Changes In Electrophysiological Parameters Research Articles

Neuronal Hyperactivity in the Hippocampus during the Early Stage of Streptozotocin-Induced Type 1 Diabetes in Mice

Introduction: Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. Methods: Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate were then measured using ultra-performance liquid chromatography with mass spectrometry. Results: CA1 neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third, and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. Conclusion: Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention.

Temporal Changes in Electrophysiological Parameters in Untreated Patients With Carpal Tunnel Syndrome.

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy worldwide.This study aimed to investigate the temporal changes in electrophysiological parameters in untreated patients with CTS. Patients were recruited among those with the symptoms of CTS who were referred to the electrophysiology laboratory of Niğde Ömer Halisdemir University Bor Physical Therapy and Rehabilitation Hospital in Niğde, Turkey. Forty-nine patients (78 hands) who had not received any sort of treatment for CTS and had prior electrophysiological examination postive for CTS were included.Laboratory records were reviewed retrospectively. Recent electrophysiological parameters of the patients were compared to their prior examinationsusing Wilcoxon signed-rank test and sign test was used to compare the change in the electrophysiological severity of the study hands between two examinations. One-way analysis of variance(ANOVA) was used to compare individual parameters of the median NCS amongelectrophysiological change groups (improved, deteriorated, and same). The mean age was 50 ± 11 years, and 43 (88%) patients were female. The mean duration of time between the two electrophysiological examinations was 37 ± 20 months. Median sensory peak latency and median motor distal latency increased significantly in the second evaluation (p=0.005 and p=0.004, respectively). Median sensory conduction velocity decreased in the second examination (p=0.002). However, CTS severity determined electrophysiologically did not differ significantly in the two examinations (p=0.286). Although there was a deterioration in electrophysiological parameters during a mean follow-up period of 37 months, the electrophysiological severity of the patients did not worsen.

Analysis of Cognitive Functions and Neurophysiological Processes in Adaptation of Human to Conditions of the Arctic Region

INTRODUCTION: The aim of the work is analysis of one of the most important problems of the modern biomedical science problem of studying the processes of human adaptation to a complex of climatic and geographic factors and conditions of the Far North in the period of increased necessity in realization of the economic, industrial and defense activity of the government. The review presents the data of scientific study of cognitive functions and neurophysiological changes in people permanently living in or arriving to the Arctic zone. In the first part, the factors are considered that evidence different disorders in memory, concentration, efficiency of performing simple and complex cognitive tasks by test persons in conditions of low temperature, seasonal photoperiodicity, a particular working regime, such as rotational team method, etc. The age-related peculiarities of dynamics of the cognitive processes in children and adolescents living in the Arctic region are considered. The second part of the article presents analysis of scientific data on changes of electrophysiological parameters of the brain structure activity under the influence of individual or complex factors of Arctic conditions. In particular, changes of the encephalographic rhythms, evoked potentials, hemispheric asymmetry and parameters of autonomic regulation of the heart rate variability in the initial condition and on exposure to the factors of the Far North, are described. A necessity of individual typological analysis of the adaptation process characteristics depending on the initial regulatory peculiarities, neurophysiological characteristics of people, duration of their stay in the mentioned conditions, is emphasized. Inconsistency or ambiguity of the presented data indicate the importance of using a complex approach to scientific research which should include systemic analysis of the dynamics of neurophysiological characteristics and parameters of achieved effectiveness of modeled or professional activity in the Arctic conditions.
 CONCLUSION: The paper substantiates the necessity of elaboration of personalized methods of increasing the adaptive reserves of people working and living in the Arctic zones; one of these may be modern systems based on biocontrol with feedback from physiological systems of a human. Besides, it is noted that application of the principles of the theory of the functional systems formulated by academician P. K. Anokhin, can contribute to deeper understanding of adaptation processes, changes of cognitive and professional abilities, their neurophysiological support in the Arctic conditions.

Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity.

Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk.

Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti-seizure medication: Levetiracetam case study.

Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to "pressure test" the CiPA approach with LEV and check the concordance of nonclinical core and follow-up S7B assays with clinical and post-marketing data. The following experiments were conducted with LEV (0.25-7.5 mM): patch clamp assays on hERG (acute or trafficking effects), NaV 1.5, CaV 1.2, Kir 2.1, KV 7.1/mink, KV 1.5, KV 4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large-variability, and high-risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV 7.1/mink at 7.5 mM, that is, 30-fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10-fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10-fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors.

Electrophysiological Changes in Patients with Carpal Tunnel Syndrome after Open Carpal Tunnel Release

Objective: Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy affecting the upper limbs. Various treatment methods exist for this disease, but only a few reports have compared the effects of various treatments using objective indicators. This study analyzed the changes in electrophysiological parameters after carpal tunnel release.Methods: In patients planning to undergo surgical treatment for CTS, electrophysiological studies, including nerve conduction studies and electromyography (EMG), of both upper extremities were performed before and 6 to 8 weeks after mini-open transverse carpal ligament release and median nerve neurolysis.Results: After surgical intervention, the onset latency and amplitude of the sensory nerve action potential (SNAP) and the onset latency of the compound muscle action potential (CMAP) of the median nerve improved. Additionally, the grade of abnormal spontaneous activity in needle EMG of the abductor pollicis brevis (APB) and the severity of the electrodiagnostic study results significantly decreased after the intervention compared to the initial evaluation.Conclusion: This study shows that the onset latency of SNAP and CMAP, the amplitude of SNAP of the median nerve, and EMG findings in the APB can be useful electrodiagnostic parameters for postoperative monitoring in CTS patients.

Abstract 11448: Feasibility and Septal Perforation Rates in Left Bundle Branch Area Pacing

Introduction: Left Bundle Branch area Pacing (LBBaP) is gaining prevalence as a more physiologic alternative to conventional right ventricular pacing. Given limited literature on LBBaP, this retrospective study assessed feasibility and septal perforation rates following LBBaP. Methods: Procedure reports and electrophysiologic parameters were reviewed of patients that underwent LBBaP since 2019. Partial septal perforation was defined as any two of: a) reduction of impedance by 200 ohms b) increase in capture threshold by 50% and c) decrease in ventricular sensing by 50% during follow-up compared to approximately 1-week post pacemaker implant. Results: Since 2019, LBBaP was attempted in 168 patients and was successful in 102 (60.7 %), partial successful in 55 (32.7%) defined as QRS reduction of &gt;20ms and duration &lt;140ms, and unsuccessful in 11 (6.6%). QRS duration shortened or remained short after successful LBBaP compared to unsuccessful (113 vs 147 ms, p &lt; 0.001). Left ventricular ejection fraction was similar following successful LBBaP (p = 0.92). Five patients (3%) had potential septal perforation based on above criteria. Lead revisions were not arranged for these patients as pacing requirements were not high and it was clinically appropriate to continue 3 monthly observations in clinic. Conclusions: We report success rates of LBBaP recently adopted in a large tertiary center. In a medium-term follow-up, we show that changes in electrophysiologic parameters likely consistent with partial septal perforation may occur spontaneously in some patients (3% in our cohort) over time. Clinical significance of these changes and confirmation with imaging requires further study.

Ventricular arrhythmias in acute myocardial ischaemia-Focus on the ageing and sex.

Annually, approximately 17 million people die from cardiovascular diseases worldwide, half of them suddenly. The most common direct cause of sudden cardiac death is ventricular arrhythmia triggered by an acute coronary syndrome (ACS). The study summarizes the knowledge of the mechanisms of arrhythmia onset during ACS in humans and in animal models and factors that may influence the susceptibility to life-threatening arrhythmias during ACS with particular focus on the age and sex. The real impact of age and sex on the arrhythmic susceptibility within the setting of acute ischaemia is masked by the fact that ACSs result from coronary artery disease appearing with age much earlier among men than among women. However, results of researches show that in ageing process changes with potential pro-arrhythmic significance, such as increased fibrosis, cardiomyocyte hypertrophy, decrease number of gap junction channels, disturbances of the intracellular Ca2+ signalling or changes in electrophysiological parameters, occur independently of the development of cardiovascular diseases and are more severe in male individuals. A review of the literature also indicates a marked paucity of research in this area in female and elderly individuals. Greater awareness of sex differences in the aging process could help in the development of personalized prevention methods targeting potential pro-arrhythmic factors in patients of both sexes to reduce mortality during the acute phase of myocardial infarction. This is especially important in an era of aging populations in which women will predominate due to their longer lifespan.

Prevalence of Prolonged QT Interval In Patients With Chronic Liver Disease

The incidence of QT prolongation in CLD patients is greater than 45% compared to approximately 5% in the general population. Multiple researches have revealed that end-stage liver disease is related with a variety of changes in electrophysiological parameters; especially in our population, a higher incidence of QT interval prolongation is observed. Prolonged QT intervals in chronic liver disease patients are related with augmented mortality and morbidity. Objective: To determine the frequency of QT prolongation in patients with chronic liver disease. Methods: A cross-sectional and descriptive study. 96 total patients aged 20-85 years of both sexes with chronic liver disease (CLD) were included. Patients with a history of coronary artery disease and the use of any anti-arrhythmic medication were excluded from the study. The 12-lead ECG was performed and interpreted by an electrophysiologist with over five years of experience. The Bazett-based QT interval (QTc) was automatically obtained using a computerized electrocardiograph to avoid inter-observer variability. Results: 20 to 60 years was the patients age in this study, with 39.44 ± 9.91 years of mean age. The maximum patients, 86 (89.58%), were 20-40 years of age. Among the 96 patients, 17 (17.71%) were female and 79 (82.17%) were male, with a M: F ratio of 1.3: 1. While the incidence of QT prolongation was found in 47 (48.96%) patients, 49 (51.04%) patients did not have QT prolongation. Conclusions: In this study it was found that the frequency of QT prolongation is quite high in patients with chronic liver disease

Genetic variants of congenital glaucoma. Analysis of the literature and description of the clinical case

Purpose. Description of a clinical case of a patient with congenital glaucoma and mutations in the CYP1B1 gene, taking into account the analysis of literature data.Material and methods. The following methods were used to examine the patient: standard ophthalmological examination, EPI (VEP for flash, mERG and rERG) and fundus photoregistration, molecular genetics study of the CYP1B1 gene. DNA research was carried out by the method of direct automatic sequencing according to Sanger (the biomaterial was used — venous blood).Results. The article describes a clinical case of congenital glaucoma in a child with an early (from birth) manifestation of glaucoma, a distant stage at the time of examination, at the age of 2 years 6 months. Revealed pronounced clinical, functional and structural changes in the eyes, as well as changes in electrophysiological parameters. The previously described pathogenic variants of the nucleotide sequence 1330C&gt; T (p.Arg444 *) and c.1405C&gt; T (Arg469Trp) in heterozygous states were found in the CYP1B1 gene.Conclusion. The severity of the clinical course of congenital glaucoma in the described clinical case is presumably due to mutations in the CYP1B1 gene. A timely, interdisciplinary approach to diagnosis is key to successful treatment of glaucoma in children.

Anodal Transcranial Direct Current Stimulation Could Modulate Cortical Excitability and the Central Cholinergic System in Akinetic Rigid-Type Parkinson's Disease: Pilot Study.

BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive technique that has been widely studied as an alternative treatment for Parkinson's disease (PD). However, its clinical benefit remains unclear. In this study, we aimed to investigate the effect of tDCS on the central cholinergic system and cortical excitability in mainly akinetic rigid-type patients with PD.MethodsIn total, 18 patients with PD were prospectively enrolled and underwent 5 sessions of anodal tDCS on the M1 area, which is on the contralateral side of the dominant hand. We excluded patients with PD who had evident resting tremor of the hand to reduce the artifact of electrophysiologic findings. We compared clinical scales reflecting motor, cognitive, and mood symptoms between pre- and post-tDCS. Additionally, we investigated the changes in electrophysiologic parameters, such as short latency afferent inhibition (SAI) (%), which reflects the central cholinergic system.ResultsThe United Parkinson's Disease Rating Scale Part 3 (UPDRS-III), the Korean-Montreal Cognitive Assessment (MoCA-K), and Beck Depression Inventory (BDI) scores were significantly improved after anodal tDCS (p < 0.01, p < 0.01, and p < 0.01). Moreover, motor evoked potential amplitude ratio (MEPAR) (%) and integrated SAI showed significant improvement after tDCS (p < 0.01 and p < 0.01). The mean values of the change in integrated SAI (%) were significantly correlated with the changes in UPDRS-III scores; however, the MoCA-K and BDI scores did not show differences.ConclusionsAnodal tDCS could influence the central cholinergic system, such as frontal cortical excitability and depression in PD. This mechanism could underlie the clinical benefit of tDCS in patients with PD.

Neonatal NaV 1.5 channels: pharmacological distinctiveness of a cancer-related voltage-gated sodium channel splice variant.

Voltage-gated sodium (NaV ) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal splice variant of NaV 1.5 (nNaV 1.5), which has several amino acid substitutions in the domain I voltage-sensor compared with its adult counterpart (aNaV 1.5). This study aimed to determine whether nNaV 1.5 channels could be distinguished pharmacologically from aNaV 1.5 channels. Cells expressing either nNaV 1.5 or aNaV 1.5 channels were exposed to low MW inhibitors, an antibody or natural toxins, and changes in electrophysiological parameters were measured. Stable expression in EBNA cells and transient expression in Xenopus laevis oocytes were used. Currents were recorded by whole-cell patch clamp and two-electrode voltage-clamp, respectively. Several clinically used blockers of NaV channels (lidocaine, procaine, phenytoin, mexiletine, ranolazine, and riluzole) could not distinguish between nNaV 1.5 or aNaV 1.5 channels. However, two tarantula toxins (HaTx and ProTx-II) and a polyclonal antibody (NESOpAb) preferentially inhibited currents elicited by either nNaV 1.5 or aNaV 1.5 channels by binding to the spliced region of the channel. Furthermore, the amino acid residue at position 211 (aspartate in aNaV 1.5/lysine in nNaV 1.5), that is, the charge reversal in the spliced region of the channel, played a key role in the selectivity, especially in antibody binding. We conclude that the cancer-related nNaV 1.5 channel can be distinguished pharmacologically from its nearest neighbour, aNaV 1.5 channels. Thus, it may be possible to design low MW compounds as antimetastatic drugs for non-toxic therapy of nNaV 1.5-expressing carcinomas.

Electrophysiological markers of advanced stages of glaucomatous optic neuropathy

Purpose: to determine the changes in electrophysiological parameters reflecting specific dysfunctions of retinal ganglion cells (RGCs) at advanced stages of glaucomatous optic neuropathy (GON).Material and methods. The study involved 35 patients (55 eyes) aged 51–76 (63.1 ± 7.7 years) with primary open-angle glaucoma (POAG), divided into two subgroups depending on POAG stages: developed (24 patients, 27 eyes) and advanced stages (24 patients, 28 eyes). The age-matched control group (aged 51–72, 59.8 ± 5.9) included 28 relatively healthy individuals (32 eyes). Transient and steady-state pattern ERG (PERG) and photopic negative response (PhNR) were recorded according to ISCEV standards.Results. A decrease in the amplitude of the transient PERG's N95 and P50-waves and steady-state PERG was found, the degree of which showed an inverse dependence on the angular size of the stimulus, which clearly distinguished the developed and advanced POAG stages from the initial GON. The developed stages are characterized by a decrease in the PhNR amplitude, calculated from the baseline, and the PhNR/b index, the reduction of which was the more significant the greater the intensity of the flash. A significant delay of the N95 peak for patterns of all angular sizes and a less pronounced lengthening of the latency of the P50 wave (significant only for small stimuli 0.8° and 0.3°) in comparison with the age norm were found. The latencies of the steady-state PERG and PhNR practically did not differ from the age norm values.Conclusion. The revealed reduction in the amplitudes of N95 and P50 waves of transient and steady-state PERG, PhNR, and the PhNR/b index, as well as an increase in the peak latency of N95 and P50 waves of transient PERG, may be markers of functional changes in the retina associated with non-adaptive plasticity or reflecting a combination of the processes of adaptive plasticity and degeneration of RGCs. Further research in this area will help give a more accurate characterization of the found regularities and apply the obtained results in clinical practice.

Altered hippocampal function and cytokine levels in a rat model of Gulf War illness

AimsGulf War illness (GWI) is a disorder affecting military personnel deployed in the Gulf War (GW) from 1990 to 1991. Here, we will use a rat model of GWI to evaluate hippocampal function and cytokine levels. Materials and methodsRats were exposed to diethyltoluamide and permethrin via dermal absorption and pyridostigmine bromide via gavage with or without a 5-min restraint for 28 days. Immediate and delayed effects of GW chemical exposure were evaluated using electrophysiology to quantitate hippocampal function, behavioral tests to assess cognitive effects and biochemical assays to measure neurotransmitter and cytokine levels. Key findingsBehavioral data revealed a statistically significant increase in motor activity at 3 months following completion of exposures, potentially indicating increased excitability, and/or restlessness. Electrophysiology data revealed statistically significant changes in paired pulse facilitation and input-output function of CA1 hippocampal neurons within 24 h and 3 months following completion of exposures. There was also a statistically significant reduction in the frequency of spontaneous firing activity of hippocampal neurons within 24 h following exposures. Naïve hippocampal slices directly incubated in GW chemicals also resulted in similar changes in electrophysiological parameters. Biochemical measurements revealed reduced hippocampal glutamate level at 3 months post-exposure. Furthermore, there was a statistically significant increase in plasma and hippocampal levels of IL-13, as well as decrease in plasma level of IL-1β. SignificanceOur data support an effect on glutamate signaling within the hippocampus as indicated by changes in PPF and hippocampal level of glutamate, with some activation of T helper type 2 immune response.

Inhibition of Small-Conductance Calcium-Activated Potassium Current (I K,Ca) Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation.

BackgroundSmall-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling.Experimental Approach and MethodsTo address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.ResultsIK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.ConclusionsIntra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

The short-term rinsing of airways by N-acetylcysteine helps expectoration: The mechanism of sodium and chloride transport

N-acetyl-L-cysteine (NAC) mucolytic and antioxidant role is well known, but the effect on epithelial ion transport has not been yet described. The aim of the study was to evaluate the short-term and prolonged influence of NAC on ion transport in the epithelium. The experiment was performed on 108 fragments of rabbit tracheae. Fragments were divided into four groups: inhibited sodium (I) and chloride (II) transport, NAC with inhibited sodium (III) and NAC with inhibited chloride (IV) transport. The changes in electrophysiological parameters were measured in stationary conditions and during mechanical-chemical stimulation after immediate (15 s) and prolonged (60 min) N-acetylcysteine administration on the tissue. Each 15-second stimulation caused repeatable changes in the electric potential of the tissue. In trachea fragments with blocked chloride ion transport, significantly lower (P &lt;0.0001) values of electric potential following prolonged NAC effect were observed when compared to short-term NAC-stimulation. The values of resistance were constant during experiments, which reflects the vitality of the tissue. Short-term NAC administration influences sodium ion transport, which is not observed in a prolonged stimulation. The use of the NAC solution to rinse the airways is of great clinical importance due to the short and intense contact with the epithelium.

The Impact of Alcohol Intake on Atrial Fibrillation.

To evaluate (1) the impact of acute and habitual alcohol consumption on atrial fibrillation (AF) and atrial remodeling and (2) the role of alcohol reduction and/or abstinence in the primary and secondary prevention of AF. Acute alcohol consumption appears to be a common AF trigger, with animal and human studies demonstrating changes in electrophysiological parameters, autonomic tone, and cellular properties expected to promote AF. Habitual consumption is associated with adverse atrial remodeling, higher risk of incident AF, and AF recurrence. Randomized data suggest that reduction in excessive alcohol consumption may reduce the risk of recurrent AF episodes and AF burden. Alcohol is an increasingly recognized risk factor for both new onset AF and discrete AF episodes. Excessive consumption should be avoided for primary and secondary prevention of AF.

Suppression of experimental atrial fibrillation in a canine model of rapid atrial pacing by the phosphodiesterase 3 inhibitor cilostazol

ObjectiveAtrial fibrillation (AF) represents the most common arrhythmia encountered in cardiology department. The purpose of this study was designed to investigate whether cilostazol, an oral phosphodiesterase 3 inhibitor (PDE3) could have protective effects on atrial remodeling in a canine model of AF and explore the potential molecular mechanisms. MethodsDogs were randomly assigned to Sham, Paced, Paced + cilostazol group, 7 dogs in each group. In Sham group, pacemaker was instrumented but without pacing. Rapid atrial pacing (RAP) at 600 or 500 bpm/min was maintained in Paced group and Paced + cilo group for 2 h or 2 weeks in acute or chronic experiment, respectively. The Paced + cilo group of dogs were pretreated with cilostazol orally (10 mg·kg−1·d−1, cilo) for 1 h or 2 days prior RAP induction and served as treatment group. Atrial effective refractory periods (AERP) at different basic cycle lengths (BCLs), inducibility, and duration time of AF were measured after pacing for 2 h. The blood sample, echocardiography, histopathology, inflammation and oxidative stress makers, protein and mRNA expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected after 2 weeks pacing in each group. ResultsSignificant changes in electrophysiological parameters were observed in the acute RAP canine model, the AERPs shortened with increased inducibility and duration of AF, which was attenuated by cilostazol (P < 0.05). The serum inflammation makers as interleukin-8 (IL-8) and toll like receptor 4 (TLR 4) levels and oxidative stress indicators like xanthine oxidative (XO) and reactive oxygen species (ROS) in the Paced group was significantly higher than that in Sham group (P < 0.01), and was significantly reduced by cilostazol treatment (P < 0.01). The level of mean platelet volume (MPV) which is one of the platelet indices was significantly elevated in Paced group (P < 0.01). While after cilostazol treated for 2 weeks, the level of MPV was obviously decreased than Paced group (P < 0.01). Pathology and echocardiography studies showed that cilostazol can also prevent RAP induced cardiac fibrosis and structural remodeling. The MPV level has close correlations with IL-8, TLR4, XO and ROS (all P < 0.01). MMP-2 and MMP-9 expression were significantly increased in Paced group (all P < 0.01), which can be attenuated by cilostazol. ConclusionsCilostazol may have protective effects on RAP-induced atrial remodeling by anti-inflammatory, anti-oxidative stress action and regulate the extracellular collagen matrix in a canine model. Moreover, MPV level is associated with inflammation and oxidative stress response of RAP, which might be an important predictors of new-onset and recurrent AF.

Clinical and pathogenetic features and correction of hyperkinetic disorders in vegetative dysfunctions

One of the early syndromes in vascular pathology is motor disorders in the form of tremor. We examined 101 patients with cerebral dystonia on the background of chronic cerebral ischemia with compensated and subcompensated stages (n = 55) and autonomic dystonia syndrome (n = 46). Pathological mechanisms of formation of trembling hyperkinesis in cerebral angiodystonia of different etiology have been studied. Participation in these processes of the autonomic nervous system (ANS) is established. It is proved that the severity of this type of motor disorders depends on the condition of the ANS at different levels of its organization, especially on the background of sympathicotonic effects, as well as the vegetative characteristics of the patient. At the same time, signifi cant changes in electrophysiological parameters, as well as data of vegetative, emotional, psychometric testing, were obtained. For an objective evaluation of the severity of the tremor, a tremograph with the calculation of an integrative tremographic index was used. Developed a complex of cerebral angiodystonia with hyperkinetic syndrome and the use of antioxidants, nootropic drugs, which allowed to reduce or eliminate subjective experiences, to increase the adaptation capacity of the organism with the normalization of sympatho-parasympathetic relationships, to the normalization of the organism. also inhibition of the implementation of trembling hyperkinesis in both research groups. The average values of the tremographic index decreased towards an adequate distribution with sympathicolytic influence on the indices of vegetative testing and caused skin sympathetic potentials. At the same time, a greater effect was achieved when using the proposed method of treatment, with the maximum — in the syndrome of autonomic dystonia, as well as in the compensated stage of chronic brain ischemia. Keywords: cerebral angioedema, cerebral ischemia, autonomic disorders, tremor, treatment

P.271Potential translation of neurofilament light chain (NfL) as a safety biomarker for neurotoxicity in spinal muscular atrophy

Branaplam is an orally available small molecule that modulates Survival Motor Neuron 2 (SMN2) transcript splicing and increases generation of full length SMN2 mRNA with inclusion of Exon 7, leading to increased amount of functional SMN protein. It is in clinical development for treatment of Spinal Muscular Atrophy (SMA). Clear evidence of benefit has been shown without clinically apparent dose-limiting toxicities. However, non-clinical safety evaluations of branaplam suggested it may have a neurotoxicity risk. In toxicity studies using daily administration, a branaplam-related subtle peripheral neuropathy was discovered microscopically in juvenile dogs. This effect was potentially caused by stabilization ofmicrotubule polymerisation by branaplam. To investigate whether neurotoxicity is monitorable early, a thirty-week time-course study in dogs was conducted including digital nerve morphometry, measurement of neurofilament light (NfL) serum concentrations , and electrophysiological measurements. A minimal axonal degeneration of large fibers was confirmed at week 21. These findings correlated with release of NfL into serum. No clinical signs or changes in electrophysiological parameters were apparent, suggesting the microscopic findings and the associated serum increase of NfL precede neurologic dysfunction and overt clinical signs. Our data show that NfL is a sensitive marker of peripheral nerve injury and that it may be useful for monitoring the onset of treatment-related peripheral neurotoxicity in SMA patients and potentially, other indications. Differentiating between disease progression/activity and treatment-related adverse effects and understanding the relevance of increased NfL concentrations requires additional investigations. Although it remains unknown whether branaplam has a neurotoxic effect in humans, the weekly regimen used clinically may allow recovery from stabilizing effects on microtubule polymerization and avoid or minimize whatever led to the findings in dogs.