Normal Action Potentials Research Articles

Lercanidipine and T-type calcium current.

Lercanidipine is a calcium antagonist with no cardiodepressant activity, long lasting antihypertensive action and reno-protective effect. Our previous data demonstrated that lercanidipine blocks L-type calcium channels (CaL). However, no data are available concerning its effects on T-type calcium channels (CaT). The aim of this study was to evaluate the effect on both CaL and CaT and the selectivity ratio of R-lercanidipine, S-lercanidipine and RS-lercanidipine. A comparison with other dihydropyridines (amlodipine and lacidipine) and the CaT blocker mibefradil was also performed. In patch-clamped guinea-pig ventricular myocytes, a voltage protocol was applied mimicking a normal action potential: HP of -90 mV, 200 ms depolarizing steps to -50/+50 mV. Lercanidipine was tested at concentrations (1-10 µM) able to block ≈ 50% CaL evoked from a HP in the range of -50 to -30 mV. Cells were superfused with a Na+ and K+ free solution pre-warmed to 35°C to abolish overlapping currents. Using the described voltage protocol, all dihydropyridines at 1 µM blocked less than 20% CaL, with the exception of lacidipine, that reduced CaL >60% of control. All calcium channel blockers (CCBs) blocked a significant amount of CaT, varying from 28% (mibefradil) to 4.3% (amlodipine). Based on the ratio between CaT and CaL blockade in each cell (T/L), mibefradil, as expected, showed the highest T affinity (T/L=1.3). Lercanidipine, either racemate or enantiomers, showed a noticeable T selectivity, T/L varying from 1.05 (S-lercanidipine) to 1.15 (R-lercanidipine). All CCBs examined in this study showed both T- and L-channel blocking activities and can be differentiated based on their relative affinity. Among tested dihydropyridines, lercanidipine showed the highest T/L selectivity.

S57. The divergence phenomenon of CMAP/SNAP in early stage of amyotrophic lateral sclerosis

To evaluate the relationship of sensory fibers and functional status of motor fibers in patients with amyotrophic lateral sclerosis(ALS) through electrophysiological approach, and analyse the results. We retrospectively reviewed 64 case with early stage of upper limb-onset ALS admitted in our hospital from January 2010 to December 2015. Patients with ALS were graded as normal compound muscle action potential (CMAP) (23 cases) and abnormal CMAP group (41 cases) according to the CMAP of median nerve 39 healthy volunteers were included as control. Median and ulnar nerves electrophysiological study were performed using the Keypoint.net (Medoc Ltd) electromyogram device. The sensory nerve action potential (SNAP) amplitudes of Median and ulnar nerves were raised (28.80 ± 15.54) μV vs (21.06 ± 7.41) μV, t = 2.91, P < 0.01, (12.44 ± 4.64) μV vs (10.46 ± 2.77) μV, t = 2.41, P = 0.01 in ALS group, compared with control group. But the sensory conduction velocities (SCVs) had no difference. SNAP amplitudes of median nerve were raised (33.13 ± 13.33) μV vs (21.06 ± 7.41) μV, F = 6.39, P < 0.01 in the normal CMAP group, compared with the control group, but the SNAP amplitudes of ulnar nerve had no difference: Compared with the control group, the SNAP amplitudes of median nerve had no difference, but the SNAP amplitudes of ulnar nerve were raised (12.92 ± 5.01) μV vs (10.46 ± 2.78) μV, F = 3.71, P < 0.05 in abnormal CMAP group. ALS patients with onset of upper limb in the early stage may have increased SNAP in median and ulnar nerve,and show CMAP/SNAP separated phenomenon.

An infantile alantoaxial dislocation with patent foramen ovale managed with titanium cabling and allogenic bone grafts.

Atlantoaxial dislocation is a disorder that is characterized with loss of stability of the atlas and axis (C1-C2) with consequential loss of usual articulation. Although this condition is very common, no one has reported a case as young as our patients. We present a 7-month infant with bilateral paralysis of the lower limbs for four (4) months with no history of trauma. Computer tomographic (CT-scan) imaging revealed alantoaxial dislocation with severe cervical spinal cord compression. The odontoid process is displaced outwardly with no bone destruction. Doppler echocardiogram done revealed patent foramen ovale. Thorough physical examination as well as radiological evaluation revealed no feather malformations. Electrophysio - logical studies reveal normal compound muscle action potentials (CMAP) and sensory nerve action potentials (SNAPs) in all the limbs. Electromyography (EMG) also revealed normal nerves in the limbs and the trunk. We attained a stable fusion and anatomical reduction using a posterior titanium wire and an iliac bone graft harvested from his mother. This is the youngest patient reported in literature. Infantile alantoaxial dislocation should be managed at early stage to prevent long-term neurologic disorders.

Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review

PurposeTo describe the clinical and genetic features of a Chinese progressive myoclonus epilepsy (PME) patient related with SCARB2 mutation without renal impairment and review 27 SCARB2-related PME patients from 11 countries. MethodsThe patient was a 27-year-old man with progressive action myoclonus, ataxia, epilepsy, dysarthria and absence of cognitive deterioration. Renal functional test was normal. Electroencephalography (EEG) showed progressively slowed background activity and sporadic generalized spike-and-wave discharges. Electromyography (EMG) showed slowed motor and sensory nerve conduction velocities and distal motor latency delay accompanied by normal compound motor action potential (CMAP) and amplitudes of sensory nerve action potential (SNAP). The amplitude of cortical components of brainstem auditory-evoked potential (BAEP) was normal with slightly prolonged latencies. Generalized atrophy, ventricle enlargement and white matter degeneration was observed in brain magnetic resonance imaging (MRI). Open muscle biopsy and genetic analysis were performed. Two hundred healthy individuals were set for control. Quantitative real time PCR (qPCR), western blotting and immunofluorescence were carried out to evaluate the fate of the SCARB2 mRNA and lysosomal-membrane type 2 (LIMP2) protein level. ResultsOne homozygous mutation in SCARB2 gene (c.1187 + 5G > T) was identified in the patient. Each of his parents carried a heterozygous variant. This mutation was not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. qPCR revealed a significantly lower level of SCARB2 mRNA in peripheral blood cell of the proband compared with his parents and healthy control individuals. Muscle biopsy showed mild variation in fiber size. Western blotting and immunofluorescence detected an extremely weak signal of LIMP2 protein from skeletal muscle of the proband. ConclusionIn this study, we identified a SCARB2-related PME patient with normal renal function and a novel homozygous splicing mutation. SCARB2 gene should be analyzed in patients with progressive action myoclonus, epilepsy, peripheral neuropathy, without cognitive deterioration or renal failure.

L-Type Calcium Channel Gating Modifiers as a New Class of Antiarrhythmic Drugs

Pharmacological treatment of cardiac arrhythmias includes the use of Ca2+ channel blockers (Class IV antiarrhythmics), that while suppressing arrhythmias, also block peak ICa,L, compromising EC coupling and contractility. To circumvent these limitations, we are studying and testing the properties of L-type Ca channel gating modifiers, rather than blockers, to selectively reduce the non-inactivating component (late ICa,L), leaving peak ICa,L minimally affected, thus preserving cardiac contractility. This strategy is based on our discovery that the selective reduction of late ICa,L potently suppress early afterdepolarizations (EADs) of the cardiac action potential (AP), recognized cellular triggers of arrhythmias (Madhvani et al., 2015). We previously reported that roscovitine, a purine analog known to reduce late ICa,L, potently suppressed H2O2-mediated EADs in rabbit ventricular myocytes. We are evaluating the robustness of this pharmacological intervention in a new model of EAD favoring condition using 600μM H2O2+1-2μM Isoproterenol. H2O2 alone (n=7) caused EADs in 83.2±5.39% APs and 85.7±7.83% APs in presence of H2O2+Isoproterenol (n=5); the perfusion of roscovitine (20 µM) efficiently suppressed EAD occurrence restoring normal AP duration in all myocytes tested. This antiarrhythmic effect was achieved without significantly perturbing calcium transients and cell shortening, indicating maintenance of normal EC coupling. We also tested roscovitine ability to suppress EAD-triggered ventricular fibrillation (VF) in isolated-perfused aged rat and rabbit hearts. We found that roscovitine suppressed VF induced by H2O2 (8/8 rat hearts, average time: 13±2.8 min) and H2O2+Isoproterenol (4/4 rabbit hearts, average time: 21±7 min), restoring sinus rhythm. Roscovitine had no significant effect on the rate-pressure product (RPP) as a measure of myocardial workload in isolated rat hearts (n=5). We propose that these findings establish roscovitine as a pilot compound to drive the development of a new class of antiarrhythmics based on Ca channel gating modification.

Selective inhibition of physiological late Na+ current stabilizes ventricular repolarization.

The physiological role of cardiac late Na+ current ( INa) has not been well described. In this study, we tested the hypothesis that selective inhibition of physiological late INa abbreviates the normal action potential (AP) duration (APD) and counteracts the prolongation of APD and arrhythmic activities caused by inhibition of the delayed rectifier K+ current ( IKr). The effects of GS-458967 (GS967) on the physiological late INa and APs in rabbit isolated ventricular myocytes and on the monophasic APs and arrhythmias in rabbit isolated perfused hearts were determined. In ventricular myocytes, GS967 and, for comparison, tetrodotoxin concentration dependently decreased the physiological late INa with IC50 values of 0.5 and 1.9 µM, respectively, and significantly shortened the APD measured at 90% repolarization (APD90). A strong correlation between inhibition of the physiological late INa and shortening of APD by GS967 or tetrodotoxin ( R2 of 0.96 and 0.97, respectively) was observed. Pretreatment of isolated myocytes or hearts with GS967 (1 µM) significantly shortened APD90 and monophasic APD90 and prevented the prolongation and associated arrhythmias caused by the IKr inhibitor E4031 (1 µM). In conclusion, selective inhibition of physiological late INa shortens the APD, stabilizes ventricular repolarization, and decreases the proarrhythmic potential of pharmacological agents that slow ventricular repolarization. Thus, selective inhibition of late INa may constitute a generalizable approach to stabilize ventricular repolarization and suppress arrhythmogenicity associated with conditions whereby AP or QT intervals are prolonged. NEW & NOTEWORTHY The contribution of physiological late Na+ current in action potential duration (APD) of rabbit cardiac myocytes was estimated. The inhibition of this current prevented the prolongation of APD in rabbit cardiac myocytes, the prolongation of monophasic APD, and generation of arrhythmias in rabbit isolated hearts caused by delayed rectifier K+ current inhibition.

Bursting dynamics in the normal and failing hearts

A failing heart differs from healthy hearts by an array of symptomatic characteristics, including impaired Ca2+ transients, upregulation of Na+/Ca2+ exchanger function, reduction of Ca2+ uptake to sarcoplasmic reticulum, reduced K+ currents, and increased propensity to arrhythmias. While significant efforts have been made in both experimental studies and model development to display the causes of heart failure, the full process of deterioration from a healthy to a failing heart yet remains deficiently understood. In this paper, we analyze a highly detailed mathematical model of mouse ventricular myocytes to disclose the key mechanisms underlying the continual transition towards a state of heart failure. We argue that such a transition can be described in mathematical terms as a sequence of bifurcations that the healthy cells undergo while transforming into failing cells. They include normal action potentials and [Ca2+]i transients, action potential and [Ca2+]i alternans, and bursting behaviors. These behaviors where supported by experimental studies of heart failure. The analysis of this model allowed us to identify that the slow component of the fast Na+ current is a key determining factor for the onset of bursting activity in mouse ventricular myocytes.

The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study.

Background: Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP) under control conditions. Variability in ion channel densities may explain differences in this susceptibility to repolarization abnormalities. Here, we quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions.Methods and Results: Sixty two AP recordings from non-diseased human heart preparations were used to construct a population of human ventricular models with normal APs and a wide range of ion channel densities. Multichannel ionic block was applied to investigate susceptibility to repolarization abnormalities. IKr block was necessary for the development of repolarization abnormalities. Models that developed repolarization abnormalities over the widest range of blocks possessed low Na+/K+ pump conductance below 50% of baseline, and ICaL conductance above 70% of baseline. Furthermore, INaK made the second largest contribution to repolarizing current in control simulations and the largest contribution under 75% IKr block. Reversing intracellular Na+ overload caused by reduced INaK was not sufficient to prevent abnormalities in models with low Na+/K+ pump conductance, while returning Na+/K+ pump conductance to normal substantially reduced abnormality occurrence, indicating INaK is an important repolarization current.Conclusions: INaK is an important determinant of repolarization abnormality susceptibility in human ventricular cardiomyocytes, through its contribution to repolarization current rather than homeostasis. While we found IKr block to be necessary for repolarization abnormalities to occur, INaK decrease, as in disease, may amplify the pro-arrhythmic risk of drug-induced IKr block in humans.

Quantitative analysis of the Ca2+ -dependent regulation of delayed rectifier K+ current IKs in rabbit ventricular myocytes.

[Ca2+ ]i enhanced rabbit ventricular slowly activating delayed rectifier K+ current (IKs ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K+ current (IKr ) amplitude and voltage dependence were unaffected by high [Ca2+ ]i . When measuring or simulating IKs during an action potential, IKs was not different during a physiological Ca2+ transient or when [Ca2+ ]i was buffered to 500nm. The slowly activating delayed rectifier K+ current (IKs ) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+ ([Ca2+ ]i ) and β-adrenergic receptor (β-AR) stimulation modulate IKs amplitude and kinetics, but details of these important IKs regulators and their interaction are limited. We assessed the [Ca2+ ]i dependence of IKs in steady-state conditions and with dynamically changing membrane potential and [Ca2+ ]i during an AP. IKs was recorded from freshly isolated rabbit ventricular myocytes using whole-cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+ ]i , we found that raising [Ca2+ ]i from 100 to 600nm produced similar increases in IKs as did β-AR activation, and the effects appeared additive. Both β-AR activation and high [Ca2+ ]i increased maximally activated tail IKs , negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well-established mathematical model of the rabbit myocyte. In both AP-clamp experiments and simulations, IKs recorded during a normal physiological Ca2+ transient was similar to IKs measured with [Ca2+ ]i clamped at 500-600nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+ ]i regulates IKs amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+ ]i , in the submembrane or junctional cleft space, is not required to maximize [Ca2+ ]i -dependent IKs activation during normal Ca2+ transients.

Electrophysiology of Hypokalemia and Hyperkalemia.

Electrophysiology of Hypokalemia and Hyperkalemia.

Calcium Activated Chloride Current in Mammalian Ventricular Myocytes

Background: Calcium activated Cl− current (ICl(Ca)) mediated by TMEM16A and/or Bestrophin-3 may contribute to cardiac arrhythmias. The true profile of ICl(Ca) during an actual ventricular action potential (AP), however, is poorly understood. Our goal was to study the current profile under normal calcium cycling and AP voltage-clamp condition as well as in case of altered intracellular calcium concentration ([Ca2+]i). The expression of TMEM16A and/or Bestrophin-3 in canine and human left ventricular myocytes was examined. The possible spatial distribution of these proteins and their co-localization with Cav1.2 was also studied.Methods: Whole-cell configuration of the patch-clamp technique and action potential voltage-clamp were used to monitor ICl(Ca), detected as 9-anthracene carboxylic acid (9-AC)-sensitive current. FURA-2-AM dye was used to measure [Ca2+]i. Expression and cellular localization of Cav1.2, Bestrophin-3 and TMEM16A was analyzed with immunocytochemistry and confocal microscopy.Results: Under AP voltage-clamp conditions the profile of ICl(Ca) contained an early fast outward (1.62±0.06 A/F) and a late inward component (−0.16±0.02 A/F), overlapping early and terminal repolarizations, respectively. Both components were reduced by ryanodine (1.05±0.03 A/F; −0.07±0.03 A/F), while fully abolished by BAPTA (0.13±0.10 A/F; −0.08±0.02 A/F), but not EGTA (1.17±0.09 A/F; −0.13±0.02 A/F). Setting [Ca2+]i to the systolic level (1.1 µM) decreased ICl(Ca), while application of Bay K8644, isoproterenol, and faster stimulation rates increased the amplitude of ICl(Ca). Both L-type Ca2+ current and ICl(Ca) were eliminated by nisoldipine. TMEM16A and Bestrophin-3 showed strong co-localization with one another and also with Cav1.2 channels both canine myocytes and human ventricular myocardium.Conclusions: Activation of ICl(Ca) in canine ventricular cells requires calcium entry through neighboring L-type Ca2+ channels and is only augmented by SR Ca2+-release. Substantial activation of ICl(Ca) requires high Ca2+ in the dyadic clefts which can be effectively buffered by BAPTA, but not EGTA.

A New Class of Antiarrhythmics for Late ICA,L

Early Afterdepolarizations (EADs) of the cardiac action potential (AP) are membrane potential oscillations arising during phase 2-3 and well-recognized cellular triggers of lethal cardiac arrhythmias. The L-type Ca2+ current (ICa,L) is a major regenerative inward current during these phases of the AP, and is therefore highly relevant to EAD upstroke and propagation at the tissue level. We recently discovered that late ICa,L reduction produced by minimally altering specific ICa,L biophysical properties (smaller pedestal ICa,L or more depolarized steady-state activation), potently suppresses EAD occurrence in rabbit ventricular myocytes under dynamic clamp. Based on these findings, we hypothesize that drugs able to mimic these late ICa,L modifications could constitute a new Class of antiarrhythmics that do not compromise inotropy. We are studying the antiarrhythmic effects of two pilots drugs, roscovitine and pregabalin, that we found to reduce late ICa,L in rabbit ventricular myocytes via two distinct mechanisms. Specifically, roscovitine reduced the non-inactivating (pedestal) ICa,L while leaving peak ICa,L intact and pregabalin induced a depolarizing shift of the steady-state activation. In this study we assessed the antiarrhythmic potential of these pilot compounds that reduce late ICa,L. We tested the ability of these drugs to suppress EADs in ventricular myocytes induced by oxidative stress (H2O2). The perfusion of roscovitine (20µM) or pregabalin (1mM) dramatically suppressed EAD occurrence (roscovitine: from 81.37%±8.1% to 0% APs with EADs; pregabalin from 64.5±17.7% to 6.6±3.8%) and restored normal AP duration. Moreover, both drugs suppressed EAD-mediated VT/VF in isolated perfused aged rat hearts, restoring sinus rhythm (roscovitine: 5/6; pregabalin: 2/2 hearts). These studies set the basis for the development of a conceptually new Class of antiarrhythmics (L-type Ca2+ channel gating modifiers) that selectively reduce late ICa,L, avoiding the negative inotropy caused by traditional CaV channel blockers used as Class IV Antiarrhythmics.

Magnetic Resonance Neurographic and Clinical Long-Term Results After Oberlin's Transfer for Adult Brachial Plexus Injuries.

The primary goal of the surgical treatment of upper brachial plexus injuries is to restore active elbow flexion. Accordingly, Oberlin's transfer has been frequently performed since 1994 and has influenced the development of other nerve transfers. However, the window of opportunity for nerve transfers remains a subject of controversy. The objective of this study was to assess magnetic resonance (MR) neurographic, clinical and electrophysiological long-term results after Oberlin's transfer. For this purpose, we performed a retrospective follow-up study. Six patients with upper brachial plexus or musculocutaneous nerve injuries were assessed; 2 were iatrogenic nerve injuries following shoulder arthroscopy or neurofibroma resection. Direct and indirect signs of neuropathy were objectified with MR neurography. Moreover, clinical and electrodiagnostic follow-up was performed and all patients completed the Disabilities of Arm, Shoulder and Hand score. Mean follow-up was 48 ± 21.9 (range, 20-73) months. Mean age was 40 ± 11.3 years and mean delay to surgery was 9 ± 3.2 months. All patients were satisfied with the functional results and the median Disabilities of Arm, Shoulder and Hand score was 21 (range, 1-57). Biceps strength was improved in 5 patients from Medical Research Council grade M0 to M4-5 and in one patient to M2-3. The donor nerve showed normal motor and sensory action potentials. Follow-up MR neurography demonstrated biceps reinnervation. Taken together, this study reports good long-term results after Oberlin's transfer. MR neurography represents an excellent, noninvasive preoperative planning tool and can be of high value in selected postoperative cases. The combined evaluation of nerves and muscles may help to indicate nerve transfers in delayed cases.

Progressive numbness of distal limbs for two years, unsteady gait for two months

A 50-year-old female was admitted to our department, complaining of progressive numbness of distal limbs for two years and unsteady gait for two months. “Peripheral neuropathy” was the presumed diagnosis. She has suffered dry mouth for months. Neurological examination revealed proximal upper muscle strength was normal and distal was 5-/5 while muscle strength in lower limbs was normal. Tendon reflexes in all limbs were reduced, and superficial sensation as well as deep sensation in all limbs was also diminished. Deep sensation below T 8-10 was diminished. Romberg’s test was positive with negative pathological reflex. Several sensory nerves action potentials (SNAPs) were diminished or absent with normal compound muscle action potentials (CMAPs). Cervical MRI showed hyperintensities in the dorsal column. Serum anti-Ro/SSA antibody was positive. Tear break-up time was abnormal in either eye (5s, normal range>10s); the rate of saliva production declined 0.02 ml/min (> 1.50 ml/15 min); parotid gland contrast sialography was abnormal; lip biopsy was positive with focal lymphocytic sialadenitis with focus score ≥1. The patient was diagnosed as primary Sjogren's syndrome and sensory neuronopathy. She received oral prednisone in dose of 1mg/(kg·d) for four weeks, then reduce the dosage with 5mg/w to 0.50mg/ (kg·d). Later she reduced the dosage with 2.5mg/per week. At the same time, she got cyclophosphamide (100mg every other day) and hydroxychloroquine (0.20g twice a day). Numbness of limbs and unsteady gait were improved when the patient was discharged. Two month later, during the follow-up, the patient’ gait was slightly improved, but the numbness still existed. DOI: 10.3969/j.issn.1672-6731.2016.11.016

Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation.

Hundreds of L1CAM gene mutations have been shown to be associated with congenital hydrocephalus, severe intellectual disability, aphasia, and motor symptoms. How such mutations impair neuronal function, however, remains unclear. Here, we generated human embryonic stem (ES) cells carrying a conditional L1CAM loss-of-function mutation and produced precisely matching control and L1CAM-deficient neurons from these ES cells. In analyzing two independent conditionally mutant ES cell clones, we found that deletion of L1CAM dramatically impaired axonal elongation and, to a lesser extent, dendritic arborization. Unexpectedly, we also detected an ∼20-50% and ∼20-30% decrease, respectively, in the levels of ankyrinG and ankyrinB protein, and observed that the size and intensity of ankyrinG staining in the axon initial segment was significantly reduced. Overexpression of wild-type L1CAM, but not of the L1CAM point mutants R1166X and S1224L, rescued the decrease in ankyrin levels. Importantly, we found that the L1CAM mutation selectively decreased activity-dependent Na(+)-currents, altered neuronal excitability, and caused impairments in action potential (AP) generation. Thus, our results suggest that the clinical presentations of L1CAM mutations in human patients could be accounted for, at least in part, by cell-autonomous changes in the functional development of neurons, such that neurons are unable to develop normal axons and dendrites and to generate normal APs.

The dual effect of ephaptic coupling on cardiac conduction with heterogeneous expression of connexin 43

Decreased and heterogeneous expression of connexin 43 (Cx43) are common features in animal heart failure models. Ephpatic coupling, which relies on the presence of junctional cleft space between the ends of adjacent cells, has been suggested to play a more active role in mediating intercellular electrical communication when gap junctions are reduced. To better understand the interplay of Cx43 expression and ephaptic coupling on cardiac conduction during heart failure, we performed numerical simulations on our model when Cx43 expression is reduced and heterogeneous. Under severely reduced Cx43 expression, we identified three new phenomena in the presence of ephaptic coupling: alternating conduction, in which ephaptic and gap junction-mediated mechanisms alternate; instability of planar fronts; and small amplitude action potential (SAP), which has a smaller potential amplitude than the normal action potential. In the presence of heterogeneous Cx43 expression, ephaptic coupling can either prevent or promote conduction block (CB) depending on the Cx43 knockout (Cx43KO) content. When Cx43KO content is relatively high, ephaptic coupling reduces the probabilities of CB. However, ephaptic coupling promotes CB when Cx43KO and wild type cells are mixed in roughly equal proportion, which can be attributed to an increase in current-to-load mismatch.

The effects of 6-weeks balance training on balance and walking speed in subjects with Multiple Sclerosis (MS).

Introduction: Multiple sclerosis (MS) is one of the most common diseases of the central nervous system which result in. It causes demyelination of nerve axons, which can lead to lack of normal action potentials as the central nervous system (CNS) attempts to communicate with the body, and vice versa. Materials and Methods : The purpose of this study The effects of 6-weeks balance training on balance and walking speed in subjects with Multiple Sclerosis (MS). 30 subjects with mild to moderate disability, by Kurtzke scale (Expanded Disability Statues Scale), Participated in this study and randomized into experimental (N=15) and control group(N=15) after being assessed with Berg balance Scale. Timed Walk test was used to assess walking speed. Experimental group involved in balance training 3days a week and control group continued their activity, both groups were tested by walking speed and balance. The results were analyzed by t-test. Level of significant was 0.05. Results: Result of this study Show that balance training has a positive effect balance and walking speed in people with multiple sclerosis . The results revealed a significant difference between control and experimental gropes in balance test (t = 3/23, P<0/05 ) and walking speed test (t= -4/44 , P< 0/05) Conclusion: The results indicated that balance training increased walking speed and balance and seemed to be a useful exercise therapy for MS. Key word : Multiple sclerosis, balance, balance training, walking speed

Two cases of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P)

We, herein, report two independent cases with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) inherited in an autosomal dominant fashion. Their common clinical features are slowly progressive proximal dominant muscular atrophy, fasciculations and mild to moderate distal sensory disturbance with areflexia. Nerve conduction study revealed an absence of sensory nerve action potentials, in contrast to almost normal compound muscle action potentials. Gene analysis in both patients elucidated heterozygous mutation (c.854C>T, p.Pro285Leu) in the TFG, which is an identical mutation, already described by Ishiura et al. Okinawa and Shiga are two foci of HMSN-P in Japan. Eventually, one patient is from Okinawa and the other is from a mountain village in Shiga prefecture. When we see a patient who has symptoms suggestive of motor neuron disease with sensory neuropathy, HMSN-P should be considered as a differential diagnosis despite the patient's actual resident place.

WHY THE LONG FACE?

We report a 63 year old lady with decreased visual acuity, no wrinkles and difficulty sucking drinks through a straw. Neurological examination revealed bilateral lower motor neuron facial weakness. There was normal tone and power in the limbs and pinprick, temperature and proprioception were intact but vibration sensation was absent to the level of the sternum. Gait was normal but there was mild clumsiness of the hands. No prior family history of neurological disease was known. Electrophysiology revealed normal sensory action potentials. Ophthalmological examination prompted the diagnosis of hereditary gelsolin amyloidosis which is recognized by the triad of corneal lattice dystrophy, progressive cranial neuropathy and cutis laxa. This was confirmed on finding a heterozygous D241N Gelsolin mutation. The unusual pattern of dissociated vibration and proprioceptive loss has been described in this condition with histopathological amyloid deposition providing eloquent demonstration of the involved anatomy. We present this rare case as an interesting and educational lesson in spinal cord anatomy.

Combined Cystometrography and Electromyography of the External Urethral Sphincter Following Complete Primary Repair of Bladder Exstrophy

Concern in patients with bladder exstrophy after reconstruction regarding potential injury to pelvic neurourological anatomy and a resultant functional deficit prompted combined (simultaneous) cystometrography and electromyography after complete primary repair of bladder exstrophy. We determined whether complete primary repair of bladder exstrophy would adversely affect the innervation controlling bladder and external urethral sphincter function. Complete primary repair of bladder exstrophy was performed via a modified Mitchell technique in newborns without osteotomy. Postoperative evaluation included combined cystometrography and needle electrode electromyography via the perineum, approximating the external urethral sphincter muscle complex. Electromyography was done to evaluate the external urethral sphincter response to sacral reflex stimulation and during voiding. Nine boys and 4 girls underwent combined cystometrography/electromyography after complete primary repair of bladder exstrophy. Age at study and time after complete primary repair of bladder exstrophy was 3 months to 10 years (median 11.5 months). Cystometrography revealed absent detrusor overactivity and the presence of a sustained detrusor voiding contraction in all cases. Electromyography showed universally normal individual motor unit action potentials of biphasic pattern, amplitude and duration. The external urethral sphincter sacral reflex response was intact with a normal caliber with respect to Valsalva, Credé, bulbocavernosus and anocutaneous (bilateral) stimulation. Synergy was documented by abrupt silencing of external urethral sphincter electromyography activity during voiding. After complete primary repair of bladder exstrophy combined cystometrography/electromyography in patients with bladder exstrophy showed normal neurourological findings, including sacral reflex responses, sustained detrusor voiding contraction and synergic voiding, in all patients postoperatively. These findings confirm the safety of complete primary repair of bladder exstrophy. Based on our results we have discontinued routine electromyography in these patients.