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Background: Increasing evidence supporting the clinical effectiveness of cooled radiofrequency ablation (RFA) therapy for genicular nerves in patients with chronic knee osteoarthritis (OA) exists. However, no study has been conducted to eliminate the potential influence of a placebo effect associated with this procedure. Therefore, we evaluated the efficacy of cooled RFA compared with a sham procedure in patients with painful knees due to OA. Methods: In this double-blind, randomized, controlled study, participants were randomly assigned to receive cooled RFA of the knee (cooled RFA group, n = 20) or a sham procedure (sham group, n = 20). The primary outcome was the proportion of successful responders at the three-month follow-up. The secondary outcomes were successful responders at one and six months; pain intensity of the knee; functional status; medication; and satisfaction at one, three, and six months after the procedures. Results: For the primary outcome, the successful responder rate was significantly higher in the cooled RFA group (76.5%) than in the sham group (33.3%) (p = 0.018). For the secondary outcome, more successful responders were observed in the cooled RFA group than in the sham group at one and six months after the procedure (p = 0.041 and 0.007, respectively). The decreased knee pain intensity was maintained throughout the six-month follow-up period in the cooled RFA group. No differences were observed in functional status, medication change, or satisfaction in both groups. Conclusions: The cooled RFA of genicular nerves offers significant pain relief and surpasses the effects attributable to a placebo.

Autonomic denervation dermatitis (ADD) is relatively a new terminology reported in dermatology literature. It is characterized by occurrence of eczematous lesions at the site of surgical incision and adjoining skin after a varying lag period. It has been commonly reported after various surgical procedures like total knee replacement, saphenous vein graft harvesting, and open fracture reduction. It is proposed that transection of dermal nerves leads to autonomic disturbance in the involved area resulting in such dermatitis. In this article, we report a series of six such cases, which were previously under reported. [ABSTRACT FROM AUTHOR]

Early detection of skeletal muscle atrophy is important to prevent further muscle weakness. However, there are few non-invasive biomarkers for skeletal muscle atrophy. Recent studies have reported that the N-terminal fragment (N-titin) of titin, a giant sarcomeric protein, is detected in the urine of patients with muscle damage. In this study, we hypothesized that urinary N-titin would be a potential early biomarker of skeletal muscle atrophy in mice caused by sciatic nerve denervation. Male mice were randomly divided into control and denervation groups, and urinary N-titin levels were assessed daily for 9 days using an enzyme-linked immunosorbent assay system. Despite reduced titin protein levels in atrophic muscles 10 days after denervation, cleaved N-titin fragments were not increased in the urine of mice with denervation-induced muscle atrophy. Furthermore, we found no uptake of Evans blue dye from the extracellular space into the cytoplasm in atrophic muscles, suggesting that the sarcomeric membrane is intact in those muscles. The present results suggest that cleaved N-titin in the urine is not suitable as an early biomarker of skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Previously, we demonstrated in pigs that renal denervation halves glucose release during hypoglycaemia and that a prenatal dexamethasone injection caused increased ACTH and cortisol concentrations as markers of a heightened hypothalamic pituitary adrenal axis (HPAA) during hypoglycaemia. In this study, we investigated the influence of an altered HPAA on renal glucose release during hypoglycaemia. Pigs whose mothers had received two late-gestational dexamethasone injections were subjected to a 75 min hyperinsulinaemic–hypoglycaemic clamp (<3 mmol/L) after unilateral surgical denervation. Para-aminohippurate (PAH) clearance, inulin, sodium excretion and arterio–venous blood glucose difference were measured every fifteen minutes. The statistical analysis was performed with a Wilcoxon signed-rank test. PAH, inulin, the calculated glomerular filtration rate and plasma flow did not change through renal denervation. Urinary sodium excretion increased significantly (p = 0.019). Side-dependent renal net glucose release (SGN) decreased by 25 ± 23% (p = 0.004). At 25 percent, the SGN decrease was only half of that observed in non-HPAA-altered animals in our prior investigation. The current findings may suggest that specimens with an elevated HPAA undergo long-term adaptations to maintain glucose homeostasis. Nonetheless, the decrease in SGN warrants further investigations and potentially caution in performing renal denervation in certain patient groups, such as diabetics at risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Background: This research examines knee osteoarthritis (OA), a prevalent orthopedic disease marked by cartilage degeneration and chronic synovitis, leading to pain, restricted mobility, and eventual loss of knee function. Notably, patellofemoral osteoarthritis constitutes a significant proportion of knee OA cases. Our study aims to assess the impact of knee arthroscopic debridement coupled with peripatellar denervation on restoring knee function in OA patients and analyze the risk factors affecting treatment outcomes. By doing so, we hope to contribute to the informed selection of clinical treatment plans, addressing a disease that, if untreated, significantly impairs patients' quality of life. Methods: A total of 211 patients with knee osteoarthritis treated in our hospital from June 2020 to June 2022 were analyzed retrospectively. Among them, 116 patients received arthroscopic knee debridement treatment alone as the control group, and 95 in the observation group were combined with denervation treatment based on the control group. The clinical efficacy of the two groups of patients after treatment was evaluated, and patients' pain was counted using the pain visual analogue score (VAS) method. The knee range of motion (ROM) was used to count the mobility of the patients and to compare the operative time, intraoperative perfusion volume, and length of stay between the two groups. According to the effectiveness after treatment, patients were divided into the improvement group (effective + markedly effective) and the non-improvement group, and the risk factors affecting the clinical efficacy of patients after treatment were analyzed by logistic regression. Results: The total treatment efficiency of patients in the control group was lower than that of those in the observation group (P < 0.05). There was no difference in intraoperative perfusion volume and length of stay between patients in both groups (P > 0.05). However, the operative time was shorter in the control group compared with that in the observation group (P < 0.001). The post-treatment VAS scores of patients in the observation group were lower than those in the control group, while the ROM scores were higher than those of the control group (P < 0.001). Age, BMI, and preoperative VAS score were found to be independent risk factors for patient outcome by logistic regression analysis (P < 0.05). Conclusion: knee arthroscopic debridement combined with peripatellar denervation has a significant improvement in the restoration of knee function in patients with knee osteoarthritis and reduces their level of pain. [ABSTRACT FROM AUTHOR]

Background: The autonomic nervous system can modulate the innate immune responses to bacterial infections via the splanchnic sympathetic nerves. Here, we aimed to determine the effects of bilateral splanchnic sympathetic nerve denervation on blood pressure, plasma cytokines, blood bacterial counts and the clinical state in sheep with established bacteremia. Methods: Conscious Merino ewes received an intravenous infusion of Escherichia coli for 30 h (1 × 109 colony forming units/mL/h) to induce bacteremia. At 24 h, sheep were randomized to have bilaterally surgically implanted snares pulled to induce splanchnic denervation (N = 10), or not pulled (sham; N = 9). Results: Splanchnic denervation did not affect mean arterial pressure (84 ± 3 vs. 84 ± 4 mmHg, mean ± SEM; PGroup = 0.7) compared with sham treatment at 30-h of bacteremia. Splanchnic denervation increased the plasma levels of the pro-inflammatory cytokine interleukin-6 (9.2 ± 2.5 vs. 3.8 ± 0.3 ng/mL, PGroup = 0.031) at 25-h and reduced blood bacterial counts (2.31 ± 0.45 vs. 3.45 ± 0.11 log10 [CFU/mL + 1], PGroup = 0.027) at 26-h compared with sham treatment. Plasma interleukin-6 and blood bacterial counts returned to sham levels by 30-h. There were no differences in the number of bacteria present within the liver (PGroup = 0.3). However, there was a sustained improvement in clinical status, characterized by reduced respiratory rate (PGroup = 0.024) and increased cumulative water consumption (PGroup = 0.008) in splanchnic denervation compared with sham treatment. Conclusion: In experimental Gram-negative bacteremia, interrupting splanchnic sympathetic nerve activity increased plasma interleukin-6, accelerated bacterial clearance, and improved clinical state without inducing hypotension. These findings suggest that splanchnic neural manipulation is a potential target for pharmacological or non-pharmacological interventions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lower-extremity spasticity and impaired gait control after central nervous system injury are challenging to improve, because spasticity limits residual motor control while providing mechanical support. Highly selective partial neurectomies (HSPNs) can substantially reduce spasticity but may have greater risks in patients with complex lower-extremity spastic gait. OBJECTIVE: To examine the potential of ultrasound- and stimulation-guided highly selective motor nerve blocks (HSMNBs) to assess the potential impact of reduced spasticity on gait. METHODS: In this retrospective series, six patients underwent HSMNBs with movement assessment before and after the block. Range of motion, strength, position angles, surface electromyography, lower limb kinematics, and patient satisfaction were assessed. RESULTS: Pre- and post-HSMNB movement analysis yielded dichotomous gait kinematics, which facilitated surgical decisions. Of the 59 metrics evaluated, 82% demonstrated a positive improvement post-block (62% improved more than one standard deviation (SD) of typically developing means, 49% improved > 2 SD) and 16% demonstrated a negative change (2% worsened > 1 SD). CONCLUSION: HSMNB provided clear efficacy in changing clinical, surface electromyography, and gait parameters. Movement analysis provided clear and robust objective and patient-centered evidence for surgical guidance. This protocol may provide utility in evaluation of patients being considered for HSPNs for complex spastic gait patterns. [ABSTRACT FROM AUTHOR]

The rising prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) poses a major challenge to global health. Existing therapeutic approaches have limitations, and there is a need for new, safe, and less invasive treatments. Interventional metabolic therapy is a new addition to the treatment arsenal for metabolic disorders. This review focuses on two interventional techniques: bariatric arterial embolization (BAE) and endovascular denervation (EDN). BAE involves embolizing specific arteries feeding ghrelin‐producing cells to suppress appetite and promote weight loss. EDN targets nerves that regulate metabolic organs to improve glycemic control in T2DM patients. We describe the current state of these techniques, their mechanisms of action, and the available safety and effectiveness data. We also propose a new territory called "Interventional Metabology" to encompass these and other interventional approaches to treating metabolic disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: The contribution of neuronal innervation to cancer development and persistence is not well understood. In the current study, a novel microsurgical technique for inducing radical and persistent denervation (R&P) on tumor growth was evaluated in a metastatic, solid tumor model in immunocompetent Sprague Dawley rats. Tumors were induced using the mammary adenocarcinoma cell line (HH-16.cl4). Surgical treatment resulted in tumor regression, and led to the long-term survival of the animals, extending to more than >1 year follow-up (long term survival; LTS = 87.5%), indicating the induction of a potent systemic anticancer response. In order to characterize further the anticancer response, multiple tumors were implanted on the same animal and treatment was applied to one of them. Both the treated (primary) and untreated (remote) tumor masses exhibited regression, leading to a 57.1% LTS. The R&P denervation strategy is in line with the results from the current translational research on cancer neurobiology. However, the clinical value of the approach will be verified in a pilot clinical study. This preliminary study seeks to determine the effect of R&P denervation on tumor growth and survival in immunocompetent rats bearing an aggressive and metastatic breast solid tumor. A novel microsurgical approach was applied "in situ", aiming to induce R&P denervation through the division of every single nerve fiber connecting the host with the primary tumor via its complete detachment and re-attachment, by resecting and reconnecting its supplying artery and vein (anastomosis). This preparation, known as microsurgical graft or flap, is radically denervated by definition, but also effectively delays or even impedes the return of innervation for a significant period of time, thus creating a critical and therapeutic time window. Mammary adenocarcinoma cells (HH-16.cl4) were injected into immunocompetent Sprague Dawley adult rats. When the tumors reached a certain volume, the subjects entered the study. The primary tumor, including a substantial amount of peritumoral tissue, was surgically isolated on a dominant artery and vein, which was resected and reconnected using a surgical microscope (orthotopic tumor auto-transplantation). Intending to simulate metastasis, two or three tumors were simultaneously implanted and only one was treated, using the surgical technique described herein. Primary tumor regression was observed in all of the microsurgically treated subjects, associated with a potent systemic anticancer effect and prolonged survival. In stark contrast, the subjects received a close to identical surgical operation; however, with the intact neurovascular connection, they did not achieve the therapeutic result. Animals bearing multiple tumors and receiving the same treatment in only one tumor exhibited regression in both the "primary" and remote- untreated tumors at a clinically significant percentage, with regression occurring in more than half of the treated subjects. A novel therapeutic approach is presented, which induces the permanent regression of primary and, notably, remote tumors, as well as, evidently, the naturally occurring metastatic lesions, at a high rate. This strategy is aligned with the impetus that comes from the current translational research data, focusing on the abrogation of the neuro–tumoral interaction as an alternative treatment strategy. More data regarding the clinical significance of this are expected to come up from a pilot clinical trial that is ongoing. [ABSTRACT FROM AUTHOR]

Aims: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and 'dying‐back' pathology in models of SOD1‐dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP‐43, a key mediator protein in ALS, is overexpressed in neurons in Thy1‐hTDP‐43WT mice. We therefore aimed to comprehensively analyse NMJ pathology in this model of ALS. Methods: Expression of TDP‐43 was assessed via western blotting. Immunohistochemistry techniques, alongside NMJ‐morph quantification, were used to analyse motor neuron number, NMJ denervation status and terminal Schwann cell morphology. Results: We present a time course of progressive, region‐specific motor neuron pathology in Thy1‐hTDP‐43WT mice. Thy1‐driven hTDP‐43 expression increased steadily, correlating with developing hindlimb motor weakness and associated motor neuron loss in the spinal cord with a median survival of 21 days. Pronounced NMJ denervation was observed in hindlimb muscles, mild denervation in cranial muscles but no evidence of denervation in either forelimb or trunk muscles. NMJ pathology was restricted to motor nerve terminals, with denervation following the same time course as motor neuron loss. Terminal Schwann cells were lost from NMJs in hindlimb muscles, directly correlating with denervation status. Conclusions: Thy1‐hTDP‐43WT mice represent a severe model of ALS, with NMJ pathology/denervation of distal muscles and motor neuron loss, as observed in ALS patients. This model therefore provides an ideal platform to investigate mechanisms of dying‐back pathology, as well as NMJ‐targeting disease‐modifying therapies in ALS. [ABSTRACT FROM AUTHOR]

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Chronic skeletal muscle degeneration is characterized by fiber atrophy accompanied by deposition of extracellular matrix (ECM) components and fatty infiltration. Excessive accumulation of ECM leads to fibrosis via the contribution of fibro-adipogenic precursors (FAPs). Fibrosis also accompanies disuse atrophy and sarcopenia without significant inflammation. The present study aimed to comparatively analyze heterogeneous population of FAPs during acute injury and immobilization (tenotomy and denervation). The comparative analysis was accomplished based on the following 3 stromal cell subpopulations: i) CD140a(+)/Sca1(+); ii) CD140a(+)/Sca1(–); iii) CD140a(–)/Sca1(+). RNASeq analysis was employed to characterize and compare their quiescent and activated states. Whereas CD140a(-)/Sca1(+) was the most predominant activated subpopulation in tenotomy, denervation stimulated the CD140a(+)/Sca1(+) subpopulation. Immobilization models lacked myofiber damage and exhibited a minute increase in CD45(+) cells, as compared to acute injury. Transcriptome analysis showed common and discordant regulation of ECM components, without profound proliferative activation. Herein, we suggest unique surface markers for further identification of the investigated cell subpopulations. FAP subpopulations show similar activation kinetics in an inflammatory environment but the present findings highlight the fact that inflammation may not be a prerequisite for FAP activation. Delayed proliferation kinetics indicate that signals beyond inflammation might trigger FAP activation, leading to irreversible stromal changes. [ABSTRACT FROM AUTHOR]

Objective: Undifferentiated chronic monosecarthritis (UCMA) is a group of inflammatory joint diseases that has the potential to progress to other diseases and can seriously affect patients' quality of life. There is yet no unified consensus regarding treatment of UCMA. This study aimed to investigate the efficacy of arthroscopic synovectomy combined with partial wrist denervation in treating Larsen 1–3 UCMA. Methods: In this case series, we reviewed 14 patients with UCMA treated by arthroscopic synovectomy combined with partial denervation from February 2017 to June 2020. The mean duration of symptoms was 17.4 months (range, 4–60 months), and the mean follow‐up was 13.3 months (range, 6–23 months). The anterior and posterior interosseous nerves were severed at the distal forearm, and the radiocarpal, midcarpal, and distal radial ulnar joint synovial membranes were arthroscopically resected at the wrist. The clinical evaluation indices included the visual analogue scale score (VAS) for pain, grip strength, range of (active) motion of the wrist, total active motion, and Mayo wrist score. Larsen's scoring method was used as the imaging evaluation index. Results: At the last follow‐up, significant clinical improvements were observed in the visual analogue scale (VAS) score for pain (6.0 (5.0–6.3) vs 1.0 (1.0–2.3), P = 0.001) and Mayo wrist score (42.1 ± 9.7 vs 61.8 ± 12.3, P < 0.0001). No significant changes were found in grip strength (15.9 ± 4.5 vs 16.6 ± 4.7, P = 0.230) or the flexion‐extension arc (58.9 ± 39.0 vs 64.3 ± 36.5, P = 0.317), although the mean and median did show positive changes. Among the three patients who showed progress in imaging, there was no significant difference in their pain and functional scores compared to those who did not progress. One patient underwent total wrist fusion 17 months after the operation. Conclusion: Arthroscopic wrist synovectomy combined with partial wrist denervation can provide sustained pain relief and functional recovery for patients with Larsen 1–3 UCMA. [ABSTRACT FROM AUTHOR]

Background and objective. In the clinical approach of the peripheral facial paralysis there are therapeutic options focused on restoring facial motor function, such as static and dynamic surgeries; however, facial asymmetry is a persistent problem. Selective facial nerve neurectomy (SFNN) is a widely used surgery for the management of synkinesias and hyperkinesias as sequelae of pasalysis. Our objective is to analyze the results in the improvement of facial asymmetry of patients undergoing SFNN for the treatment of contralateral hyperkinesia of facial paralysis through the implementation of the Sunnybrook Facial Grading Scale (SFGS). Methods. A prospective observational descriptive study is designed for a sample of 100 patients diagnosed with peripheral facial paralysis treated at the Hospital de San José, Bogotá, Colombia. Demographic variables were described, and once the patients undergoing SFNN were identified, the clinical history is used to carry out the staging of the scale described and the results are compared in the pre and postoperative period. A description of the surgical technique used was made. Results. A difference in the SFGS scale classification score was identified due to an increase in the score in the postoperative period of 4 patients that were treated with SFNN with statistically significant differences. Conclusions. In our experience, SFNN is useful in the management of persistent facial asymmetry as a consequence of facial palsy. [ABSTRACT FROM AUTHOR]

The common neuropathy Cubital Tunnel Syndrome (CuTS) causes sensory impairment. Numerous patients also exhibit muscle atrophy as a symptom of severe and persistent nerve damage, which typically portends a poor prognosis. In the majority of individuals with minor nerve dysfunction, nonsurgical treatment aimed at reducing both compression and traction on the ulnar nerve at the elbow is successful. The optimum care for a patient with this pathology requires prompt and accurate evaluation, diagnosis, and testing, as well as evidence-based therapy choices. The goal of this review article was to offer an updated summary of the most recent research on the results of several surgical procedures for CuTS. A clinician must use the available information to develop a diagnosis and treatment plan that are unique to the patient. The most effective surgical methods for CuTS need to be discovered through more in-depth scientific investigation. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder in which catecholamine release during exercise or emotional stress cause fatal tachyarrhythmias. In this paper, we discuss methods to minimize the sympathetic stimulation that can occur during the perioperative period in patients undergoing left cardiac sympathetic denervation to surgically treat CPVT. [ABSTRACT FROM AUTHOR]

Functions of nerves on bone has been a subject of intense research. The aim of this study is to observe initial bone healing of rat tooth extraction socket after inferior alveolar nerve transection. The bilateral mandible second molars of eighteen Wistar rats were extracted in the study. The rats also suffered from right inferior alveolar nerve transection simultaneously (D + E group), only extraction as control (E group). One, two and four weeks after extraction, the mandibles were taken out for histological observation, TRAP staining, immunofluorescence, immunohistochemistry and micro-computed tomography (Micro-CT). Mouse bone marrow derived macrophages (BMMs) were cultured in vitro. Expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) were detected in vivo and vitro. The alveolar sockets had been filled to a large extent with new bone at 4 weeks, but BV/TV and BMD decreased in the D + E group. Accordingly, Expressions of osteocalcin (OCN) and osteopontin (OPN) were down-regulated in the D + E group. Denervation increased TRAP-positive osteoclasts and decreased expressions of Nrf2 at 2 weeks after extraction. Decreased Nrf2 promoted osteoclast differentiation of BMMs in vitro. Denervation delays initial bone healing of rat tooth extraction socket. Osteoclast activation induced by decreased Nrf2 might participated in the process. [ABSTRACT FROM AUTHOR]

BACKGROUND: The trapeziometacarpal or first carpometacarpal (CMC) joint is the second most common joint affected in osteoarthritis (OA) of the hand. Surgical intervention may be required when conservative measures fail to alleviate symptoms. OBJECTIVE: To investigate operative and post-operative management of trapeziometacarpal osteoarthritis in Ireland. METHODS: An on-line Qualtrics survey was used to determine practice patterns of hand surgeons and therapists including surgical technique, patterns of referral to therapy, treatment protocol and perceived pain impact. RESULTS: Twenty surgeon's responses were received. Trapeziectomy with Ligament Reconstruction and Tendon Interposition (LRTI) was the most common procedure for all stages of arthritis for sedentary and manual patients. Sixty seven percent (n = 18) stated they perform an additional procedure if stage IV arthritis is present. Eighty percent (n = 16) stated they would perform an additional procedure for MCP joint hyperextension. There were 28 therapist responses. Almost all respondents indicated that patients are initially casted post-surgery with 88% (n = 24) indicating they remain casted for 1-2 weeks. A rigid long thumb spica and neoprene splint are most commonly used. The commencement of exercises differed between respondents and surgical procedures. All participants stated that pain is an issue in the rehabilitation of these patients. CONCLUSIONS: There was consistency in the surgical procedure choice. The stage of arthritis and functional level of the patient was not found to be an important factor for choosing this procedure. There is some consensus for post-operative casting and splinting but more variability in terms of exercise prescription. Pain is a factor to consider post-operatively. [ABSTRACT FROM AUTHOR]

The cation-chloride cotransporters KCC2 and NKCC1 regulate the intracellular Cl- concentration and cell volume of neurons and/or glia. The Cl- extruder KCC2 is expressed at higher levels than the Cl- transporter NKCC1 in mature compared to immature neurons, accounting for the developmental shift from high to low Cl- concentration and from depolarizing to hyperpolarizing currents through GABA-A receptors. Previous studies have shown that KCC2 expression is downregulated following central nervous system injury, returning neurons to a more excitable state, which can be pathological or adaptive. Here, we show that deafferentation of the dendritic segments of granule cells in the outer (oml) and middle (mml) molecular layer of the dentate gyrus via entorhinal denervation in vivo leads to cell-type- and layer-specific changes in the expression of KCC2 and NKCC1. Microarray analysis validated by reverse transcription-quantitative polymerase chain reaction revealed a significant decrease in Kcc2 mRNA in the granule cell layer 7 days post-lesion. In contrast, Nkcc1 mRNA was upregulated in the oml/mml at this time point. Immunostaining revealed a selective reduction in KCC2 protein expression in the denervated dendrites of granule cells and an increase in NKCC1 expression in reactive astrocytes in the oml/mml. The NKCC1 upregulation is likely related to the increased activity of astrocytes and/or microglia in the deafferented region, while the transient KCC2 downregulation in granule cells may be associated with denervation-induced spine loss, potentially also serving a homeostatic role via boosting GABAergic depolarization. Furthermore, the delayed KCC2 recovery might be involved in the subsequent compensatory spinogenesis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect and value of electrophysiology in the 'triple operation' (selective excision of spastic muscles in the neck, selective resection of the posterior branch of the cervical nerve and accessory neurotomy) of spastic torticollis. Methods: Preoperative electromyography (EMG) examination was performed on 96 patients with spastic torticollis treated in our hospital from January 2015 to December 2019. The results were used to assess the responsible muscles' primary or secondary position and the function of antagonistic muscles and to formulate a personalised surgical plan. A Cascade PRO 16-channel electrophysiological diagnostic system (produced by Cadwell, USA) was used to record the evoked EMG. Target muscles were denervated under intraoperative electrophysiological monitoring and re-examined by EMG six months later to evaluate the efficacy. Results: The satisfactory rate of target muscle denervation was 95%, and the overall good rate was 79.1%. Conclusion: Electrophysiological examination and intraoperative application may have a positive value in the selection of the operative method, improving the rate of denervation and evaluating the prognosis of the 'triple operation'. [ABSTRACT FROM AUTHOR]

Objective: The pandemic coronavirus disease-2019 (COVID-19) is caused by a novel type of coronavirus named severe acute respiratory syndrome coronavirus-2 and is rapidly spreading all over the world. In addition to various neurological symptoms, acute facial palsy was diagnosed as the main neurological symptom in some COVID-19 patients. The current study aimed to analyze the variation and any possible association in the case numbers or medical symptoms of patients with facial palsy before and during the COVID-19 pandemic. Methods: The clinical files of patients who were diagnosed with facial palsy in the Neurology Department of Medicalpoint Hospital, University of Economics Faculty of Medicine, İzmir were retrospectively investigated. To compare the facial palsy cases according to different periods, two patient groups were formed: before the COVID-19 pandemic and during the COVID-19 pandemic. The pandemic group was further divided into two subgroups as COVID-19-positive and COVID-19-negative patients to compare the effects of COVID-19 on facial palsy. Results: During the specified COVID-19 period (May 2020-January 2021) of the study, 38 patients were admitted to the hospital for facial palsy; 34 facial palsy patients were admitted in the same calendar period as the two previous years (May 2018-January 2019). There was no significant difference in the frequency of facial palsy between these two time periods. There were significant differences between before and during the COVID-19 pandemic groups regarding response to cortisone therapy (p<0.001), facial palsy grade (p<0.001), electromyography findings (p=0.005), denervation (p<0.001), and 6 months recovery (p<0.001) data. There were also significant differences between the COVID- 19-positive and COVID-19-negative subgroups regarding response to cortisone therapy (p=0.015) and facial palsy grade (p=0.001). Conclusion: The current study findings support the possible association between the severity of the clinical course of facial palsy and COVID-19. Further studies are needed to prove a direct association between facial palsy and COVID-19. [ABSTRACT FROM AUTHOR]

Background: A hallmark of Parkinson's disease (PD) is progressive loss of dopamine terminals in the basal ganglia, with clinical symptoms including motor and non‐motor manifestations such as bradykinesia, rigidity, and cognitive impairment. Dopamine transporter single‐photon emission computed tomography (DaT‐SPECT) can be used to assess dopaminergic denervation by detecting loss of striatal dopamine transporters (DaT). Objective: We examined DaT binding scores' (DaTbs) association with motor outcomes in PD and explored its usefulness as a predictor of disease progression. Faster dopaminergic denervation in the basal ganglia was hypothesized to have stronger correlation and predictive value for poor motor outcomes. Methods: Data was analyzed from the Parkinson's Progression Markers Initiative. DaTbs in the putamen and caudate nucleus were correlated with Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) scores for walking and balance difficulties, gait difficulties, and presence of dyskinesias. A predictive model using baseline speed of drop in DaT binding score was performed for each motor outcome. Results: All motor outcomes had mild, significantly negative correlation with DaTbs in the putamen and caudate nucleus, with similar degree of correlation per region. Speed of drop was predictive of only substantial gait difficulties when evaluated in the putamen but not the caudate. Conclusions: These findings suggest that analyzing speed of drop in DaTbs, which occurs early in the motor phase of the disease, may be helpful for predicting clinical outcomes in PD. Longer observation of this cohort may provide further data to investigate DaTbs as a prognostic marker in PD. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the clinical effectiveness of patella rim electrocautery "denervation" versus no denervation in patients undergoing total knee arthroplasty (TKA). We conducted a single-center, double-blind randomized controlled trial. Patients aged 40 years or older, due to undergo a TKA who did not have patella resurfacing (usual care) were randomized with or without circumferential patella electrocautery. This was undertaken according to a randomly generated sequence of treatment allocation that was placed into numbered, sealed opaque envelopes. Participants were blinded to treatment allocation. There was no crossover. The primary outcome was Oxford Knee Score at 1 year postoperatively. Secondary outcomes were Bartlett Patella Score, Western Ontario and McMaster Universities Arthritis Index (WOMAC), and 12-Item Short Form Survey. Linear regression analyses were performed with adjustments by age, sex, and baseline (preoperative) scores. There were 142 participants recruited, of which 49 (35%) were allocated to the denervation intervention. Recruitment was stopped early when interim statistical analyses confirmed adequate numbers in both groups despite an imbalance in early treatment allocation rates due to the randomization method. The mean patient age was 71 years (range, 50 to 85) and 51% (n = 74) were women. No difference in Oxford Knee Score was detected at 1 year (mean difference [MD] 1.87; 95% confidence interval [CI] −1.28 to 5.03). No difference was detected in Bartlett Patella Score (MD 0.490; 95% CI −1.61 to 2.59) or 12-Item Short Form Survey (MD 0.196; 95% CI −2.54 to 2.93). A statistically significant difference in WOMAC was detected, but at a level less than the minimal clinically important difference for WOMAC (MD 4.79; 95% CI 1.05 to 8.52). No clinically relevant benefit was detected from patella rim electrocautery in patients undergoing TKA who did not have patella resurfacing (including no benefit in terms of anterior knee pain). This treatment is therefore not recommended for clinical practice. Level 1. [ABSTRACT FROM AUTHOR]

Ulnar wrist denervation has been a successful treatment for patients with ulnar-sided wrist pain. The purpose of this study was to characterize the articular branches of the dorsal branch of the ulnar nerve (DBUN) and validate a technique for selective peripheral nerve blockade. In cadavers, we performed simulated local anesthetic injections using 0.5 mL of 0.5% methylene into the subcutaneous tissue at a point midway between the palpable borders of the pisiform and ulnar styloid. We then dissected the DBUN, characterized its articular branching pattern, and measured staining intensity of the DBUN and the ulnar nerve relative to a standard. The DBUN branched from the ulnar nerve 7.0 ± 1.2 cm proximal to the ulnar styloid. Among 17 specimens, the DBUN provided an average of 1.2 (range, 0–2) ulnocarpal branches and 1.0 (range, 0–2) carpometacarpal articular branches. A simulated local anesthetic injection successfully stained 100% of the DBUN articular branches at or proximal to their takeoff. There was no staining of the proper ulnar nerves. In all specimens, the DBUN supplied at least one articular branch. A point midway between the palpable border of the pisiform and ulnar styloid may be an effective location for selectively blocking the DBUN articular afferents. In this study, we were able to identify a point halfway between the pisiform and ulnar styloid that has the potential to produce a selective peripheral nerve block of the portion of the DBUN that supplies articular fibers to the ulnocarpal joint and the fifth carpometacarpal joint. This technique may prove useful to surgeons treating ulnar-sided wrist pain. [ABSTRACT FROM AUTHOR]

Denervation contributes to loss of force-generating capacity in aged skeletal muscles, but problems with quantification of denervated fibers mean the precise impact of denervation on muscle function remains unclear. This study therefore looked to develop a reliable assay for identifying denervated muscle fibers, and used this to explore the impact of denervation on age-related force-generation in mouse skeletal muscle. Thirteen young (6-month-old) and 10 old (24-months-old) C57Bl/6 J female mice were utilized. Anaesthetized mice were infused with the fluorescent deoxyglucose analog 2[N-(7-nitrobenz-2-oxa-1,2-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG) and the tibial nerve was repeatedly stimulated to label active skeletal muscle fibers by activity-dependent uptake of 2-NBDG. Data on muscle force generation were acquired as part of the stimulation routine. Labeled muscles were removed, snap frozen, sectioned, and slide mounted. Sections were imaged to show accumulation of 2-NBDG in activated fibers and lack of 2-NBDG accumulation in quiescent (denervated) fibers, then processed using immunohistochemistry to allow collection of data on fiber number and morphology. Soleus muscles from older mice had nine times as many denervated fibers as those from young mice (average n = 36 vs 4, old vs young). Older muscles developed significantly more passive force and less specific force, but denervation only partly accounted for age-related deficits in specific force. Further investigations are required to definitively identify contributors to the decrease in force generation that remain unaccounted for. [ABSTRACT FROM AUTHOR]

Abstract Amyotrophic lateral sclerosis (ALS) is a disease characterized by upper and lower motor neuron (MN) loss with a signature feature of cytoplasmic aggregates containing TDP-43, which are detected in nearly all patients. Mutations in the gene that encodes TDP-43 (TARBDP) are known to result in both familial and sporadic ALS. In ALS, disruption of neuromuscular junctions (NMJs) constitutes a critical event in disease pathogenesis, leading to denervation atrophy, motor impairments and disability. Morphological defects and impaired synaptic transmission at NMJs have been reported in several TDP-43 animal models and in vitro, linking TDP-43 dysregulation to the loss of NMJ integrity in ALS. Through the lens of the dying-back and dying-forward hypotheses of ALS, this review discusses the roles of TDP-43 related to synaptic function, with a focus on the potential molecular mechanisms occurring within MNs, skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.

Summary: Nerve injury of the saphenous nerve or infrapatellar branch seems to be a frequent complication following knee surgery or trauma. Denervation results vary, and in some cases, no pain relief is achieved. This might be due to anatomic variation. The purpose of this anatomical study is to identify the variation in the course of the infrapatellar branch and saphenous nerve.We dissected 18 cadavers from adult donors. Medial to the knee, the saphenous nerve and infrapatellar branch were identified and followed proximally to the point where the infrapatellar branch branched from the saphenous nerve. The location where the infrapatellar branch came off from the saphenous nerve relative to the knee joint and where it passed the knee joint were measured.A total of 23 infrapatellar branches were found. We identified 10 branches between 0–10 cm proximal to the knee joint, 3 branches at 10–20 cm, and 9 branches at >20 cm. Between the patella and semitendinosus tendon, the knee joint was crossed by 5 branches in the anterior, 15 in the middle, and 2 in the posterior one-third.The origin of the infrapatellar branch and the location at which it passes the knee are highly variable. This, in addition to people having multiple branches, might explain why denervation is frequently unsuccessful. Based on the anatomical findings, we propose a more proximal diagnostic nerve block to help differentiate between a distal-middle or proximal origin of the infrapatellar branch. Appropriate placement of the nerve block might help identify people who benefit from denervation.

In obstetric brachial plexus palsy (OBPP), the operative time window for nerve reconstruction of the intrinsic muscles of the hand (IMH) is much shorter than that of biceps. The reason is that the atrophy of IMH becomes irreversible more quickly than that of biceps. A previous study confirmed that the motor endplates of denervated intrinsic muscles of the forepaw (IMF) were destabilized, while those of denervated biceps remained intact. However, the specific molecular mechanism of regulating the self-repair of motor endplates is still unknown. In this study, we use a rat model of OBPP with right C5-C6 rupture plus C7-C8-T1 avulsion and left side as a control. Bilateral IMF and biceps are harvested at 5 weeks postinjury to assess relative protein and mRNA expression. We also use L6 skeletal myoblasts to verify the effects of signaling pathways regulating acetylcholine receptor (AChR) protein synthesis in vitro. The results show that in the OBPP rat model, the protein and mRNA expression levels of NRG-1/ErbB4 and phosphorylation of Akt/mTOR/p70S6K are lower in denervated IMF than in denervated biceps. In L6 myoblasts stimulated with NRG-1, overexpression and knockdown of ErbB4 lead to upregulation and downregulation of AChR subunit protein synthesis and Akt/mTOR/p70S6K phosphorylation, respectively. Inhibition of mTOR abolishes protein synthesis of AChR subunits elevated by NRG-1/ErbB4. Our findings suggest that in the OBPP rat model, lower expression of AChR subunits in the motor endplates of denervated IMF is associated with downregulation of NRG-1/ErbB4 and phosphorylation of Akt/mTOR/p70S6K. NRG-1/ErbB4 can promote protein synthesis of the AChR subunits in L6 myoblasts via phosphorylation of Akt/mTOR/p70S6K.

Abstract Severe peripheral nerve injury leads to the irreparable disruption of nerve fibers. This leads to disruption of synapses with the designated muscle, which consequently go through progressive atrophy and damage of muscle function. The molecular mechanism that underlies the re-innervation process has yet to be evaluated using proteomics or transcriptomics. In the present study, multi-dimensional data were therefore integrated with transcriptome and proteome profiles in order to investigate the mechanism of re-innervation in muscles. Two simulated nerve injury muscle models in the rat tibial nerve were compared: the nerve was either cut (denervated, DN group) or crushed but with the nerve sheath intact (re-innervated, RN group). The control group had a preserved and intact tibial nerve. At 4 weeks, the RN group showed better tibial nerve function and recovery of muscle atrophy compared to the DN group. As the high expression of Myh3, Postn, Col6a1 and Cfi, the RN group demonstrated superior re-innervation as well. Both differentially expressed genes (DEGs) and proteins (DEPs) were enriched in the peroxisome proliferator-activated receptors (PPARs) signaling pathway, as well as the energy metabolism. This study provides basic information regarding DEGs and DEPs during re-innervation-induced muscle atrophy. Furthermore, the crucial genes and proteins can be detected as possible treatment targets in the future.

Renal denervation (RDN) suppresses the activity of the renin–angiotensin–aldosterone system and inflammatory cytokines, leading to the prevention of cardiac remodeling. Limited studies have reported the effects of renal denervation on ventricular electrophysiology. We aimed to use optical mapping to evaluate the effect of RDN on ventricular structural and electrical remodeling in a tachycardia-induced cardiomyopathy rabbit model. Eighteen rabbits were randomized into 4 groups: sham control group (n = 5), renal denervation group receiving RDN (n = 5), heart failure group receiving rapid ventricular pacing for 1 month (n = 4), and RDN-heart failure group (n = 4). Rabbit hearts were harvested for optical mapping. Different cycle lengths were paced (400, 300, 250, 200, and 150 ms), and the results were analyzed. In optical mapping, the heart failure group had a significantly slower epicardial ventricular conduction velocity than the other three groups. The RDN-heart failure, sham control, and RDN groups had similar velocities. We then analyzed the 80% action potential duration at different pacing cycle lengths, which showed a shorter action potential duration as cycle length decreased (P for trend < 0.01), which was consistent across all groups. The heart failure group had a significantly longer action potential duration than the sham control and RDN groups. Action potential duration was shorter in the RDN-heart failure group than the heart failure group (P < 0.05). Reduction of conduction velocity and prolongation of action potential duration are significant hallmarks of heart failure, and RDN reverses these remodeling processes. [ABSTRACT FROM AUTHOR]

For post-menopausal women, stroke is complicated by the variable effects of estrogen therapy and the age-related therapeutic consequences involved. Estrogen therapy has been shown to have an age-dimorphic effect, which is neuroprotective in young females, but non-neuroprotective, even neurotoxic in acyclic females. We hypothesized that arterial baroreflex (ABR) and its downstream acetylcholine-a7 nicotinic acetylcholine receptor (a7nAChR) anti-inflammatory pathways are involved in estrogen efficacy toward cerebral ischemic damage. Our data showed that estrogen supplements contributed to ABR improvement and neuroprotection in adult, not aged, ovariectomized (OVX) rats. In adult rats, OVX-induced estrogen deficiency aggravated middle cerebral artery occlusion (MCAO), which induced brain infarction and reduced ABR function, with decreased a7nAChR expression of the brain and exaggerated inflammation following MCAO; these effects were significantly prevented by supplementation with estrogen. ABR impairment by sinoaortic denervation partly attenuated the estrogen effect on baroreflex sensitivity (BRS) and ischemic damage in adult rats, as well as a7nAChR expression and inflammatory response. These data suggested that ABR and acetylcholine-a7nAChR anti-inflammatory pathways are involved in the neuroprotection of estrogen in adult OVX rats. In contrast, aged rats exhibited more severe ischemic damage and inflammatory response than adult rats, as well as poorer baroreflex function and lower a7nAChR expression. Estrogen supplements did not improve BRS or confer neuroprotection in aged rats without affecting brain a7nAChR and post-ischemic inflammation. Most importantly, ketanserin restored ABR function and significantly postponed the onset of stroke in aged female strokeprone spontaneously hypertensive rats, whereas estrogen treatment failed to delay the development of stroke. Our findings reveal that estrogen is protective against ischemic stroke (IS) in adult female rats and that ABR played a role in this beneficial action. Dysfunction of ABR and unresponsiveness to estrogen in aged female rats may contribute to a reduced estrogen efficacy against cerebral ischemia. [ABSTRACT FROM AUTHOR]

Background: Renal denervation (RDN) has emerged in recent years as a possible treatment for hypertension. The first sham-controlled trial showed a small magnitude and non-significant in the blood pressure (BP) lowering effect, also due to a substantial decrease of BP in sham arm. Considering this, we aimed to quantify the magnitude of BP decrease within the sham arm of Randomized Controlled Trials (RCT) with RDN in patients with hypertension. Methods: Electronic databases were searched since inception until January 2022 for randomized sham-controlled trials which assessed the efficacy in lowering BP of the sham intervention for catheter-based RDN in adult patients with hypertension. The outcomes were change in ambulatory/office systolic and diastolic BP. Results: A total of 9 RCT were included in the analysis enrolling a total of 674 patients. Sham intervention showed a decrease in all evaluated outcomes. Office systolic BP had a reduction of -5.52 mmHg [95%CI -7.91, -3.13] and office diastolic BP of -2.13 mmHg [95%CI -3.08, -1.17]. Sham procedure for RDN also showed a reduction of -3.41 mmHg [95%CI -5.08, -1.75] in ambulatory systolic BP and − 2.44 mmHg [95%CI -3.31, -1.57] in ambulatory diastolic BP. Conclusion: Despite recent data indicating that RDN might be an effective treatment for patients with resistant hypertension when compared to a sham intervention, our results indicate that the sham intervention for RDN also has a significant effect on lowering Office and Ambulatory (24-h) Blood Pressure in adult patients with hypertension. This highlights that BP itself might be sensitive to placebo-like effect and also brings further difficulties in establishing the BP lowering efficacy of invasive interventions due to the magnitude of the sham effect. [ABSTRACT FROM AUTHOR]

Background: Lumbar facet joint pain is a common disorder. The main symptom is chronic lumbar pain, which can reduce quality of life. Radiofrequency has often been used to treat lumbar facet joint pain. However, the effectiveness of this technique has been controversial. This study was conducted to compare the effectiveness of pulsed radiofrequency (PRF) and radiofrequency denervation (RD) for lumbar facet joint pain. Methods: One hundred and forty-two patients with lumbar facet joint pain were allocated to two treatment groups: PRF group (N = 72) and RD group (N = 70). Patients enrolled in the study were assessed using a visual analogue scale (VAS), Roland-Morris questionnaire (RMQ), Oswestry disability index (ODI) and Short-Form 36 (SF-36) questionnaire before therapy, 3 months and 12 months later. Results: There were no significant differences in VAS, RMQ score, ODI score and SF-36 score at 3 months (p > 0.05). Significant differences in pain control were observed in both groups at 12 months (3.09 ± 1.72 vs. 2.37 ± 1.22, p = 0.006). There was a significant difference in RMQ score (11.58 ± 3.58 vs. 8.17 ± 2.34, p < 0.001) and ODI score (43.65 ± 11.01 vs. 35.42 ± 11.32, p < 0.001) at 12 months. The total SF-36 score was higher in the RD group than in the PRF group at 12 months (58.45 ± 6.97 vs. 69.36 ± 6.43, p < 0.001). In terms of complications, skin numbness occurred in three patients. Mild pain such as burning and pinking at the puncture site in two patients. One patient experienced a decrease in back muscle strength and back muscle fatigue. These complications disappeared in 3 weeks without any treatment. There were no serious adverse events in the PRF group. Conclusion: Radiofrequency is an effective and safe treatment option for patients with lumbar facet joint pain. RD could provide good and lasting pain relief, with significant improvement in lumbar function and quality of life at long-term follow-up. [ABSTRACT FROM AUTHOR]

Thoracic spinal cord injuries are well known to entail the degradation of spinal motoneurons, accompanied by axonal degeneration. In the present study, the functional integrity of neuromuscular transmission was assessed via stimulation mechanomiography in Wistar rats. We demonstrated a decrease in the modulating activity of ATP in the cholinergic synapse due to spinal cord injury (a model of spinal cord contusion injury) vs. hypodynamia (a model of anti-orthostatic hindlimb suspension). The revealed abnormal purine-mediated modulation of the neuromuscular junction provides evidence for axonal degeneration and suggests that trans-synaptic degeneration of motor neurons may occur below the spinal cord injury level in patients with similar traumas. [ABSTRACT FROM AUTHOR]

Objective: We aimed to analyze the effectiveness of external neurolysis on the common peroneal nerve (CPN) in patients with posture-induced compressive peroneal neuropathy (PICPNe). Further, we aimed to examine the utility of magnetic resonance imaging (MRI) in assessing the severity of denervation status and predicting the postoperative prognosis. Methods: We included 13 patients (eight males and five females) with foot drop who underwent CPN decompression between 2018 and 2020. We designed a grading system for assessing the postoperative functional outcome. Additionally, we performed MRI to evaluate the denervation status of the affected musculature and its effect on postoperative recovery. Results: The median time to surgery was 3 months. The median preoperative ankle dorsiflexion and eversion grades were both 3, while the average functional grade was 1. Posterior crural intermuscular septum was the most common cause of nerve compression, followed by deep tendinous fascia and anterior crural intermuscular septum. There was a significant postoperative improvement in the median postoperative ankle dorsiflexion and eversion grades and average postoperative functional (4, 5, and 2.38, respectively). Preoperative ankle eversion was significantly correlated with denervation status. Additionally, the devernation status on MRI was positively correlated with the outcome favorability. However, denervation atrophy led to a less favorable outcome. Conclusion: Among patients with intractable PICPNe despite conservative management, surgical intervention could clinically improve motor function and functional ability. Additionally, MRI examination of the affected muscle could help diagnose CPNe and assess the postoperative prognosis. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy occurs rapidly as a result of inactivity. Although there are many reports on changes in gene expression during the early phase of muscle atrophy, the patterns of up-and downregulated gene expression after long-term and equilibrated muscle atrophy are poorly understood. In this study, we comprehensively examined the changes in gene expression in long-term denervated mouse muscles using RNA-Seq. The murine right sciatic nerve was denervated, and the mice were housed for five weeks. The cross-sectional areas of the hind limb muscles were measured using an X-ray CT system 35 days after denervation. After 28 d of denervation, the cross-sectional area of the muscle decreased to approximately 65% of that of the intact left muscle and reached a plateau. Gene expression in the soleus and extensor digitorum longus (EDL) muscles on the 36th day was analyzed using RNA-Seq and validated using RT-qPCR. RNA-Seq analysis revealed that three genes—Adora1, E230016M11Rik, and Gm10718—were upregulated and one gene—Gm20515—was downregulated in the soleus muscle; additionally, four genes—Adora1, E230016M11Rik, Pigh, and Gm15557—were upregulated and one gene—Fzd7—was downregulated in the EDL muscle (FDR < 0.05). Among these genes, E230016M11Rik, one of the long non-coding RNAs, was significantly upregulated in both the muscles. These findings indicate that E230016M11Rik could be a candidate gene for the maintenance of atrophied skeletal muscle size and an atrophic state. [ABSTRACT FROM AUTHOR]

The nuance of autonomic cardiac control has been studied for more than 400 years, yet little is understood. This review aimed to provide a comprehensive overview of the current understanding, clinical implications, and ongoing studies of cardiac sympathetic modulation and its anti-ventricular arrhythmias' therapeutic potential. Molecular-level studies and clinical studies were reviewed to elucidate the gaps in knowledge and the possible future directions for these strategies to be translated into the clinical setting. Imbalanced sympathoexcitation and parasympathetic withdrawal destabilize cardiac electrophysiology and confer the development of ventricular arrhythmias. Therefore, the current strategy for rebalancing the autonomic system includes attenuating sympathoexcitation and increasing vagal tone. Multilevel targets of the cardiac neuraxis exist, and some have emerged as promising antiarrhythmic strategies. These interventions include pharmacological blockade, permanent cardiac sympathetic denervation, temporal cardiac sympathetic denervation, etc. The gold standard approach, however, has not been known. Although neuromodulatory strategies have been shown to be highly effective in several acute animal studies with very promising results, the individual and interspecies variation between human autonomic systems limits the progress in this young field. There is, however, still much room to refine the current neuromodulation therapy to meet the unmet need for life-threatening ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Skeletal muscle is a highly pliable tissue and various adaptations such as muscle hypertrophy or atrophy are induced by overloading or disuse, respectively. However, the combined effect of overloading and disuse on the quantitative adaptation of skeletal muscle is unknown. Thus, the aim of this study was to investigate the effects of the combined stimuli of overloading and disuse on mouse skeletal muscle mass and the expression of regulatory factors for muscle protein anabolism or catabolism. Male mice from the Institute Cancer Research were subjected to denervation concomitant with unilateral functional overload or functional overload concomitant with unilateral denervation. Disuse and functional overload were induced by sciatic nerve transection (denervation) and synergist ablation, respectively, and the plantaris muscle was harvested 14 days after the operation. Our results showed that denervation attenuated functional overload‐induced muscle hypertrophy and functional overload partially ameliorated the denervation‐induced muscle atrophy. P70S6K phosphorylation, an indicator of mechanistic target of rapamycin complex 1 (mTORC1) activation, was not increased by unilateral functional overload in denervated muscles or by unilateral denervation in functional overloaded muscles. Denervation did not affect the increase of LC3‐II, a marker of autophagy activation, and ubiquitinated protein expression upon unilateral functional overload. Also, functional overload did not affect ubiquitinated protein expression during unilateral denervation. Thus, our findings suggest that functional overload‐induced muscle hypertrophy or denervation‐induced muscle atrophy was attenuated by the combined stimuli of overload and denervation. [ABSTRACT FROM AUTHOR]