Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.

Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery.

The Tibial Slope in Patients With Achondroplasia: Its Characterization and Possible Role in Genu Recurvatum Development.

BACKGROUND: Genu recurvatum, a posterior resting position of the knee, is a common lower extremity deformity in patients with achondroplasia and has been thought to be secondary to ligamentous laxity. To the best of our knowledge, the role of the tibial slope has not been investigated, and no studies describe the tibial slope in patients with achondroplasia. Our goals were to characterize the tibial slope in children and adults with achondroplasia, explore its possible role in the development of genu recurvatum, and compare the tibial slope in patients with achondroplasia to that in the general population. METHODS: We reviewed 252 lateral knee radiographs of 130 patients with achondroplasia seen at our clinic from November 2007 through September 2013. Patients were excluded if they had previous lower extremity surgery or radiographs with extreme rotation. We analyzed patient demographics and, on all radiographs, the tibial slope. We then compared the mean tibial slope to norms in the literature. Tibial slopes >90 degrees had an anterior tibial slope and received a positive prefix. Statistical analysis included intraclass and interclass reliability, Pearson correlation coefficient, and the Student t tests (significance, P<0.05). RESULTS: The overall mean tibial slope for the 252 knees was +1.32±7 degrees, which was significantly more anterior than the normal slopes reported in the literature for adults (7.2 to 10.7 degrees, P=0.0001) and children (10 to 11 degrees, P=0.0001). The Pearson correlation coefficient for mean tibial slope and age showed negative correlations of -0.4011 and -0.4335 for left and right knees, respectively. This anterior tibial slope produces proximal and posterior vector force components, which may shift the knee posteriorly in weightbearing. CONCLUSIONS: The mean tibial slope is significantly more anterior in patients with achondroplasia than in the general population; however, this difference diminishes as patients' age. An anterior tibial slope may predispose to a more posterior resting knee position, also known as genu recurvatum. LEVEL OF EVIDENCE: Level IV-retrospective case series.

Glucocorticoid signaling in myeloid cells worsens acute CNS injury and inflammation.

Glucocorticoid stress hormones (GCs) are well known for being anti-inflammatory, but some reports suggest that GCs can also augment aspects of inflammation during acute brain injury. Because the GC receptor (GR) is ubiquitously expressed throughout the brain, it is difficult to know which cell types might mediate these unusual "proinflammatory" GC actions. We examined this with cell type-specific deletion or overexpression of GR in mice experiencing seizure or ischemia. Counter to their classical anti-inflammatory actions, GR signaling in myeloid cells increased Iba-1 and CD68 staining as well as nuclear p65 levels in the injured tissue. GCs also reduced levels of occludin, claudin 5, and caveolin 1, proteins central to blood-brain-barrier integrity; these effects required GR in endothelial cells. Finally, GCs compromised neuron survival, an effect mediated by GR in myeloid and endothelial cells to a greater extent than by neuronal GR.

Results From a Modified Bleb Needling Procedure With Continuous Infusion Performed in the Operating Room.

PURPOSE: Needling of a scarred trabeculectomy bleb is often performed in the office using a slit-lamp microscope as an alternative to additional surgery to lower intraocular pressure (IOP). However, the success rate in an office setting is highly variable, with reported success rates as low as 13%. We report a retrospective assessment of an intraoperative needling technique for reviving failed blebs. DESIGN: A retrospective chart review. PARTICIPANTS: Patients undergoing the intraoperative modified bleb revision technique in the setting of a failed trabeculectomy due to scarring at the Wilmer Eye Institute, Johns Hopkins Hospital between August 16, 2010 and August 29, 2012. METHODS: Patients with uncontrolled IOP were operated on using a modified bleb needling technique. In this technique, a 25-G infusion cannula is placed in the anterior chamber and fibrotic adhesions within the bleb are lysed with a 25-G needle. The continuous infusion of balanced salt solution from the anterior chamber causes bleb elevation, which helps to guide the endpoint of lysis for the procedure. A subconjunctival injection of 5-fluorouracil is given at the conclusion of each case. MAIN OUTCOME MEASURES: IOP reduction and number of glaucoma medications at postoperative day 1, week 1, month 1, month 3, month 6, and month 12. RESULTS: A total of 33 eyes of 30 patients were included. At the visit before the procedure, the mean (±SD) IOP was 22.1±9.2 (range, 11 to 58) and subjects were using an average of 2.3±1.4 (range, 0 to 4) glaucoma medications. The mean IOP reduction was 8.7 mm Hg [95% confidence interval (CI), 5.6-11.8] at postoperative day 1, 8.1 mm Hg (95% CI, 4.0-12.3) at week 1, 8.9 mm Hg (95% CI, 5.3-12.5) at month 1, 8.1 mm Hg (95% CI, 4.2-12.0) at month 3, 8.2 mm Hg (95% CI, 3.9-12.5) at month 6, and 6.2 mm Hg (95% CI, 3.6-8.7) at month 12. IOP was reduced about 30% to 40% compared with baseline at each time point (P<0.05). The average reduction in medications used was 1.7 at day 1, 1.0 at month 1, 1.2 at month 3, 1.5 at month 6, and 0.5 at month 12. Seven patients underwent repeat needling. Overall, 64% of subjects maintained IOP at or below their target after 12 months. CONCLUSIONS: A modified bleb needling procedure performed in the operating room can successfully lower IOP in the setting of a previous trabeculectomy in over 60% of subjects a year after the procedure.