The onset of spontaneous seizures in the pilocarpine model of epilepsy causes a hyperpolarized shift in the voltage-dependent activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (I h ) in CA1 hippocampal pyramidal neuron dendrites, contributing to neuronal hyperexcitability and possibly to epileptogenesis. However, the specific mechanisms by which spontaneous seizures cause downregulation of HCN channel gating are yet unknown. We asked whether the seizure-dependent downregulation of HCN channel gating was due to altered phosphorylation signaling mediated by the phosphatase calcineurin (CaN) or the kinase p38 mitogen-activated protein kinase (p38 MAPK). We first found that CaN inhibition upregulated HCN channel gating and reduced neuronal excitability under normal conditions, showing that CaN is a strong modulator of HCN channels. We then found that an in vitro model of seizures (1 h in 0 Mg 2ϩ and 50 M bicuculline at 35-37°C) reproduced the HCN channel gating change seen in vivo. Pharmacological inhibition of CaN or activation of p38 MAPK partially reversed the in vitro seizure-induced hyperpolarized shift in HCN channel gating, and the shift was fully reversed by the combination of CaN inhibition and p38 MAPK activation. We then demonstrated enhanced CaN activity as well as reduced p38 MAPK activity in vivo in the CA1 hippocampal area of chronically epileptic animals. Pharmacological reversal of these phosphorylation changes restored HCN channel gating downregulation and neuronal hyperexcitability in epileptic tissue to control levels. Together, these results suggest that alteration of two different phosphorylation pathways in epilepsy contributes to the downregulation of HCN channel gating, which consequently produces neuronal hyperexcitability and thus may be a target for novel antiepileptic therapies.

A short, scalable values affirmation intervention reduces the achievement gap between underrepresented minority students and white students in an introductory biology course.

No abstract

Objective: To describe a contemporary series of open abdominal aortic aneurysm (AAA) repairs in patients not anatomically suitable for endovascular AAA repair.Methods: A prospectively maintained database including consecutive nonruptured open aneurysm repairs from March 1, 2000, through July 31, 2007, was reviewed. Patient demographic characteristics and perioperative outcomes were evaluated and stratified based on proximal aortic cross-clamp placement.Results: A total of 185 patients with AAA underwent 103 infrarenal and 82 suprarenal cross-clamp repairs. Overall, the complication rate was 37.0% with infrarenal and 61.0% with suprarenal cross-clamps (P=.001). The 30-day mortality was 2.9% with infrarenal and 6.1% with suprarenal cross-clamps (P=.18). Postoperative renal insufficiency (29.3% vs 7.8%; P Ͻ.001) and pulmonary complications (25.6% vs 12.6%; P = .03) were more frequent with suprarenal cross-clamps. Suprarenal crossclamps were associated with greater intraoperative blood loss (2586 mL vs 1638 mL; P= .006), operative duration (391 min vs 355 min; P=.005), use of adjunctive renal and/or visceral grafts (43.9% vs 1.9%; P Ͻ.001), duration of intensive care unit stay (4.5 days vs 3.0 days; P=.006), and hospital length of stay (9 days vs 7 days; P = .04). Of patients who received a suprarenal crossclamp, 25.6% required temporary nursing home placement vs 17.5% with an infrarenal cross-clamp (P=.14).Conclusions: Until fenestrated and branched endografts are available, open AAA repairs will become increasingly complex. Suprarenal cross-clamping is associated with increased rates of complications but similar mortality rates and need for nursing home placement. With the disappearance of straightforward open aneurysm repair, trainees in vascular surgery will have to learn AAA repair almost exclusively by operating on patients with complex AAAs. Fewer surgeons will perform these repairs, and fewer fellows will be able to complete the operation independently immediately after training.

Most of the T2ELs resulted in spontaneous occlusion and were not associated with sac enlargement. A low-resistance, high-flow or to-fro flow T2EL has higher chances of sac enlargement, rupture, and requiring reintervention.