Fiber Action Potentials Research Articles

Hyperalgesia by low doses of the local anesthetic lidocaine involves cannabinoid signaling: An fMRI study in mice

Lidocaine is clinically widely used as a local anesthetic inhibiting propagation of action potentials in peripheral nerve fibers. Correspondingly, the functional magnetic resonance imaging (fMRI) response in mouse brain to peripheral noxious input is largely suppressed by local lidocaine administered at doses used in a clinical setting. We observed, however, that local administration of lidocaine at doses 100× lower than that used clinically led to a significantly increased sensitivity of mice to noxious forepaw stimulation as revealed by fMRI. This hyperalgesic response could be confirmed by behavioral readouts using the von Frey filament test. The increased sensitivity was found to involve a type 1 cannabinoid (CB1) receptor-dependent pathway as global CB1 knockout mice, as well as wild-type mice pretreated systemically with the CB1 receptor blocker rimonabant, did not display any hyperalgesic effects after low-dose lidocaine. Additional experiments with nociceptor-specific CB1 receptor knockout mice indicated an involvement of the CB1 receptors located on the nociceptors. We conclude that low concentrations of lidocaine leads to a sensitization of the nociceptors through a CB1 receptor-dependent process. This lidocaine-induced sensitization might contribute to postoperative hyperalgesia.

Effect of membrane properties on skeletal muscle fiber excitability: a sensitivity analysis

In this study, the sensitivity of skeletal muscle fiber excitability to changes in temperature and a range of geometrical, electrical and ionic membrane properties was examined using model simulation. A mathematical model of the propagating muscle fiber action potential (AP) was used to simulate muscle fiber APs while changing individual muscle fiber parameters in isolation to examine how they affect muscle fiber AP amplitude, shape and conduction velocity (CV). The behavior of the model was verified by comparison with previously reported experimental data from both in vivo studies conducted at physiological temperatures and in vitro and in silico studies conducted at lower temperatures. The simulation results presented demonstrate the sensitivity of AP amplitude, shape and CV and, therefore, muscle fiber excitability to small changes in a wide range of different muscle fiber parameters. Furthermore, they demonstrate the potential of computational modeling as a tool for investigating the underlying mechanisms of complex phenomena such as those which govern skeletal muscle excitation.

GABAA receptors increase excitability and conduction velocity of cerebellar parallel fiber axons

In the adult mammalian brain, GABA(A) receptors (GABA(A)Rs) are responsible for the predominant forms of synaptic inhibition, but these receptors can excite neurons when the chloride equilibrium potential (E(Cl)) is depolarized. In many mature neurons, GABA(A)Rs are found on presynaptic terminals where they exert depolarizing effects. To understand whether excitatory GABA action affects axonal function, we used transverse cerebellar slices to measure the effects of photolysis of caged GABA on the initiation and propagation of compound parallel fiber (PF) action potentials (APs). Photolysis of caged GABA increased the amplitude and conduction velocity of PF APs; GABA reuptake blockers and a positive modulator of GABA(A)Rs enhanced these effects. In contrast, a modulator selective for δ-subunit-containing GABA(A)Rs did not enhance these effects and responsiveness remained in δ(-/-) mice, arguing that δ-subunit-containing GABA(A)Rs are not required. Synaptically released GABA also increased PF excitability, indicating that the mechanism is engaged by physiological signals. A Hodgkin-Huxley-style compartmental model of the PF axon and granule cell body was constructed, and this model recapitulated the GABA-dependent decrease in AP threshold and the increase in conduction velocity, features that were sensitive to E(Cl) and to the voltage dependence of sodium channel inactivation. The model also predicts that axonal GABA(A)Rs could affect orthodromic spike initiation. We conclude that GABA acting on cerebellar PFs facilitates both spike generation and propagation, allowing axons of granule cells to passively integrate signals from inhibitory interneurons and influence information flow in the input layer to the cerebellar cortex.

Electrophysiological effects of hydrogen sulfide on human atrial fibers.

It has been reported that endogenous or exogenous hydrogen sulfide (H(2)S) exerts physiological effects in the vertebrate cardiovascular system. We have also demonstrated that H(2)S acts as an important regulator of electrophysiological properties in guinea pig papillary muscles and on pacemaker cells in sinoatrial nodes of rabbits. This study was to observe the electrophysiological effects of H(2)S on human atrial fibers. Human atrial samples were collected during cardiac surgery. Parameters of action potential in human atrial specialized fibers were recorded using a standard intracellular microelectrode technique. NaHS (H(2)S donor) (50, 100 and 200 µmol/L) decreased the amplitude of action potential (APA), maximal rate of depolarization (V(max)), velocity of diastolic (phase 4) depolarization (VDD) and rate of pacemaker firing (RPF), and shortened the duration of 90% repolarization (APD(90)) in a concentration-dependent manner. ATP-sensitive K(+) (K(ATP)) channel blocker glibenclamide (Gli, 20 µmol/L) partially blocked the effects of NaHS (100 µmol/L) on human atrial fiber cells. The L-type Ca(2+) channel agonist Bay K8644 (0.5 µmol/L) also partially blocked the effects of NaHS (100 µmol/L). An inhibitor of cystathionine γ-lyase (CSE), DL-propargylglycine (PPG, 200 µmol/L), increased APA, V(max), VDD and RPF, and prolonged APD(90). H(2)S exerts a negative chronotropic action and accelerates the repolarization of human atrial specialized fibers, possibly as a result of increases in potassium efflux through the opening of K(ATP) channels and a concomitant decrease in calcium influx. Endogenous H(2)S may be generated by CSE and act as an important regulator of electrophysiological properties in human atrial fibers.

Effects of changes in the shape of the intracellular action potential on the peak-to-peak ratio of single muscle fibre potentials

In situ recording of the intracellular action potential (IAP) of human muscle fibres is not yet feasible, and consequently, knowledge about certain IAP characteristics of these IAPs is still limited. The ratio between the amplitudes of the second and first phases (the so-called peak-to-peak ratio, PPR) of a single fibre action potential (SFAP) is known to be closely related to the IAP profile. The PPR of experimentally recorded SFAPs has been found to be largely independent of changes in the fibre-to-electrode (radial) distance. The main goal of this paper is to analyze the effect of changes in different aspects of the IAP spike on the relationship between PPR and radial distance. Based on this analysis, we hypothesize about the characteristics of IAPs obtained experimentally. It was found that the sensitivity of the SFAP PPR to changes in radial distance is essentially governed by the duration of the IAP spike. Assuming that, for mammals, the duration of the IAP rising phase lies within the range 0.2–0.4 ms, we tentatively suggest that the duration of the IAP spike should be over approximately 0.75 ms, with the shape of the spike strongly asymmetric. These IAP characteristics broadly coincide with those observed in mammal IAPs.

The metabolic efficiency of myelinated vs unmyelinated axons

Understanding the metabolic efficiency of axons is of critical importance in neuroscience: such as interpreting fMRI and other imaging data, understanding the impact of metabolic conditions and anoxia/hypoxia on the CNS, and finally because current data suggests that metabolic cost places severe limits on neuronal activity[1]. Surprisingly, the metabolic cost of action potential (AP) in myelinated nerve fibers has not been directly estimated, unlike the cost of unmyelinated axons[1,2]. We calculated the metabolic cost of saltatory APs using detailed stochastic, biophysical models of a human myelinated peripheral axon and compared it to APs in unmyelinated axons of equal diameter. We modelled both axon types using the Modigliani stochastic simulator[3,4]. For the human myelinated axon, we modelled a heterogeneous multi-compartment cable of 3 cm length. Each Node of Ranvier is surrounded by paranodal regions and separated by a myelinated internode. Ion channel kinetics and axonal geometry were taken from published physiological and anatomical data[5]. Parameters for the unmyelinated axon were taken from[6]. We measured the metabolic cost of APs as the amount of ATP needed for Na-K-pumps to restore ion concentrations after an AP [1,2,8]. This allowed us to systematically investigate how metabolic cost depends on factors such as axonal geometry and ion channel densities. E.g comparing myelinated and unmyelinated axons with the same axon diameter of 1µm (fibre diameter including myelin sheath was 3.7 µm) we find the following: single APs at a myelinated axon’s Node of Ranvier have a metabolic cost of 3.5 pmol/cm² ATP per unit membrane area. This is approximately 7 times the amount per AP in hippocampal mossy fibre (0.53 pmol/cm2;[2]) but less than leaky squid axons (5 pmol/cm2). However, Node of Ranvier cover only 0.33% in our myelinated axon. The internodal regions contain hardly any Na+ channels, but a low density of K+ channels (3 µm-2) along internodes, and higher densities at the paranode (80 µm-2). We estimate overall energy consumption based on Na currents at the Node and K along a segment comprising half the internodal fibre on both sides of a node. This yields an AP cost per myelinated axon segment of 0.05 pmol/cm2 ATP per unit membrane area. Thus, per unit length the myelinated axon is 70 times metabolically cheaper than mossy fibers. The added bulk of the myelin allows 13 unmyelinated axons of same diameter to fit in the volume of one myelinated fibre, suggesting that the ratio of energy demand over wiring density is 5 times higher for myelinated fibers vs unmyelinated axons. Our findings are novel, as the costs of saltatory APs were not calculated from the bottom-up before. They are important, as it was generally assumed that myelinated axons evolved mainly for speed of propagation[7] at the cost of achievable wiring density[6,8], but energy may be as important: in cortical grey matter unmyelinated axons operate close to the noise limits to wiring miniaturisation[6], yet still contains myelinated axons[9]. We can explain this with a four-way trade-off between time delay, metabolic cost, volume constraints and noise limits to axonal anatomy.

Activity-dependent changes in impulse conduction of single human motor axons: A stimulated single fiber electromyography study

Objective The aim of this study is to develop a novel method to assess activity-dependent hyperpolarization in human single motor axons at a constant stimulus frequency by using intra-muscular axonal stimulating single fiber electromyography (s-SFEMG). Methods We performed s-SFEMG in the extensor digitorum communis (EDC) muscle of 10 normal subjects, and measured changes in latencies for single muscle fiber action potentials (MAPs) during 500 stimuli delivered at 5, 10 and 20 Hz. The data were analyzed with a repeated measurement analysis, and multiple comparisons were performed. Results A total of 585 MAPs were examined at 5 Hz ( n = 190), 10 Hz ( n = 210), and 20 Hz ( n = 185) steady stimulation. There was a progressive linear prolongation of latencies, as the stimulus rate increased ( F = 95.6, p < 0.001); the least square means (SEM) of latency change were 100.7 (0.28)% at 5 Hz, 102.3 (0.27)% at 10 Hz and 105.3 (0.28)% at 20 Hz. There were statistically significant differences between frequencies by Tukey–Kramer’s method. Despite the significant latency prolongation, no activity-dependent conduction block developed. A 20 Hz electric stimulation to intramuscular axons was well-tolerated in all the subjects. Conclusions Tetanic stimulation at a constant rate results in significant latency increase in single human motor axons, the extent of which depends on the stimulus frequency. The findings imply that physiological discharge rates will activate the Na +/K + pump and thereby produce axonal hyperpolarization in single motor axons. Significance This technique may detect activity-dependent conduction block if the safety margin of impulse transmission is significantly reduced by demyelination or increased branching due to collateral sprouting in a variety of neuromuscular disorders.

Stimulus level effects on neural excitation and eCAP amplitude

The common assumption that the electrically evoked compound action potential (eCAP) has a linear relationship with the number of excited nerve fibres is derived from the acoustical unitary response concept. This study tests the validity of this hypothesis for electrical stimulation. Five guinea pigs were implanted with the tip of a human HiFocus electrode. eCAPs were measured with the forward masking paradigm, using anodic- and cathodic-leading biphasic current pulses and the inter-pulse interval was varied. Masker and probe amplitudes were varied either individually or simultaneously. Surprisingly, at high levels decreasing eCAP amplitudes were measured with increasing stimulus current. In search for an explanation, the experimental conditions were implemented in our 3D computational model of the implanted guinea pig cochlea to perform a functional comparison. In the final experiment, with fixed inter-pulse interval (IPI) and anodic-leading pulses, increasing stimulus currents showed growing numbers of excited nerve fibres and decreasing eCAP amplitudes at high levels, again. While simulating the relative contribution of single fibres to the overall eCAP, an explanation for this could be found in a waveform change in the modelled single fibre action potentials at high levels. We conclude that highly stimulated nerve fibres have another contribution to the eCAP response than lower stimulated fibres, which leads to a reduction of the eCAP amplitude at high levels.

Simultaneous In Vivo Assessment of Contractile Properties and Electromyographic (EMG) Activities in a Knock-Out Mouse Model of Myotonic Dystrophy

Myotonic dystrophy is a dominantly inherited disorder characterized by myotonia and delayed muscle relaxation due to repetitive action potentials in the muscle fibers (hyperexcitability). In this study, a knockout mouse model for the muscle blind proteins (Mbnl1ΔE3∕ΔE3), a valid model for myotonic dystrophy, was assessed, using an in vivo force assessment device, used in conjunction with EMG recording. The aim of the study was to verify whether the muscle force assessment device we developed was capable to sensitively detect the typical characteristics of myotonic muscle. To date, two wild-type and four myotonic female mice have been assessed. After anesthetic induction by isoflurane, the mice were positioned in the apparatus. Hindlimb muscles were stimulated noninvasively by electrodes placed on the muscle of the leg being stimulated. After establishing optimal muscle length, muscle force was assessed after single pulse stimulation at supramaximal voltage followed by double, triple and quadruple pulses. Both legs from each animal were tested and included in the analyses. Muscle force characteristics (peak force, half relaxation time, and area under the force curve (AUC)) and EMG data were recorded and analyzed. Peak forces generated in the myotonic mice were significantly lower (P&lt;0.02), half relaxation times significantly prolonged (P&lt;0.02), and AUCs significantly increased (P&lt;0.002) as compared with the wild-type mice. The recorded EMGs showed characteristic after depolarizations for the myotonic mice. In conclusion, the muscle force assessment device we developed here was able to detect the typical myotonic features in both reproducible and sensitive ways. This device can be considered as a valid tool for future projects concentrating on the in vivo effects of anesthetic agents or therapies on mouse models of myotonia.

Neuromuscular adjustments that constrain submaximal EMG amplitude at task failure of sustained isometric contractions

The amplitude of the surface EMG does not reach the level achieved during a maximal voluntary contraction force at the end of a sustained, submaximal contraction, despite near-maximal levels of voluntary effort. The depression of EMG amplitude may be explained by several neural and muscular adjustments during fatiguing contractions, including decreased net neural drive to the muscle, changes in the shape of the motor unit action potentials, and EMG amplitude cancellation. The changes in these parameters for the entire motor unit pool, however, cannot be measured experimentally. The present study used a computational model to simulate the adjustments during sustained isometric contractions and thereby determine the relative importance of these factors in explaining the submaximal levels of EMG amplitude at task failure. The simulation results indicated that the amount of amplitude cancellation in the simulated EMG (∼ 40%) exhibited a negligible change during the fatiguing contractions. Instead, the main determinant of the submaximal EMG amplitude at task failure was a decrease in muscle activation (number of muscle fiber action potentials), due to a reduction in the net synaptic input to motor neurons, with a lesser contribution from changes in the shape of the motor unit action potentials. Despite the association between the submaximal EMG amplitude and reduced muscle activation, the deficit in EMG amplitude at task failure was not consistently associated with the decrease in neural drive (number of motor unit action potentials) to the muscle. This indicates that the EMG amplitude cannot be used as an index of neural drive.

Estimating the duration of intracellular action potentials in muscle fibres from single-fibre extracellular potentials

In situ recording of the intracellular action potential (IAP) of human muscle fibres is not yet possible, and consequently, knowledge concerning certain IAP characteristics is still limited. According to the core-conductor theory, close to a fibre, a single fibre action potential (SFAP) can be assumed to be proportional to the IAP second derivative. Thus, we might expect to be able to derive some characteristics of the IAP, such as the duration of its spike, from the SFAP waveform. However, SFAP properties not only depend on the IAP shape but also on the fibre-to-electrode (radial) distance and other physiological properties of the fibre. In this paper we, first, propose an SFAP parameter (the negative phase duration, NPD) appropriate for estimating the IAP spike duration and, second, show that this parameter is largely independent of changes in radial distance and muscle fibre propagation velocity. Estimation of the IAP spike duration from a direct measurement taken from the SFAP waveform provides a possible way to enhance the accuracy of SFAP models. Because IAP spike duration is known to be sensitive to the effects of fatigue and calcium accumulation, the proposed SFAP parameter, the NPD, has potential value in electrodiagnosis and as an indicator of IAP profile changes due to peripheral fatigue.

Open- and closed-state fast inactivation in sodium channels

The role of sodium channel closed-state fast inactivation in membrane excitability is not well understood. We compared open- and closed-state fast inactivation, and the gating charge immobilized during these transitions, in skeletal muscle channel hNaV1.4. A significant fraction of total charge movement and its immobilization occurred in the absence of channel opening. Simulated action potentials in skeletal muscle fibers were attenuated when pre-conditioned by sub-threshold depolarization. Anthopleurin A, a site-3 toxin that inhibits gating charge associated with the movement of DIVS4, was used to assess the role of this voltage sensor in closed-state fast inactivation. Anthopleurin elicited opposing effects on the gating mode, kinetics and charge immobilized during open- versus closed-state fast inactivation. This same toxin produced identical effects on recovery of channel availability and remobilization of gating charge, irrespective of route of entry into fast inactivation. Our findings suggest that depolarization promoting entry into fast inactivation from open versus closed states provides access to the IFMT receptor via different rate-limiting conformational translocations of DIVS4.

Experimental and modelling investigation of surface EMG spike analysis

A pattern classification method based on five measures extracted from the surface electromyographic (sEMG) signal is used to provide a unique characterization of the interference pattern for different motor unit behaviours. This study investigated the sensitivity of the five sEMG measures during the force gradation process. Tissue and electrode filtering effects were further evaluated using a sEMG model. Subjects ( N = 8) performed isometric elbow flexion contractions from 0 to 100% MVC. The sEMG signals from the biceps brachii were recorded simultaneously with force. The basic building block of the sEMG model was the detection of single fibre action potentials (SFAPs) through a homogeneous, equivalent isotropic, infinite volume conduction medium. The SFAPs were summed to generate single motor unit action potentials. The physiologic properties from a well-known muscle model and motor unit recruitment and firing rate schemes were combined to generate synthetic sEMG signals. The following pattern classification measures were calculated: mean spike amplitude, mean spike frequency, mean spike slope, mean spike duration, and the mean number of peaks per spike. Root-mean-square amplitude and mean power frequency were also calculated. Taken together, the experimental data and modelling analysis showed that below 50% MVC, the pattern classification measures were more sensitive to changes in force than traditional time and frequency measures. However, there are additional limitations associated with electrode distance from the source that must be explored further. Future experimental work should ensure that the inter-electrode distance is no greater than 1 cm to mitigate the effects of tissue filtering.

A comparison of three models for the principal pitch of vibrato tones.

Vibrato is the more ubiquitous manifestation of a non‐stationary tone that can evoke a single overall pitch, called principal pitch. Some recent results using non‐symmetrical vibrato tones suggest that the perceived pitch could be governed by some stability‐sensitive mechanism. A recently proposed one‐parameter model based on time‐frequency reassignment was able to predict previously reported results. [B. Mesz and M. C. Eguia, Ann. N.Y. Acad. Sci. 1169, 126–130 (2009)]. The proposed model has some biological plausibility since the local computations at each auditory channel needed for pitch estimation are based on phase information, so they could be implemented in principle using the time interval between action potentials in the auditory nerve fibers. In order to test this new model against two previously formulated models of vibrato pitch [H. Gockel et al., J. Acoust. Soc. Am. 109, 701–712 (2001)] and pitch saliency [Cariani. Proc. VIII Intl. Conf. Music Perception & Cognition, Evanston, IL (2004)], a p...

Simulation of the Interaction Between Muscle Fiber Conduction Velocity and Instantaneous Firing Rate

In this study, the relationships between the early and late afterpotentials and velocity and amplitude recovery functions (VRF and ARF) in skeletal muscle were examined using model simulation. A mathematical model of the muscle fiber action potential, that incorporated a tubular slow potassium conductance, was developed and used to simulate muscle fiber action potentials at a range of interpulse intervals. The slow potassium conductance produced an afterhyperpolarization which resulted in supernormal action potential conduction velocity and amplitude for interpulse intervals>7 ms. Increasing the number of conditioning stimuli caused a further increase in conduction velocity and amplitude, and an additional phase of supernormality, with a peak at approximately 100 ms. Positive correlations between instantaneous firing rate and both conduction velocity and amplitude were also observed during simulation of repetitive stimulation of the muscle fiber. The relationships were eliminated when the slow potassium conductance channel was removed from the model. The results suggest that an afterhyperpolarization, possibly due to a slow tubular potassium conductance, could cause the VRF and ARF observed in muscle. They additionally suggest that the positive correlations between instantaneous firing rate, conduction velocity, and amplitude are directly related to the VRF and ARF.

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

BackgroundPlatinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study.MethodsTwenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle.ResultsAbnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6).ConclusionsAbnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post-treatment. Objective EMG assessment of motor nerve excitability could compliment patient-reported symptomatic endpoints of acute oxaliplatin-induced neurotoxicity in future studies.

Analysis of the relationship between the rise-time and the amplitude of single-fibre potentials in human muscles

Using the core-conductor theory, a single fibre action potential (SFAP) can be expressed as the convolution of a biolectrical source and a weight function. In the Dimitrov–Dimitrova (D–D) SFAP convolutional model, the first temporal derivative of the intracellular action potential (IAP) is used as the source. The present work evaluates the relationship between the SFAP peak-to-peak amplitude ( V pp) and peak-to-peak interval (rise-time, RT) at different fibre-to-electrode distances using simulated signals obtained by the D–D model as well as real recordings. With a single fibre electrode, we recorded 63 sets of consecutive SFAPs from the m. tibialis anterior of four normal subjects. The needle was intentionally moved whilst recording each SFAP set. We used the observed changes in RT and V pp within each SFAP set as a point of reference with which to evaluate how closely the relationship between RT and V pp provided by the D–D model reflects real data. We found that half of the recorded SFAP sets had rise-times higher than those generated by the D–D model. We also showed the influence of the IAP spatial length on the sensitivity of RT and V pp with radial distance. The study reveals some inaccuracies in simulated SFAPs whose origin might be related to the assumptions made in the core-conductor theory.

EXPERIENCE WITH COMBINATION THERAPY WITH AMELOTEX®AND COMPLIGAM B®IN PATIENTS WITH MANIFESTATIONS OF SYNOVITIS IN THE PRESENCE OF KNEE OSTEOARTHROSI

Objective: to study the efficiency of combination therapy with Amelotex®and Compligam B®in patients with osteoarthrosis with the signs of knee joint synovitis. Subjects and methods. The efficiency of combination therapy with Amelotex®and Compligam B®was studied in 40 patients. During a Phase I trial, Amelotex®was administered in a dose of 1,5 ml (15 mg) as periarticular blocks, by alternating intramuscular Compligam B®in a dose of 2,0 ml. In a Phase II trial, the intramuscular injection of these drugs was alternated. Electroneuromyography (ENMG) was performed and the levels of proinflammatory cytokine interleukin-1β (IL-1β) and IL-8 were determined over time (before and on 10 and 20 days of therapy). Quality of life was assessed by a 100-mm visual analog scale before and after therapy. Results. The early sign of therapeutic efficiency was a significant reduction in the magnitude of knee joint pain, which was observed just after completion of the Phase I trial. Diminished limb cacesthesia and crepitation were most important after the end of Phase II. Synovitis cases significantly reduced in number. Recovered peripheral nerve function was objectively supported by an increase in ENMG parameters, such as the amplitude of M responses in the peroneal nerve and sensor fiber action potential in the sural nerve. After termination of the therapy, IL-1β levels became significantly lower. Quality of life improved, as shown by VAS scores. Conclusion. The findings suggest that combination therapy with Amelotex® and Compligam B® shows clinical effectivene

Influence of fatigue on the simulated relation between the amplitude of the surface electromyogram and muscle force

A linear relation between surface electromyogram (EMG) amplitude and muscle force is often assumed and used to estimate the contributions of selected muscles to various tasks. In the presence of muscle fatigue, however, changes in the properties of muscle fibre action potentials and motor unit twitch forces can alter the relation between surface EMG amplitude and force. A novel integrative model of motor neuron control and the generation of muscle fibre action potentials was used to simulate surface EMG signals and muscle force during three fatigue protocols. The change in the simulated relation between surface EMG amplitude and force depended on both the level of fatigue and the details of the fatiguing contraction. In general, surface EMG amplitude overestimated muscle force when fatigue was present. For example, surface EMG amplitudes corresponding to 60 per cent of the amplitude obtained at maximal force without fatigue corresponded to forces in the range 10-40% of the maximal force across three representative fatigue protocols. The results indicate that the surface EMG amplitude cannot be used to predict either the level of muscle activation or the magnitude of muscle force when the muscle exhibits any fatigue.

ATP-induced morphological changes in supporting cells of the developing cochlea

The developing cochlea of mammals contains a large group of columnar-shaped cells, which together form a structure known as Kölliker's organ. Prior to the onset of hearing, these inner supporting cells periodically release adenosine 5'-triphosphate (ATP), which activates purinergic receptors in surrounding supporting cells, inner hair cells and the dendrites of primary auditory neurons. Recent studies indicate that purinergic signaling between inner supporting cells and inner hair cells initiates bursts of action potentials in auditory nerve fibers before the onset of hearing. ATP also induces prominent effects in inner supporting cells, including an increase in membrane conductance, a rise in intracellular Ca(2+), and dramatic changes in cell shape, although the importance of ATP signaling in non-sensory cells of the developing cochlea remains unknown. Here, we review current knowledge pertaining to purinergic signaling in supporting cells of Kölliker's organ and focus on the mechanisms by which ATP induces changes in their morphology. We show that these changes in cell shape are preceded by increases in cytoplasmic Ca(2+), and provide new evidence indicating that elevation of intracellular Ca(2+) and IP(3) are sufficient to initiate shape changes. In addition, we discuss the possibility that these ATP-mediated morphological changes reflect crenation following the activation of Ca(2+)-activated Cl(-) channels, and speculate about the possible functions of these changes in cell morphology for maturation of the cochlea.