, dif fusion-weighted magnetic resonance imaging; MABP, mean ar terial blood pressure; MCAO, middle cerebral artery occlusion; MRI, magnetic resonance imaging; ROI, region of interest; SIR, signal intensity ratio; TlW, Tl-weighted; T2W, T2-weighted. 597mal saline and subsequently scanned again 30 and 60 min after treatment. In the control group, the area of hyper intense lesions continued to increase, by 55% in the cor tex and 57% in the basal ganglia. MK801 therapy signif icantly (p < 0.01) reduced the area of damage by the third DWI scan at 60 min posttreatment ( -50% cortex, -22% basal ganglia, -41% total hemisphere) compared to pre treatment scans. Tetrazolium (TTC) stains at 24 h con firmed that MK801 significantly reduced the volumes of infarction (p < 0.05). These results demonstrate that sig nificant portions of the acute ischemic lesion on DWI are reversible with pharmacologic intervention.