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The hypoplastic lateral lip element within the cleft lip presentation is a recognized entity that has been recently shown to be more common on the right side. The spectrum of such change is yet to be defined. The authors propose the Melbourne classification system of cleft lip hypoplasia and see it as an important step towards discerning the relevance of these anatomical observations to the management of cleft lip/palate patients.This is a retrospective observational study of patients with complete unilateral cleft lips treated by the senior author (DKC) at the Royal Children's Hospital, Melbourne. Patient charts were retrospectively reviewed and patients were classified into different degrees of hypoplasia based on preoperative, intraoperative, and postoperative photography. Data was reported using descriptive statistics.Fifty-nine patients with complete unilateral cleft lip deformity were grouped according to lateral lip element hypoplasticity. Twenty patients had right-sided clefts and 39 patients had cleft lips on the left side. Of those with right-sided clefts, 18 patients had evidence of hypoplasia (90%). Three patients had Type 1 deformities, 3 patients were Type 2, and 12 patients were Type 3. Patients with left-sided clefts were found to have hypoplasia less frequently with 15 patients showing evidence (38.5%).The authors report a classification system of hypoplasia involving the lateral lip element in complete unilateral cleft lip. The authors propose this classification system as a new measure of cleft severity that will have implications for patient expectations, surgical planning, and future outcome studies.

Background: The Anatomical Subunit Approximation cleft lip repair advantageously achieves a balanced lip contour with the line of repair placed along seams of aesthetic subunits. Since Fisher’s original description, it has been adopted widely and adapted, but some surgeons find the transition away from a cut-as-you-go approach challenging. Methods: We present an adapted Anatomic Subunit Approximation technique based on essential components of Fisher’s repair. The order of surgical execution is emphasized. Paradigm shifts are presented to help the surgeon used to more traditional rotation advancement techniques understand the Subunit philosophy. Minor adaptations such as surgically releasing lateral lip elements prior to marking are discussed. Results: A total of 53 eligible patients were treated with unilateral cleft lip repair by the senior author (D.C.) between February 2008 and April 2012 at Royal Children’s Hospital in Melbourne, Australia. Representative cases were chosen to demonstrate achievable results with the described technique. Conclusion: The proposed technique employs essential skin markings to achieve an anatomic subunit approximation lip repair, and appears to facilitate surgical outcomes with a high degree of symmetry. Core principles of repair include precise anatomical planning, tissue component separation, and muscle-driven advancement.

Recalcitrant auricular keloids are keloids that have recurred after any previous treatment. They have been shown to have an increased likelihood of recurrence. There is no consensus on how best to treat recalcitrant auricular keloids. Here, we perform the first systematic review and meta-analysis investigating the evidence for treating recalcitrant auricular keloids.We searched MEDLINE, EMBASE, CINAHL, and EBM Reviews using specific keywords. Prespecified inclusion and exclusion criteria were used to assess article eligibility. Data were extracted for number of recalcitrant keloids, treatment modality, recurrence, and minimum follow-up time. Included articles were stratified by treatment and assigned a level of evidence (LOE) based on the Oxford Centre for Evidence-Based Medicine guidelines. A meta-analysis was performed to estimate recurrence rates with 95% confidence intervals for each treatment modality.A total of 887 unique articles were identified and 13 included. Eleven were LOE III and 2 were LOE IV. Recurrence rates were found to be 9% (95% CI: 3%-25%) for excision with adjuvant brachytherapy, 14% (95% CI: 12%-17%) for excision with adjuvant compression therapy, 17% (95% CI: 3%-56%) for excision with adjuvant external beam radiation, and 18% (95% CI: 4%-53%) for excision with adjuvant steroid injections. No statistical significant difference was found.Data for treatment of auricular keloids are heterogeneous with few high-quality studies. Excision with adjuvant brachytherapy has the lowest recurrence rate in our analysis. Narrow confidence intervals reported here for brachytherapy and compression therapy may help surgeons more confidently recommend either of these treatment modalities to patients.Les chéloïdes auriculaires récalcitrantes sont celles qui se manifestent de nouveau après un traitement. Il est démontré que leur risque de récurrence est plus élevé. Il n’y a pas de consensus au sujet de leur traitement. Les chercheurs procèdent à la première analyse systématique et méta-analyse sur les données probantes relatives au traitement des chéloïdes auriculaires récalcitrantes.Les chercheurs ont fouillé les bases de données MEDLINE, EMBASE, CINAHL et EBM Reviews au moyen de mots-clés précis. Ils ont utilisé des critères d’inclusion et d’exclusion préétablis pour évaluer l’admissibilité des articles. Ils ont extrait les données relatives au nombre de chéloïdes récalcitrantes, à la modalité thérapeutique, à la récurrence et à la durée minimale du suivi. Ils ont stratifié les articles retenus d’après le traitement utilisé et leur ont attribué une qualité de preuve (QdP) en fonction des directives de l’Les chercheurs ont relevé 887 articles uniques et en ont retenu 13. De ce nombre, 11 avaient une QdP III et deux, une QdP IV. Ils ont constaté un taux de récurrence de 9 % (IC à 95 %, 3 % à 25 %) après une excision et une curiethérapie adjuvante, de 14 % (IC à 95 %, 12 % à 17 %) après une excision et une thérapie de compression adjuvante, de 17% (IC à 95 %, 3 % à 56 %) après une excision et une radiothérapie externe adjuvante, et de 18 % (IC à 95 %, 4 % à 53 %) après une excision et des injections adjuvantes de stéroïdes. Ils n’ont constaté aucune différence statistiquement significative.Les données relatives au traitement des chéloïdes auriculaires sont hétérogènes, et peu d’études sont de qualité. À l’analyse, l’excision avec curiethérapie adjuvante présente le taux de récurrence le plus faible. Les faibles intervalles de confiance liés à la curiethérapie et à la thérapie de compression pourraient inciter les chirurgiens à recommander avec conviction l’une de ces deux modalités thérapeutiques aux patients.

Background Macrotextured breast implants are associated with double capsules. There is little agreement as to what defines double capsules, how they present, and whether different degrees of double capsule exist. Objectives This study aimed to define double capsules and report an association between double-capsule type and degree of tissue adherence. Methods Consecutive aesthetic patients undergoing explantation of Biocell (Allergan, Inc., Irvine, CA) implants between May 2018 and November 2018 were included if they were found to have double capsules intraoperatively. Patient demographics, implant characteristics, explantation reason, implant adherence, and intraoperative findings were recorded. Both adherent and double capsules were histologically examined. Data were analyzed by descriptive statistics. Results Eleven patients had 22 Biocell implants explanted during the study period. The average explantation time was 8.0 years. Sixteen implants were found to have some degree of nonadherence, and all areas of nonadherence were associated with double-capsule formation. Double capsules were either partial or complete. The architecture of the inner layer of double capsules varied between an organized capsular layer and a thin area of nascent capsule. Histologically, all capsular specimens demonstrated an overall hypocellular fibrous capsule with scattered chronic inflammatory infiltrates. Synovial metaplasia was present in all capsule types and spaces/cracks in the capsule were disproportionately represented in partially adherent capsules. Conclusions This is the first study to identify a clinical and pathological correlation between double capsules and failed tissue adherence. Double capsules represent a spectrum of inner capsule formation ranging between nascent capsular tissue to a mature inner capsular layer. Level of Evidence: 4

Rapid advances in information and communication technologies present a challenge to information systems (IS) professors. Not only do these advances frequently make course materials out of date, but also IS professors may struggle to stay current with popular technology applications. In a sense, these forces lead to a paradox that students may be more techno-savvy than their professors (at least in certain areas). Furthermore, students may feel frustrated when techno-savvy professors cannot efficiently teach them in learning technologies. In this paper, we synthesize the panel titled "The Elephant in the Classroom: Do Information Systems Professors Need to be more Techno-Savvy than Students?" at the 55th ACM SIGMIS Computer and People Research Conference in Nashville, Tennessee. Thomas Ferratt, Michael Gallivan, Yaojie Li, Thomas Stafford, Mary Sumner, and Crag Van Slyke served as panelists. We use their discussion to develop techno-savviness as a construct in the IS education context and to describe distinct types of techno-savviness.

Patients with horizontal lower lid laxity undergoing lower lid blepharoplasty are at a high risk for lid malposition. Prophylactic correction of horizontal lower lid laxity during blepharoplasty may alleviate this risk. In this article, the authors describe a novel lower lid blepharoplasty technique, the KS-pexy (named after its originators, Kuhnt and Szymanowski), for correcting horizontal lower lid laxity.All cases of KS-pexy between September of 2009 and June of 2018 from an aesthetic practice were reviewed retrospectively. All patients were diagnosed with horizontal lower lid laxity and requested lower lid blepharoplasty for aesthetic concerns. Patient demographics, clinical presentation, procedure details, and intraoperative findings were analyzed.Sixty-two patients underwent KS-pexy performed by the senior author. The average follow-up was 41.1 months, ranging from 2 to 107 months. Thirteen patients had a negative vector, 54 patients received a KS-pexy in combination with another facial procedure, and 14 patients had their KS-pexy as a secondary procedure. The overall success rate was 96.8 percent. The complication profile was as follows: chemosis (27.4 percent), new-onset dry eyes persisting longer than 8 weeks (6.5 percent), temporary lower eyelid malposition (4.8 percent), lower eyelid malposition requiring surgical intervention (3.2 percent), poor scar quality (1.6 percent), lower lid abscess (1.6 percent), transient conjunctivitis (1.6 percent), lateral fat compartment swelling (1.6 percent), canthopexy dehiscence (1.6 percent), hordeolum (1.6 percent), and temporary V2 paresthesia (1.6 percent).The KS-pexy is an effective means to treat horizontal eyelid laxity prophylactically in patients requesting lower eyelid blepharoplasty for aesthetic reasons.Therapeutic, IV.

The burn treatment room at our tertiary-care centre is run by a multidisciplinary team, providing care to primarily burn patients who require moderate to deep sedation to undergo dressing changes in a monitored setting outside the operating room. There is little literature on the safety, efficacy, and logistics of treating outpatient pediatric burn patients in this manner. This study reviews the safety of deep sedation in the burn treatment room.A retrospective chart review of patients with burns treated in the burn treatment room from 2013 to 2015 was conducted. Patient demographics, diagnosis, procedure details, sedation, and adverse events were recorded. Data were analyzed descriptively.Sevety-four patients with burns had a total of 308 visits in the burn treatment room for burn bath and/or dressing changes. Scald burns were the most common mechanism of injury (n = 56). Most burns were superficial and mid-dermal (54%), initially estimated at 5% to 10% TBSA (50%). Of the 308 visits, 304 required sedation. Adverse events were recorded in 11 (3.6%) of 304 sedated procedures. None of these events were critical: 7 patients required intravenous conversion due to inadequate oral sedation, 2 experienced brief apnea episodes but recovered spontaneously, and 2 had delayed discharge of more than 2 hours due to residual sedation.The burn treatment room is a safe and effective setting for treating pediatric burn patients, bypassing what might historically require operating suite inpatient management.La salle de traitement des brûlures du centre de soins tertiaires des chercheurs est dirigée par une équipe multidisciplinaire qui soigne surtout des patients brûlés ayant besoin d’une sédation modérée à profonde pour faire changer leurs pansements dans un milieu surveillé hors du bloc opératoire. Peu de publications portent sur l’innocuité, l’efficacité et la logistique de ce type de traitement ambulatoire pour les patients brûlés d’âge pédiatrique. La présente étude analyse l’innocuité de la sédation profonde à la salle de traitement des brûlures.Les chercheurs ont procédé à une analyse rétrospective des dossiers de patients brûlés traités à la salle de traitement des brûlures entre 2013 et 2015. Ils ont noté les caractéristiques démographiques, le diagnostic, le détail des interventions, la sédation et les événements indésirables des patients et fait une analyse descriptive des données.Soixante-quatorze patients brûlés sont allés un total de 308 fois à la salle de traitement des brûlures pour faire laver leurs brûlures ou changer leurs pansements. Les brûlures par liquide chaud étaient les plus courantes (n = 56). La plupart étaient superficielles et touchaient le derme moyen (54 %), pour une estimation initiale de 5 % à 10 % de la surface corporelle (50 %). Des 308 visites, 304 ont fait l’objet d’une sédation. Onze événements indésirables (3,6 %), dont aucun n’était critique, ont découlé des 304 interventions sous sédation. En effet, neuf patients ont dû passer à une sédation intraveineuse parce que la sédation orale était inadéquate, deux ont présenté de brefs épisodes d’apnée, mais se sont rétablis spontanément, et le congé de deux cas a dû être retardé de plus de deux heures à ause d’une sédation résiduelle.La salle de traitement des brûlures est un lieu sécuritaire et efficace pour traiter les patients brûlés d’âge pédiatrique et permet d’éviter ce qui nécessitait auparavant un passage au bloc opératoire et une hospitalisation.

Ventriculoperitoneal (VP) shunt complications involving the breast are rare, with the majority involving the formation of a cerebrospinal fluid pseudocyst. We present the case of a 22-year-old woman with recurrent cerebrospinal fluid pseudocyst secondary to fracture of a VP shunt at the time of breast surgery for breast asymmetry. We review the literature on this topic and present our case that highlights the need of the breast surgeon to take into account the position of VP shunts placed at birth. Shunts placed on the chest wall may result in breast asymmetry requiring surgery in the adolescent. Shunts in place since birth may be at greater risk of fracture during breast implant placement due to manipulation of a calcified and fragile shunt leading to formation of a cerebrospinal fluid pseudocyst.

Background:. The Mustardé otoplasty is a commonly used procedure for the correction of the prominent ear deformity. Complication rates related to suture extrusion and long-term outcomes are variable in the literature. The study’s purpose was to examine the efficacy and safety of the Mustardé otoplasty and its resource utilization, using an “iron triangle” methodology incorporating quality, time, and cost. Methods:. Retrospective data were collected on patients under 18 years who underwent primary Mustardé otoplasty between 2009 and 2018. Patient demographics, intraoperative details, complications, follow-up, and satisfaction were collected and analyzed. Results:. There were 119 Mustardé otoplasties performed on 68 patients, with a median follow-up of 72 weeks (24–476 weeks). In total, 51 of the 68 patients underwent bilateral procedures. The median operative time was 95 minutes (31–133 minutes), translating to a facility case cost of $2046. A total of 24 complications were reported in 17 patients. Minor complications included the following: suture extrusion (n = 20), hematoma (n = 1), and suture abscess (n = 1). Major complications included reoperation (n = 2). The series had a revision rate of 1.7% (n = 2). No additional procedures were documented at other hospitals in the province. The majority (97%) of ear outcomes demonstrated both patient and surgeon satisfaction. Conclusions:. The Mustardé otoplasty demonstrated a high efficacy in the correction of the prominent ear, with low reoperation rates and high patient and surgeon satisfaction. The procedure demonstrated intriguing results in resource utilization, with brief operative times, a “knife and fork” supply chain, and minimal overall case costs. This technique qualifies as a good, fast, and cheap outpatient otoplasty option.

Background Augmentation mammaplasty is the most common aesthetic procedure. Textured implants control implant position and have improved capsular contracture rates; however, the impact of texturing on longevity and clinical findings at explantation is unclear. Methods All cases of explantation between January of 2005 and April of 2017 from an aesthetic practice were reviewed retrospectively. Patient demographics, implant characteristics, time to explantation, and clinical presentation and intraoperative findings at explantation were analyzed. Results Five hundred thirty-nine breast implants were explanted during the study period: 249 saline, 147 smooth gel, 123 Biocell, and 20 other nonaggressively textured breast implants. Average time from placement to explantation was 7.5, 5.6, 4.9, and 4.0 years for saline, other textured, smooth gel, and Biocell implants, respectively (p = 3.25e-08). The percentage of implants removed associated with implant performance failure was 50.3, 57.4, 75.0, and 85.4 percent for smooth gel, saline, other textured, and Biocell implants, respectively (p = 7.25e-09). In addition, 21.1 percent of Biocell implants versus 1.4 percent of all other implants presented with pain (p = 2.71e-15). Forty-five Biocell implants had double capsules; this phenomenon was not observed with any other implant type (p = 5.85e-37). Seven Biocell implants had late seromas, compared to three late seromas with any other implant type (p = 0.0013). Conclusions Here, the authors provide evidence that Biocell implants have the shortest time to explantation and the highest proportion of implants associated with implant performance failure. This information should complement the informed consent process when selecting an appropriate implant.

Objectives: The hospital can be saturated with noxious smells. Anecdotally, medical staff apply products to surgical masks to lessen the impact of these smells. This study aimed to determine the odour-masking ability of 4 inexpensive and convenient products. Methods: A randomized, single-blinded crossover study was conducted in Vancouver, Canada. Participants, 19 to 30 years old, were invited to participate. Participants with active allergies, upper respiratory tract infection, alteration to sense of smell, or failure of olfactory screen were excluded from the study. An experimental odour was used in lieu of a noxious surgical odour. After smelling the experimental odour without barriers, participants were re-exposed to the odour using 5 surgical masks in randomized order. Each mask was lined with a test product (cherry lip balm, tincture of benzoin, Mastisol, mint toothpaste, and control [plain mask]). Participants rated the effectiveness of products at masking the experimental odour from 0 to 100 (0 = completely ineffective, 100 = completely effective). Participants also rated the pleasantness of the products, recorded if the products made them feel unwell, and identified their preferred product overall. Results: Eighty participants were included in the study (33 male, 47 female), averaging 24.2 years of age. Mean odour-masking effectiveness for cherry lip balm was 66.5 (±24.6), tincture of benzoin: 62.6 (±25.0), Mastisol: 61.3 (±23.9), mint toothpaste: 57.5 (±27.4), and control: 21.9 (±21.8). All products performed better than the control ( P < .001), but there was no significant difference in performance between products. Cherry lip balm was the most preferred odour-masking product (29 participants), followed by mint toothpaste (22), Mastisol (14), tincture of benzoin (10), and control (5). Conclusions: All tested products demonstrated equivalent odour-masking abilities. If health care professionals choose to use an odour-masking product, they should consider their own olfactory preferences.

Tissue expansion in the lower extremity is controversial, with studies reporting complication rates as high as 83%. Few studies have looked at tissue expansion prior to orthopaedic correction of severe foot and ankle deformities, and those available are restricted to clubfoot in the pediatric population. Here, we report the largest case series on the use of tissue expanders for the reconstruction of severe foot and ankle deformity and the only report in adults.This is a retrospective chart review of the senior author's practice over a 16-year study period. All patients over 18 years of age who underwent tissue expansion prior to definitive orthopaedic correction of a severe foot and ankle deformity were included. Patient demographics, etiology of deformity, rate of expansion, and complications were recorded. Major complications were defined as those which required surgical intervention. Data were analyzed using descriptive statistics.Nineteen cases were performed on 16 patients. Our overall complication rate was 31.6% (6/19), with major complications occurring in 21.1% (4/19) of cases, and minor complications occurring in 10.5% (2/19) of cases. Despite this, 94.7% (18/19) of cases went on to receive definitive orthopaedic correction after tissue expansion. No demographic parameters were associated with occurrence of complications.This represents the largest report on lower extremity tissue expansion for severe foot and ankle deformity correction. While we observed complications in 31.6% of patients, 94.7% of cases went on to receive definitive orthopaedic correction with successful primary closure.L’expansion tissulaire des membres inférieurs est controversée, car des études font état d’un taux de complications atteignant les 83 %. Peu d’études ont porté sur l’expansion tissulaire avant la correction orthopédique de graves déformations du pied et de la cheville, et celles qui existent se limitent au pied bot dans la population pédiatrique. Les auteurs rendent compte de la plus grande série de cas sur l’utilisation d’expandeurs tissulaires en vue de la reconstruction de graves déformations du pied et de la cheville, la seule à être menée chez des adultes.La présente étude rétrospective traite des dossiers de l’auteur principal sur une période de 16 ans. Tous les patients de plus de 18 ans qui ont subi une expansion tissulaire avant la correction orthopédique définitive d’une grave déformation du pied et de la cheville en ont fait partie. Les chercheurs ont consigné la démographie des patients, l’étiologie des déformations, le taux d’expansion et les complications. Ils ont défini les complications majeures comme celles qui exigent une intervention chirurgicale. Ils ont analysé les données à l’aide de statistiques descriptives.Les chercheurs ont relevé 19 cas chez 16 patients. Le taux de complications global s’élevait à 31,6 % (six cas sur 19). Des complications majeures se sont produites dans 21,1 % des cas (quatre sur 19) et des complications, mineures, dans 10,5 % des cas (deux sur 19). Malgré tout, 94,7 % des cas (18 sur 19) ont subi une correction orthopédique définitive après l’expansion tissulaire. Aucun paramètre démographique ne laissait présager les complications.La présente étude est le rapport le plus vaste des expansions tissulaires pour corriger de graves déformations du pied et de la cheville. Les auteurs ont observé des complications chez 31,6 % des patients, mais 94,7 % des cas ont profité d’une correction orthopédique définitive et d’une fermeture primaire réussie.

Background Many plastic surgeons advocate smoking cessation before patients undergo cosmetic surgery with extensive soft-tissue dissection. Smoking cessation rates after cosmetic surgery are unknown. The preoperative consultation may be an opportunity to promote long-term smoking cessation. Methods This is a retrospective, cross-sectional cohort study. All patients over an 8-year study period who smoked before their preoperative consultation; who quit 2 weeks before surgery; and who subsequently underwent rhytidectomy, abdominoplasty, or mastopexy were included. Patients were asked to complete a Web-based survey at long-term follow-up. Results Eighty-five smokers were included, and 47 patients completed the survey, for a response rate of 55.3 percent. Average follow-up was 63.3 months. Five respondents were social smokers and thus excluded. Of the 42 daily smokers, 17 patients (40.5 percent) were no longer smoking cigarettes on a daily basis at long-term follow-up. Of these 17 patients, 10 (23.8 percent) had not smoked since their operation. A total of 24 patients (57.1 percent) had reduced their cigarette consumption by any amount, and 70.8 percent (17 of 24) of these patients agreed that discussing adverse surgical outcomes related to smoking influenced their ability to quit/reduce. Twenty-one of 42 patients (50.0 percent) admitted that they were not compliant with the preoperative smoking cessation instructions. Conclusions This is the first report to investigate long-term smoking cessation from a cosmetic surgery practice. The authors have shown a positive association between smoking cessation and cosmetic surgery. Requesting a period of cessation before cosmetic surgery may promote long-lasting smoking cessation.

hERG K(+) channel function is vital for normal cardiac rhythm, yet the mechanisms underlying the unique biophysical characteristics of the channel, such as slow activation and deactivation gating, are incompletely understood. The S4-S5 linker is thought to transduce voltage sensor movement to opening of the pore gate, but may also integrate signals from cytoplasmic domains. Previously, we showed that substitutions of G546 within the S4-S5 linker destabilize the closed state of the channel. Here, we present results of a glycine-scan in the background of 546L. We demonstrate site-specific restoration of WT-like activation which suggests that flexibility in the N-terminal portion of the S4-S5 linker is critical for the voltage dependence of hERG channel activation. In addition, we show that the voltage dependence of deactivation, which was recently shown to be left-shifted from that of activation due to voltage sensor mode-shift, is also modulated by the S4-S5 linker. The G546L mutation greatly attenuated the coupling of voltage sensor mode-shift to the pore gate without altering the mode-shift itself. Indeed, all of the S4-S5 linker mutations tested similarly reduced coupling of the mode-shift to the pore gate. These data demonstrate a key role for S4-S5 linker in the unique activation and deactivation gating of hERG channels. Furthermore, uncoupling of the mode-shift to the pore by S4-S5 linker mutations parallels the effects of mutations in the N-terminus suggestive of functional interactions between the two regions.

The Zebrafish Model Organism Database (ZFIN; zfin.org) serves as the central repository for genetic and genomic data produced using zebrafish (Danio rerio). Data in ZFIN are either manually curated from peer-reviewed publications or submitted directly to ZFIN from various data repositories. Data types currently supported include mutants, transgenic lines, DNA constructs, gene expression, phenotypes, antibodies, morpholinos, TALENs, CRISPRs, disease models, movies, and images. The rapidly changing methods of genomic science have increased the production of data that cannot readily be represented in standard journal publications. These large data sets require web-based presentation. As the central repository for zebrafish research data, it has become increasingly important for ZFIN to provide the zebrafish research community with support for their data sets and guidance on what is required to submit these data to ZFIN. Regardless of their volume, all data that are submitted for inclusion in ZFIN must include a minimum set of information that describes the data. The aim of this chapter is to identify data types that fit into the current ZFIN database and explain how to provide those data in the optimal format for integration. We identify the required and optional data elements, define jargon, and present tools and templates that can help with the acquisition and organization of data as they are being prepared for submission to ZFIN. This information will also appear in the ZFIN wiki, where it will be updated as our services evolve over time.

Human ether-a-go-go related gene (hERG) channel gating is associated with slow activation, yet the mechanistic basis for this is unclear. Here, we examine the effects of mutation of a unique glycine residue (G546) in the S4–S5 linker on voltage sensor movement and its coupling to pore gating. Substitution of G546 with residues possessing different physicochemical properties shifted activation gating by ∼−50 mV (with the exception of G546C). With the activation shift taken into account, the time constant of activation was also accelerated, suggesting a stabilization of the closed state by ∼1.6–4.3 kcal/mol (the energy equivalent of one to two hydrogen bonds). Predictions of the α-helical content of the S4–S5 linker suggest that the presence of G546 in wild-type hERG provides flexibility to the helix. Deactivation gating was affected differentially by the G546 substitutions. G546V induced a pronounced slow component of closing that was voltage-independent. Fluorescence measurements of voltage sensor movement in G546V revealed a slow component of voltage sensor return that was uncoupled from charge movement, suggesting a direct effect of the mutation on voltage sensor movement. These data suggest that G546 plays a critical role in channel gating and that hERG channel closing involves at least two independently modifiable reconfigurations of the voltage sensor.

Keloids are cosmetically, psychologically and functionally debilitating wounds that have proven difficult to treat with surgical excision alone. Large keloids are particularly challenging to treat because many of the current therapies for keloids are unsuitable, and the remaining defect after excision is difficult to close. The authors report a case involving a large disfiguring keloid on the head and neck, which was treated with surgical excision and immediate reconstruction with a free anterolateral thigh fasciocutaneous flap. No further adjuvant therapy was undertaken. At one-year follow-up, there was no recurrence at the recipient site, and the donor site healed without deformity. The free fasciocutaneous anterolateral thigh flap may be effective at treating large keloids in the head and neck region; however, well-controlled clinical studies are needed to establish this.

In cases of median nerve injury alongside an unsalvageable ulnar nerve, a vascularized ulnar nerve graft to reconstruct the median nerve is a viable option. While restoration of median nerve sensation is consistently reported, recovery of significant motor function is less frequently observed. The authors report a case involving a previously healthy man who sustained upper arm segmental median and ulnar nerve injuries and, after failure of sural nerve grafts, was treated with a pedicled vascularized ulnar nerve graft to restore median nerve function. Long-term follow-up showed near full fist, with 12 kg of grip strength, key pinch with 1.5 kg of strength and protective sensation in the median nerve distribution. The present case demonstrates that pedicled ulnar vascularized nerve grafts can provide significant improvements to median nerve sensory and motor function in a heavily scarred environment.

Extracellular acidosis shifts hERG channel activation to more depolarized potentials and accelerates channel deactivation; however, the mechanisms underlying these effects are unclear. External divalent cations, e.g., Ca(2+) and Cd(2+), mimic these effects and coordinate within a metal ion binding pocket composed of three acidic residues in hERG: D456 and D460 in S2 and D509 in S3. A common mechanism may underlie divalent cation and proton effects on hERG gating. Using two-electrode voltage clamp, we show proton sensitivity of hERG channel activation (pKa = 5.6), but not deactivation, was greatly reduced in the presence of Cd(2+) (0.1 mM), suggesting a common binding site for the Cd(2+) and proton effect on activation and separable effects of protons on activation and deactivation. Mutational analysis confirmed that D509 plays a critical role in the pH dependence of activation, as shown previously, and that cooperative actions involving D456 and D460 are also required. Importantly, neutralization of all three acidic residues abolished the proton-induced shift of activation, suggesting that the metal ion binding pocket alone accounts for the effects of protons on hERG channel activation. Voltage-clamp fluorimetry measurements demonstrated that protons shifted the voltage dependence of S4 movement to more depolarized potentials. The data indicate a site and mechanism of action for protons on hERG activation gating; protonation of D456, D460 and D509 disrupts interactions between these residues and S4 gating charges to destabilize the activated configuration of S4.

The hERG cardiac K+ channel is characterized by unusually slow activation and deactivation gating kinetics compared to Shaker-like voltage-gated K+ (Kv) channels. In Shaker-like Kv channels movement of the voltage sensor upon depolarization is mechanically transduced by the α-helical S4-S5 linker to S6 activation gate opening. Given the unique gating properties of hERG channels, the details of voltage sensor coupling with the S6 activation gate are of significant interest. We have recently shown that substitution of a glycine residue (G546) within the S4-S5 linker with a leucine residue destabilizes the closed state (left-shifts the V1/2 of activation by ∼50 mV and accelerates the rate of channel opening) and suggested that flexibility of the linker may be a key determinant of the closed-open equilibrium in hERG channels. Here, we have investigated this further by re-introducing glycine residues within the S4-S5 linker (from position 539 to 552) in the G546L background to determine whether flexibility introduced at different positions within the helix restores WT-like gating. We found a cluster of sites in the N-terminal portion of the S4-S5 linker (D540, R541, Y542, E544) that, when replaced with a glycine residue, rescued the −50 mV shift caused by the G546L mutation restoring a WT-like voltage dependence of activation. None of these mutations affected the voltage dependence of activation in the WT background. All other mutations tested did not rescue WT function and presented the destabilized closed state phenotype that is characteristic of the G546L mutation. These results suggest that flexibility of the N-terminal S4-S5 linker contributes to stabilization of hERG channels in the closed state and that the native glycine, G546, affords this flexibility in WT channels.

Human ether-a-go-go-related gene (hERG) potassium channels are critical determinants of cardiac repolarization. Loss of function of hERG channels is associated with Long QT Syndrome, arrhythmia, and sudden death. Acidosis occurring as a result of myocardial ischemia inhibits hERG channel function and may cause a predisposition to arrhythmias. Acidic pH inhibits hERG channel maximal conductance and accelerates deactivation, likely by different mechanisms. The mechanism underlying the loss of conductance has not been demonstrated and is the focus of the present study. The data presented demonstrate that, unlike in other voltage-gated potassium (Kv) channels, substitution of individual histidine residues did not abolish the pH dependence of hERG channel conductance. Abolition of inactivation, by the mutation S620T, also did not affect the proton sensitivity of channel conductance. Instead, voltage-dependent channel inhibition (δ = 0.18) indicative of pore block was observed. Consistent with a fast block of the pore, hERG S620T single channel data showed an apparent reduction of the single channel current amplitude at low pH. Furthermore, the effect of protons was relieved by elevating external K+ or Na+ and could be modified by charge introduction within the outer pore. Taken together, these data strongly suggest that extracellular protons inhibit hERG maximal conductance by blocking the external channel pore.

We examine the challenges associated with implementing distributed interorganizational systems (DIOS), which can play an enabling role in information sharing required by many organizational forms. In particular, we discuss the role that middleware and information infrastructures play in facilitating DIOS. An example of how an infrastructure is used is discussed. Also, a research agenda is presented which, when completed, will enhance understanding of the role of middleware and information infrastructures in enabling DIOS.

hERG channel gating is associated with relatively slow voltage sensor movement that limits the rate of channel opening and closing. The mechanistic basis underlying the constraints upon sensor movement in these channels is unclear. Here, we have used voltage clamp fluorimetry (VCF) to study the effects of mutations within the S4-S5 linker on voltage sensor movement and its coupling to the pore. Mutations at G546 had two separable effects on activation and deactivation gating. Substitution of G546 with residues possessing different physico-chemical properties all (with the exception of G546C) shifted activation gating by ∼30mV in the hyperpolarizing direction. With the activation shift taken into account, the time constant of ionic current activation was also accelerated. In addition, a number of G546 mutants affected deactivation gating, although the effects of different mutations varied. In the most dramatic case, the G546V mutation induced biphasic deactivation with a pronounced slow component that was voltage-independent. Deletion of the N-terminus accelerated the fast component, but the slow component remained pronounced, suggesting that the slow component was not mediated by altered interaction with the N-terminus. VCF measurements of voltage sensor movement in G546V channels revealed fast and slow components of fluorescence change associated with deactivation, suggesting that the slow component of ionic current deactivation is due to slow voltage sensor return that is uncoupled from charge movement. Taken together, these data suggest: 1) reduced flexibility of the S4-S5 linker helix reduces constraints on voltage sensor movement during activation gating; 2) normal hERG channel closing involves at least two reconfigurations of the voltage sensor that are rate-limiting for pore closure.

Acidic pH reduces conductance in a number of voltage-gated potassium (Kv) channels via stabilization of inactivated states. However, the site and mechanism of action of protons responsible for inhibition of human ether-a-go-go related gene (hERG) Kv channels is unclear. Consistent with previous observations that suggest that a stabilization of inactivated states is not responsible, we show that protons reduce maximal conductance in S620T inactivation-removed channels to the same extent as WT hERG channels. A Woodhull characterization of the voltage-dependence of channel inhibition indicate that protons experience ∼20% of the electric field (δ=0.18) at their binding site. An apparent reduction of the single channel conductance was observed in measurements of hERG single channel activity. These data suggest that rapid block of the hERG channel pore underlies the proton-mediated loss of conductance. Consistent with a block of the outer pore, external K+ (Kd=1 mM, pH5.5) or Na+ relieved the effect of acidic pH. The negatively charged residue E637 in the outer pore mouth is a potential proton binding site; however, we could not test this since neutralization of this site resulted in non-functional channels. As an alternative strategy, we engineered a glutamate at H587, a site previously shown to face into the outer mouth of the pore. H587E reduced the voltage dependence of the proton block indicating that the binding site was shifted to a site that experiences little of the electric field. This implies that the proton binding site in WT channels lies deeper within the pore than H587. Taken together, these data suggest that extracellular protons inhibit hERG maximal conductance by blocking the external channel pore.