Neuromuscular Research Articles

Improving Examination Skills in Neuromuscular Disorders Through an Educational Video.

The acquisition of practical skills is a key objective of medical education. Improving knowledge and skills is essential for early diagnosis of patients suffering from neuromuscular (NM) diseases. Multimedia tools have proved to be useful and effective for learning clinical skills. We developed a video to learn the NM examination, the main pathological signs and their semiological value. We developed a video to learn the NM examination, the main pathological signs and their semiological value. Twenty-seven medical students (group A) watched the NM video. A control group (B, n = 15) watched a control video on OMS examination. Both groups filled out NM and control questionnaires before and after watching the video. Group A significantly improved their score on the NM questionnaire (6.36 ± 1.62 vs. 9.12 ± 0.69, p < 0.001) but not on the control questionnaire. Group B significantly improved the score on the control questionnaire (6.03 ± 1.39 vs. 8.22 ± 1.12, p < 0.0001) but not on the NM questionnaire. Students self-scored their NM knowledge at 5/10 and 7.4/10 on a visual analogue scale (VAS) before and after watching the NM video. The overall usefulness of the NM video was scored 8.7/10. Students considered it useful for learning the NM examination, illustrating rare semiological signs, preparing for practical evaluations and reinforcing self-confidence. Didactic videos can be used to complement classical teaching to improve the learning of practical skills and to strengthen students' self-confidence. They can also be useful for other medical disciplines and health professionals, improving the recognition and management of these rare diseases.

BoNT/Action beyond neurons.

Botulinum neurotoxin type A (BoNT/A) has expanded its therapeutic uses beyond neuromuscular disorders to include treatments for various pain syndromes and neurological conditions. Originally recognized for blocking acetylcholine release at neuromuscular junctions, BoNT/A's effects extend to both peripheral and central nervous systems. Its ability to undergo retrograde transport allows BoNT/A to modulate synaptic transmission and reduce pain centrally, influencing neurotransmitter systems beyond muscle control. BoNT/A also interacts with glial cells, such as Schwann cells, satellite glial cells, astrocytes, microglia, and oligodendrocytes. Schwann cells, key to peripheral nerve regeneration, are directly influenced by BoNT/A, which promotes their proliferation and enhances remyelination. Satellite glial cells, involved in sensory neuron regulation, show reduced glutamate release in response to BoNT/A, aiding in pain relief. In the CNS, BoNT/A modulates astrocyte activity, reducing excitotoxicity and inflammation, which is relevant in conditions like epilepsy. Microglia, the CNS's immune cells, shift from a pro-inflammatory to a neuroprotective state when treated with BoNT/A, enhancing tissue repair. Additionally, BoNT/A promotes oligodendrocyte survival and remyelination, especially after spinal cord injury. Overall, BoNT/A's ability to target both neurons and glial cells presents a multifaceted therapeutic strategy for neurological disorders, pain management, and CNS repair. Further research is necessary to fully elucidate its mechanisms and optimize its clinical application.

Bioelectricity is a universal multifaced signaling cue in living organisms.

The cellular electrical signals of living organisms were discovered more than a century ago and have been extensively investigated in the neuromuscular system. Neuronal depolarization and hyperpolarization are essential for our neuromuscular physiological and pathological functions. Bioelectricity is being recognized as an ancient, intrinsic, fundamental property of all living cells, and it is not limited to the neuromuscular system. Instead, emerging evidence supports a view of bioelectricity as an instructional signaling cue for fundamental cellular physiology, embryonic development, regeneration, and human diseases, including cancers. Here, we highlight the current understanding of bioelectricity and share our views on the challenges and perspectives.

Mitochondrial ROS modulate presynaptic plasticity in the drosophila neuromuscular junction.

The elevated emission of reactive oxygen species (ROS) from presynaptic mitochondria is well-documented in several inflammatory and neurodegenerative diseases. However, the potential role of mitochondrial ROS in presynaptic function and plasticity remains largely understudied beyond the context of disease. Here, we investigated this potential ROS role in presynaptic function and short-term plasticity by combining optogenetics, whole cell electrophysiological recordings, and live confocal imaging using a well-established protocol for induction and measurement of synaptic potentiation in Drosophila melanogaster neuromuscular junctions (NMJ). Optogenetic induction of ROS emission from presynaptic motorneuron mitochondria expressing mitokiller red (mK) resulted in synaptic potentiation, evidenced by an increase in the frequency of spontaneous mini excitatory junction potentials. Notably, this effect was not observed in flies co-expressing catalase, a cytosolic hydrogen peroxide (H2O2) scavenging enzyme. Moreover, the increase in electrical activity did not coincide with synaptic structural changes. The absence of Wnt1/Wg release from synaptic boutons suggested involvement of alternative or non-canonical signaling pathway(s). However, in existing boutons we observed an increase in the active zone (AZ) marker Brp/Erc1, which serves as docking site for the neurotransmitter vesicle release pool. We propose the involvement of putative redox switches in AZ components as the molecular target of mitochondrial H2O2. These findings establish a novel framework for understanding the signaling role of mROS in presynaptic structural and functional plasticity, providing insights into redox-based mechanisms of neuronal communication.

Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.

Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia. To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint). During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8-endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10-endpoint vs. Sham, p < 0.05), fibre atrophy (-16% to -24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8-fold; D14-endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (-55%, p = 0.0074) and diaphragm excursion (-43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation. In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.

Comparative Efficacy and Acceptability of Non-surgical Treatments with or without Exercise for Diastasis Recti Abdominis in Postpartum Women: A Network Meta-Analysis of Randomized Controlled Trials.

Diastasis recti abdominis (DRA), commonly occurring in postpartum women, is not only an aesthetic issue but is also highly associated with functional impairments. Various conservative treatment modalities have been employed in clinical practice to alleviate DRA. However, the comparative efficacy of these non-surgical treatments for improving the inter-recti distance (IRD) remains to be determined. This current network meta-analysis (NMA) aims to compare the efficacy and acceptability of different non-surgical treatments with or without exercise for improving DRA in postpartum women. This NMA adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ClinicalKey, Cochrane Library, CINAHL, Embase, PubMed, Web of Science, and ClinicalTrials.gov were systematically searched for randomized controlled trial (RCT) studies up to April 2024. The analysis included studies that met the following criteria: (1) postpartum women diagnosed with DRA defined as an IRD greater than 2cm; (2) intervention: any non-surgical treatments for at least 2weeks; (3) comparator: no-treatment control; and (4) outcome: changes in IRD and acceptability. The relative efficacy between the non-surgical treatments tested and the probability of treatments were evaluated. Twenty-one RCTs comprising 1195 participants aged from 18 to 45years old were included. The forest plot revealed that exercise coupling with neuromuscular electrical stimulation systems (NMES) [mean difference (MD) - 1.12cm, 95% confidence interval (CI) - 1.66 to - 0.58], acupuncture (MD - 0.81cm, 95% CI - 1.54 to - 0.08), corset (MD - 0.65cm, 95% CI - 1.24 to - 0.06), and exercise alone (MD - 0.48cm, 95% CI - 0.80 to - 0.16) led to significant reductions in IRD compared with control. Further, the treatment ranking indicated that the combination of NMES with exercise has the highest probability (91.0%) of being the best treatment for reducing IRD, followed by acupuncture with exercise (71.1%). Treatments combined with exercise demonstrated better rankings for reducing IRD than individual treatments without exercise. Acceptability did not significantly differ between the groups. This NMA encountered limitations due to participant variability, differing measurement methods, and sparse data, necessitating careful interpretation of findings regarding postpartum DRA interventions. This NMA suggests NMES combined with exercise as the best treatment tested for DRA in postpartum women. CRD42024541345.

Dynein-driven regulation of postsynaptic membrane architecture and synaptic function.

Cytoplasmic dynein is essential in motoneurons for retrograde cargo transport that sustains neuronal connectivity. Little, however, is known about dynein's function on the postsynaptic side of the circuit. Here we report distinct postsynaptic roles for dynein at neuromuscular junctions (NMJs). Intriguingly, we show that dynein punctae accumulate postsynaptically at glutamatergic synaptic terminals. Moreover, Skittles, a phosphatidylinositol 4-phosphate 5-kinase that produces PI(4,5)P2 to organize the spectrin cytoskeleton, also localizes specifically to glutamatergic synaptic terminals. Depletion of postsynaptic dynein disrupts the accumulation of Skittles, PI(4,5)P2 phospholipid, and organization of the spectrin cytoskeleton at the postsynaptic membrane. Coincidental with dynein depletion, we observe an increase in the size of ionotropic glutamate receptor (iGluRs) fields, and an increase in the amplitude and frequency of mEJPs. PI(4,5)P2 levels do not affect iGluR clustering, nor does dynein affect the levels of iGluR subunits at the NMJ. Our observations suggest a separate, transport independent function for dynein in iGluR cluster organization. Based on the close apposition of dynein punctae to the iGluR fields, we speculate that dynein at the postsynaptic membrane contributes to the organization of the receptor fields, hence ensuring proper synaptic transmission.

Congenital myasthenia syndrome due to CHRNA1 mutation resulting in respiratory failure

CMS is an inherited disorder, characterized by defective transmission at Neuromuscular Junction affecting from birth or soon after. It results in fatigue and muscle weakness because of genetic abnormalities that interfere with the neuromuscular junction's ability to function. The most typical signs of CMS include eyelid drooping, breathing difficulties, muscle weakness and weariness with variations depending on specific genetic mutations. Clinical examinations, neurophysiologic tests, and genetic analyses are frequently combined to make the diagnosis of CMS. Although there is no known treatment for CMS, many patients may control their symptoms and lead relatively normal lives with the right care. A newborn with CMS due to CHRNA1 gene mutation is described in this article, along with its very early onset. The CHRNA1 mutation is a rare variant in the Indian population. Due to muscle weakness, the neonate in this case developed severe respiratory distress and later succumbed to death despite rigorous life-saving measures.

New and Emerging Biological Therapies for Myasthenia Gravis: A Focussed Review for Clinical Decision-Making.

Myasthenia gravis (MG) is a rare autoimmune disease characterised by exertion-induced muscle weakness that can lead to potentially life-threatening myasthenic crises. Detectable antibodies are directed against specific postsynaptic structures of the neuromuscular junction. MG is a chronic condition that can be improved through therapies, but to date, not cured. Standard treatment has been unchanged for decades and includes symptomatic treatment with acetylcholine-esterase inhibitors and disease-modifying treatment with steroids, steroid-sparing immunosuppressants and thymectomy. Overall, a relevant proportion of patients does not achieve a satisfactory clinical improvement under standard treatment. Additionally, long-term therapy with steroids can cause significant side effects and latency to clinical improvement with standard steroid-sparing immunosuppressants and after thymectomy can take months to years. In recent years, treatment of MG has changed fundamentally due to improved evidence from phase 3 trials and the regulatory approval of complement inhibitors and FcRn inhibitors as add-on treatment options. This provides new optimism for substantially more patients reaching minimal manifestation status and has led to a shift in treatment strategy with more targeted therapies being employed early in the course of the disease, especially in patients with high disease activity. In this focussed review, we provide an overview of the diagnosis, classification and standard treatment of MG, followed by data from randomised controlled trials on the modern drugs already available for therapy and those still in the final stages of clinical development. In the second part, we provide an overview of real-world data for already approved therapies and outline how the availability of new biologicals is changing both clinical decision-making and patient journey.

МОРФОФУНКЦИОНАЛЬНЫЕ И БИОЭЛЕКТРИЧЕСКИЕ ХАРАКТЕРИСТИКИ НЕКОТОРЫХ МЫШЦ ЗАПЯСТНОГО СУСТАВА У СОБАКИ: ПИЛОТНОЕ ИССЛЕДОВАНИЕ

The paper presents the morphofunctional characteristics of some muscles of the dog's wrist joint, as well as their bioelectrical characteristics. The purpose of the study is to describe the bioelectrical characteristics of the radial and ulnar extensor carpi of the dog, taking into account the morphofunctional characteristics of these muscles. Objectives of the study: to conduct a morphological and electrophysiological study of the radial and ulnar extensor wrist muscles in dogs; identify patterns of EMG formation depending on the internal structure and innervation of muscles, and conduct a comparative assessment of the morphological and bioelectrical characteristics of the muscles being studied. Research was carried out at the Department of Anatomy, Histology, Physiology and Pathological Anatomy of the Omsk State Agrarian University named after P.A. Stolypin (Omsk). As a result of the studies, it was revealed that the innervation of the muscle fibers of the dog’s extensor carpi ulnaris and radialis has a similar, group character, that is, groups of muscle fibers have a large number of motor units. These groups are reflected on the EMG as separate complexes. An individual set of action potentials in the EMG signal pattern has duration of 0.01–0.014 s and a frequency of 600–800 Hz. The length of the muscle bundles inboth muscles is different: for the extensor carpi ulnaris it is 0.5 cm, for the radial one, respectively, 3.5 cm. Thus, it was found that the characteristics of the innervation and internal structure of the muscle affect the pattern of the EMG signal. The influence of muscle structure by the type of feathering and the length of muscle fibers (in feathery muscles) was not revealed. Thus, the resulting pattern (pattern) of the EMG signal is characteristic of statodynamic muscles. The proposed model of EMG signal formation, as a result of further development, will have the prospect of being used for qualitative and quantitative interpretation and assessment of the functional state of the neuromuscular system in animals and humans.

Rapid iPSC-derived neuromuscular junction model uncovers motor neuron dominance in amyotrophic lateral sclerosis cytopathy

The neuromuscular junction (NMJ) is essential for transmitting signals from motor neurons (MNs) to skeletal muscles (SKMs), and its dysfunction can lead to severe motor disorders. However, our understanding of the NMJ is limited by the absence of accurate human models. Although human induced pluripotent stem cell (iPSC)-derived models have advanced NMJ research, their application is constrained by challenges such as limited differentiation efficiency, lengthy generation times, and cryopreservation difficulties. To overcome these limitations, we developed a rapid human NMJ model using cryopreserved MNs and SKMs derived from iPSCs. Within 12 days of coculture, we successfully recreated NMJ-specific connectivity that closely mirrors in vivo synapse formation. Using this model, we investigated amyotrophic lateral sclerosis (ALS) and replicated ALS-specific NMJ cytopathies with SOD1 mutant and corrected isogenic iPSC lines. Quantitative analysis of 3D confocal microscopy images revealed a critical role of MNs in initiating ALS-related NMJ cytopathies, characterized by alterations in the volume, number, intensity, and distribution of acetylcholine receptors, ultimately leading to impaired muscle contractions. Our rapid and precise in vitro NMJ model offers significant potential for advancing research on NMJ physiology and pathology, as well as for developing treatments for NMJ-related diseases.

Peptidergic modulation of the lobster cardiac system has opposing action on neurons and muscles

Abstract Modulation of neuronal networks, primarily through neuropeptides, generates variations in motor patterns that allow organisms to adapt to environmental changes or sensory inputs. Modulation is complex, with receptors for neuromodulators expressed at various locations within a nervous system; neuromodulators can thus alter muscle dynamics peripherally via the neuromuscular junction (NMJ) and the muscle itself. The neurogenic cardiac neuromuscular system of the American lobster (Homarus americanus) is a well-characterized model for investigating peptidergic modulation. Myosuppressin (pQDLDHVFLRFamide) is an endogenous peptide that interestingly, decreases contraction frequency while also increasing contraction force by acting at both the lobster heart central pattern generator (CPG; the cardiac ganglion) and the periphery (cardiac muscles). Myosuppressin decreases heartbeat frequency by decreasing the burst frequency of the cardiac ganglion (CG). Here, we investigated the remaining question, does myosuppressin exerts its peripheral effects directly on the cardiac muscle, the NMJ, or both? To elucidate myosuppressin's effects on the cardiac muscle, the muscle was isolated from the CPG, and contractions were evoked using focal application of the endogenous neurotransmitter, L-glutamate, while superfusing myosuppressin over the heart. Myosuppressin increased glutamate-evoked contraction amplitude in the isolated muscle, suggesting that myosuppressin exert its peripheral effects directly on the cardiac muscle. To examine effects on the NMJ, excitatory junction potentials were evoked by stimulating the motor nerve and recording the intracellular membrane voltage from a single muscle fiber both in control saline and in the presence of myosuppressin. Myosuppressin did not modulate the amplitude of EJPs suggesting that myosuppressin acts directly on the muscle and not via the NMJ, to cause an increase in contraction force.

Age, cancer, and the dual burden of cancer and doxorubicin in skeletal muscle wasting in femalerats: which one to blame?

Sarcopenia and cancer cachexia are two life-threatening conditions often misdiagnosed. The skeletal muscle is one of the organs most adversely affected by these conditions, culminating in poor quality of life and premature mortality. In addition, it has been suggested that chemotherapeutic agents exacerbate cancer cachexia, as is the case of doxorubicin. Herein, we sought to investigate markers of inflammation and neuromuscular junction (NMJ) remodeling during aging and in response to cancer or cancer with chemotherapy. To address this, we utilized female rats across three age groups-young, adult, and old-to examine age-related changes, with old rats serving as a sarcopenia model. Additionally, a chemically-induced breast cancer (BCa) model was implemented in female adult rats, both without (adult BCa) or with doxorubicin administration (adult BCaDOX), to study cancer cachexia. The atrophy of the gastrocnemius muscle was observed in old, adult BCa and adult BCaDOX rats compared to adult ones. No signs of inflammation or NMJ impairment were observed in adult BCa or adult BCaDOX rats, except for the low levels of the subunit α1 of the acetylcholine receptor in adult BCaDOX rats compared to adult ones. In contrast, old rats presented high serum levels of interleukin 6, brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide compared to young rats. In the gastrocnemius muscle, BDNF levels were decreased in old rats compared to adult rats, suggesting impaired skeletal muscle regeneration upon age-induced damage. The BDNF muscle levels were inversely correlated with its levels in circulation in adult and old rats. Hence, this work highlights BDNF as a specific biomarker of age-induced skeletal muscle atrophy, at least, in the differential diagnosis against cancer- or cancer with chemotherapy-induced muscle wasting.

Sarcoglycans are enriched at the neuromuscular junction in a nerve-dependent manner

Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. Although there are 6 different sarcoglycan isoforms, sarcoglycanopathies are caused exclusively by mutations in genes coding for one of the four sarcoglycan transmembrane proteins (alpha, beta, gamma and delta) forming the sarcoglycan complex (SGC) in skeletal and cardiac muscle. Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that nerve presence precedes the sarcoglycan enrichment at NMJ, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans’ participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.

GsMTx-4 combined with exercise improves skeletal muscle structure and motor function in rats with spinal cord injury.

Motor dysfunction and muscle atrophy are typical symptoms of patients with spinal cord injury (SCI). Exercise training is a conventional physical therapy after SCI, but exercise intervention alone may have limited efficacy in reducing secondary injury and promoting nerve regeneration and functional remodeling. Our previous research found that intramedullary pressure after SCI is one of the key factors affecting functional prognosis. It has been reported that GsMTx-4, a specific blocker of the mechanosensitive ion channels Piezo1, can protect the integrity of the neuromuscular junction and promote nerve regeneration, and thus has the potential as a therapeutic agent for SCI. In this study, we observed the combined and separate therapeutic effect of GsMTx-4 and exercise on the structure of the soleus muscle and motor function in rats with SCI. At 42 days post-injury, compared with SCI rats, the Basso-Beattie-Bresnahan score (P = 0.0007) and Gait Symmetry (P = 0.0002) were significantly improved after combination therapy. On histology of rat soleus muscle, compared with SCI rats, the combined treatment significantly increased the wet weight ratio, muscle fiber cross-sectional area and acetylcholinesterase (all P<0.0001). On histology of rat spinal tissue, compared with SCI rats, the combined treatment significantly increased neuron counts and BDNF levels, and significantly reduced the percentage of TUNEL-positive cells (all P<0.0001). On physiology of rat soleus muscle, compared with SCI rats, the combined treatment increased the succinate dehydrogenase expression (P<0.0001), while the expression of α-glycerophosphate dehydrogenase (P<0.0001) and GDF8 protein (P = 0.0008) decreased. Results indicate the combination therapy effectively improves histopathology of spinal cord and soleus muscle in SCI rats, enhancing motor function. This study was conducted on animal models, it offers insights for SCI treatment, advancing understanding of lower limb muscle pathology post-SCI. Further research is needed for clinical validation in the future.

Anesthesia for pregnant patients with symptomatic neurological disease: 13 years’ experience from a tertiary care center

BackgroundImprovements in diagnostics and clinical care have allowed more women of childbearing age, suffering from neurological diseases, to safely have pregnancy, reducing peripartum complications. However, these patients remain at risk and are a constant challenge for anesthesiologists in the delivery room.MethodsTo assess the type of anesthesiologic management performed for delivery in obstetric patients with preexisting neurological disease and who reported significant neurological symptoms during pregnancy, a retrospective observational study was carried out between 1 October 2008 and 30 September 2021.ResultsData from 49,202 pregnant women were assessed over 13 years; 239 pregnant women with a diagnosis of preexisting neurological disease and who reported significant neurological symptoms during pregnancy were identified (prevalence 0.49%). The main neurological disorders that affected pregnant women included vascular abnormalities and intracranial bleeding (N = 42, 17.6%), central nervous system tumors (N = 35, 14.6%), epilepsy and episodic and paroxysmal disorders of the central nervous system (N = 34, 14.2%), diseases of the neuromuscular junction and muscles (N = 26, 10.9%), demyelinating central nervous system diseases (N = 24, 10%). A total of 234 (97.9%) pregnant women with neurological disorders and significant neurological symptoms underwent cesarean section: 192 (80.3% of the total cesarean sections) were elective, 39 (16.3%) were urgent type 2 and 3; 3 (1.2%) were emergency cesarean sections. General anesthesia was administered to 73 patients (30.5%), while 166 patients (69.5%) were managed with neuraxial techniques. 2 patients who had had neuraxial block reported worsening neurological symptoms that required a change in medical therapy. Postoperative multiparameter monitoring was performed for less than 24 h in the recovery room for 226 patients (94.6%). 3 patients (1.2%) were observed with multiparameter monitoring in the post-anesthesia care unit (PACU) for more than 24 hours; 10 patients (4.2%) were moved to the postoperative intensive care unit (ICU). The median hospitalization duration was 4 days (with an interquartile difference of 3–6 days).ConclusionsIn our experience, when neuraxial anesthesia was feasible, it proved to be a safe option for pregnant patients with symptomatic neurological disease, resulting in uncommon maternal complications.

HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity.

The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function.

Guidelines for animal models of endurance and resistance exercise.

This mini-review details the guideline for implementing the most common exercise patterns in small laboratory rodents (mice/rats) and the advantages and disadvantages of each, in ways that are comparable to humans. Also, criteria for targeted selection and control of workload and intensity of activity are proposed in different exercise programs. As an available and low-cost intervention in physiological, biochemical and cellular-molecular assessments, different exercise programs can be effective in the prevention/treatment of many skeletal-structural, behavioral and neurodegenerative disorders. Exercise tolerance/intolerance is an indicator of the complex function of the physiological, metabolic, neuromuscular, cardiovascular and respiratory systems, and in this sense, animal models of exercise are of interest to researchers by creating a controllable and precise environment. Considering the different species of laboratory animals and various exercise paradigms, selecting the type, intensity and duration of the program in an optimal manner is a difficult task, especially in conditions such as old age or illness, and if necessary, existing research tools and protocols should be reviewed. In fact, one of the most attractive applications of exercise models is the discovery of preventive/therapeutic strategies for many disorders, which necessitates more knowledge about exercise protocols. Animal models of endurance/resistance exercise on land/water make it possible to evaluate physiological/pathological conditions. However, to obtain optimal and reproducible results in human samples, the effectiveness of anesthetic drugs, surgical procedures, and the stress caused by exercise tools and equipment must be carefully controlled.

Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models.

Background/Objectives: Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. Methods: We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred SOD1G93A mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. Results: The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. Conclusions: Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common Il6R Asp358Ala variant.

Analysis of the effect of combined rehabilitation training and transcutaneous vagus nerve electrical stimulation on promoting central nervous system remodeling in stroke patients.

To explore the effect of combined rehabilitation training and transcutaneous vagus nerve electrical stimulation (t-VNS) on promoting central nervous system remodeling and neurological function recovery in stroke patients. A total of 124S patients admitted to our hospital from January to December 2023 were included in this study. The therapeutic effects were evaluated using the Modified Barthel Index (MBI) and the simplified Fugl-Meyer Assessment Scale (sFMA) to measure patients' activities of daily living and motor function recovery. Additionally, neurophysiological assessments, including electromyography (EMG) and motor evoked potentials (MEPs), were conducted to evaluate changes in neuromuscular and central nervous system function. Changes in neural activity in the frontal lobe and motor cortex were assessed through transcutaneous vagus nerve stimulation and electroencephalography. Moreover, all adverse events were recorded. After treatment, patients in the t-VNS combined with rehabilitation training group showed significant improvements in sFMA and MBI scores compared to the pure rehabilitation training group (P<0.05). In terms of neurophysiology, patients in the combined treatment group exhibited significant increases in electromyographic activity and MEPs (P<0.05). EEG results indicated enhanced neuroplasticity of the frontal lobe and motor cortex with t-VNS treatment. The incidence of skin stimulation and ear pain in the combined treatment group was significantly higher than that in the pure rehabilitation training group. Combined rehabilitation training and transcutaneous vagus nerve electrical stimulation have significant effects on neurological function recovery and central nervous system remodeling in stroke patients, effectively improving patients' motor function and activities of daily living.