Time-Dependent Block and Resurgent Tail Currents Induced by Mouse β4154–167 Peptide in Cardiac Na+ Channels

Resurgent tail Na+ currents were first discovered in cerebellar Purkinje neurons. A recent study showed that a 14-mer fragment of a mouse β4 subunit, β4154–167, acts as an intracellular open-channel blocker and elicits resurgent currents in Purkinje neurons (Grieco, T.M., J.D. Malhotra, C. Chen, L.L. Isom, and I.M. Raman. 2005. Neuron. 45:233–244). To explore these phenotypes in vitro, we characterized β4154–167 actions in inactivation-deficient cardiac hNav1.5 Na+ channels expressed in human embryonic kidney 293t cells. Intracellular β4154–167 from 25–250 μM elicited a conspicuous time-dependent block of inactivation-deficient Na+ currents at 50 mV in a concentration-dependent manner. On and off rates for β4154–167 binding were estimated at 10.1 μM−1s−1 and 49.1 s−1, respectively. Upon repolarization, large tail currents emerged with a slight delay at −140 mV, probably as a result of the rapid unblocking of β4154–167. Near the activation threshold (approximately −70 mV), resurgent tail currents were robust and long lasting. Likewise, β4154–167 induces resurgent currents in wild-type hNav1.5 Na+ channels, although to a lesser extent. The inactivation peptide acetyl-KIFMK-amide not only restored the fast inactivation phenotype in hNav1.5 inactivation-deficient Na+ channels but also elicited robust resurgent currents. When modified by batrachotoxin (BTX), wild-type hNav1.5 Na+ channels opened persistently but became resistant to β4154–167 and acetyl-KIFMK-amide block. Finally, a lysine substitution of a phenylalanine residue at D4S6, F1760, which forms a part of receptors for local anesthetics and BTX, rendered cardiac Na+ channels resistant to β4154–167. Together, our in vitro studies identify a putative S6-binding site for β4154–167 within the inner cavity of hNav1.5 Na+ channels. Such an S6 receptor readily explains (1) why β4154–167 gains access to its receptor as an open-channel blocker, (2), why bound β4154–167 briefly prevents the activation gate from closing by a “foot-in-the-door” mechanism during deactivation, (3) why BTX inhibits β4154–167 binding by physical exclusion, and (4) why a lysine substitution of residue F1760 eliminates β4154–167 binding

Perioperative management of face transplantation: A survey

Background: Since the first facial allograft transplantation was reported in France in 2005, 18 cases have been performed in 4 countries and the rate is increasing. Methods: We have devised a survey to assess anesthesia-related management and rationale of facial allograft transplantation. It was sent to the lead anesthesiologists of the first 14 face transplants performed worldwide. Results: Responses were received corresponding to 13 face transplants. The median duration of surgery and anesthesia was 19 hours (95% confidence interval 15-23 hours). The surgical preparation and dissection of multiple small anatomical structures of the recipient was time-consuming for 11 cases. Blood loss was considerable. All patients received packed red blood cells (median 20 U, 95% confidence interval 5-28 U). A median of 13 L of crystalloid was administered (95% confidence interval 10-18 L). Conclusions: During facial allograft transplantation, the anesthesiologist must be prepared for a long anesthetic with rapid blood loss after reperfusion of the graft. Comment in Out on a limb with composite tissue allografts: expanding the immunology toolbox. [Anesth Analg. 2012

Ephedrine Blocks Rat Sciatic Nerve In Vivo and Sodium Channels In Vitro

Background: The sympathomimetic drug ephedrine has been used intrathecally as the sole local anesthetic for labor and delivery. Because ephedrine may be a useful adjuvant to local anesthetics, the authors investigated the local anesthetic properties of ephedrine in a rat sciatic nerve block model and the underlying mechanism in cultured cells stably expressing N

The Impact of Domestic Energy Efficiency Retrofit Schemes on Householder Attitudes and Behaviours

Retrofitting existing housing stock to improve energy efficiency is often required to meet climate mitigation, public health and fuel poverty targets. Increasing uptake and effectiveness of retrofit schemes requires understanding of their impacts on householder attitudes and behaviours. This paper reports results of a survey of 500 Kirklees householders in the UK, where the Kirklees Warm Zone scheme took place. This was a local government led city-scale domestic retrofit programme that installed energy efficiency measures at no charge in over 50,000 houses. The results highlight key design features of the scheme, socio-economic and attitudinal factors that affected take-up of energy efficiency measures and impacts on behaviour and energy use after adoption. The results emphasise the role that positive feedback plays in reinforcing pro-environmental attitudes and behaviours of participants and in addressing concerns of non-participants. Our findings have implications for the design and operation of future domestic energy efficiency retrofit schemes

Heparin requirements for full anticoagulation are higher for patients on dabigatran than for those on warfarin – a model-based study

Purpose Dabigatran (D) is increasingly used for chronic anticoagulation in place of warfarin (W). These patients may present for catheter-based procedures requiring full anticoagulation with heparin. This study compares the heparin sensitivity of patients previously on dabigatran, on warfarin, or on no chronic anticoagulant during ablation of atrial fibrillation. Patients and methods In a retrospective study of patients treated with D, W, or neither drug (N) undergoing atrial ablation, the timing of heparin doses and resulting activated clotting times were collected. First, the initial activated clotting time response to the first heparin bolus was compared. Then, a non-linear mixed effects modelling (NONMEM) analysis was performed, fitting a pharmacokinetic and -dynamic model to the entire anticoagulation course of each patient. Resulting model coefficients were used to compare the different patient groups. Results: Data for 66 patients on dabigatran, 95 patients on warfarin, and 27 patients on no anticoagulation were retrieved. The last dose of dabigatran or warfarin had occurred 27 hours and 15 hours before the procedure. Groups D and N both responded significantly less (P<0.05) to the initial heparin bolus than Group W (approximately 50%). Likewise, the model coefficients resulting from the fit to each group reflected a significantly lower heparin sensitivity in groups D and N compared to W. Clearances of the heparin effect in the model did not differ significantly among groups. Conclusion: Patients on warfarin with an average INR of 1.5 or higher are more sensitive to heparin than patients not previously anticoagulated or patients who discontinued dabigatran 27 hours earlier (approximately two half-lives) warfarin

Perioperative management of face transplantation: A survey

Background: Since the first facial allograft transplantation was reported in France in 2005, 18 cases have been performed in 4 countries and the rate is increasing. Methods: We have devised a survey to assess anesthesia-related management and rationale of facial allograft transplantation. It was sent to the lead anesthesiologists of the first 14 face transplants performed worldwide. Results: Responses were received corresponding to 13 face transplants. The median duration of surgery and anesthesia was 19 hours (95% confidence interval 15-23 hours). The surgical preparation and dissection of multiple small anatomical structures of the recipient was time-consuming for 11 cases. Blood loss was considerable. All patients received packed red blood cells (median 20 U, 95% confidence interval 5-28 U). A median of 13 L of crystalloid was administered (95% confidence interval 10-18 L). Conclusions: During facial allograft transplantation, the anesthesiologist must be prepared for a long anesthetic with rapid blood loss after reperfusion of the graft. Comment in Out on a limb with composite tissue allografts: expanding the immunology toolbox. [Anesth Analg. 2012