Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve domi...Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles.A new method of ulnar nerve compound muscle action potential measurement was developed in 2020,which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist.This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential.In this prospective cross-sectional study,we included 64 patients with amyotrophic lateral sclerosis and 64 age-and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital.The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage.In the controls,no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings.In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy,the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2(P<0.01).Using the new method,damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method,in particular for patients in early stage amyotrophic lateral sclerosis.In addition,the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores.These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position,and that this method is more suitable for monitoring disease progression than the traditional montage.This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.展开更多
Ageing is associated with declined activity of behaviors, physiology and metabolic processes （Arking, 2006）. In- vestigations in model organisms have indicated the exis- tence of ＂functional senescence＂, the progr...Ageing is associated with declined activity of behaviors, physiology and metabolic processes （Arking, 2006）. In- vestigations in model organisms have indicated the exis- tence of ＂functional senescence＂, the progressive decline of biological functions with age and the decline in the activity may vary from tissue to tissue. Consequently, studies per- taining to the key organs/tissues whose functions deterio- rate/fail with age have led to the development of tissue specific ageing biomarkers （Grotewiel et al., 2005; Demontis et al., 2013）.展开更多
Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the mole...Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.展开更多
Olfactory ensheathing cells from the olfactory bulb and olfactory mucosa have been tbund to increase axonal sprouting and pathfinding and promote the recovery of vibrissae motor performance in facial nerve transection...Olfactory ensheathing cells from the olfactory bulb and olfactory mucosa have been tbund to increase axonal sprouting and pathfinding and promote the recovery of vibrissae motor performance in facial nerve transection injured rats. However, it is not yet clear whether olfactory ensheathing cells promote the reparation of facial nerve defects in rats. In this study, a collagen sponge and silicone tube neural conduit was implanted into the 6-mm defect of the buccal branch of the facial nerve in adult rats. Olfactory ensheathing cells isolated from the olfactory bulb of newborn Sprague-Dawley rats were injected into the neural conduits connecting the ends of tile broken nerves, the morphology and function of the regenerated nerves were compared between the rats implanted with olfactory ensheathing cells with the rats injected with saline. Facial paralysis was assessed. Nerve electrography was used to measure facial nerve-induced action potentials. Visual inspection, anatomical microscopy and hematoxylin-eosin staining were used to assess the histomorphology around the trans planted neural conduit and the morphology of the regenerated nerve. Using fluorogold retrograde tracing, toluidine blue staining and lead uranyl acetate staining, we also measured the number of neurons in the anterior exterior lateral f：acial nerve motor nucleus, the number of myelinated nerve fibers, and nerve fiber diameter and myelin sheath thickness, respectively. After surgery, olfactory ensheathing cells de- creased facial paralysis and the latency of the facial nerve-induced action potentials. There were no differences in the general morphology of the regenerating nerves between the rats implanted with olfactory ensheathing cells and the rats injected with saline. Between-group results showed that olfactory ensheathing cell treatment increased the number of regenerated neurons, improved nerve fiber morphology, and increased the number of myelinated nerve fibers, nerve fiber diameter, and myelin sheath thickness. In conclusion, implantation of olfactory ensheathing cells can promote regeneration and functional recovery after facial nerve damage in rats.展开更多
Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic...Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic molecules,at present,a satisfactory method to ensuring successful recovery does not exist.For successful molecular therapy in nerve regeneration,it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth.Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination.Therefore,any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration.Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system,so they could be candidates for nervous system regeneration.This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration.Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves.We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves,and accelerates functional recovering.This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves.The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells.展开更多
Acellular nerve allografts conducted via chemical extraction have achieved satisfactory results in bridging whole facial nerve defects clinically,both in terms of branching a single trunk and in connecting multiple br...Acellular nerve allografts conducted via chemical extraction have achieved satisfactory results in bridging whole facial nerve defects clinically,both in terms of branching a single trunk and in connecting multiple branches of an extratemporal segment.However,in the clinical treatment of facial nerve defects,allogeneic donors are limited.In this experiment,we exposed the left trunk and multiple branches of the extratemporal segment in six rhesus monkeys and dissected a gap of 25 mm to construct a monkey model of a whole left nerve defect.Six monkeys were randomly assigned to an autograft group or a xenogeneic acellular nerve graft group.In the autograft group,the 25-mm whole facial nerve defect was immediately bridged using an autogenous ipsilateral great auricular nerve,and in the xenogeneic acellular nerve graft group,this was done using a xenogeneic acellular nerve graft with trunk-branches.Examinations of facial symmetry,nerve-muscle electrophysiology,retrograde transport of labeled neuronal tracers,and morphology of the regenerated nerve and target muscle at 8 months postoperatively showed that the faces of the monkey appeared to be symmetrical in the static state and slightly asymmetrical during facial movement,and that they could actively close their eyelids completely.The degree of recovery from facial paralysis reached House-Brackmann grade II in both groups.Compound muscle action potentials were recorded and orbicularis oris muscles responded to electro-stimuli on the surgical side in each monkey.Fluoro Gold-labeled neurons could be detected in the facial nuclei on the injured side.Immunohistochemical staining showed abundant neurofilament-200-positive axons and soluble protein-100-positive Schwann cells in the regenerated nerves.A large number of mid-graft myelinated axons were observed via methylene blue staining and a transmission electron microscope.Taken together,our data indicate that xenogeneic acellular nerve grafts from minipigs are safe and effective for repairing whole facial nerve defects in rhesus monkeys,with an effect similar to that of autologous nerve transplantation.Thus,a xenogeneic acellular nerve graft may be a suitable choice for bridging a whole facial nerve defect if no other method is available.The study was approved by the Laboratory Animal Management Committee and the Ethics Review Committee of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University,China(approval No.2018-D-1)on March 15,2018.展开更多
This study presents a novel compound muscle action potential(CMAP)examination of motor unit changes in paretic muscle post stroke.CMAP scan of the first dorsal interosseous(FDI)muscle was performed bilaterally in 16 c...This study presents a novel compound muscle action potential(CMAP)examination of motor unit changes in paretic muscle post stroke.CMAP scan of the first dorsal interosseous(FDI)muscle was performed bilaterally in 16 chronic stroke subjects.Various parameters were derived from the CMAP scan to examine paretic muscle changes,including CMAP amplitude,D50,step index(STEPIX)and amplitude index(AMPIX).A significant decrease in CMAP amplitude and STEPIX was observed in paretic muscles compared with contralateral muscles(CMAP amplitude:paretic(9.0±0.5)mV,contralateral(11.3±0.9)mV,P=0.024;STEPIX:paretic 101.2±7.6,contralateral 121.9±6.5,P=0.020).No significant difference in D50 and AMPIX was observed between the paretic and contralateral sides(P>0.05).The findings revealed complex paretic muscle changes including motor unit degeneration,muscle fiber denervation,reinnervation and atrophy,providing useful insights to help understand neuromuscular mechanisms associated with weakness and other functional deterioration post stroke.The CMAP scan experimental protocols and the applied processing methods are noninvasive,convenient,and automated,offering practical benefits for clinical application.展开更多
Background Hypoxic pulmonary hypertension (HPH) is initiated by inhibition of O 2 sensitive, voltage gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs) The mechanism of hypoxic pulmonary hyp...Background Hypoxic pulmonary hypertension (HPH) is initiated by inhibition of O 2 sensitive, voltage gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs) The mechanism of hypoxic pulmonary hypertension has not yet been fully elucidated The mitochondrial ATP sensitive K + channel (MitoK ATP ) is extremely sensitive to hypoxia, and is a decisive factor in the control of mitochondrial membrane potential (ΔΨ m) This study investigated the changes of cell membrane potential and Kv channel in cultured human pulmonary artery smooth muscle cell (hPASMC) exposed to 24 hour hypoxia, and explored the role of MitoK ATP and ΔΨ m in this condition Methods Fresh human lung tissues were obtained from the patients undergoing a chest operation hPASMCs were isolated, cultured, and divided into 6 groups: ① control group, cultured under normoxia; ② diazoxide group, cultured in normoxia with diazoxide, an opener of MitoK ATP ; ③ 5 HD group, cultured in normoxia with sodium 5 hydroxydecanoate (5 HD), an antagonist of MitoK ATP ; ④ 24 hour hypoxia group; ⑤ 24 hour hypoxia + diazoxide group; and ⑥ 24 hour hypoxia + 5HD group Whole cell patch clamp technique was used to trace the cell membrane K + currents The expressions of cell membrane Kv1 5 mRNA and protein were determined by RT PCR and Western blot technique, respectively The relative changes in mitochondrial potential were tested with rhodamine fluorescence (R 123) technique Results After exposure to diazoxide for 24 hours, the intensity of R 123 fluorescence in normoxic hPASMCs was significantly increased compared with control group ( P <0 05), but there were no significant changes in these tests after the hPASMCs had been exposed to 5 HD for 24 hours Twenty four hour hypoxia or 24 hour hypoxia + diazoxide could markedly increase the intensity of R 123 fluorescence in hPASMC and the changes were more significant in 24 hour hypoxia +diazoxide group than in 24 hour hypoxia group ( P <0 05) although 5 HD could partly weaken the effect of 24 hour hypoxia on the intensity of R 123 fluorescence After exposure to diazoxide for 24 hours, the cell membrane K + currents and the expression of cell membrane Kv1 5 mRNA and protein in normoxic hPASMCs were significantly decreased compared with control group ( P <0 05), but there were no significant changes in these tests after the hPASMCs had been exposed to 5 HD for 24 hours Also, 24 hour hypoxia or 24 hour hypoxia + diazoxide decreased the cell membrane K + currents and the expression of Kv1 5 mRNA and protein ( P <0 05) but the changes were more significant in 24 hour hypoxia + diazoxide group than in 24 hour hypoxia group ( P <0 05) Again, 5 HD could partly weaken the inhibitory effect of 24 hour hypoxia on the cell membrane K + currents and the expression of Kv1 5 mRNA or protein ( P <0 05) Conclusions The opening of MitoK ATP followed by a depolarization of ΔΨ m in hypoxia might contribute to the alterations in the expression of cell membrane Kv1 5 mRNA and protein leading to change in the cell membrane potential of hypoxic hPASMCs This might be a mechanism of the development of hypoxic pulmonary hypertension展开更多
ObjectiveeToinvestigate theclinical and neuroelectrophysiological characteristics of NOTCH2NLC gene-related neuronal intranuclear inclusion disease(NIID).Methods One hundred and forty patients with NOTCH2NLCC gene-rel...ObjectiveeToinvestigate theclinical and neuroelectrophysiological characteristics of NOTCH2NLC gene-related neuronal intranuclear inclusion disease(NIID).Methods One hundred and forty patients with NOTCH2NLCC gene-related NIID diagnosed in the Department of Neurology and Department of Geriatrics,Xiangya Hospital,Central South University from January 2018 to June 2024 were selected as the research subjects.Their clinical data as well as neuroelectrophysiological results were collected.Their clinical and neuroelectrophysiological characteristics were summarized.Results The onset age of 140 patients with NOTCH2NLC gene-related NIID was 56.00(45.25,62.75)years.Among them,55.0%(77/140)of patients with NIID presented with peripheral nerve symptoms,but up to 98.6%(138/140)of patients with NIID had peripheral nerve involvement.Out of the patients studied,97.1%(136/140)exhibited a reduction in motor nerve conduction velocity and 66.4%(93/140)showed a decreasee in sensory nerve conductionnvelocity.Furthermore,53.6%(75/140)of patients had mild decrease in compound muscle action potential,and 55.7%(78/140)of patients showed mild reduction in sensory nerve action potential.Motor nerve involvement was more severe than sensory nerve impairment,and lower limb involvement was more severe than upper limb involvement.The nerve conduction abnormalities in the muscle weakness type(n=32)of NIID patients were more severe than those in the non-muscle weakness type(cognitive impairment type,n=41;movement disorder type,n=43;paroxysmal symptom type,n=24),showing mixed demyelinating and axonal sensorimotor neuropathy,while the non-muscle weakness type of NID patients mostly showed mild demyelinating sensorimotor neuropathy.There was no significant difference in nerve conduction related electrophysiological results among the patientswith3 non-muscleweaknessphenotypes.Conclusion Peripheral neuropathy is common in NIID patients.The neuroelectrophysiological characteristics of NIID patients include slight demyelinating sensorimotor neuropathy,and some of NIID patients are also accompanied bymildaxonaldamage.Neuroelectrophysiological evaluation is helpful for the diagnosis of NIID.展开更多
Objective To investigate changes in the delayed rectifier K + channel (Kv) function and the regulation of Kv by the protein kinase C (PKC) pathway in bronchial myocytes from asthmatic rats. Methods The Kv currents an...Objective To investigate changes in the delayed rectifier K + channel (Kv) function and the regulation of Kv by the protein kinase C (PKC) pathway in bronchial myocytes from asthmatic rats. Methods The Kv currents and membrane potentials in bronchial myocytes from asthmatic rats and from controls were observed, using whole cell voltage- and current-patch clamp techniques.Results Bronchial myocytes from asthmatic rats showed a significant reduction in Kv-current density (51.6±9.4 pA/pF, n=14, P<0.01) in comparison with those from control rats (72.4±12.3 pA/pF, n=14) at +50 mV. The current-voltage relationship curve exhibited a significant downward shift. Bronchial myocytes from asthmatic rats had no significantly different capacitances (P>0.05), but had more positive membrane potential ( P<0.01) compared with those from controls. 1 μmol/L phorbol 12-myristate 13-acetate, a PKC activator, caused an obvious reduction in Kv-current density (P<0.01) and a significant downward shift in the current-voltage relationship curve, an effect which was partly abolished by 1 μmol/L Ro31-8220 (a PKC inhibitor); 1 μmol/L phorbol 12-myristate 13-acetate caused more positive membrane potential (Em), from -36.8±5.7 mV to -30.4±7.3 mV, in rat bronchial myocytes (P<0.05). This effect was partly abolished by 1 μmol/L Ro31-8220. Conclusions Bronchial myocytes from asthmatic rats have inhibited Kv function, more positive membrane potential, and higher excitability, all of which can also be induced by PKC activation. These characteristics may contribute to the development of airway hyperreactivity in asthma.展开更多
Background： Few studies have focused on peripheral nerve conduction during exposure to microgravity. The -6° head-down tilt （HDT） comprises an experimental model used to simulate the space flight environment. ...Background： Few studies have focused on peripheral nerve conduction during exposure to microgravity. The -6° head-down tilt （HDT） comprises an experimental model used to simulate the space flight environment. This study investigated nerve conduction characteristics of rhesus monkeys before and alter prolonged exposure to H DT. Methods： Six rhesus monkeys （3-4 years old） were tilted backward 6° from the horizontal. Nerve conduction studies （NCSs） were performed on the median, ulnar, tibial, and fibular motor nerves. Analysis of variance with a randomized block design was conducted to compare the differences in the NCS belbre and 7, 2 l, and 42 days alter the 6° HDT. Results： The proximal amplitude of the CMAP of the median nerve was significantly decreased at 21 and 42 days of HDT compared with the amplitude before HDT （4.38 ± 2.83 vs. 8.40 ±2.66 mV, F = 4.85, P = 0.013 and 3.30± 2.70 vs. 8.40± 2.66 mV, F = 5.93, P = 0.004, respectively）. The distal amplitude of the CMAP of the median nerve was significantly decreased at 7, 21, and 42 days of HDT compared with the amplitude before HDT （7.28 ± 1.27 vs. 10.25 ± 3.40 mV, F= 4.03, P = 0.039; 5.05 ± 2.01 vs. 10.25 ± 3.40 mV, F = 6.25, P = 0.04; and 3.95 ± 2.79 vs. 10.25 ± 3.40 mV, F = 7.35, F=- 0.01; respectively）. The proximal amplitude of the CMAP of the tibial nerve was significantly decreased at 42 days of HDT compared with the amplitude betbre HDT （6.14± 1.94 vs. 11.87± 3.19 mV, F = 5.02, P = 0.039）. Conclusions： This study demonstrates that the compound muscle action potential amplitudes of nerves are decreased under simulated microgravity in rhesus monkeys. Moreover, rhesus monkeys exposed to HDT might be served as an experimental model for the study of NCS under microgravity.展开更多
Background：Congenital myasthenic syndromes are a group orrare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction.Here,we d...Background：Congenital myasthenic syndromes are a group orrare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction.Here,we described a Chinese family that presented with phenotypes of classic slow-channel congenital myasthenic syndrome （SCCMS）.Methods：Clinical characteristics and electrophysiological features of three patients from a Chinese family were examined,and next-generation sequencing followed by direct sequencing was carried out.Results：The patients revealed variability in clinical and electrophysiological features.However,weakness,scoliosis,and repetitive-compound muscle action potential were found in all affected members in the family.A heterozygous C〉T missense mutation at nucleotide 865 in acetylcholine receptor epsilon-subunit （CHRNE） gene that causes a leucine-to-phenylalanine substitution at position 289 （L289F） was found.Conclusions：We reported a SCCMS family of Chinese origin.In the family,classical clinical phenotype with phenotypic variability among different members was found.Genetic testing could help diagnose this rare disease.展开更多
Vagus nerve stimulation(VNS)is an important treatment option for drug-refractory epilepsy(DRE),with well-established efficacy and safety in clinical practice for more than 20 years.However,it is very difficult to find...Vagus nerve stimulation(VNS)is an important treatment option for drug-refractory epilepsy(DRE),with well-established efficacy and safety in clinical practice for more than 20 years.However,it is very difficult to find the optimal electrophysiological indicators for the effectiveness of VNS on DRE because the mechanism of action is unknown.In this review,we provide an update of the potential applications of VNS outcomes in patients with drug-resistant epilepsy.Electroencephalographic(EEG)activity,event-related potentials,EEG synchronization levels,magnetoencephalographic,laryngeal muscle evoked potentials,and heart rate variability are potential biomarkers for VNS outcomes in people with DRE.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81873784,82071426Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(all to DSF)。
文摘Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles.A new method of ulnar nerve compound muscle action potential measurement was developed in 2020,which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist.This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential.In this prospective cross-sectional study,we included 64 patients with amyotrophic lateral sclerosis and 64 age-and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital.The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage.In the controls,no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings.In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy,the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2(P<0.01).Using the new method,damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method,in particular for patients in early stage amyotrophic lateral sclerosis.In addition,the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores.These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position,and that this method is more suitable for monitoring disease progression than the traditional montage.This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.
基金supported by financial assistance from Department of Science and Technology and Department of Biotechnology,Government of India and Indian Institute of Science to Upendra Nongthomba
文摘Ageing is associated with declined activity of behaviors, physiology and metabolic processes （Arking, 2006）. In- vestigations in model organisms have indicated the exis- tence of ＂functional senescence＂, the progressive decline of biological functions with age and the decline in the activity may vary from tissue to tissue. Consequently, studies per- taining to the key organs/tissues whose functions deterio- rate/fail with age have led to the development of tissue specific ageing biomarkers （Grotewiel et al., 2005; Demontis et al., 2013）.
基金Natural Science Foundation of Beijing,No.7244428(to WZ)Peking University Medicine Sailing Program for Young Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+1 种基金the National Natural Science Foundation of China,Nos.81873784(to DF),82071426(to DF)Clinical Cohort Construction Program of Peking University Third Hospital,Nos.BYSYDL2019002(to DF)and BYSYZD2021004(to DF).
文摘Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.
基金supported by the Foundation for Military Medicine,China,No.BWS11J035(to JPF)the Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai of China,No.PWZxq2017-09(to XPC and JPF)
文摘Olfactory ensheathing cells from the olfactory bulb and olfactory mucosa have been tbund to increase axonal sprouting and pathfinding and promote the recovery of vibrissae motor performance in facial nerve transection injured rats. However, it is not yet clear whether olfactory ensheathing cells promote the reparation of facial nerve defects in rats. In this study, a collagen sponge and silicone tube neural conduit was implanted into the 6-mm defect of the buccal branch of the facial nerve in adult rats. Olfactory ensheathing cells isolated from the olfactory bulb of newborn Sprague-Dawley rats were injected into the neural conduits connecting the ends of tile broken nerves, the morphology and function of the regenerated nerves were compared between the rats implanted with olfactory ensheathing cells with the rats injected with saline. Facial paralysis was assessed. Nerve electrography was used to measure facial nerve-induced action potentials. Visual inspection, anatomical microscopy and hematoxylin-eosin staining were used to assess the histomorphology around the trans planted neural conduit and the morphology of the regenerated nerve. Using fluorogold retrograde tracing, toluidine blue staining and lead uranyl acetate staining, we also measured the number of neurons in the anterior exterior lateral f：acial nerve motor nucleus, the number of myelinated nerve fibers, and nerve fiber diameter and myelin sheath thickness, respectively. After surgery, olfactory ensheathing cells de- creased facial paralysis and the latency of the facial nerve-induced action potentials. There were no differences in the general morphology of the regenerating nerves between the rats implanted with olfactory ensheathing cells and the rats injected with saline. Between-group results showed that olfactory ensheathing cell treatment increased the number of regenerated neurons, improved nerve fiber morphology, and increased the number of myelinated nerve fibers, nerve fiber diameter, and myelin sheath thickness. In conclusion, implantation of olfactory ensheathing cells can promote regeneration and functional recovery after facial nerve damage in rats.
基金supported by the Swiss National Science FoundationSUVA foundationNovartis foundation
文摘Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic molecules,at present,a satisfactory method to ensuring successful recovery does not exist.For successful molecular therapy in nerve regeneration,it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth.Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination.Therefore,any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration.Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system,so they could be candidates for nervous system regeneration.This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration.Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves.We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves,and accelerates functional recovering.This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves.The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells.
基金financially supported by the National Natural Science Foundation of China,No.81770990(to GCZ)Jiangsu Provincial Key Research and Development Program of China,No.BE2018628(to GCZ)+2 种基金Six Talent Peaks Project in Jiangsu Province of China,No.2019-WSW-141(to GCZ)Major Medicine Projects of Wuxi Health Commission of Jiangsu,China,No.Z201802(to DJX)Precision Medicine Projects of Wuxi Health Commission of Jiangsu,China,No.J202002(to GCZ)。
文摘Acellular nerve allografts conducted via chemical extraction have achieved satisfactory results in bridging whole facial nerve defects clinically,both in terms of branching a single trunk and in connecting multiple branches of an extratemporal segment.However,in the clinical treatment of facial nerve defects,allogeneic donors are limited.In this experiment,we exposed the left trunk and multiple branches of the extratemporal segment in six rhesus monkeys and dissected a gap of 25 mm to construct a monkey model of a whole left nerve defect.Six monkeys were randomly assigned to an autograft group or a xenogeneic acellular nerve graft group.In the autograft group,the 25-mm whole facial nerve defect was immediately bridged using an autogenous ipsilateral great auricular nerve,and in the xenogeneic acellular nerve graft group,this was done using a xenogeneic acellular nerve graft with trunk-branches.Examinations of facial symmetry,nerve-muscle electrophysiology,retrograde transport of labeled neuronal tracers,and morphology of the regenerated nerve and target muscle at 8 months postoperatively showed that the faces of the monkey appeared to be symmetrical in the static state and slightly asymmetrical during facial movement,and that they could actively close their eyelids completely.The degree of recovery from facial paralysis reached House-Brackmann grade II in both groups.Compound muscle action potentials were recorded and orbicularis oris muscles responded to electro-stimuli on the surgical side in each monkey.Fluoro Gold-labeled neurons could be detected in the facial nuclei on the injured side.Immunohistochemical staining showed abundant neurofilament-200-positive axons and soluble protein-100-positive Schwann cells in the regenerated nerves.A large number of mid-graft myelinated axons were observed via methylene blue staining and a transmission electron microscope.Taken together,our data indicate that xenogeneic acellular nerve grafts from minipigs are safe and effective for repairing whole facial nerve defects in rhesus monkeys,with an effect similar to that of autologous nerve transplantation.Thus,a xenogeneic acellular nerve graft may be a suitable choice for bridging a whole facial nerve defect if no other method is available.The study was approved by the Laboratory Animal Management Committee and the Ethics Review Committee of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University,China(approval No.2018-D-1)on March 15,2018.
基金supported by the National Natural Science Foundation of China(82102179)the Shandong Provincial Natural Science Foundation(ZR2020KF012,ZR2021QH267,ZR2021QH053)+2 种基金the Shanghai Municipal Key Clinical Specialty(shslczdzk02701)the National Institutes of Health(7 R21 NS113716-02)the National Institute on Disability and Rehabilitation Research(90REMM0001-01-00).
文摘This study presents a novel compound muscle action potential(CMAP)examination of motor unit changes in paretic muscle post stroke.CMAP scan of the first dorsal interosseous(FDI)muscle was performed bilaterally in 16 chronic stroke subjects.Various parameters were derived from the CMAP scan to examine paretic muscle changes,including CMAP amplitude,D50,step index(STEPIX)and amplitude index(AMPIX).A significant decrease in CMAP amplitude and STEPIX was observed in paretic muscles compared with contralateral muscles(CMAP amplitude:paretic(9.0±0.5)mV,contralateral(11.3±0.9)mV,P=0.024;STEPIX:paretic 101.2±7.6,contralateral 121.9±6.5,P=0.020).No significant difference in D50 and AMPIX was observed between the paretic and contralateral sides(P>0.05).The findings revealed complex paretic muscle changes including motor unit degeneration,muscle fiber denervation,reinnervation and atrophy,providing useful insights to help understand neuromuscular mechanisms associated with weakness and other functional deterioration post stroke.The CMAP scan experimental protocols and the applied processing methods are noninvasive,convenient,and automated,offering practical benefits for clinical application.
基金Thestudywassupportedbya grantfromtheNationalNaturalScienceFoundationofChina (No 3 0 3 70 62 3 )
文摘Background Hypoxic pulmonary hypertension (HPH) is initiated by inhibition of O 2 sensitive, voltage gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs) The mechanism of hypoxic pulmonary hypertension has not yet been fully elucidated The mitochondrial ATP sensitive K + channel (MitoK ATP ) is extremely sensitive to hypoxia, and is a decisive factor in the control of mitochondrial membrane potential (ΔΨ m) This study investigated the changes of cell membrane potential and Kv channel in cultured human pulmonary artery smooth muscle cell (hPASMC) exposed to 24 hour hypoxia, and explored the role of MitoK ATP and ΔΨ m in this condition Methods Fresh human lung tissues were obtained from the patients undergoing a chest operation hPASMCs were isolated, cultured, and divided into 6 groups: ① control group, cultured under normoxia; ② diazoxide group, cultured in normoxia with diazoxide, an opener of MitoK ATP ; ③ 5 HD group, cultured in normoxia with sodium 5 hydroxydecanoate (5 HD), an antagonist of MitoK ATP ; ④ 24 hour hypoxia group; ⑤ 24 hour hypoxia + diazoxide group; and ⑥ 24 hour hypoxia + 5HD group Whole cell patch clamp technique was used to trace the cell membrane K + currents The expressions of cell membrane Kv1 5 mRNA and protein were determined by RT PCR and Western blot technique, respectively The relative changes in mitochondrial potential were tested with rhodamine fluorescence (R 123) technique Results After exposure to diazoxide for 24 hours, the intensity of R 123 fluorescence in normoxic hPASMCs was significantly increased compared with control group ( P <0 05), but there were no significant changes in these tests after the hPASMCs had been exposed to 5 HD for 24 hours Twenty four hour hypoxia or 24 hour hypoxia + diazoxide could markedly increase the intensity of R 123 fluorescence in hPASMC and the changes were more significant in 24 hour hypoxia +diazoxide group than in 24 hour hypoxia group ( P <0 05) although 5 HD could partly weaken the effect of 24 hour hypoxia on the intensity of R 123 fluorescence After exposure to diazoxide for 24 hours, the cell membrane K + currents and the expression of cell membrane Kv1 5 mRNA and protein in normoxic hPASMCs were significantly decreased compared with control group ( P <0 05), but there were no significant changes in these tests after the hPASMCs had been exposed to 5 HD for 24 hours Also, 24 hour hypoxia or 24 hour hypoxia + diazoxide decreased the cell membrane K + currents and the expression of Kv1 5 mRNA and protein ( P <0 05) but the changes were more significant in 24 hour hypoxia + diazoxide group than in 24 hour hypoxia group ( P <0 05) Again, 5 HD could partly weaken the inhibitory effect of 24 hour hypoxia on the cell membrane K + currents and the expression of Kv1 5 mRNA or protein ( P <0 05) Conclusions The opening of MitoK ATP followed by a depolarization of ΔΨ m in hypoxia might contribute to the alterations in the expression of cell membrane Kv1 5 mRNA and protein leading to change in the cell membrane potential of hypoxic hPASMCs This might be a mechanism of the development of hypoxic pulmonary hypertension
文摘ObjectiveeToinvestigate theclinical and neuroelectrophysiological characteristics of NOTCH2NLC gene-related neuronal intranuclear inclusion disease(NIID).Methods One hundred and forty patients with NOTCH2NLCC gene-related NIID diagnosed in the Department of Neurology and Department of Geriatrics,Xiangya Hospital,Central South University from January 2018 to June 2024 were selected as the research subjects.Their clinical data as well as neuroelectrophysiological results were collected.Their clinical and neuroelectrophysiological characteristics were summarized.Results The onset age of 140 patients with NOTCH2NLC gene-related NIID was 56.00(45.25,62.75)years.Among them,55.0%(77/140)of patients with NIID presented with peripheral nerve symptoms,but up to 98.6%(138/140)of patients with NIID had peripheral nerve involvement.Out of the patients studied,97.1%(136/140)exhibited a reduction in motor nerve conduction velocity and 66.4%(93/140)showed a decreasee in sensory nerve conductionnvelocity.Furthermore,53.6%(75/140)of patients had mild decrease in compound muscle action potential,and 55.7%(78/140)of patients showed mild reduction in sensory nerve action potential.Motor nerve involvement was more severe than sensory nerve impairment,and lower limb involvement was more severe than upper limb involvement.The nerve conduction abnormalities in the muscle weakness type(n=32)of NIID patients were more severe than those in the non-muscle weakness type(cognitive impairment type,n=41;movement disorder type,n=43;paroxysmal symptom type,n=24),showing mixed demyelinating and axonal sensorimotor neuropathy,while the non-muscle weakness type of NID patients mostly showed mild demyelinating sensorimotor neuropathy.There was no significant difference in nerve conduction related electrophysiological results among the patientswith3 non-muscleweaknessphenotypes.Conclusion Peripheral neuropathy is common in NIID patients.The neuroelectrophysiological characteristics of NIID patients include slight demyelinating sensorimotor neuropathy,and some of NIID patients are also accompanied bymildaxonaldamage.Neuroelectrophysiological evaluation is helpful for the diagnosis of NIID.
基金ThisstudywassupportedbytheNationalNaturalScienceFoundationofChina (No 3 0 2 70 5 83 ) .
文摘Objective To investigate changes in the delayed rectifier K + channel (Kv) function and the regulation of Kv by the protein kinase C (PKC) pathway in bronchial myocytes from asthmatic rats. Methods The Kv currents and membrane potentials in bronchial myocytes from asthmatic rats and from controls were observed, using whole cell voltage- and current-patch clamp techniques.Results Bronchial myocytes from asthmatic rats showed a significant reduction in Kv-current density (51.6±9.4 pA/pF, n=14, P<0.01) in comparison with those from control rats (72.4±12.3 pA/pF, n=14) at +50 mV. The current-voltage relationship curve exhibited a significant downward shift. Bronchial myocytes from asthmatic rats had no significantly different capacitances (P>0.05), but had more positive membrane potential ( P<0.01) compared with those from controls. 1 μmol/L phorbol 12-myristate 13-acetate, a PKC activator, caused an obvious reduction in Kv-current density (P<0.01) and a significant downward shift in the current-voltage relationship curve, an effect which was partly abolished by 1 μmol/L Ro31-8220 (a PKC inhibitor); 1 μmol/L phorbol 12-myristate 13-acetate caused more positive membrane potential (Em), from -36.8±5.7 mV to -30.4±7.3 mV, in rat bronchial myocytes (P<0.05). This effect was partly abolished by 1 μmol/L Ro31-8220. Conclusions Bronchial myocytes from asthmatic rats have inhibited Kv function, more positive membrane potential, and higher excitability, all of which can also be induced by PKC activation. These characteristics may contribute to the development of airway hyperreactivity in asthma.
文摘Background： Few studies have focused on peripheral nerve conduction during exposure to microgravity. The -6° head-down tilt （HDT） comprises an experimental model used to simulate the space flight environment. This study investigated nerve conduction characteristics of rhesus monkeys before and alter prolonged exposure to H DT. Methods： Six rhesus monkeys （3-4 years old） were tilted backward 6° from the horizontal. Nerve conduction studies （NCSs） were performed on the median, ulnar, tibial, and fibular motor nerves. Analysis of variance with a randomized block design was conducted to compare the differences in the NCS belbre and 7, 2 l, and 42 days alter the 6° HDT. Results： The proximal amplitude of the CMAP of the median nerve was significantly decreased at 21 and 42 days of HDT compared with the amplitude before HDT （4.38 ± 2.83 vs. 8.40 ±2.66 mV, F = 4.85, P = 0.013 and 3.30± 2.70 vs. 8.40± 2.66 mV, F = 5.93, P = 0.004, respectively）. The distal amplitude of the CMAP of the median nerve was significantly decreased at 7, 21, and 42 days of HDT compared with the amplitude before HDT （7.28 ± 1.27 vs. 10.25 ± 3.40 mV, F= 4.03, P = 0.039; 5.05 ± 2.01 vs. 10.25 ± 3.40 mV, F = 6.25, P = 0.04; and 3.95 ± 2.79 vs. 10.25 ± 3.40 mV, F = 7.35, F=- 0.01; respectively）. The proximal amplitude of the CMAP of the tibial nerve was significantly decreased at 42 days of HDT compared with the amplitude betbre HDT （6.14± 1.94 vs. 11.87± 3.19 mV, F = 5.02, P = 0.039）. Conclusions： This study demonstrates that the compound muscle action potential amplitudes of nerves are decreased under simulated microgravity in rhesus monkeys. Moreover, rhesus monkeys exposed to HDT might be served as an experimental model for the study of NCS under microgravity.
文摘Background：Congenital myasthenic syndromes are a group orrare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction.Here,we described a Chinese family that presented with phenotypes of classic slow-channel congenital myasthenic syndrome （SCCMS）.Methods：Clinical characteristics and electrophysiological features of three patients from a Chinese family were examined,and next-generation sequencing followed by direct sequencing was carried out.Results：The patients revealed variability in clinical and electrophysiological features.However,weakness,scoliosis,and repetitive-compound muscle action potential were found in all affected members in the family.A heterozygous C〉T missense mutation at nucleotide 865 in acetylcholine receptor epsilon-subunit （CHRNE） gene that causes a leucine-to-phenylalanine substitution at position 289 （L289F） was found.Conclusions：We reported a SCCMS family of Chinese origin.In the family,classical clinical phenotype with phenotypic variability among different members was found.Genetic testing could help diagnose this rare disease.
文摘Vagus nerve stimulation(VNS)is an important treatment option for drug-refractory epilepsy(DRE),with well-established efficacy and safety in clinical practice for more than 20 years.However,it is very difficult to find the optimal electrophysiological indicators for the effectiveness of VNS on DRE because the mechanism of action is unknown.In this review,we provide an update of the potential applications of VNS outcomes in patients with drug-resistant epilepsy.Electroencephalographic(EEG)activity,event-related potentials,EEG synchronization levels,magnetoencephalographic,laryngeal muscle evoked potentials,and heart rate variability are potential biomarkers for VNS outcomes in people with DRE.
