Reduced Nerve Conduction Velocity Research Articles

Protective Role of MerTK in Diabetic Peripheral Neuropathy via Inhibition of the NF-κB Signaling Pathway.

Diabetic peripheral neuropathy (DPN) impacts patient quality of life. In such patients, increased expression of mer tyrosine kinase (MerTK) has been demonstrated; however, its mechanism of action remains unclear. In this study, type 2 diabetes mellitus (T2DM) and DPN models were established in Sprague Dawley rats via low-dose streptozotocin and a high-fat diet and the mode of action of MerTK was examined. MerTK-specific inhibitors were administered by gavage once daily for 2 weeks. Sciatic nerve conduction velocity and nerve structure were measured. The levels of MerTK, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and relevant biochemical indexes were detected. The study revealed upregulation of MerTK expression in T2DM and more so in DPN groups. Inhibiting MerTK led to reduced nerve conduction velocity and further deterioration of sciatic nerve structure, as evidenced by structural morphology. Concurrently, serum levels of total cholesterol, glycated hemoglobin, and triglyceride significantly increased. Moreover, levels of NF-κB increased in both serum and nerve tissue, alongside a significant rise in TNF-α and IL-1β expressions. MerTK could bind to the inhibitor of kappa B kinase beta (Ikbkb) in Schwann cells, establishing Ikbkb as a precursor to NF-κB activation. Inhibition of MerTK exacerbates neuropathy, indicating its protective role in DPN by suppressing the NF-κB pathway, highlighting a potential new target for its diagnosis and treatment.

Peripheral neuropathy and nerve electrophysiological changes with enfortumab vedotin in patients with advanced urothelial carcinoma: a prospective multicenter cohort study.

Enfortumab vedotin is a novel antibody-drug conjugate used as a third-line therapy for the treatment of urothelial cancer. We aimed to elucidate the effect of enfortumab vedotin-related peripheral neuropathy on its efficacy and whether enfortumab vedotin-induced early electrophysiological changes could be associated with peripheral neuropathy onset. Our prospective multicenter cohort study enrolled 34 patients with prior platinum-containing chemotherapy and programmed cell death protein 1/ligand 1 inhibitor-resistant advanced urothelial carcinoma and received enfortumab vedotin. The best overall response, progression-free survival, overall survival, and safety were assessed. Nerve conduction studies were also performed in 11 patients. The confirmed overall response rate and disease control rate were 52.9% and 73.5%, respectively. The median overall progression-free survival and overall survival were 6.9 and 13.5months, respectively, during a median follow-up of 8.6months. The patients with disease control had significantly longer treatment continuation and overall survival than did those with uncontrolled disease. Peripheral neuropathy occurred in 12.5% of the patients. The overall response and disease control rates were 83.3% and 100%, respectively: higher than those in patients without peripheral neuropathy (p = 0.028 and p = 0.029, respectively). Nerve conduction studies indicated that enfortumab vedotin reduced nerve conduction velocity more markedly in sensory nerves than in motor nerves and the lower limbs than in the upper limbs, with the sural nerve being the most affected in the patients who developed peripheral neuropathy (p = 0.011). Our results indicated the importance of focusing on enfortumab vedotin-induced neuropathy of the sural nerve to maximize efficacy and improve safety.

Whole Body Cryostimulation: A New Adjuvant Treatment in Central Sensitization Syndromes? An Expert Opinion.

Central sensitisation is defined as a multifactorial etiopathogenetic condition involving an increase in the reactivity of nociceptive neurons and alterations in pain transmission and perception in the central nervous system. Patients may present with widespread chronic pain, fatigue, sleep disturbance, dizziness, psychological (e.g., depression, anxiety, and anger) and social impairment. Pain can be spontaneous in onset and persistence, characterised by an exaggerated response and spread beyond the site of origin, and sometimes triggered by a non-painful stimulus. Whole-body cryostimulation (WBC) could be an adjuvant therapy in the management of this type of pain because of its global anti-inflammatory effect, changes in cytokines and hormone secretion, reduction in nerve conduction velocity, autonomic modulation, and release of neurotransmitters involved in the pain pathway. In several conditions (e.g., fibromyalgia, rheumatoid arthritis, and chronic musculoskeletal pain), WBC affects physical performance, pain perception, and psychological aspects. Given its multiple targets and effects at different organs and levels, WBC appears to be a versatile adjuvant treatment for a wide range of conditions of rehabilitation interest. Further research is needed to fully understand the mechanisms of analgesic effect and potential actions on pain pathways, as well as to study long-term effects and potential uses in other chronic pain conditions.

Vanillic Acid Ameliorates Demyelination in a Cuprizone-Induced Multiple Sclerosis Rat Model: Possible Underlying Mechanisms.

To investigate the effect of vanillic acid (VA) on a Cuprizone (Cup) demyelinating rat model and the mechanisms behind such effect. Thirty adult male Sprague Dawley (SD) rats were randomly divided into three groups: control, Cuprizone, and VA groups. Cuprizone was administrated at a dose of 450 mg/kg per day orally via gastric gavage for 5 weeks. The nerve conduction velocity (NCV) was studied in an isolated sciatic nerve, and then the sciatic nerve was isolated for histopathological examination, electron microscope examination, immunohistochemical staining, and biochemical and PCR assay. The level of IL17 was detected using ELISA, while the antioxidant genes Nrf2, HO-1 expression at the level of mRNA, expression of the myelin basic protein (MBP), interferon-gamma factor (INF)-γ and tumor necrosis factor (TNF)-α, and apoptotic marker (caspase-3) were measured using immunohistochemistry in the sciatic nerve. There was a significant reduction in NCV in Cup compared to normal rats (p < 0.001), which was markedly improved in the VA group (p < 0.001). EM and histopathological examination revealed significant demyelination and deterioration of the sciatic nerve fibers with significant improvement in the VA group. The level of IL17 as well as the expression of INF-γ and caspase-3 were significantly increased with a significant reduction in the expression of MBP, Nrf2, and HO-1 in the sciatic nerve (p < 0.01), and VA treatment significantly improved the studied parameters (p < 0.01). The current study demonstrated a neuroprotective effect for VA against the Cup-induced demyelinating rat model. This effect might be precipitated by the inhibition of inflammation, oxidative stress, and apoptosis.

A study on occupational peripheral nerve disorders: a general view

The studies on occupational peripheral nerve disorders (OPD) in the workplace and future issues of OPD were overviewed based on the author's experiences. The author shows four case studies because of four chemicals; cross-sectional studies using nerve conduction velocity (NCV) on the effect on the peripheral nerve among workers exposed to carbon disulphide (CS2) in rayon manufacturing factories and studies on OPD among patients with vibration syndrome (VS) and non-specific cervicobrachial disorders (CBD). Four cases of OPD due to chronic poisoning because of inorganic lead, thallium, n-hexane, and methyl bromide, respectively, were presented with clinical signs and symptoms of OPD and the cause-and-effect relationships were described. Cross-sectional epidemiological studies clarified that workers exposed to approximately 5 ppm of CS2 showed NCV reduction in the lower extremities and those exposed to > 5 ppm showed NCV reduction in the upper extremities. Multifocal damages due to VS was presented through high rate of patients with sensory nerve conduction velocity (SCV) reduction in multiple nerves. SCV reduction of the radial nerve in the index finger among patients with CBD was presented. The various OPD phases were shown by case, patient, and epidemiological study. However, the recent decrease of work-related illness due to chemicals may result to OPD reduction. The issue of OPD including other factors and differential diagnosis, will remain eventually owing to introducing chemicals of which toxicity are unclear.

Ablation of Argonaute 2 in Schwann cells accelerates the progression of diabetic peripheral neuropathy.

Schwann cells (SCs) form myelin and provide metabolic support for axons, and are essential for normal nerve function. Identification of key molecules specific to SCs and nerve fibers may provide new therapeutic targets for diabetic peripheral neuropathy (DPN). Argonaute2 (Ago2) is a key molecular player that mediates the activity of miRNA-guided mRNA cleavage and miRNA stability. Our study found that Ago2 knockout (Ago2-KO) in proteolipid protein (PLP) lineage SCs in mice resulted in a significant reduction of nerve conduction velocities and impairments of thermal and mechanical sensitivities. Histopathological data revealed that Ago2-KO significantly induced demyelination and neurodegeneration. When DPN was induced in both wild-type and Ago2-KO mice, Ago2-KO mice exhibited further decreased myelin thickness and exacerbated neurological outcomes compared with wild-type mice. Deep sequencing analysis of Ago2 immunoprecipitated complexes showed that deregulated miR-206 in Ago2-KO mice is highly related to mitochondrial function. In vitro data showed that knockdown of miR-200 induced mitochondrial dysfunction and apoptosis in SCs. Together, our data suggest that Ago2 in SCs is essential to maintain peripheral nerve function while ablation of Ago2 in SCs exacerbates SC dysfunction and neuronal degeneration in DPN. These findings provide new insight into the molecular mechanisms of DPN.

Peripheral Nerve Injury Induced by Japanese Encephalitis Virus in C57BL/6 Mouse.

Japanese encephalitis virus (JEV), with neurotoxic and neuroinvasive properties, is the major cause of human viral encephalitis in Asia. Although Guillain-Barré syndrome caused by JEV infections is not frequent, a few cases have been reported in recent years. To date, no existing animal model for JEV-induced peripheral nerve injury (PNI) has been established, and thus the pathogenic mechanism is not clarified. Therefore, an animal model is urgently required to clarify the correlation between JEV infection and PNI. In the present study, we used JEV GIb strain of NX1889 to establish a mouse model of JEV infection. The general neurological signs emerged on day 3 of modeling. The motor function continued to deteriorate, reaching a maximum at 8 to 13 days postinfection (dpi) and gradually recovered after 16 dpi. The injuries of 105 PFU and 106 PFU groups were the most severe. Transmission electron microscopy and immunofluorescence staining showed varying degrees of demyelination and axonal degeneration in the sciatic nerves. The electrophysiological recordings demonstrated the presence of demyelinating peripheral neuropathy with reduced nerve conduction velocity. The decreased amplitudes and the prolonged end latency revealed axonal-type motor neuropathy. Demyelination is predominant in the early stage, followed by axonal injury. The expression level of JEV-E protein and viral RNA was elevated in the injured sciatic nerves, suggesting that it may cause PNI at the early stage. Inflammatory cell infiltration and increased inflammatory cytokines indicated that neuroinflammation is involved in JEV-induced PNI. IMPORTANCE JEV is a neurotropic flavivirus belonging to the Flaviviridae family and causes high mortality and disability rates. It invades the central nervous system and induces acute inflammatory injury and neuronal death. Thus, JEV infection is a major global public health concern. Previously, motor dysfunction was mainly attributed to central nervous system damage. Our knowledge regarding JEV-induced PNI is vague and neglected. Therefore, a laboratory animal model is essential. Herein, we showed that C57BL/6 mice can be used to study JEV-induced PNI through multiple approaches. We also demonstrated that viral loads might be positively correlated with lesion severity. Therefore, inflammation and direct virus infection may be the putative mechanisms underlying JEV-induced PNI. The results of this study laid the foundation for further elucidation of the pathogenesis mechanisms of PNI caused by JEV.

Novel mutation in the MPZ gene causes early-onset but slow-progressive Charcot–Marie–Tooth disease in a Russian family: a case report

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of peripheral neuropathies most of which are associated with mutations in four genes including peripheral myelin protein-22 (PMP22), myelin protein zero (MPZ), gap junction protein beta1 (GJB1) and mitofusin2 (MFN2). This current case report describes the clinical and genetic characteristics of a 6-year-old male proband. A physical examination revealed muscular hypotonia. He started walking on his own at 18 months. A nerve conduction study with needle electromyography revealed conduction block. A novel MPZ mutation (c.398C > T, p.Pro133Leu) was revealed in the proband. This mutation was also found in the 32-year-old father of the proband. The father had had deformity of the feet and distal muscle weakness since childhood. The novel p.Pro133Leu pathogenic mutation was responsible for early onset but slowly progressive CMT1B. We assume that this site is an intolerant to change region in the MPZ gene. This variant in the MPZ gene is an important contributor to hereditary neuropathy with reduced nerve conduction velocity in the Russian population. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of CMT associated with a mutation in the MPZ gene.

Neuronal deletion of MnSOD in mice leads to demyelination, inflammation and progressive paralysis that mimics phenotypes associated with progressive multiple sclerosis

Neuronal oxidative stress has been implicated in aging and neurodegenerative disease. Here we investigated the impact of elevated oxidative stress induced in mouse spinal cord by deletion of Mn-Superoxide dismutase (MnSOD) using a neuron specific Cre recombinase in Sod2 floxed mice (i-mn-Sod2 KO). Sod2 deletion in spinal cord neurons was associated with mitochondrial alterations and peroxide generation. Phenotypically, i-mn-Sod2 KO mice experienced hindlimb paralysis and clasping behavior associated with extensive demyelination and reduced nerve conduction velocity, axonal degeneration, enhanced blood brain barrier permeability, elevated inflammatory cytokines, microglia activation, infiltration of neutrophils and necroptosis in spinal cord. In contrast, spinal cord motor neuron number, innervation of neuromuscular junctions, muscle mass, and contractile function were not altered. Overall, our findings show that loss of MnSOD in spinal cord promotes a phenotype of demyelination, inflammation and progressive paralysis that mimics phenotypes associated with progressive multiple sclerosis.

Nerve Conduction Study in Healthy Elderly Subjects in Central India: A Cross-Sectional Study.

BackgroundThere are many physiological changes that accompany aging. Slowing of muscle contraction, alteration of muscle metabolism and neuromuscular junction, and reduction of nerve conduction velocity (NCV) are among these physiological changes. The present study was conducted to elucidate the effect of physiological factors like gender, height, and Body Mass Index (BMI) on motor and sensory nerve conduction study (NCS) of the upper limb and find out the normal data for healthy elderly subjects in central India.MethodsA cross-sectional study among 382 healthy adult participants of central India aged 60 years and above. The study was carried out in the department of Physiology, Acharya Vinoba Bhave Rural Hospital, Wardha, India, from July 2017 to June 2022. An NCS was performed using the Neuron Spectrum 5 machine (Neurosoft, Ivanovo, Russia). A Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, Washington, United States) was used to tabulate the information gathered. For statistical analysis, IBM SPSS Statistics for Windows, Version 22.0 (Released 2013; IBM Corp., Armonk, New York, United States) was used.ResultsAll NCS parameters were greater in males as compared to females. As age advances, longer distal motor latency (DML) and F-wave minimum latency, decreasing amplitude, and slowing of conduction velocity (CV) were observed. As height increases, increasing DML and F-wave minimum latency, decreasing amplitude, and slowing of CV were observed. Higher BMI was found to be associated with lower amplitudes and slowing of CVs.ConclusionAge and height have a negative influence on amplitude and CV is a positive influence on DML and F-min latency. Higher BMI has a negative influence on amplitude and CV.

Neurological and Inflammatory Effects of Radio Frequency and Cryoablation in a Rat Sciatic Nerve Model of Submucosal Nerve Ablation.

Minimally-invasive ablation with radio frequency (RF) and cryoablation have been widely adopted to treat conditions with aberrant neural activity such as excessive mucus production in rhinitis, but neurological and inflammatory effects on treated tissues are poorly understood. To gain an understanding of the physiological changes caused by nerve ablation using RF and cryoablation devices. Using clinical devices for rhinitis treatment that ablate nerves with access from the nasal cavity, we applied temperature-controlled RF and cryoablation to rat sciatic nerves. To model the ablation through mucosal tissue similarly to the rhinitis procedure, RF ablation and cryoablation were applied through a layer of muscle. Both ablation techniques induced acute and sustained neurodegeneration visualized with histological sections at two days and one month after treatment. After both treatments, rats showed a change in muscle tone, but small increases in sensitivity measured by a von Frey test were only observed 2 days after cryoablation and one month after the RF ablation. Both treatments caused reductions in nerve conduction velocity at one month after treatment. Inflammation in treated nerves and surrounding tissues that persisted to one month. The two neurolytic devices used in the clinic work similarly by axonal disintegration and which leads to disruption of electrical signals. The data suggest that these methods are effective methods of nerve ablation that could be used to treat diseases related to elevated neuron activity such as rhinitis.

P 72 Antibody depletion in nodo-paranodopathy: Clinical and electrophysiological long-term follow-up

Nodo-paranodopathies are rare immune-mediated neuropathies with autoantibodies against proteins of the node of Ranvier. The antibodies cause conduction failure and a destruction of nodal architecture in vivo and in vitro. Affected patients show severe motor and sensory involvement and signs of demyelination in electroneurography, fulfilling EFNS/PNS criteria for CIDP. Response to standard treatment is poor, but good clinical response to rituximab has been reported. Little is known about long-term outcome after antibody depletion and electroneurographic follow-up. We conducted a cohort study of 7 patients with neuropathy with anti-paranodal antibodies treated at the University Hospital of Würzburg (n = 3 anti-contactin-1, n = 4 anti-Caspr-1) who showed an antibody decrease in the course of the disease either spontaneously (n = 2) or treatment-induced by B-cell depletion with Rituximab (n = 5). Antibody titers and Neurofilament Light-Chain (NfL) levels were assessed at first diagnosis/ recruitment and in follow-up serum samples by ELISA and Ella. Clinical data, scores and electrophysiological data were assessed retrospectively with a mean follow-up period of 48.6 (8-78) months and compared using paired t-test and Spearman correlation. At recruitment, mean disease duration was 43.6 (0.25-180) months. Patients showed sensorimotor tetraparesis with a mean Overall Disability Sum Score (ODSS) of 7.43 (5-10) and MRC sum score of 48.29 (40-57). The antibody titer ranged from 1:100 – 1:10,000 and did not correlate with inter-individual disease severity. Electroneurography revealed demyelinating features with highly elevated distal motor latency (dml), loss/ reduction of F-waves and reduced nerve conduction velocity, but also signs of severe, length-dependent compound motor action potential (CMAP) amplitude decrease and spontaneous activity in electromyography in 5/ 7 patients. After antibody depletion, we found a significant reduction in the Overall Disability Sum Score (ODSS, p < 0.007) and improvement in the MRC sum score. Electrophysiological demyelinating parameters improved significantly. The mean increase in tibial nerve dml correlated with the increase in MRC sum score (r = 0.922, p < 0.003). Median nerve CMAP amplitudes increased significantly (p < 0.009), with a significant negative correlation to ODSS (r = -0.7, p < 0.03). Tibial nerve CMAP on the other hand remained severely reduced. In patients with autoantibody-mediated nodo-paranodopathy, the depletion of antibodies leads to a clinical and electrophysiological improvement, even after a long disease duration. In our cohort, distal, length dependent axonal damages could not be fully reversed. Our data therefore suggest that early antibody depletion should be a main therapeutic goal in nodo-paranodopathy. Although the antibody titer cannot be used as an inter-individual indicator of disease severity, it may serve as a valuable intra-individual marker for treatment reevaluation and prognosis.

Nerve Conduction Study in Healthy Elderly Subjects in Central India

Background: Electrodiagnostic study is performed in a neurophysiology lab diagnosed peripheral neuropathy. Effect of ageing on nerve and muscle inform of muscle contractility decreased, change in the metabolism of muscle and neuromuscular junction transmission and reduced nerve conduction velocity. As the ageing population increases, information regarding the course of normal ageing, its impact on the nervous system, ways to maintain wellness, and disease that impact the elderly and their management is necessary. Therefore, this proposed study aims to elucidate the effect of physiological factors (height, Body Mass Index and gender) on nerve conduction study and find out the normative data for healthy elderly subjects in central India.&#x0D; Objectives:&#x0D; 1) To establish normative data of nerve conduction study in Ulnar, median Tibial, and Peroneal nerves in normal healthy elderly subjects.&#x0D; 2) To find out the effect of height, body mass index and gender on nerve conduction in healthy elderly subjects.&#x0D; Methodology: This will be a Cross-sectional study with participants aged &gt; 60 years of both healthy subjects will be included in the study. The procedure will be performed after written consent from all the subjects. A normative data consist of parameters as distal motor Latency, peak to peak Amplitude and conduction velocity in motor nerve; peak to peak amplitude and nerve conduction velocity for sensory nerves. F wave minimum latency of motor nerve&#x0D; Nerve conduction study will be performed on Neuron Spectrum 5 (Neurosoft) machine. &#x0D; Results: Normative data will compare with globally published literature.&#x0D; Conclusion: The study is expected to draw observation in relation to variables cited with the objectives, which will be compared to draw inference over normative data of nerve conduction studies in healthy elderly subjects from the Wardha district.

Surgical Procedures Required for Measurement Reduce Nerve Conduction Velocity: An In Vivo and In Vitro Comparative Study

Background: Although in vitro methods have disadvantages, they are still commonly used to measure nerve conduction velocity (NCV) in experimental studies. Therefore, this study was designed to demonstrate the effect of the surgical procedures required for in vitro methods on nerve fibers and the effect of in vivo and in vitro methods on the results of electrophysiological measurements. Methods: Rats were assigned to the in vivo (control-1, injury-1, and diabetic-1) and in vitro (control-2, injury-2, and diabetic-2) groups. The NCV and compound action potential amplitudes were measured, and the nerve fibers were histologically examined. Results: Damaged axons and myelin sheaths were observed in the control-2 group. The electrophysiological values of the in vitro groups were lower than those of the in vivo groups. Furthermore, these values were lower for the diabetic and injury groups than for the control groups. Conclusions: This study showed that the surgical procedures required for the in vitro method reduced the measured values. Owing to the previous and current disadvantages of the in vitro method, the in vivo method was more sensitive for the NCV measurement. Moreover, measurements can be performed using the current in vivo method for small nerve fibers.

Precision mouse models of Yars/dominant intermediate Charcot-Marie-Tooth disease type C and Sptlc1/hereditary sensory and autonomic neuropathy type 1.

Animal models of neurodegenerative diseases such as inherited peripheral neuropathies sometimes accurately recreate the pathophysiology of the human disease, and sometimes accurately recreate the genetic perturbations found in patients. Ideally, models achieve both, but this is not always possible; nonetheless, such models are informative. Here we describe two animal models of inherited peripheral neuropathy: mice with a mutation in tyrosyl tRNA-synthetase, YarsE196K , modeling dominant intermediate Charcot-Marie-Tooth disease type C (diCMTC), and mice with a mutation in serine palmitoyltransferase long chain 1, Sptlc1C133W , modeling hereditary sensory and autonomic neuropathy type 1 (HSAN1). YarsE196K mice develop disease-relevant phenotypes including reduced motor performance and reduced nerve conduction velocities by 4months of age. Peripheral motor axons are reduced in size, but there is no reduction in axon number and plasma neurofilament light chain levels are not increased. Unlike the dominant human mutations, the YarsE196K mice only show these phenotypes as homozygotes, or as compound heterozygotes with a null allele, and no phenotype is observed in E196K or null heterozygotes. The Sptlc1C133W mice carry a knockin allele and show the anticipated increase in 1-deoxysphingolipids in circulation and in a variety of tissues. They also have mild behavioral defects consistent with HSAN1, but do not show neurophysiological defects or axon loss in peripheral nerves or in the epidermis of the hind paw or tail. Thus, despite the biochemical phenotype, the Sptlc1C133W mice do not show a strong neuropathy phenotype. Surprisingly, these mice were lethal as homozygotes, but the heterozygous genotype studied corresponds to the dominant genetics seen in humans. Thus, YarsE196K homozygous mice have a relevant phenotype, but imprecisely reproduce the human genetics, whereas the Sptlc1C133W mice precisely reproduce the human genetics, but do not recreate the disease phenotype. Despite these shortcomings, both models are informative and will be useful for future research.

Reversal of Bortezomib-Induced Neurotoxicity by Suvecaltamide, a Selective T-Type Ca-Channel Modulator, in Preclinical Models.

Simple SummaryChemotherapy-induced peripheral neurotoxicity (CIPN) is a side-effect of anti-cancer medications, which can lead to pain, disruptions to movement, and eventually results in the need to interrupt or stop chemotherapy. This study sought to test whether the drug suvecaltamide could help to reduce the impact of the chemotherapy agent bortezomib (BTZ) on symptoms of CIPN using animal models and human cells. Suvecaltamide did reverse negative changes in nerve conduction velocity and intraepidermal nerve fiber density indicative of CIPN in rats, and did not interfere with the anti-cancer effect of BTZ. These results indicate that suvecaltamide could potentially be useful for patients experiencing CIPN, although further mechanistic and molecular studies in vitro and in vivo are required before clinical trials.This study evaluated suvecaltamide, a selective T-type calcium channel modulator, on chemotherapy-induced peripheral neurotoxicity (CIPN) and anti-cancer activity associated with bortezomib (BTZ). Rats received BTZ (0.2 mg/kg thrice weekly) for 4 weeks, then BTZ alone (n = 8) or BTZ+suvecaltamide (3, 10, or 30 mg/kg once daily; each n = 12) for 4 weeks. Nerve conduction velocity (NCV), mechanical threshold, β-tubulin polymerization, and intraepidermal nerve fiber (IENF) density were assessed. Proteasome inhibition was evaluated in peripheral blood mononuclear cells. Cytotoxicity was assessed in human multiple myeloma cell lines (MCLs) exposed to BTZ alone (IC50 concentration), BTZ+suvecaltamide (10, 30, 100, 300, or 1000 nM), suvecaltamide alone, or vehicle. Tumor volume was estimated in athymic nude mice bearing MCL xenografts receiving vehicle, BTZ alone (1 mg/kg twice weekly), or BTZ+suvecaltamide (30 mg/kg once daily) for 28 days, or no treatment (each n = 8). After 4 weeks, suvecaltamide 10 or 30 mg/kg reversed BTZ-induced reduction in NCV, and suvecaltamide 30 mg/kg reversed BTZ-induced reduction in IENF density. Proteasome inhibition and cytotoxicity were similar between BTZ alone and BTZ+suvecaltamide. BTZ alone and BTZ+suvecaltamide reduced tumor volume versus the control (day 18), and BTZ+suvecaltamide reduced tumor volume versus BTZ alone (day 28). Suvecaltamide reversed CIPN without affecting BTZ anti-cancer activity in preclinical models.

Показники стимуляційної електронейроміографії в пацієнтів iз первинним гіпотиреозом

Мета дослідження — виявити електронейроміографічні особливості ураження периферичної нервової системи в пацієнтів iз первинним гіпотиреозом на фоні автоімунного тиреоїдиту (АІТ) та післяопераційного гіпотиреозу шляхом проведення стимуляційної електрoнейроміографії (ЕНМГ). Матеріали та методи. Обстежено 56 хворих на гіпотиреоз на фоні АІТ та 19 пацієнтів iз післяопераційним гіпотиреозом. Контрольну групу становили 20 практично здорових осіб. П’ятдесят сім (76 %) пацієнтів отримували замісну терапію синтетичними похідними L-тироксину, у 18 (24 %) хворих був субклінічний гіпотиреоз. Проведено комплексне клініко-неврологічне та електрофізіологічне обстеження хворих, що включало ЕНМГ-тестування моторних (малогомілкові, великогомілкові, серединні) та сенсорних (малогомілкові, литкові) нервів. При дослідженні моторних нервів оцiнювали наступні показники: амплітуду та тривалість М-відповіді, площу М-відповіді на стимуляцію нерву в дистальній та проксимальній точках, термінальну латентність, резидуальну латентність, швидкість проведення збудження (ШПЗ), при вивченні сенсорних нервів — амплітуду потенціалу дії та ШПЗ. Результати. За АІТ спостерігалось ураження сенсорних нервів нижніх кінцівок (поверхневi малогомілковi та литковi) за змішаним типом. Аксонопатія проявлялась у зменшенні амплітуди потенціалу дії поверхневого малогомілкового нерва на 32,7 % (p &lt; 0,05) та литкового на 27,5 % (p &lt; 0,05) порівняно з контрольною групою, також відмічали зниження ШПЗ малогомілковими нервами на 21,9 % (p &lt; 0,05), що свідчить про пошкодження мієлінової оболонки. У пацієнтів iз післяопераційним гіпотиреозом спостерігалися переважно ознаки аксонопатії, про що свідчило зменшення амплітуди потенціалу дії поверхневого малогомілкового нерва на 27,9 % (p &lt; 0,05). При дослідженні функції рухових волокон периферичних нервів (сере­динний, малогомілковий та великогомілковий) виявлено, що ураження моторних волокон мало демієлінізуючий характер у 78,8 % випадків, у решти хворих (22,2 %) полінейропатія була змішаною (з ознаками ураження мієлінової оболонки та аксонів). Пошкодження ліктьових та великогомілкових нервів було облігатним, у той же час ознаки ураження серединного нерва спостерігалися в 72,8 % випадків. Про демієлінізацію швидкопровідних волокон малогомілкових та великогомілкових нервів свідчило подовження резидуальної латентності на 31,7 % (p &lt; 0,05) та 31,6 % відповідно (p &lt; 0,05), зниження ШПЗ при тестуванні малогомілкових нервів на 21,5 % (p &lt; 0,05) та на 19,4 % — при дослiдженні великогомілкових нервів. З боку серединних нервів відмічалося незначне зниження амплітуди дистальної М-відповіді, на ураження мієлінової оболонки вказувало статистично вірогідне підвищення резидуальної латентності та незначне зниження ШПЗ. У 22,2 % хворих з АІТ відмічалися ознаки поєднаного ураження мієлінової оболонки та аксонального пошкодження, коли крім зниження ШПЗ руховими волокнами великогомілкового та малогомілкового нервів на 21,7 та 21,4 % та деякого підвищення резидуальної латентності спостерігалося вірогідне зниження амплітуди М-відповіді на 15,6 та 14,8 % відповідно. У пацієнтів iз післяопераційним гіпотиреозом відмічалися лише ознаки мієлінопатії. Висновки. ЕНМГ дозволила виявити демієлінізуючий та змішаний характер ураження моторних волокон та аксональний характер ураження сенсорних периферичних нервів, причому більш виражені зміни спостерігалися при АІТ, ніж при полінейропатії на фоні післяопераційного гіпотиреозу.

MiR-214-3p plays a protective role in diabetic neuropathic rats by regulating Nav1.3 and TLR4.

This study aimed to investigate the functions of miR-214-3p in diabetic neuropathic rodents. The diabetic neuropathy was induced by intraperitoneal injection of streptozotocin (STZ) in rats, and miR-214-3p was delivered via tail vein injection of lentivirus. Hot or cold stimulus tests demonstrated that STZ induced thermal hyperalgesia. Neurophysiological measurements revealed that motor and sensory nerve conduction velocity and nerve blood flow were decreased in diabetic neuropathic rats. However, the STZ-induced hyperalgesia, and reduced nerve conduction velocity and nerve blood flow were all significantly reversed by miR-214-3p administration. HE staining, TUNEL, ELISA, and immunoblotting demonstrated that STZ led to obvious pathological lesion, cell apoptosis, and inflammation in dorsal root ganglion (DRG), evidenced by altered levels of apoptosis-related protein molecules and inflammatory factors, and activation of Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88/nuclear factor kappa B signaling. The pathological alterations in diabetic neuropathic rats in DRG were significantly ameliorated by miR-214-3p application. In addition, sodium channel protein type 3 subunit alpha isoform 1 (Nav1.3) and TLR4 were identified as targets of miR-214-3p via dual-luciferase reporter assay. MiR-214-3p may play its roles by downregulating Nav1.3 and TLR4. In summary, miR-214-3p alleviated diabetes-induced nerve injury, and pathological lesion, cell apoptosis, and inflammation in DRG by regulating Nav1.3 and TLR4 in STZ-induced rats. These findings may provide novel therapeutic targets for clinical treatment of diabetic neuropathy.

Prevalence of peripheral neuropathy in newly diagnosed type 2 diabetics in sub-district hospital Bishnah

Background: Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Screening and early identification of neuropathy among diabetics can be a crucial opportunity for course modulation for keeping the glycemic control to optimal levels and within recommended targets.Methods: A cross sectional observational study were conducted on 100 patients older than 30 years, of newly diagnosed type 2 diabetes mellitus (T2DM) and attending medicine OPD of sub district hospital Bishnah, district Jammu, Jammu and Kashmir from April 2020 to January 2021. Diabetic peripheral neuropathy (DPN) was diagnosed if two or more of the abnormalities of neuropathy symptoms score or neuropathy disability score were present.Results: Among the studied subjects, 59% were males and 41% were females. Mean age was 49.22±10.63 years for diabetics. 29% patients were alcoholic and 24% were smokers and body mass index (BMI) of more than 25 was found in 20% of patients. Most common of symptoms was tingling (37.14%). 29 subjects had neuropathic signs and neuropathy disability score (NDS) more than or equal to 2 with 28 of them having reduced nerve conduction velocity and loss of vibration in 65.52% patients. A higher prevalence of DPN was found among DM duration of greater than 5 years.Conclusions: The present study showed a significant correlation between DPN, duration of diabetes and BMI. Detection of neuropathic symptoms and complications is therefore essential among patients with T2DM before it hampers their quality of life.

AAV2/9-mediated silencing of PMP22 prevents the development of pathological features in a rat model of Charcot-Marie-Tooth disease 1\u2009A

Charcot-Marie-Tooth disease 1 A (CMT1A) results from a duplication of the PMP22 gene in Schwann cells and a deficit of myelination in peripheral nerves. Patients with CMT1A have reduced nerve conduction velocity, muscle wasting, hand and foot deformations and foot drop walking. Here, we evaluate the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9) expressing GFP and shRNAs targeting Pmp22 mRNA in animal models of Charcot-Marie-Tooth disease 1 A. Intra-nerve delivery of AAV2/9 in the sciatic nerve allowed widespread transgene expression in resident myelinating Schwann cells in mice, rats and non-human primates. A bilateral treatment restore expression levels of PMP22 comparable to wild-type conditions, resulting in increased myelination and prevention of motor and sensory impairments over a twelve-months period in a rat model of CMT1A. We observed limited off-target transduction and immune response using the intra-nerve delivery route. A combination of previously characterized human skin biomarkers is able to discriminate between treated and untreated animals, indicating their potential use as part of outcome measures.