Regulation of glutamate release by heteromeric nicotinic receptors in layer V of the secondary motor region (Fr2) in the dorsomedial shoulder of prefrontal cortex in mouse

We studied how nicotinic acetylcholine receptors (nAChRs) regulate glutamate release in the secondary motor area (Fr2) of the dorsomedial murine prefrontal cortex, in the presence of steady agonist levels. Fr2 mediates response to behavioral situations that require immediate attention and is a candidate for generating seizures in the frontal epilepsies caused by mutant nAChRs. Morphological analysis showed a peculiar chemoarchitecture and laminar distribution of pyramidal cells and interneurons. Tonic application of 5 µM nicotine on Layer V pyramidal neurons strongly increased the frequency of spontaneous glutamatergic excitatory postsynaptic currents. The effect was inhibited by 1 µM dihydro‐β‐erythroidine (which blocks α4‐containing nAChRs) but not by 10 nM methyllicaconitine (which blocks α7‐containing receptors). Excitatory postsynaptic currents s were also stimulated by 5‐iodo‐3‐[2(S)‐azetidinylmethoxy]pyridine, selective for β2‐containing receptors, in a dihydro‐β‐erythroidine ‐sensitive way. We next studied the association of α4 with different populations of glutamatergic terminals, by using as markers the vesicular glutamate transporter type (VGLUT) 1 for corticocortical synapses and VGLUT2 for thalamocortical projecting fibers. Immunoblots showed higher expression of α4 in Fr2, as compared with the somatosensory cortex. Immunofluorescence showed intense VGLUT1 staining throughout the cortical layers, whereas VGLUT2 immunoreactivity displayed a more distinct laminar distribution. In Layer V, colocalization of α4 nAChR subunit with both VGLUT1 and VGLUT2 was considerably stronger in Fr2 than in somatosensory cortex. Thus, in Fr2, α4β2 nAChRs are expressed in both intrinsic and extrinsic glutamatergic terminals and give a major contribution to control glutamate release in Layer V, in the presence of tonic agonist levels. Synapse 00:000–000, 2013 . © 2013 Wiley Periodicals, Inc.     

Impact of suprarenal neck angulation on endovascular aneurysm repair outcomes

BackgroundHostile infrarenal proximal neck (β) anatomy of abdominal aortic aneurysm has been associated with increased risk of aneurysm-related complications after endovascular aneurysm repair (EVAR). However, there is a paucity of literature addressing the suprarenal angle (α). The aim of this study was to evaluate short- and long-term outcomes after EVAR in patients with severe suprarenal neck angulation (α >60 degrees).MethodsA retrospective review of the medical records of 561 patients who underwent EVAR between January 2005 and December 2017 was performed. The main exclusion criteria were preoperative aneurysm rupture and fenestrated or branched endograft placement. High-resolution computed tomography images of 452 patients were available. Patients were grouped into angulated (α >60 degrees) and nonangulated (α ≤60 degrees) groups. The primary end point was freedom from type IA endoleak. Secondary end points included 30-day mortality, long-term survival, primary clinical success, and freedom from aneurysm rupture and graft migration. Primary clinical success was defined according to Society for Vascular Surgery guidelines as clinical success without the need for an additional or secondary surgical or endovascular procedure.ResultsOf 452 patients, 45 (10%) were included in the angulated group (α >60 degrees). Median follow-up time was 34 months (interquartile range, 14-56 months). Compared with patients in the nonangulated group, those in the angulated group had larger neck diameter at the level of the renal arteries (mean [standard deviation], 25.6 [3.8] mm vs 24.6 [3.4] mm; P = .06) and increased β angle (mean [standard deviation], 50.5 [22.9] degrees vs 41.6 [23.9] degrees; P = .01). The 3-year freedom from type IA endoleak estimate was 80.2% for the angulated group compared with 97.8% for the nonangulated group (P < .001). The angulated group showed significantly higher 30-day mortality (11.1% vs 0.25%; P < .001).The 3-year results showed that patients in the nonangulated group had higher rates of primary clinical success (90.2% vs 67.1%; P < .001), freedom from rupture (99% vs 97.1%; P = .02), freedom from migration (100% vs 92.4%; P < .001), and long-term survival (91.6% vs 75.8%; P = .006) compared with those in the angulated group. After adjustment for age, sex, neck diameter, and β angle, severe suprarenal neck angulation was associated with higher odds of type IA endoleak (adjusted hazard ratio, 8.9; 95% confidence interval [CI], 2.9-27), loss of primary clinical success (adjusted hazard ratio, 4.8; 95% CI, 2.6-8.9), and 30-day mortality (adjusted odds ratio, 52.5; 95% CI, 5.3-514) compared with α ≤60 degrees (all P < .001).ConclusionsThis is the first report to show a significant increase in operative mortality in patients undergoing EVAR with severely angulated suprarenal neck. Patients who survive the operation are at increased risk of secondary interventions. These findings suggest that EVAR should be used with caution in patients with severe α angulation and underpin the role of close follow-up in this particular population.     

Recovery of insulin sensitivity and Slc2a4 mRNA expression depend on T3 hormone during refeeding

Objective

GLUT4 protein, encoded by the Slc2a4 gene, plays a key role in muscle glucose uptake, and its expression decreases in muscles under insulin resistance. Slc2a4/GLUT4 decreases with fasting and rapidly increases with refeeding and the same occurs to plasma glucose, amino acids, insulin and T3. Thus, they might be potential regulators of the Slc2a4 gene, which makes them promising targets for strategies to improve GLUT4 expression. Herein, we investigate the role of metabolic–hormonal parameters triggered by refeeding upon the Slc2a4 expression.

Materials/Methods

Plasma glucose/insulin/T3, and gastrocnemius Slc2a4 mRNA contents were measured in rats studied at the end of 48-h fasting, and subsequently at: i) 2–4 h after spontaneous refeeding; ii) 2–4 h after T3 injection, without refeeding; and iii) 0.5–2 h after intravenous infusion of insulin, insulin + glucose and insulin + amino acids, without refeeding.

Results

Refeeding increased plasma glucose/insulin/T3 and muscle Slc2a4 mRNA, reverting insulin resistance. Post-fasting infusions surprisingly induced a further Slc2a4 mRNA decrease (~ 20%, P < 0.05 vs. fasting), but T3 injection induced a ~ 2-fold increase in Slc2a4 mRNA, 2–4 h later (P < 0.001). Moreover, T3 increased glycemia and insulinemia to the 2 h-refed rats levels, suggesting that T3 elevation is a key factor to the mechanisms of metabolic balance during refeeding.

Conclusions

Refeeding induces a rapid increase in muscle Slc2a4 expression, not associated with increased plasma glucose, insulin or amino acids, but highly correlated to increased plasma T3 concentration. This result points out T3 hormone as a powerful Slc2a4 enhancer, an effect that may be acutely explored in situations of insulin resistance.     

Modulation of the Frequency Response of Shaker Potassium Channels by the Quiver Peptide Suggesting a Novel Extracellular Interaction Mechanism

Abstract:

Recent studies have indicated that the Shaker potassium channel regulates sleep in Drosophila. The Drosophila quiver (qvr) gene encodes a novel potassium channel subunit that modulates the Shaker potassium channel. The Qvr peptide contains a signal sequence for extracellular localization and may regulate a unique feature of the Shaker I_A current that confers special neuronal excitability patterns. Thus, studies of the Shaker channel properties in the qvr mutant background should provide an opportunity to uncover a new form of physiologic modulation of potassium channels. We have begun to investigate the impact of qvr protein on the Shaker channel properties and its implications in synaptic function in vivo. We studied synaptic transmission at the larval neuromuscular junction and characterized the transient potassium current I_A in larval muscles. We identified two different functional states of I_A in qvr larval muscles, as reflected by two distinct components, I_AF and I_AS, differing in their kinetics of recovery from inactivation and sensitivity to a K⁺ channel blocker. Correspondingly, qvr mutant larvae exhibit multiple synaptic discharges following individual nerve stimuli during repetitive activity.