Primary erythromelalgia (PE) is an autosomal dominant neurological disorder characterized by severe burning pain and erythema in the extremities upon heat stimuli or exercise. Mutations in human SCN9A gene, encoding the α–subunit of the voltage-gated sodium channel, Nav1.7, were found to be responsible for PE. Three missense mutations of SCN9A gene have recently been identified in Taiwanese patients including a familial (I136V) and two sporadic mutations (I848T, V1316A). V1316A is a novel mutation and has not been characterized yet. Topologically, I136V is located in DI/S1 segment and both I848T and V1316A are located in S4-S5 linker region of DII and DIII domains, respectively. To characterize the elelctrophysiological manifestations, the channel conductance with whole-cell patch clamp was recorded on the over-expressed Chinese hamster overy cells. As compared with wild type, the mutant channels showed a significant hyperpolarizing shift in voltage dependent activation and a depolarizing shift in steady-state fast inactivation. The recovery time from channel inactivation is faster in the mutant than in the wild type channels. Since warmth can trigger and exacerbate symptoms, we then examine the influence of tempearture on the sodium channel conduction. At 35°C, I136V and V1316A mutant channels exhibit a further hyperpolarizing shift at activation as compared with wild type channel, even though wild type channel also produced a significant hyperpolarizing shift compared to that of 25°C. High temperature caused a significant depolarizing shift in steady-state fast inactivation in all three mutant channels. These findings may confer to the hyperexcitability of sensory neurons, especially at high temperature. In order to identifying an effective treatment, we tested the IC50 values of selective sodium channel blockers, lidocaine and mexiletine. The IC50 for mexiletine is lower for I848T mutant channel as compared to that of the wild type and other two mutants which is comparable to the clinical observations.

The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first demonstrate that the Navβ4 peptide acts as a gating modifier rather than an open channel blocker competing with the inactivating peptide to give rise to resurgent currents in the Nav1.7 channel. Moreover, there are two distinct open and two corresponding fast inactivated states in the genesis of resurgent Na+ currents. One is responsible for the resurgent route and practically existent only in the presence of Navβ4 peptide, whereas the other is responsible for the “silent” route of recovery from inactivation. In this regard, the p.V1316A mutation makes hyperpolarization shift in the activation curve, and depolarization shift in the inactivation curve, vividly uncoupling inactivation from activation. In terms of molecular gating operation, the most important changes caused by the p.V1316A mutation are both acceleration of the transition from the inactivated states to the activated states and deceleration of the reverse transition, resulting in much larger sustained as well as resurgent Na+ currents. In summary, the genesis of the resurgent currents in the Nav1.7 channel is ascribable to the transient existence of a distinct and novel open state promoted by the Navβ4 peptide. In addition, S4–5 linker in domain III where V1316 is located seems to play a critical role in activation–inactivation coupling, chiefly via direct modulation of the transitional kinetics between the open and the inactivated states. The sustained and resurgent Na+ currents may therefore be correlatively enhanced by specific mutations involving this linker and relevant regions, and thus marked hyperexcitability in corresponding neural tissues as well as IEM symptomatology.

Aims and objectives To assess the willingness of nurses to receive vaccines as recommended by Taiwan's “Immunization Recommendations for Healthcare Personnel” (IRHCP), as well as the factors associated with their willingness. Background Immunisation for healthcare personnel (HCP) is a means of reducing pathogen transmission. Also, vaccinating HCP reduces personnel and labour costs during an epidemic. Methods A cross‐sectional study was conducted. A self‐administered questionnaire survey targeting nurses working in various service units at three hospitals was used. In total, 413 nurses completed the questionnaire. The main outcome measure was the willingness to receive vaccines recommended by the IRHCP, and the variables we assessed included knowledge regarding the IRHCP, individual perceptions (perceived risk of contracting the infection, perceived severity of the infection and perceived transmissibility after disease onset), perceived benefits and barriers to the vaccination, cues to the vaccination and demographics. This study followed the STROBE checklist for reporting this study. Results The willingness of nurses to receive vaccines recommended by the IRHCP was high; the highest level of willingness was for the hepatitis B vaccine. The nurses’ willingness to receive various vaccines recommended by the IRHCP was predicted by the knowledge regarding the IRHCP and perceived transmissibility after disease onset. Except the diphtheria–tetanus–acellular pertussis vaccine, perceived benefits and perceived barriers were also predictors of the willingness to receive vaccines. Conclusions Our results showed that interventions focusing on increasing the knowledge regarding the IRHCP and perceived transmissibility after disease onset, emphasising the benefits of the vaccination and reducing the perceived barriers to the vaccination are needed to increase nurses’ willingness to receive vaccines. Relevance to clinical practice It is suggested using health education courses and mass media broadcasts at the individual and societal levels to raise awareness regarding the benefits of vaccines and enhance nurse’ confidence in vaccination programs.

Inherited erythromelalgia (IEM), caused by mutations in Na v 1.7 channel is characterized by episodic neuropathic pain triggered especially by warm temperature. However, the mechanism underlying the temperature–dependent episodic attacks of IEM remains elusive. We investigated the electrophysiological effect of temperature changes on Na v 1.7 channels with three different mutations, p.I136V, p. I848T, and p.V1316A, both in vitro and in vivo . In vitro b iophysical studies of the mutant channels show consistent temperature-dependent enhancement of the relative resurgent currents if normalized to the transient currents, as well as temperature-dependent changes in the time to peak and the kinetics of decay of the resurgent currents, but no congruent temperature–dependent changes in steady–state parameters such as shift of activation/inactivation curves and changes of the absolute size of the window or resurgent currents. In vivo nerve excitability tests (NET) in IEM patients reveal the essentially normal indices of NET at a single stimulus. However, there are evident abnormalities if assessed with preconditioning pulses, such as the decrease of threshold elevation in hyperpolarizing threshold electrotonus (50–100 ms), the increase of inward rectification in current–voltage curve, and the increase of refractoriness at the interpulse interval of 2–6 ms in recovery cycle, probably also implicating derangements in temperature dependence of inactivation and of recovery from inactivation in the mutant channels. The pathogenesis of heat–enhanced pain in IEM could be attributed to deranged temperature dependence of Na v 1.7 channels responsible for the genesis of resurgent currents.

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