[Current mortality from war injuries-A narrative review]. / Aktuelle Mortalität von Kriegsverletzungen ­ eine narrative Übersichtsarbeit.

BACKGROUND: The war in Ukraine has led to a strategic reorientation of the German Armed Forces towards national and alliance defense. This has also raised the need for medical and surgical adaptation to scenarios of conventional warfare. In order to develop appropriate and effective concepts it is necessary to identify those war injuries that are associated with a relevant primary and secondary mortality and that can be influenced by medical measures (potentially survivable injuries). OBJECTIVE: The aim of this selective literature review was to identify war injuries with high primary and secondary mortality. METHODS: A selective literature review was performed in the PubMed® database with the search terms war OR combat AND injury AND mortality from 2001 to 2023. Studies including data of war injuries and associated mortality were included. RESULTS: A total of 33 studies were included in the analysis. Severe traumatic brain injury and thoracoabdominal hemorrhage were the main contributors to primary mortality. Injuries to the trunk, neck, traumatic brain injury, and burns were associated with relevant secondary mortality. Among potentially survivable injuries, thoracoabdominal hemorrhage accounted for the largest proportion. Prehospital blood transfusions and short transport times significantly reduced war-associated mortality. CONCLUSION: Control of thoracoabdominal hemorrhage has the highest potential to reduce mortality in modern warfare. Besides that, treatment of traumatic brain injury, burns and neck injuries has a high relevance in reducing mortality. Hospitals of the German Armed Forces need to focus on these requirements.

Outcome of Laparoscopic Versus Open Appendectomy for Acute Appendicitis-Results of a Propensity Score Matching Analysis of 542 Patients and Consequences for the Military Surgeon.

INTRODUCTION: Appendectomy is the treatment of choice for acute appendicitis. The procedure can be performed open or laparoscopically. However, laparoscopy is not available on military missions abroad. It is unclear whether treatment outcomes differ between the two surgical approaches. MATERIALS AND METHODS: Treatment data of all patients undergoing open and laparoscopic appendectomies in the German Armed Forces Hospital of Ulm from 2013 to 2017 were collected retrospectively. A propensity score matching analysis was performed to minimize the influence of potential confounders and to assess the influence of surgical approach on outcome (reoperations, superficial and deep surgical infections, length of postoperative ileus, need for intravenous analgesics, and operative time). RESULTS: A total of 542 patients with complete datasets were included in the propensity score matching analysis, among these 64 with open and 478 laparoscopic procedures. There were no statistically significant differences between open and laparoscopic surgeries with respect to all outcome variables, with the exception of a 25-minute prolonged operative time for the open approach. CONCLUSIONS: Open appendectomy can be considered equivalent in outcome to the laparoscopic procedure and thus can be performed on military missions abroad without compromising outcome. Military surgeons must continue to be trained and confident in open appendectomy.

Use of Indocyanine Green Fluorescence Angiography and Prophylactic Endoscopic Stenting in Esophagectomy for Acute Esophageal Necrosis.

Acute esophageal necrosis (AEN) is a rare condition with high mortality. We describe a case of an AEN accompanied with multiple esophageal perforations in a 40-year-old patient. This was addressed via emergency Ivor-Lewis-esophagectomy with intraoperative Indocyanine-Green-Angiography (ICGA) and prophylactic placement of a self-expanding metal-stent (SEMS).

Primary gastric squamous cell carcinoma - a case report of diagnosis, treatment, histological findings and follow-up.

Primary squamous cell carcinoma (PSCC) of the stomach is a rare oncologic disease with a reported incidence of only 0.04%. Therefore, there are no evidence-based recommendations for treatment. We present the case of a 73-year-old patient with PSSC. Multivisceral resection had to be performed to achieve tumor-free resection margins. Preoperative investigations, surgical treatment, histologic criteria and findings, and follow-up are presented.

Diagnostic options for blunt abdominal trauma.

PURPOSE: Physical examination, laboratory tests, ultrasound, conventional radiography, multislice computed tomography (MSCT), and diagnostic laparoscopy are used for diagnosing blunt abdominal trauma. In this article, we investigate and evaluate the usefulness and limitations of various diagnostic modalities on the basis of a comprehensive review of the literature. METHODS: We searched commonly used databases in order to obtain information about the aforementioned diagnostic modalities. Relevant articles were included in the literature review. On the basis of the results of our comprehensive analysis of the literature and a current case, we offer a diagnostic algorithm. RESULTS: A total of 86 studies were included in the review. Ecchymosis of the abdominal wall (seat belt sign) is a clinical sign that has a high predictive value. Laboratory values such as those for haematocrit, haemoglobin, base excess or deficit, and international normalised ratio (INR) are prognostic parameters that are useful in guiding therapy. Extended focused assessment with sonography for trauma (eFAST) has become a well established component of the trauma room algorithm but is of limited usefulness in the diagnosis of blunt abdominal trauma. Compared with all other diagnostic modalities, MSCT has the highest sensitivity and specificity. Diagnostic laparoscopy is an invasive technique that may also serve as a therapeutic tool and is particularly suited for haemodynamically stable patients with suspected hollow viscus injuries. CONCLUSIONS: MSCT is the gold standard diagnostic modality for blunt abdominal trauma because of its high sensitivity and specificity in detecting relevant intra-abdominal injuries. In many cases, however, clinical, laboratory and imaging findings must be interpreted jointly for an adequate evaluation of a patient's injuries and for treatment planning since these data supplement and complement one another. Patients with blunt abdominal trauma should be admitted for clinical observation over a minimum period of 24 h since there is no investigation that can reliably rule out intra-abdominal injuries.

Comparison of Vascular Closure Devices vs Manual Compression After Femoral Artery Puncture in Patients on Oral Anticoagulation - Post Hoc Analysis of the ISAR-CLOSURE Trial.

OBJECTIVES: To compare vascular closure devices (VCD) with manual compression (MC) in patients on chronic oral anticoagulation (OAC) who undergo diagnostic coronary angiography in terms of vascular access-site complications. METHODS: This is a subanalysis of 604 patients that had undergone transfemoral diagnostic coronary angiography and were randomly assigned to arteriotomy closure with either VCDs (intravascular FemoSeal VCD or extravascular EXOSEAL VCD) or MC within the large scale, randomized ISAR-CLOSURE trial. Primary endpoint was the composite of access-site-related vascular complications at 30 days. Secondary endpoints were time to hemostasis and repeat MC. RESULTS: Vascular access-site complications were similar in patients assigned to VCDs compared to MC (8.2% vs 10.6%; P=.33). There was no interaction of treatment effect and OAC (P interaction = 0.59). Rates of pseudoaneurysms were lower with VCDs (0.8% vs 3.2%; P=.02). Time to hemostasis was significantly shortened with VCDs compared to MC (1 [IQR 0.5-2.0] min vs 12 [IQR 10-15] min; P<.001). There was no difference regarding repeat MC in both groups (VCD 1.5% vs MC 0.5%; P=.23). Time to hemostasis (0.5 [0.2-1.0] min, vs 2.0 [1.75-2.0] min; P<.001) and closure device failure (3.7% vs 17.2%; P<.001) were lower with the intravascular VCD, compared with the extravascular VCD. CONCLUSIONS: In patients on chronic OAC undergoing transfemoral diagnostic coronary angiography, the use of VCDs was comparable to MC regarding the primary combined endpoint of vascular access-site related complications. VCDs reduced the occurrence of pseudoaneurysms and time to hemostasis.

Emissions of Tetrafluoromethane (CF4) and Hexafluoroethane (C2F6) From East Asia: 2008 to 2019.

The perfluorocarbons (PFCs), tetrafluoromethane (CF4) and hexafluoroethane (C2F6), are potent greenhouse gases with very long atmospheric lifetimes. They are emitted almost entirely from industrial sources, including the aluminum and rare earth metal smelting industries that emit them as by-products, and the semiconductor and flat panel display manufacturing industries that use them and vent unutilized amounts to the atmosphere. Despite extensive industrial efforts to quantify and curb these emissions, "top-down" PFC emission estimates derived from atmospheric measurements continue to rise and are significantly greater than reported process- and inventory-based "bottom-up" emissions. In this study, we estimate emissions of CF4 and C2F6 from East Asia, where PFC emitting industries are heavily concentrated, using a top-down approach (a Bayesian inversion) with high-frequency atmospheric measurements at Gosan (Jeju Island, South Korea) for 2008-2019. We also compile and analyze the available bottom-up CF4 and C2F6 emissions in East Asia from industrial and government reports. Our results suggest that the observed increases in global PFC emissions since 2015 are driven primarily by China's aluminum industry, with significant contributions from Japan's and Korea's semiconductor industry. Our analysis suggests that Chinese emissions occur predominantly from the aluminum industry, although their emissions per production ratio may be improving. Our results for Japan and Korea find significant discrepancies between top-down and bottom-up emissions estimates, suggesting that the effectiveness of emission reduction systems (abatement) used in their semiconductor industries may be overestimated. Overall, our top-down results for East Asia contribute significantly to reducing the gap in the global PFC emission budgets.

[Functional Results after Laparoscopic versus Robot-assisted Sigmoid Resection in Diverticulitis]. / Funktionelle Ergebnisse nach laparoskopischer vs. roboterassistierter Sigmaresektion bei Divertikulitis.

BACKGROUND: Sigmoid resection in diverticulitis is one of the most frequently performed colonic operations. A minimally invasive approach by laparoscopy is the surgical gold standard. For a few years now, sigmoid resections have also been performed robotically (da Vinci® System). It is unclear whether there are relevant differences between the two procedures in terms of functional outcome. METHODS: A postoperative follow-up was performed on all patients who underwent laparoscopic or robotic sigmoid resection for diverticulitis between November 2013 and November 2018, with a minimum interval of 6 months between surgery. Continence disorders, the development of symptoms compared to preoperative, changes in bowel movement (constipation, diarrhoea), impairment in daily life and pain were recorded. Differences between the groups were checked for statistical significance using the chi-square test. RESULTS: During the study period, a total of 106 minimally invasive sigmoid resections for diverticulitis were performed (laparoscopic: n = 46, robot-assisted: n = 60). Of these, 74 patients (70%; laparoscopic: n = 28, robot-assisted: n = 46) answered the questionnaire and were included in the evaluation. Continence disorders were reported in a total of 22% of cases. There was no statistically significant difference between the groups in any of the variables surveyed. CONCLUSION: With regard to functional results after minimally invasive sigmoid resection for diverticulitis, laparoscopic and robot-assisted sigmoid resection can be considered equivalent procedures.

[Value of laparoscopy in blunt and penetrating abdominal trauma-a systematic review]. / Wertigkeit der Laparoskopie beim penetrierenden und stumpfen Abdominaltrauma ­ ein systematisches Review.

BACKGROUND: The range of indications for laparoscopic procedures has been continuously widened in recent years. At the same time, however, the diagnostic and therapeutic role of laparoscopy in the management of blunt and penetrating abdominal trauma remains controversial. METHODS: A systematic literature search was carried out in PubMed from 2008 to 2019 on the use of laparoscopy in blunt and penetrating abdominal trauma. Studies were analyzed in terms of relevant operative and perioperative event rates (rate of missed injuries, conversion rate, postoperative complication rate). On the basis of this analysis, an algorithm for the use of laparoscopy in abdominal trauma was developed for clinical practice. RESULTS: A total of 15 full texts with 5869 patients were found. With a rate of 1.4%, laparoscopically missed injuries were very rare for both penetrating and blunt abdominal trauma. Of all trauma laparoscopies 29.3% were converted to open surgery (laparotomy). Among the non-converted laparoscopies 60.5% were therapeutic. Complications occurred after trauma laparoscopy in 8.6% of cases. CONCLUSION: By means of systematic laparoscopic exploration, missed injuries in abdominal trauma are extremely rare, so that concerns in this respect no longer seem justified. A large proportion of intra-abdominal injuries can be treated using laparoscopy or laparoscopically assisted procedures.

Robotic Versus Laparoscopic Sigmoid Resection for Diverticular Disease: A Single-Center Experience of 106 Cases.

Background: Laparoscopic sigmoid resection is the surgical standard for the treatment of diverticulitis. Robotic sigmoid resection with the da Vinci Xi® platform may offer advantages over the laparoscopic approach. Materials and Methods: One hundred and six patients with uncomplicated, complicated, or recurrent diverticular disease underwent robotic (n = 60) or laparoscopic (n = 46) sigmoid resection at our institution between 2013 and 2018. Patient demographics and characteristics, perioperative measures, and complications were retrospectively analyzed. Results: There were no statistically significant differences between the robotic and laparoscopic group with regard to operative time (130 versus 118 minutes; P = .23), anastomotic leakage (6.7% versus 6.5%; P = 1.0), need for stoma (6.7% versus 4.3%; P = 1.0), conversion rate (1.7% versus 0%; P = .36), reoperation (8.3% versus 15.2%; P = .27), overall complications according to the Clavien-Dindo classification (30.0% versus 30.4%; P = .8), mortality (1.7% versus 0%; P = 1.0), and need for intravenous analgesics (3.0 versus 2.1 days; P = .21). The duration of postoperative ileus was significantly shorter in the robotic group (2.2 versus 2.8 days; P = .01). Conclusion: Robotic sigmoid resection for uncomplicated, complicated, or recurrent diverticular disease is a safe and feasible procedure. However, robotic sigmoid resection for diverticulitis is not associated with relevant clinical benefits for patients compared to laparoscopic resection except for a slightly shorter duration of postoperative ileus.

Comparison of Vascular Closure Devices Versus Manual Compression After Femoral Artery Puncture in Women.

BACKGROUND: The value of vascular closure devices (VCD) in women undergoing transfemoral catheterization has not been sufficiently investigated. METHODS AND RESULTS: This is a sex-specific analysis of 1395 women enrolled in a large-scale, randomized, multicenter trial, in which patients undergoing transfemoral diagnostic coronary angiography were randomly assigned in a 1:1:1 ratio to arteriotomy closure with an intravascular VCD, extravascular VCD, or manual compression (MC). Primary objective was to assess the safety and efficacy of 2 different VCD compared with MC regarding vascular access-site complications at 30 days. A secondary comparison was between 2 different types of contemporary VCD. Overall, women were at higher risk for vascular access-site complications compared with men (9.0% versus 6.4%; P=0.002). Vascular access-site complications were comparable in women assigned to VCD and MC (8.6% versus 9.8%; P=0.451). There was no interaction of treatment effect and sex ( Pinteraction=0.970). Time to hemostasis was significantly shortened with VCD compared with MC (1 [interquartile range, 0.5-2.0] minutes) versus 11 [interquartile range, 10-15] minutes; P<0.001); however, more women with VCD required repeat MC (2.4% versus 0.6%; P=0.018). The use of the intravascular compared with the extravascular VCD was associated with a numerical reduction in vascular access-site complications (6.6% versus 10.7%; P=0.027) and significant reductions in time to hemostasis and VCD failure. CONCLUSIONS: In women undergoing diagnostic coronary angiography via the common femoral artery, VCD and MC provided comparable safety, while time to hemostasis was reduced with VCD. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01389375.

Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain.

OBJECTIVE: Develop and validate a low-intensity sinusoidal electrical stimulation paradigm to preferentially activate C-fibers in human skin. METHODS: Sinusoidal transcutaneous stimulation (4Hz) was assessed psychophysically in healthy volunteers (n = 14) and neuropathic pain patients (n = 9). Pursuing laser Doppler imaging and single nociceptor recordings in vivo in humans (microneurography) and pigs confirmed the activation of "silent" C-nociceptors. Synchronized C-fiber compound action potentials were evoked in isolated human nerve fascicles in vitro. Live cell imaging of L4 dorsal root ganglia in anesthetized mice verified the recruitment of small-diameter neurons during transcutaneous 4-Hz stimulation of the hindpaw (0.4mA). RESULTS: Transcutaneous sinusoidal current (0.05-0.4mA, 4Hz) activated "polymodal" C-fibers (50% at ∼0.03mA) and "silent" nociceptors (50% at ∼0.04mA), intensities substantially lower than that required with transcutaneous 1-ms rectangular pulses ("polymodal" ∼3mA, "silent" ∼50mA). The stimulation induced delayed burning (nonpulsating) pain and a pronounced axon-reflex erythema, both indicative of C-nociceptor activation. Pain ratings to repetitive stimulation (1 minute, 4Hz) adapted in healthy volunteers by Numeric Rating Scale (NRS) -3 and nonpainful skin sites of neuropathic pain patients by NRS -0.5, whereas pain even increased in painful neuropathic skin by approximately NRS +2. INTERPRETATION: Sinusoidal electrical stimulation at 4Hz enables preferential activation of C-nociceptors in pig and human skin that accommodates during ongoing (1-minute) stimulation. Absence of such accommodation in neuropathic pain patients suggest axonal hyperexcitability that could be predictive of alterations in peripheral nociceptor encoding and offer a potential therapeutic entry point for topical analgesic treatment. Ann Neurol 2018;83:945-957.

Low-Frequency Stimulation of Silent Nociceptors Induces Secondary Mechanical Hyperalgesia in Human Skin.

Secondary mechanical hyperalgesia to punctate mechanical stimuli and light touch (allodynia) are prominent symptoms in neuropathic pain states. In a combined microneurographic and psychophysical study, we investigated the role of mechano-insensitive (silent) nociceptors regarding induction. Electrical thresholds of mechano-sensitive and silent nociceptors were assessed by microneurography with two closely spaced intracutaneous electrodes (i.c.) and a transcutaneous configuration (t.c.) in the foot dorsum. For t.c. stimulation there was a marked difference between silent (median, quartiles; 60, 50-70 mA, n = 63) and mechano-sensitive fibers (3, 2-5 mA, n = 107). In silent fibers, thresholds were lower for i.c. stimulation (16, 14-19 mA, n = 8), but higher in mechano-sensitive units (6, 5-6 mA, n = 13). Corresponding psychophysical tests showed no difference between the stimulation configuration for pain thresholds, but lower thresholds for the i.c. stimulation in axon reflex erythema (12 vs. 21 mA), punctate hyperalgesia (9 vs. 15 mA) and allodynia (15 vs. 18 mA). Punctate hyperalgesia was evoked at very low stimulation frequencies of 1/20 Hz (7/7 subjects), whereas the induction of an axon reflex flare required stimulation at 1/5 Hz. Electrical stimulation which is sufficient to excite mechano-insensitive C nociceptors can induce secondary mechanical hyperalgesia even at low frequencies supporting a role of such low-level input to clinical pain states. Thus, differential nociceptor class-specific input to the spinal cord adds to the complexity of modulatory mechanisms that determine nociceptive processing in the spinal cord.

[The Relevance of Surgeon-performed Ultrasound For the Detection of Acute Appendicitis: a Review of the Literature and a Practical Diagnostic Algorithm]. / Stellenwert der chirurgischen Sonografie in der Diagnostik der akuten Appendizitis: Literaturübersicht und ein praxisnaher Diagnosealgorithmus.

Background The relevance of ultrasound (US) in diagnosing acute appendicitis is controversial. The validity of US in comparison with other imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), is unclear, as is the difference between surgeon-performed ultrasound (SPUS) and radiologist-performed ultrasound (RPUS). On the basis of a review of current literature, our study aimed to develop a US-based algorithm to simplify the choice between additional diagnostic measures and surgery. Methods MEDLINE (PubMed®) was searched for literature published between 2010 and 2016. A total of 53 relevant full-text articles were eventually evaluated. Results Ultrasound (US) is an established part of algorithms used to diagnose acute appendicitis and has already replaced CT as the imaging technique of choice. The differences between SPUS and RPUS with regard to sensitivity, specificity, and positive and negative predictive values (PPV, NPV) are not statistically significant. The benefit of SPUS over RPUS is the simultaneous clinical assessment of the patient by the surgeon while the sonogram is performed (sonopalpation), which can increase diagnostic accuracy even further. Radiation exposure as a result of CT could be avoided or significantly reduced through the routine use of US, which is increasingly being used and is widely available. Conclusions SPUS should be the first imaging technique used to diagnose patients with suspected appendicitis. Additional diagnosis using CT or MRI is only recommended if sonographic imaging of the appendix is impossible in combination with specific clinical and laboratory criteria. A structured diagnostic approach with obligatory use of (SP)US, as described in the diagnostic algorithm, should be used for detection of acute appendicitis.

Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype.

The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of α-galactosidase A (Gla-/0). The skin innervation of Gla-/0 mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla-/0 mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla-/0 nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla-/0 nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.

Extensive Chemical Modifications in the Primary Protein Structure of IgG1 Subvisible Particles Are Necessary for Breaking Immune Tolerance.

A current concern with the use of therapeutic proteins is the likely presence of aggregates and submicrometer, subvisible, and visible particles. It has been proposed that aggregates and particles may lead to unwanted increases in the immune response with a possible impact on safety or efficacy. The aim of this study was thus to evaluate the ability of subvisible particles of a therapeutic antibody to break immune tolerance in an IgG1 transgenic mouse model and to understand the particle attributes that might play a role in this process. We investigated the immunogenic properties of subvisible particles (unfractionated, mixed populations, and well-defined particle size fractions) using a transgenic mouse model expressing a mini-repertoire of human IgG1 (hIgG1 tg). Immunization with proteinaceous subvisible particles generated by artificial stress conditions demonstrated that only subvisible particles bearing very extensive chemical modifications within the primary amino acid structure could break immune tolerance in the hIgG1 transgenic mouse model. Protein particles exhibiting low levels of chemical modification were not immunogenic in this model.

[A rare case of coecal volvulus after colonoskopy due to a mobile coekum - diagnosis, surgical therapy and postoperative complications]. / Ein seltener Fall eines Volvulus des Coecums nach Koloskopie bei Coecum mobile ­ Darstellung von Diagnostik, operativer Therapie und postoperativen Komplikationen.

Colonoscopy, either performed as screening or as a therapeutic proceedure, is, in general, very safe with only a few cases of serious complications. Most cases of bleeding after endoscopic polypectomy can be safely managed endoscopically. The rare cases of colonic perforations still have to be managed by surgical intervention. The postpolypectomy-coagulation syndrome and a cecal volvulus are very rare complicatoions after colonoscopy. In the current manuscript, we describe a rare case of a cecal volvulus after routine colonoscopy due to an unknown mobile coecum as a predisposition. We discuss the endoscopic, clinical and radiological findings of the patient. Moreover, we describe the performed surgical procedure and the further clinical course of the patient. A cecal volvulus should always be considered as a possible rare, but serious, complication in the differential diagnosis of abdominal pain after colonoscopy. The standard therapy of a cecal volvulus is the right hemicolectomy. As an alternative, a coecopexy without resection could be performed as long as the colonic wall is still vital.

Pathological nociceptors in two patients with erythromelalgia-like symptoms and rare genetic Nav 1.9 variants.

INTRODUCTION: The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear. METHODS: C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography. RESULTS: Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed. CONCLUSIONS: Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function.

SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing.

Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p.M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p.M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences.