Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy involving the limbic structures of the temporal lobe. Layer II neurons of the entorhinal cortex (EC) form the major excitatory input into the hippocampus via the perforant path and consist of non-stellate and stellate neurons. These neurons are spared and hyper-excitable in TLE. The basis for the hyperexcitability is likely multifactorial and may include alterations in intrinsic properties. In a rat model of TLE, medial EC (mEC) non-stellate and stellate neurons had significantly higher action potential (AP) firing frequencies than in control. The increase remained in the presence of synaptic blockers, suggesting intrinsic mechanisms. Since sodium (Na) channels play a critical role in AP generation and conduction we sought to determine if Na channel gating parameters and expression levels were altered in TLE. Na channel currents recorded from isolated mEC TLE neurons revealed increased Na channel conductances, depolarizing shifts in inactivation parameters and larger persistent (I NaP ) and resurgent (I NaR ) Na currents. Immunofluorescence experiments revealed increased staining of Na v 1.6 within the axon initial segment and Na v 1.2 within the cell bodies of mEC TLE neurons.These studies provide support for additional intrinsic alterations within mEC layer II neurons in TLE and implicate alterations in Na channel activity and expression, in part, for establishing the profound increase in intrinsic membrane excitability of mEC layer II neurons in TLE. These intrinsic changes, together with changes in the synaptic network, could support seizure activity in TLE.
Renal artery fibromuscular dysplasia (FMD) may be underdiagnosed. We evaluated the prevalence of FMD in CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) renal artery stent trial participants, in which FMD was an exclusion criterion for inclusion. We also evaluated the prevalence of FMD in a relatively healthy population of patients undergoing computed tomographic angiographic (CTA) screening for renal donor evaluation. All renal donor CTAs performed at our institution from January 2003 through November 2011 were retrospectively reviewed for the presence of FMD along with patient sex and age. These results were compared to angiographic core lab (ACL) findings for the CORAL trial. The CORAL ACL database contained 997 patients (mean age 69.3 years; 50% female). Fifty-eight (5.8%) CORAL trial patients (mean age 71.8 years; 75.9% female) demonstrated incidental FMD. The renal donor cohort included 220 patients (mean age 40.5 years; 64.5% female). Five (2.3%) demonstrated FMD (mean age 48.6 years; all female). The odds of FMD in the CORAL cohort were 2.65 times that seen in the renal donor cohort (95% CI: 1.12, 7.57). In conclusion, the 5.8% prevalence of renal artery FMD in the CORAL trial population, the presence of which was biased against, suggests underdiagnosis.
Hermitamides A and B are lipopeptides isolated from a Papau New Guinea collection of the marine cyanobacterium Lyngbya majuscula. We hypothesized that the hermitamides are ligands for the human voltage-gated sodium channel (hNaV) based on their structural similarity to the jamaicamides. Herein, we describe the nonracemic total synthesis of hermitamides A and B and their epimers. We report the ability of the hermitamides to displace [3H]-BTX at 10 μM more potently than phenytoin, a clinically used sodium channel blocker, a potential binding mode for (S)-hermitamide B in the BTX-binding site, and electrophysiology showing that these compounds are potent blockers of the hNav1.2 voltage-gated sodium channel.
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