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Purpose: Presenting the case of unusual onset hypokalemic periodic paralysis (HypoPP) where myopathy had developed two years before paralysis occurred. Material and methods: A Polish three-generation family with HypoPP and mutation in CACNA1S (R1239G) has been investigated. Clinical presentation with unusual onset of the disease, biopsy results and genetic research in one family member were described. Conclusion: HypoPP is a rare disease it needs to be taken into consideration not only in cases of paroxysmal weakness but also when there is myopathy of unknown origin. [ABSTRACT FROM AUTHOR]

We present experimental data of the precessional dynamics of the free layer of CoFeB/MgO/CoFeB based magnetic tunnel junctions (MTJ) in the presence of thermal gradients across the MTJ. The free layer precession is investigated by noise spectroscopy. Thermal gradients of the order of tens of mK/nm across the MTJ are generated by electrical heating. Without applied thermal gradients we find spin transfer torque modified magnetization precession. With increasing thermal gradients we generally observe a decrease of the precession frequency which could be related to an increasing overall free layer temperature. However an asymmetry of the line width behavior for parallel and antiparallel orientation points towards additional effects beyond thermal activation. This could be a hint for the modification of the precessional dynamics in magnetic tunnel junctions by thermal spin torques. [ABSTRACT FROM AUTHOR]

We investigate the frequency of thermally excited vortex oscillations in Co-Fe-B magnetic tunnel junction (MTJ) pillars in the presence of defects. Under a variable in-plane magnetic field, a characteristic behavior is observed: the frequency oscillates from a maximum at certain field values to a steep minimum, which tends towards zero frequency. These frequency variations are described qualitatively well by an analytical model based on the Thiele equation taking into account a single Gaussian pinning potential. It is thus possible to calculate the in-plane depinning field for certain pinning potential parameters. For steep potentials, the depinning is hysteretic and jumps between the pinned and unpinned regime occur due to the presence of an energy barrier. A sharp frequency minimum occurs at an applied field, where a large flat region in the energy landscape is present. From the experiments, the pinning potentials are estimated to be between -0.2eV and -0.4eV. We also perform micromagnetic simulations of the vortex oscillations in the presence of a distribution of pinning centers. The simulations confirm the validity of the Thiele-approach showing that the vortex remains sufficiently rigid. [ABSTRACT FROM AUTHOR]

Hyperkalemic periodic paralysis ( HyperPP) is a dominantly inherited muscle disease caused by mutations in SCN4A gene encoding skeletal muscle voltage gated Na v1.4 channels. We identified a novel Na v1.4 mutation I692M in 14 families out of the 104 genetically identified HyperPP families in the Neuromuscular Centre Ulm and is therefore as frequent as I693T (13 families out of 14 HyperPP families) in Germany. Surprisingly, in 13 families, a known polymorphism S906T was also present. It was on the affected allele in at least 10 families compatible with a possible founder effect in central Europe. All affected members suffered from episodic weakness; myotonia was also common. Compared with I692M patients, I692M-S906T patients had longer weakness episodes, more affected muscles, CK elevation and presence of permanent weakness. Electrophysiological investigation showed that both mutants had incomplete slow inactivation and a hyperpolarizing shift of activation which contribute to membrane depolarization and weakness. Additionally, I692M-S906T significantly enhanced close-state fast inactivation compared with I692M alone, suggesting a higher proportion of inactivated I692M-S906T channels upon membrane depolarization which may facilitate the initiation of weakness episodes and therefore clinical manifestation. Our results suggest that polymorphism S906T has effects on the clinical phenotypic and electrophysiological severity of a novel borderline Na v1.4 mutation I692M, making the borderline mutation fully penetrant. [ABSTRACT FROM AUTHOR]

We investigated the temperature dependence of the switching current for a perpendicularly magnetized CoFeB film deposited on a nanocrystalline tungsten film with large oxygen content: nc-W(O). The effective spin Hall angle |ΘSHeff| ≈ 0.22 is independent of temperature, whereas the switching current increases strongly at low temperature. The increase indicates that the current induced switching itself is thermally activated, in agreement with a recent theoretical prediction. The dependence of the switching current on the in-plane assist field suggests the presence of an interfacial Dzyaloshinskii--Moriya interaction with D≈0.23 mJ/m², intermediate between the Pt/ CoFe and Ta/CoFe systems. We show that the nc-W(O) is insensitive to annealing, which makes this system a good choice for the integration into magnetic memory or logic devices that require a high-temperature annealing process during fabrication. [ABSTRACT FROM AUTHOR]

This exploratory study aims to create an evidence-based comprehensive characterization of hyperkalemic periodic paralysis (hyperPP). HyperPP is a rare genetic disorder that causes episodes of flaccid paralysis. Disease descriptions in the literature are based upon isolated clinical encounters and case reports. We describe the experience of a large cohort of genetically diagnosed individuals with hyperPP. We surveyed genetically characterized individuals age 18 and over to assess disease comorbidities, diagnostic testing, management, and quality of life issues relevant to hyperPP. Myotonia was reported by 55.8 % of subjects and paramyotonia by 45.3 %. There is a relative risk of 3.6 ( p < 0.0001) for thyroid dysfunction compared to the general population. Twenty-five percent of subjects experienced their sentinel attack in the second decade of life. It took an average of 19.4 years and visits to four physicians to arrive at the diagnosis of hyperPP. In addition to limbs and hands being affected during attacks, 26.1 % of subjects reported their breathing musculature was affected and 62.0 % reported their facial muscles were affected. There was a lifelong trend of increasing attack frequency, which was particularly common during childhood and adolescence. Approximately one-third of individuals experienced progressive myopathy. Permanent muscle weakness was evident and worsened during childhood and after age 40. Those with no chronic treatment regimen have a RR of 2.3 for inadequate disease control compared to those taking long-term medications. This study revealed a multitude of heretofore unidentified characteristics of hyperPP, in addition to providing a different perspective on some previously held notions regarding the condition. [ABSTRACT FROM AUTHOR]

Background A common form of congenital myotonia, myotonia congenita ( MC), is caused by mutations in the skeletal muscle Cl− channel gene type 1 (CLCN1). Due to the reduced Cl− conductance of the mutated channels, the patients may develop generalized muscle rigidity and hypermetabolism during general anaesthesia. The clinical symptoms resemble malignant hyperthermia (MH), which may lead to mistreatment of the patient. Methods Muscle specimens of ADR mice (an animal model of MC) as well as of human individuals were used and exposed to potent ryanodine receptor type 1 ( RyR1) activators and increasing K+ concentration. Muscle force was monitored by a standardized diagnostic method for MH, the so-called in vitro contracture test. Results Neither muscle of ADR mice nor MC muscle (murine and human myotonic muscle) showed pathological contractures after exposure to the potent RyR1 agonists caffeine and halothane. Increasing concentrations of K+ had a dose-dependent preventive effect on myotonic stiffness. Conclusion We conclude that the adverse anaesthetic MH-like episodes observed in MC patients do not primarily originate from an altered Ca2+ release in skeletal muscle. In MC muscle, this hypermetabolism is facilitated by a (pharmacologically induced) sustained depolarization due to an instable membrane potential. The in vitro results suggest that these patients benefit from tight K+ monitoring because of the membrane potential stabilizing effect of K+. [ABSTRACT FROM AUTHOR]

To assess the presence and persistence of muscular edema and increased myoplasmic sodium (Na) concentration in Duchenne muscular dystrophy (DMD). We examined eight DMD patients (mean age 9.5 ± 5.4 years) and eight volunteers (mean age 9.5 ± 3.2 years) with 3-tesla proton (H) and Na density-adapted 3D-radial MR sequences. Seven DMD patients were re-examined about 7 months later without change of therapy. The eighth DMD patient was re-examined after 5 and 11 months under medication with eplerenone. We quantified muscle edema on STIR images with background noise as reference and fatty degeneration on T1-weighted images using subcutaneous fat as reference. Na was quantified by a muscular tissue Na concentration (TSC) sequence employing a reference containing 51.3 mM Na with 5 % agarose. With an inversion-recovery (IR) sequence, we determined mainly the myoplasmic Na. The normalized muscular Na IR signal intensity was higher in DMD than in volunteers ( n = 8, 0.75 ± 0.07 vs. 0.50 ± 0.05, p < 0.001) and persisted at second measurement ( n = 7, 1st 0.75 ± 0.07, 2nd 0.73 ± 0.06, p = 0.50). When compared to volunteers (25.6 ± 2.0 mmol/l), TSC was markedly increased in DMD (38.0 ± 5.9 mmol/l, p < 0.001) and remained constant ( n = 7, 1st 37.9 ± 6.4 mmol/l, 2nd 37.0 ± 4.0 mmol/l, p = 0.49). Muscular edema (15.6 ± 3.5 vs. 6.9 ± 0.7, p < 0.001) and fat content (0.48 ± 0.08 vs. 0.38 ± 0.01, p = 0.003) were elevated in DMD when compared to volunteers. This could also be confirmed during follow-up ( n = 7, p = 0.91, p = 0.12). Eplerenone slightly improved muscle strength and reduced muscular sodium and edema. The permanent muscular Na overload in all DMD patients is likely osmotically relevant and responsible for the persisting, mainly intracellular muscle edema that may contribute to the progressive muscle degeneration. [ABSTRACT FROM AUTHOR]

Abstract: This article reviews recent developments on magnetoresistive detection of magnetic beads or nanoparticles by nanoscale sized sensors. Sensors are analyzed from an experimental and a numerical point of view in respect to their capability to either localize the position of a single magnetic particle or to detect the number of particles in a certain range. Guidelines are shown up on how to extend single sensors to sensor arrays with very high spatial resolution and how to modify the sensor shape in order to provide long distance measurements. Further, sensors in biological lab-on-a-chip environments are discussed. The magnetic ratchet and a gravitation based microfluidic component are reviewed as important tools to position and, therefore, detect biological components in continuous-flow devices. [ABSTRACT FROM AUTHOR]

Kornblum C, Lutterbey GG, Czermin B, Reimann J, von Kleist-Retzow J-C, Jurkat-Rott K, Wattjes MP. Whole-body high-field MRI shows no skeletal muscle degeneration in young patients with recessive myotonia congenita. Acta Neurol Scand: 2010: 121: 131–135. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – Muscle magnetic resonance imaging (MRI) is the most sensitive method in the detection of dystrophic and non-dystrophic abnormalities within striated muscles. We hypothesized that in severe myotonia congenita type Becker muscle stiffness, prolonged transient weakness and muscle hypertrophy might finally result in morphologic skeletal muscle alterations reflected by MRI signal changes. Aim of the study – To assess dystrophic and/or non-dystrophic alterations such as fatty or connective tissue replacement and muscle edema in patients with severe recessive myotonia congenita. Methods – We studied three seriously affected patients with myotonia congenita type Becker using multisequence whole-body high-field MRI. All patients had molecular genetic testing of the muscle chloride channel gene ( CLCN1) . Results – Molecular genetic analyses demonstrated recessive CLCN1 mutations in all patients. Two related patients were compound heterozygous for two novel CLCN1 mutations, Q160H and L657P . None of the patients showed skeletal muscle signal changes indicative of fatty muscle degeneration or edema. Two patients showed muscle bulk hypertrophy of thighs and calves in line with the clinical appearance. Conclusions – We conclude that (i) chloride channel dysfunction alone does not result in skeletal muscle morphologic changes even in advanced stages of myotonia congenita, and (ii) MRI skeletal muscle alterations in myotonic dystrophy must be clear consequences of the dystrophic disease process. [ABSTRACT FROM AUTHOR]

Abstract: The deposition of metals using thermal CVD in a hydrogen-free atmosphere was investigated starting from nontoxic metalorganic precursors. A remarkably simple process, which relies on the chemical reduction by alcohols, allows the deposition of high-quality films of a variety of metals and alloys. The growth characteristics of metal films are investigated as a function of temperature, and their performance is discussed in terms of electrical resistivity. Near-bulk resistivities were obtained for Ni, Co, Cu, and Ag, while Fe presents a 37-fold higher resistivity than the bulk because of the poor packing of crystallites. In this work, the deposition conditions for the growth of single-phase cubic or hexagonal nickel were determined. [Copyright &y& Elsevier]

The vortex state, characterized by a curling magnetization, is one of the equilibrium configurations of soft magnetic materials and occurs in thin ferromagnetic square and disk-shaped elements of micrometre size and below. The interplay between the magnetostatic and the exchange energy favours an in-plane, closed flux domain structure. This curling magnetization turns out of the plane at the centre of the vortex structure, in an area with a radius of about 10 nanometres—the vortex core. The vortex state has a specific excitation mode: the in-plane gyration of the vortex structure about its equilibrium position. The sense of gyration is determined by the vortex core polarization. Here we report on the controlled manipulation of the vortex core polarization by excitation with small bursts of an alternating magnetic field. The vortex motion was imaged by time-resolved scanning transmission X-ray microscopy. We demonstrate that the sense of gyration of the vortex structure can be reversed by applying short bursts of the sinusoidal excitation field with amplitude of about 1.5 mT. This reversal unambiguously indicates a switching of the out-of-plane core polarization. The observed switching mechanism, which can be understood in the framework of micromagnetic theory, gives insights into basic magnetization dynamics and their possible application in data storage. [ABSTRACT FROM AUTHOR]

Abstract: We report on a magneto-optical Kerr effect (MOKE) investigation of alternating wide and narrow Fe bars, forming a two-dimensional periodic array. The magnetization reversal was studied by regular longitudinal Vector-MOKE in specular geometry as well as in Bragg-MOKE geometry, using the diffraction spots from the grating for hysteresis measurements. With Vector-MOKE a two-step switching process for the wide and narrow Fe bars is observed, indicative for a narrow switching field distribution in this array. In addition, hysteresis loops were determined as a function of the diffraction order for the hard and easy axis direction. The loops at different orders of diffraction can qualitatively and quantitatively be described by Fourier transformations of micromagnetic simulations. [Copyright &y& Elsevier]

The intrinsic dc conductivity of long, individual lambda phage dsDNA molecules has been investigated by ultrasensitive low current–voltage-spectroscopy (IV) under ambient conditions and controlled low humidity inert gas atmosphere on microfabricated metal–insulator–metal gap structures. We found a strong dependence of the measured conductivity on the apparent humidity, which we attribute to capillary condensation of water to the immobilized DNA molecules, giving rise to additional ionic currents. Additional IV-spectroscopy experiments under controlled argon atmosphere always revealed a significant drop in electrical conductivity to 4 × 10-15 A V-1 μm-1, indicating almost no considerable contribution of electrical long range charge transport. [Copyright &y& Elsevier]

Focuses on the guidelines for molecular diagnosis of inherited neurologic diseases established by EFNS task force. Coverage of the guidelines; Diagnosis of skeletal muscle channelopathies; Discussion on molecular diagnosis of inherited neuropathies.

We have set up an atomic beam of cesium for the study of spin-dependent electron-cesium scattering. The beam is produced by an effusive oven with continuous recirculation of the condensed metal. The beam is optically pumped by circularly polarized light from two laser diodes tuned to the 6 S( F=3)→6 P( F′=4) and 6 S( F=4)→6 P( F′=5) transitions, respectively. Nearly all atoms are transferred into the F=4, m=+4 or m=−4 Zeeman level of the ground state, depending on the sense of circular polarization of the pumping light. The population distribution in the optically pumped beam is analyzed in terms of the m=−1/2 and m=+1/2 components with a Stern-Gerlach magnet. We find the atomic polarization to be very close to unity at a density of 8×10 atoms/cm in the scattering center. The polarization decreases slightly with increasing density of the cesium beam due to radiation trapping. A spin flipper serves as a means of polarization reversal, introducing no systematic errors in the spin asymmetry measurements. Lock-in technique is used to stabilize the atomic beam polarization by detecting fluorescence light signals. [ABSTRACT FROM AUTHOR]

Presents a study that prepared magnetic cobalt nanocrystals using different chemical preparation methods. Analysis of the hysteresis loop of the nanoparticles; Measurement of the size distribution of the cobalt nanoparticles; Analysis of the transmission electron micrograph of the nanocrystals.

CMV, a ubiquitous herpesvirus, elicits an extraordinarily large T cell response that is sustained or increases over time, a phenomenon termed 'memory inflation.' Remarkably, even latent, non-productive infection can drive memory inflation. Despite intense research on this phenomenon, the infected cell type(s) involved are unknown. To identify the responsible cell type(s), we designed a Cre-lox murine CMV (MCMV) system, where a spread-deficient (ΔgL) virus expresses recombinant SIINFEKL only in Cre+ host cells. We found that latent infection of endothelial cells (ECs), but not dendritic cells (DCs) or hepatocytes, was sufficient to drive CD8 T cell memory inflation. Infection of Lyve-1-Cre and Prox1-CreERT2 mice revealed that amongst EC subsets, infection of lymphatic ECs was sufficient. Genetic ablation of β2m on lymphatic ECs did not prevent inflation, suggesting another unidentified cell type can also present antigen to CD8 T cells during latency. This novel system definitively shows that antigen presentation by lymphatic ECs drives robust CD8 T cell memory inflation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Munks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

According to the adaptive modulation hypothesis, digestive enzyme activities are matched to their respective dietary substrate level so that ingested nutrients are not wasted in excreta due to insufficient digestive capacity, and so membrane space or expenditures building/maintaining the intestinal hydrolytic machinery are not wasted when substrate levels are low. We tested predictions in juvenile northern bobwhites (Colinus virginianus) and juvenile and adult domestic chickens (Gallus gallus domesticus) by feeding them on diets varying in starch, protein, and lipid composition for 7-9 d (bobwhites) or 15 d (chickens). Birds were euthanized, intestinal tissue harvested, and enzyme activities measured in tissue homogenates from proximal, medial and distal small intestine. We found that (1) α-glucosidase (AG; maltase and sucrase) activities were induced by dietary starch in both juvenile and adult chickens but not in northern bobwhites; (2) aminopeptidase-N (APN) activities were induced by dietary protein in both bobwhites and juvenile but not adult chickens; (3) AG activities were suppressed by an increase in dietary lipid in both bobwhites and juvenile but not adult chickens; and (4) APN activities were not suppressed by high dietary lipid in any birds. We review findings from 35 analogous trials in 16 avian species. 100% of avian omnivores modulate at least one enzyme in response to change in dietary substrate level. AG induction by dietary carbohydrate occurs in more members of Galloanserae than in Neoaves, and all omnivorous members of Neoaves tested so far increase APN activity on high dietary protein, whereas fewer of the Galloanserae do., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, hyperkalemia and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca 2+ release from myotubes via the ryanodine receptor type 1 (RYR1) and the voltage-dependent L-type calcium channel (CACNA1S). As more than 300 variants of unknown significance have been detected to date, we examined whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants. In this diagnostic accuracy study, blood samples from 235 individuals with a history of a clinical malignant hyperthermia or their close relatives were genetically screened for RYR1 variants of all 106 RYR1 exons and additionally for known variants of CACNA1S. In vitro contracture tests were conducted on muscle biopsies obtained from all individuals, independently of whether a pathogenic variant, a variant of unknown significance or no variant was detected. Comparisons were made to three established bioinformatic pathogenicity detection tools to identify the clinical impact of the variants of unknown significance. All detected genetic variants were tested for pathogenicity by three in silico approaches and compared to the in vitro contracture test. Sensitivity and specificity of exon screening of all individuals listed in our MH database was analyzed. Exon screening identified 97 (41%) of the 235 individuals as carriers of pathogenic variants. Variants of unknown significance were detected in 21 individuals. Variants of unknown significance were subdivided into 19 malignant-hyperthermia-susceptible individuals and 2 non-malignant-hyperthermia-susceptible individuals. All pathogenic variants as well as the malignant-hyperthermia-suspectible variants were correctly identified by the bioinformatic prediction tools. Sensitivity of in silico approaches ranged between 0.71 and 0.98 (Polyphen 0.94 [CI 95% 0.75; 0.99]; Sift 0.98 [CI 95% 0.81; 0.99]; MutationTaster 0.92 [CI 95% 0.75; 0.99]). Specificity differed depending on the used tool (Polphen 0.98 [CI 95% 0.32; 0.99]; Sift 0.98 [CI 95% 0.32; 0.99]; MutationTaster 0.00 [CI 95% 0.00; 0.60]). All pathogenic variants and variants of unknown significance were scored as probably damaging in individuals, demonstrating a high sensitivity. Specificity was very low in one of the three tested programs. However, due to potential genotype-phenotype discordance, bioinformatic prediction tools are currently of limited value in diagnosing pathogenicity of MH-susceptible variants.

Reduced Cl - conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca 2+ - and voltage-activated K + channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK -/- ) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro . Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T 90/10 ) were monitored. Compared to wild type, fast-twitch muscle specimen of BK -/- mice resulted in a significantly decreased T 90/10 in presence of 9-AC. Paxilline significantly shortened T 90/10 of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T 90/10 . The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC)., (Copyright © 2020 Hoppe, Sartorius, Chaiklieng, Wietzorrek, Ruth, Jurkat-Rott, Wearing, Lehmann-Horn and Klingler.)

In myotonia, reduced Cl - conductance of the mutated ClC-1 channels causes hindered muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. Repetitive contraction temporarily decreases myotonia, a phenomena called "warm up." The underlying mechanism for the reduction of hyperexcitability in warm-up is currently unknown. Since potassium displacement is known to reduce excitability in, for example, muscle fatigue, we characterized the role of potassium in native myotonia congenita (MC) muscle. Muscle specimens of ADR mice (an animal model for low gCl - conductance myotonia) were exposed to increasing K + concentrations. To characterize functional effects of potassium ion current, the muscle of ADR mice was exposed to agonists and antagonists of the big conductance Ca 2+ -activated K + channel (BK) and the voltage-gated Kv7 channel. Effects were monitored by functional force and membrane potential measurements. By increasing [K + ] 0 to 5 mM, the warm-up phenomena started earlier and at [K + ] 0 7 mM only weak myotonia was detected. The increase of [K + ] 0 caused a sustained membrane depolarization accompanied with a reduction of myotonic bursts in ADR mice. Retigabine, a Kv7.2-Kv7.5 activator, dose-dependently reduced relaxation deficit of ADR myotonic muscle contraction and promoted the warm-up phenomena. In vitro results of this study suggest that increasing potassium conductivity via activation of voltage-gated potassium channels enhanced the warm-up phenomena, thereby offering a potential therapeutic treatment option for myotonia congenita.

We report a young wheelchair-dependent patient with an unclear proximal myopathy and a heterozygous, de-novo Cav1.1-R1239G mutation suggesting hypokalemic periodic paralysis (HypoPP). Sonography showed a loss of the pennate pattern indicative of an edema, whereas fatty degeneration was excluded. Within 7 days of therapy with spironolactone, potassium and physical therapy, muscle strength almost completely normalized, a normal pennate pattern appeared and the edema was markedly reduced. She learned to walk without aid and to do sports and has continued to do so for 11 years until now. Over the years, we tested serum potassium values, muscle strength, muscle edema and muscular sodium content by 1.5 T, 3 T and 7 T 1 H and 23 Na magnetic resonance imaging. No fatty muscle degeneration developed. Muscular edema-like changes only occurred when she was pregnant and was set to reduced therapy. Because of the ability to do sports again, her mobility was further increased. Our observational study on this single patient may suggest that: (1) muscle imaging and molecular genetics are important diagnostic tools, (2) weakness in periodic paralysis may be reversible, and (3) continued adequate therapy may preserve muscle structure and strength on a longterm, whereas weakness due to fatty degeneration could be considered progressive and irreversible. Although HypoPP is a rare disease, it should be included in differential diagnosis not only if there is paroxysmal weakness, but also in cases of myopathy of unknown origin.

Key Points: During myotonia congenita, reduced chloride (Cl - ) conductance results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction. Repetitive contraction of myotonic muscle decreases or even abolishes myotonic muscle stiffness, a phenomenon called 'warm up'. Pharmacological inhibition of low Cl - channels by anthracene-9-carboxylic acid in muscle from mice and ADR ('arrested development of righting response') muscle from mice showed a relaxation deficit under physiological conditions compared to wild-type muscle. At increased osmolarity up to 400 mosmol L -1 , the relaxation deficit of myotonic muscle almost reached that of control muscle. These effects were mediated by the cation and anion cotransporter, NKCC1, and anti-myotonic effects of hypertonicity were at least partly antagonized by the application of bumetanide., Abstract: Low chloride-conductance myotonia is caused by mutations in the skeletal muscle chloride (Cl - ) channel gene type 1 (CLCN1). Reduced Cl - conductance of the mutated channels results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction. Exercise decreases muscle stiffness, a phenomena called 'warm up'. To gain further insight into the patho-mechanism of impaired muscle stiffness and the warm-up phenomenon, we characterized the effects of increased osmolarity on myotonic function. Functional force and membrane potential measurements were performed on muscle specimens of ADR ('arrested development of righting response') mice (an animal model for low gCl - conductance myotonia) and pharmacologically-induced myotonia. Specimens were exposed to solutions of increasing osmolarity at the same time as force and membrane potentials were monitored. In the second set of experiments, ADR muscle and pharmacologically-induced myotonic muscle were exposed to an antagonist of NKCC1. Upon osmotic stress, ADR muscle was depolarized to a lesser extent than control wild-type muscle. High osmolarity diminished myotonia and facilitated the warm-up phenomenon as depicted by a faster muscle relaxation time (T 90/10 ). Osmotic stress primarily resulted in the activation of the NKCC1. The inhibition of NKCC1 with bumetanide prevented the depolarization and reversed the anti-myotonic effect of high osmolarity. Increased osmolarity decreased signs of myotonia and facilitated the warm-up phenomenon in different in vitro models of myotonia. Activation of NKCC1 activity promotes warm-up and reduces the number of contractions required to achieve normal relaxation kinetics., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

The fascial system builds a three-dimensional continuum of soft, collagen-containing, loose and dense fibrous connective tissue that permeates the body and enables all body systems to operate in an integrated manner. Injuries to the fascial system cause a significant loss of performance in recreational exercise as well as high-performance sports, and could have a potential role in the development and perpetuation of musculoskeletal disorders, including lower back pain. Fascial tissues deserve more detailed attention in the field of sports medicine. A better understanding of their adaptation dynamics to mechanical loading as well as to biochemical conditions promises valuable improvements in terms of injury prevention, athletic performance and sports-related rehabilitation. This consensus statement reflects the state of knowledge regarding the role of fascial tissues in the discipline of sports medicine. It aims to (1) provide an overview of the contemporary state of knowledge regarding the fascial system from the microlevel (molecular and cellular responses) to the macrolevel (mechanical properties), (2) summarise the responses of the fascial system to altered loading (physical exercise), to injury and other physiological challenges including ageing, (3) outline the methods available to study the fascial system, and (4) highlight the contemporary view of interventions that target fascial tissue in sport and exercise medicine. Advancing this field will require a coordinated effort of researchers and clinicians combining mechanobiology, exercise physiology and improved assessment technologies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Periodic paralyses (PP) are recurrent episodes of flaccid limb muscle weakness. Next to autosomal dominant forms, sporadic PP (SPP) cases are known but their genetics are unclear., Methods: In a patient with hypokalemic SPP, we performed exome sequencing to identify a candidate gene. We sequenced this gene in 263 unrelated PP patients without any known causative mutations. Then we performed functional analysis of all variants found and molecular modelling for interpretation., Results: Exome sequencing in the proband yielded three heterozygous variants predicted to be linked to disease. These encoded p.Thr140Met in the Kir2.2 potassium channel, p.Asp229Asn in protein kinase C theta, and p.Thr15943Ile in titin. Since all hitherto known causative PP genes code for ion channels, we studied the Kir2.2-encoding gene, KCNJ12 , for involvement in PP pathogenesis. KCNJ12 screening in 263 PP patients revealed three further variants, each in a single individual and coding for p.Gly419Ser, p.Cys75Tyr, and p.Ile283Val. All four Kir2.2 variants were functionally expressed. Only p.Thr140Met displayed relevant functional alterations, i.e. homo-tetrameric channels produced almost no current, and hetero-tetrameric channels suppressed co-expressed wildtype Kir2.1 in a dominant-negative manner. Molecular modelling showed Kir2.2 p.Thr140Met to reduce movement of potassium ions towards binding sites in the hetero-tetramer pore compatible with a reduced maximal current. MD simulations revealed loss of hydrogen bonding with the p.Thr140Met substitution., Discussion: The electrophysiological findings of p.Thr140Met are similar to those found in thyrotoxic PP caused by Kir2.6 mutations. Also, the homologous Thr140 residue is mutated in Kir2.6. This supports the idea that Kir2.2 p.Thr140Met conveys susceptibility to SPP and should be included in genetic screening.

Hypokalemic periodic paralysis is a skeletal muscle disease characterized by episodic weakness associated with low serum potassium. We compared clinical and biophysical effects of R222W, the first hNa V 1.4 domain I mutation linked to this disease. R222W patients exhibited a higher density of fibers with depolarized resting membrane potentials and produced action potentials that were attenuated compared to controls. Functional characterization of the R222W mutation in heterologous expression included the inactivation deficient IFM/QQQ background to isolate activation. R222W decreased sodium current and slowed activation without affecting probability. Consistent with the phenotype of muscle weakness, R222W shifted fast inactivation to hyperpolarized potentials, promoted more rapid entry, and slowed recovery. R222W increased the extent of slow inactivation and slowed its recovery. A two-compartment skeletal muscle fiber model revealed that defects in fast inactivation sufficiently explain action potential attenuation in patients. Molecular dynamics simulations showed that R222W disrupted electrostatic interactions within the gating pore, supporting the observation that R222W promotes omega current at hyperpolarized potentials. Sodium channel inactivation defects produced by R222W are the primary driver of skeletal muscle fiber action potential attenuation, while hyperpolarization-induced omega current produced by that mutation promotes muscle fiber depolarization.

Gliadin, an immunogenic protein present in wheat, is not fully degraded by humans and after the normal gastric and pancreatic digestion, the immunodominant 33-mer gliadin peptide remains unprocessed. The 33-mer gliadin peptide is found in human faeces and urine, proving not only its proteolytic resistance in vivo but more importantly its transport through the entire human body. Here, we demonstrate that 33-mer supramolecular structures larger than 220 nm induce the overexpression of nuclear factor kappa B (NF-κB) via a specific Toll-like Receptor (TLR) 2 and (TLR) 4 dependent pathway and the secretion of pro-inflammatory cytokines such as IP-10/CXCL10 and TNF-α. Using helium ion microscopy, we elucidated the initial stages of oligomerisation of 33-mer gliadin peptide, showing that rod-like oligomers are nucleation sites for protofilament formation. The relevance of the 33-mer supramolecular structures in the early stages of the disease is paving new perspectives in the understanding of gluten-related disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Topological crystalline insulators represent a new state of matter, in which the electronic transport is governed by mirror-symmetry protected Dirac surface states. Due to the helical spin-polarization of these surface states, the proximity of topological crystalline matter to a nearby superconductor is predicted to induce unconventional superconductivity and, thus, to host Majorana physics. We report on the preparation and characterization of Nb-based superconducting quantum interference devices patterned on top of topological crystalline insulator SnTe thin films. The SnTe films show weak anti-localization, and the weak links of the superconducting quantum interference devices (SQUID) exhibit fully gapped proximity-induced superconductivity. Both properties give a coinciding coherence length of 120 nm. The SQUID oscillations induced by a magnetic field show 2π periodicity, possibly dominated by the bulk conductivity.

Subarachnoid hemorrhage (SAH) remains a challenging neurosurgical disease. The ryanodine receptor type 1 Ca2+ channel (RyR1) plays a crucial role in vasoconstriction and hemostasis. Mutations of the encoding gene, RYR1, are known to cause susceptibility to malignant hyperthermia (MH). Recently, a RYR1 mutation was found to be associated with abnormal bleeding times. Therefore, an assessment of the RYR1 gene might be of high relevance in patients with aneurysmatic SAH. In the presented pilot study, we screened 10 patients suffering from SAH for RYR1 variants and, for the first time in SAH, performed an assessment of pathogenicity of these variants using protein prediction software. Four of the patients showed a RYR1 variant. For three of the variants, p.Glu79Lys, p.Arg885C, p.Glu2635 Val, all three programs predicted pathogenicity. Their prevalence in the general population is very low i.e. under 0.005%. For the fourth variant, p.Pro4501Leu (RS73933023), the results of the prediction programs were discrepant and the prevalence in the general population was high, i.e. almost 0.5%, which is too frequent to be associated with the rare SAH phenotype. Clinical evaluation revealed that no differences concerning neurological outcome, presence of vasospasm, ischemic deficits and mean hospital stay between patients with and without variants were found. However, in our series SAH patients have an increased frequency of rare RYR1 variants. Hence, potentially contributing to the pathogenesis of SAH. Further data is needed to confirm this preliminary result., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life., Methods: Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration., Results: In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels., Discussion: Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.

In this pilot study we tested whether a low dose application of a mild diuretic substance such as eplerenone is beneficial in early stages of Duchenne muscular dystrophy using 23 Na und 1 H imaging, myometry, and clinical testing versus the glucocorticoid gold standard. Two 7-years old patients with DMD were examined on a 3T MRI system. 1 H MRI and 23 Na density-adapted 3-dimensional radial MRI sequences were performed both before and 1, 3 and 6 months after therapy with eplerenone respectively cortisone. We quantified fatty infiltration on T1-weighted images using subcutaneous fat as reference and fat fraction with a two-point DIXON sequence. Muscle oedema was quantified on STIR images and DIXON water maps with background noise as reference. We quantified Na + by a muscular tissue concentration sequence with a 51.3mM Na + with 5% agarose reference tube. A Na + IR-sequence was used for determination of mainly myoplasmic Na + . Correspondingly myometry of muscles and tendons were assessed. Clinical tests (i.e. 4-steps-test) and blood counts (i.e. K + ) were done by a pediatrician. Under eplerenone therapy we detected a reduction of muscular oedema, intracellular-weighted sodium IR signal and muscular sodium concentration. The oedema reduction in the DMD patient receiving eplerenone was more pronounced to the patient with cortisone. Myometric-measured tissue parameters such as muscle stiffness had a more pronounced effect in the child treated with eplerenone after a first increase in muscle stiffness both after eplerenone and cortisone treatment. Clinical abilities during both therapies were mostly constant. Eplerenone might be a possible new therapy option in DMD patients.

In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp studies show that the mutation slows inactivation and accelerates recovery, in line with other paramyotonia variants with destabilized fast inactivation as pathomechanism. Additionally, p.IleI1455 causes a loss-of-function by reduced membrane insertion, right-shift of activation, and slowed kinetics. Molecular dynamics simulations comparing wild type and mutant Nav1.4 showed that threonine substitution hindered D4S4 mobility in response to membrane depolarization, consistent with effects of the mutation on channel inactivation. The fixed myopathy is likely to be associated to gain-of-function leading to sodium accumulation, regional edema, T-tubular swelling and mitochondrial stress. A possible contribution of the loss-of-function features towards myotonia and myopathy is discussed., (Copyright © 2016. Published by Elsevier B.V.)

Magnetostrictive tunnel magnetoresistance (TMR) sensors pose a bright perspective in micro- and nano-scale strain sensing technology. The behavior of TMR sensors under mechanical stress as well as their sensitivity to the applied stress depends on the magnetization configuration of magnetic tunnel junctions (MTJ)s with respect to the stress axis. Here, we propose a configuration resulting in an inverse effect on the tunnel resistance by tensile and compressive stresses. Numerical simulations, based on a modified Stoner-Wohlfarth (SW) model, are performed in order to understand the magnetization reversal of the sense layer and to find out the optimum bias magnetic field required for high strain sensitivity. At a bias field of -3.2 kA/m under a 0.2 × 10 - 3 strain, gauge factors of 2294 and -311 are calculated under tensile and compressive stresses, respectively. Modeling results are investigated experimentally on a round junction with a diameter of 30 ± 0.2 μ m using a four-point bending apparatus. The measured field and strain loops exhibit nearly the same trends as the calculated ones. Also, the gauge factors are in the same range. The junction exhibits gauge factors of 2150 ± 30 and -260 for tensile and compressive stresses, respectively, under a -3.2 kA/m bias magnetic field. The agreement of the experimental and modeling results approves the proposed configuration for high sensitivity and ability to detect both tensile and compressive stresses by a single TMR sensor., Competing Interests: The authors declare no conflict of interest.

Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na + channel Na V 1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant Na V 1.1 channels, which were transiently expressed in human tsA201 cells together with β 1 and β 2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.