Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects.

BACKGROUND: Modulation of glutamatergic synaptic transmission by N-methyl-D-aspartate receptors can produce rapid and sustained antidepressant effects. Rapastinel (GLYX-13), initially described as a N-methyl-D-aspartate receptor partial glycine site agonist, exhibits rapid antidepressant effect in rodents without the accompanying dissociative effects of N-methyl-D-aspartate receptor antagonists. METHODS: The relationship between rapastinel's in vitro N-methyl-D-aspartate receptor pharmacology and antidepressant efficacy was determined by brain microdialysis and subsequent pharmacological characterization of therapeutic rapastinel concentrations in N-methyl-D-aspartate receptor-specific radioligand displacement, calcium mobilization, and medial prefrontal cortex electrophysiology assays. RESULTS: Brain rapastinel concentrations of 30 to 100 nM were associated with its antidepressant-like efficacy and enhancement of N-methyl-D-aspartate receptor-dependent neuronal intracellular calcium mobilization. Modulation of N-methyl-D-aspartate receptors by rapastinel was independent of D-serine concentrations, and glycine site antagonists did not block rapastinel's effect. In rat medial prefrontal cortex slices, 100 nM rapastinel increased N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents and enhanced the magnitude of long-term potentiation without any effect on miniature EPSCs or paired-pulse facilitation responses, indicating postsynaptic action of rapastinel. A critical amino acid within the NR2 subunit was identified as necessary for rapastinel's modulatory effect. CONCLUSION: Rapastinel brain concentrations associated with antidepressant-like activity directly enhance medial prefrontal cortex N-methyl-D-aspartate receptor activity and N-methyl-D-aspartate receptor-mediated synaptic plasticity in vitro. At therapeutic concentrations, rapastinel directly enhances N-methyl-D-aspartate receptor activity through a novel site independent of the glycine coagonist site. While both rapastinel and ketamine physically target N-methyl-D-aspartate receptors, the 2 molecules have opposing actions on N-methyl-D-aspartate receptors. Modest positive modulation of N-methyl-D-aspartate receptors by rapastinel represents a novel pharmacological approach to promote well-tolerated, rapid, and sustained improvements in mood disorders.

[Endovascular embolization for traumatic carotid-cavernous fistula].

OBJECTIVE: To evaluate the choice of approaches, surgical techniques and clinical outcome of endovascular embolization for treating traumatic carotid cavernous fistula (TCCF). METHODS: A retrospective analysis of 119 patients with TCCF was conducted, in whom totally 128 embolizations were performed. In these procedures, the femoral artery approach was adopted in 112 cases, femoral vein approach in 5 cases, and superior ophthalmic vein approach in 2 cases. For the embolization materials, balloons were used in 101 cases, microcoils in 13 cases, both materials in 2 cases, and lyophilized dura mater in 3 cases. After the embolization procedures, 110 patients were followed-up for 3 months to 10 years, and 29 patients reexamined with angiography. RESULTS: Successful embolization for TCCF in a single procedure was achieved in 111 cases, and failure occurred due to balloon leakage in 8 cases, all embolized successfully in a second attempt. The total success rate was 100% in these cases, with a rate of internal carotid artery patency of 90.8% (108/119). No perioperative mortality or complication occurred, nor was TCCF recurrence seen during the follow-up. CONCLUSIONS: In general, TCCF can be successfully treated by balloon embolization via the femoral artery, while microcoil embolization has better performance for small fistula. Embolization can be done through venous approach when the internal carotid artery is ligated or occluded, and no procedure should be performed at the convenient expense of the internal carotid artery. Right choices of the approaches and embolization materials are key to the success of the procedure.

[Comparative assessment of clinical efficacy of percutaneous transhepatic metal versus plastic biliary stent implantation for malignant biliary obstruction: a multi-centered investigation].

OBJECTIVE: To compare the clinical efficacy of metal versus plastic biliary stent implantation for treatment of malignant biliary obstruction. METHODS: Percutaneous transhepatic implantations of self-expandable metal stent (MS, n=61) or 10F plastic stent (PS, n=34) were performed in 95 patients with malignant biliary obstruction selected from 3 hospitals of Guangdong Province. All patients were followed up until death or at least one year after the procedure. Kaplan-Meier analysis was used to compare the patients' survival and stent patency rates. RESULTS: The 30-day mortality rate was lower in MS group (6/61, 9.8%) than in PS group (9/34, 26.5%, P<0.05). The 30-day reobstruction rate and incidence of complications were 15.0%, 16.4% in MS group and 32.4%, 29.4% in PS group, respectively (P<0.01). The median patency period of the stents and median survival period of the patients were 230 d, 224 d in MS group and 90 d, 94 d in PS group, respectively (P<0.01). CONCLUSION: Metal stent implantation is superior to plastic stent for treatment of malignant biliary obstruction.

Percutaneous transhepatic metal versus plastic biliary stent in treating malignant biliary obstruction: a multiple center investigation.

OBJECTIVE: To compare the efficacy of metal versus plastic biliary stent implantation in the treatment of malignant biliary obstruction. METHODS: Percutaneous transhepatic self-expandable metal stent (MS, n=61) and 10F plastic stent (PS, n=34) were placed in 95 patients with malignant biliary obstruction in three hospitals of Guangdong province. All patients were followed up until death or at least one year after the procedure. Kaplan-Meier analysis was used to compare the survival of the patients and the rates of stent patency. RESULTS: The 30-day mortality rate was lower in the MS group (6/61, 9.8%) than in the PS group (9/34, 26.5%, P<0.05). The 30-day reobstruction rate and the complication rate were 15.0%, 16.4% in the MS group and 32.4%, 29.4% in the PS group, respectively (P<0.01). The median patency period of stents and median survival period of the patients were 230 days, 224 days in the MS group and 90 days, 94 days in the PS group, respectively (P<0.01). CONCLUSION: Metal stent is clinically superior to plastic stent in the treatment of malignant biliary obstruction.

Emergence of temporal-pattern sensitive neurons in the midbrain of weakly electric fish Gymnarchus niloticus.

Sensitivity of neurons in the torus semicircularis of a weakly electric fish, Gymnarchus niloticus, to two stimulus parameters that are critical for its behavior the jamming avoidance response was examined. The first parameter is the sign of frequency difference between discharge frequencies of fish's own electric organ and that of a neighbor's. The second parameter is the spatial orientation of neighbor's electric field. Whereas neuronal ambiguity of frequency coding for different orientations of neighbor's electric field is predicted, unambiguous JAR occurs at the behavioral level. Most neurons in the torus semicircularis showed sensitivity to the sign of frequency difference. Although a small number of neurons showed preference to a consistent sign of the frequency difference, the coding of the sign of frequency differences was found to be ambiguous with a highly variable pattern of responses for different orientations in most of neurons.