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.

Segmentation of pulmonary nodules using adaptive local region energy with probability density function-based similarity distance and multi-features clustering.

BACKGROUND: Pulmonary nodules in computerized tomography (CT) images are potential manifestations of lung cancer. Segmentation of potential nodule objects is the first necessary and crucial step in computer-aided detection system of pulmonary nodules. The segmentation of various types of nodules, especially for ground-glass opacity (GGO) nodules and juxta-vascular nodules, present various challenges. The nodule with GGO characteristic possesses typical intensity inhomogeneity and weak edges, which is difficult to define the boundary; the juxta-vascular nodule is connected to a vessel, and they have very similar intensities. Traditional segmentation methods may result in the problems of boundary leakage and a small volume over-segmentation. This paper deals with the above mentioned problems. METHODS: A novel segmentation method for pulmonary nodules is proposed, which uses an adaptive local region energy model with probability density function (PDF)-based similarity distance and multi-features dynamic clustering refinement method. Our approach has several novel aspects: (1) in the proposed adaptive local region energy model, the local domain for local energy model is selected adaptively based on k-nearest-neighbour (KNN) estimate method, and measurable distances between probability density functions of multi-dimension features with high class separability are used to build the cost function. (2) A multi-features dynamic clustering method is used for the segmentation refinement of juxta-vascular nodules, which is based on the nodule segmentation using active contour model (ACM) with adaptive local region energy and vessel segmentation using flow direction feature (FDF)-based region growing method. (3) it handles various types of nodules under a united framework. RESULTS: The proposed method has been validated on a clinical dataset of 113 chest CT scans that contain 157 nodules determined by a ground truth reading process, and evaluating the algorithm on the provided data leads to an average Tanimoto/Jaccard error of 0.17, 0.20 and 0.24 for GGO, juxta-vascular and GGO juxta-vascular nodules, respectively. CONCLUSIONS: Experimental results show desirable performances of the proposed method. The proposed segmentation method outperforms the traditional methods.

Dual-energy CT angiography for the diagnosis of intracranial dural arteriovenous fistula.

PURPOSE: To investigate the clinical utility of dual-source dual-energy CT angiography (DSDECTA) for diagnosing intracranial dural arteriovenous fistula (DAVF). METHODS: Nine intracranial DAVF patients were examined using Siemens DSDECTA and cerebral digital subtraction angiography (DSA). Imaging data were retrospectively analyzed to evaluate the concordance between the imaging modalities. RESULTS: DSDECTA examination showed that the blood-supplying arteries were thickened and the draining veins and dural sinuses were expanded in all 9 patients. The presence and characteristics of intracranial DAVF were confirmed using DSA. Head CT showed subarachnoid hemorrhage in 4 cases and intracerebral hematoma in 3 cases. CONCLUSION: Although DSA is the gold standard for DAVF diagnosis, DSDECTA is less invasive and more suitable for revealing the three-dimensional structure of secondary intracranial lesions as well as other DAVF characteristics. Thus, DSDECTA may be a new alternative for noninvasive screening of suspected DAVF patients before interventional embolization and surgical resection.

Presynaptic inhibition by α2 receptor/adenylate cyclase/PDE4 complex at retinal rod bipolar synapse.

G-protein-coupled receptor (GPCR)-mediated presynaptic inhibition is a fundamental mechanism regulating synaptic transmission in the CNS. The classical GPCR-mediated presynaptic inhibition in the CNS is produced by direct interactions between the G(ßγ) subunits of the G-protein and presynaptic Ca(2+) channels, K(+) channels, or synaptic proteins that affect transmitter release. This mode of action is shared by well known GPCRs such as the α2, GABA(B), and CB1 receptors. We report that the α2 receptor-mediated inhibition of presynaptic Ca(2+) channel and transmitter release in rat retinal rod bipolar cells depends on the G(α) subunit via a G(α)-adenylate cyclase-cAMP cascade and requires participation of the type 4 phosphodiesterase (PDE4), a new role for phosphodiesterase in neural signaling. By using the G(α) instead of the G(ßγ) subunits, this mechanism is able to use a cyclase/PDE enzyme pair to dynamically control a cyclic nucleotide second messenger (i.e., cAMP) for the regulation of synaptic transmission, an operating strategy that shows remarkable similarity to that of dynamic control of cGMP and transmitter release from photoreceptors by the guanylate cyclase/PDE6 pair in phototransduction. Our results demonstrate a new paradigm of GPCR-mediated presynaptic inhibition in the CNS and add a new regulatory mechanism at a critical presynaptic site in the visual pathway that controls the transmission of scotopic information. They also provide a presynaptic mechanism that could contribute to neuroprotection of retinal ganglion cells by α2 agonists, such as brimonidine, in animal models of glaucoma and retinal ischemia and in glaucoma patients.

Nimodipine enhancement of alpha2 adrenergic modulation of NMDA receptor via a mechanism independent of Ca2+ channel blocking.

PURPOSE: To further understand alpha2 receptor signaling in the retina and the mechanisms that mediate ocular beneficial effects of brimonidine (an alpha2 agonist) and nimodipine (an L-type Ca(2+) channel blocker). METHODS: The authors used in situ retinal ganglion cells (RGCs) in the isolated rat retina to characterize alpha2 modulation of NMDA receptor function and a rabbit retinal NMDA excitotoxicity model to verify in vitro findings under in vivo conditions. Electrophysiological (whole-cell patch clamp) recordings and Ca(2+) imaging were used to characterize NMDA receptor function and to verify the effect of various Ca(2+) channel blockers. In vivo drug application in rabbits was achieved by intravitreal injections. RESULTS: Application of NMDA elicited a robust whole-cell inward current in individual in situ RGCs voltage clamped at -70 mV. Pretreatment with brimonidine significantly reduced NMDA-elicited currents in RGCs. This suppressive effect of brimonidine was substantially enhanced by background addition of nimodipine or isradipine, but not by diltiazem, verapamil, or cadmium. This effect of nimodipine was blocked by either a selective alpha2 antagonist, a cyclic adenosine monophosphate (cAMP) analogue, or an adenylate cyclase activator, indicating that nimodipine acts through the alpha2 receptor-G(alphai)-coupled pathway. Brimonidine protects RGCs in the rabbit excitotoxicity model. This brimonidine protection is also enhanced significantly by application of nimodipine but not of diltiazem. CONCLUSIONS: These in vitro and in vivo findings demonstrate a novel neural mechanism involving nimodipine enhancement of alpha2 signaling in RGCs. This nimodipine effect appears to be independent of its classic L-type Ca(2+) channel-blocking action.

Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity.

PURPOSE: alpha2 Agonists, such as brimonidine, have been shown to protect retinal ganglion cells (RGCs) in animal models of glaucoma and acute retinal ischemia. In this study, the authors investigated the neural mechanism that may underlie alpha2 neuroprotection of RGCs. METHODS: The authors used in situ RGCs in the isolated rat retina to investigate possible interactions between alpha2 and N-methyl-D-aspartate (NMDA) receptors and rat glaucoma or rabbit retinal NMDA excitotoxicity models to verify in vitro findings under in vivo conditions. RESULTS: Application of NMDA elicited a robust intracellular Ca(2+) signal and inward current in individual in situ RGCs voltage clamped at -70 mV. NMDA-elicited responses were blocked by D-AP5 (D-2-amino-5-phosphonopentanoic acid), a selective NMDA receptor antagonist. Brimonidine pretreatment also significantly reduced NMDA-elicited whole-cell currents and cytosolic Ca(2+) signals in RGCs. This suppressive action of brimonidine was blocked by alpha2 antagonists, cAMP analogs, an adenylate cyclase activator, and a cAMP-specific phosphodiesterase (PDE4) inhibitor, indicating that this brimonidine effect is mediated by the alpha2 receptor through a reduction of intracellular cAMP production. Brimonidine or NMDA receptor blockers protected RGCs in rat glaucoma and rabbit retinal NMDA excitotoxicity models. The brimonidine neuroprotective effect was abolished by an alpha2 antagonist or a PDE4 inhibitor in both in vivo models. CONCLUSIONS: The results demonstrate alpha2 modulation of NMDA receptor function as an important mechanism for neuroprotection. These results suggest a new therapeutic approach based on neuromodulation, instead of direct inhibition, of the NMDA receptor for the treatment of glaucoma and other CNS disorders associated with NMDA receptor overactivation.

Alpha2 adrenergic receptor-mediated modulation of cytosolic Ca++ signals at the inner plexiform layer of the rat retina.

PURPOSE: Compelling evidence suggests that alpha2 agonists, such as brimonidine, protect retinal ganglion cells (RGCs) from injury in a wide range of animal models. However, the mechanism of action for this protection and the physiological role of the alpha2 adrenergic system in the retina is not well understood. A major goal of this work was to explore the role of the alpha2 adrenergic system in the modulation of cytosolic Ca(2+) signaling at retinal synaptic layers, particularly the inner plexiform layer (IPL), where communication between RGCs and their presynaptic cells takes place. METHODS: Functional Ca(2+) imaging at the inner plexiform layer (IPL) and outer plexiform layer (OPL) of living rat retinal slices was conducted with a high-speed confocal system. The relative changes of cytosolic free Ca(2+) were monitored with the fluorescent Ca(2+) dye fluo-4. The Ca(2+) signal was elicited by membrane depolarization produced by a high K(+) (40 mM) Ringer solution that was delivered rapidly and briefly to the test regions of the retinal slice by a custom-made multichannel local perfusion system. RESULTS: A brief application (8 seconds) of high K(+) Ringer elicited a robust cytosolic Ca(2+) increase at the IPL and OPL. In both cases, this Ca(2+) signal was eliminated by nimodipine, a selective L-type voltage-gated Ca(2+)-channel blocker, or when the extracellular Ca(2+) in the Ringer was replaced with equal molar EGTA. At IPL, the Ca(2+) signal was also suppressed in a dose-dependent manner by brimonidine and other alpha2 receptor agonists, such as medetomidine. The suppressive action of brimonidine and medetomidine was completely blocked by classic alpha2 receptor antagonists, such as yohimbine, rauwolscine, and atipamezole. Interestingly, the alpha2 receptor agonists had no effect on the high K(+) Ringer-elicited cytosolic Ca(2+) signal at OPL. Blocking the N-methyl-d-aspartate (NMDA) type of ionotropic glutamate receptor with D-AP5 attenuated this high K(+)-elicited Ca(2+) signal by approximately 20% at IPL. D-AP5 had no effect on the Ca(2+) signal at OPL. CONCLUSIONS: These findings provide the first direct evidence of alpha2 receptor-mediated modulation of L-type Ca(2+) channel activity in the CNS (the retina is part of the CNS). This alpha2 modulation appears to occur at the IPL but not at the OPL of the retina. These findings suggest that a physiological function of the retinal alpha2 system is the regulation of synaptic transmission at IPL and that brimonidine and other alpha2 agonists may protect RGCs under disease conditions by preventing abnormal elevation of cytosolic free Ca(2+) either in RGCs, in their presynaptic cells, or in both.

[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.