GDNF to the rescue: GDNF delivery effects on motor neurons and nerves,and muscle re-innervation after peripheral nerve injuries

Peripheral nerve injuries commonly occur due to trauma,like a traffic accident.Peripheral nerves get severed,causing motor neuron death and potential muscle atrophy.The current golden standard to treat peripheral nerve lesions,especially lesions with large(≥3 cm)nerve gaps,is the use of a nerve autograft or reimplantation in cases where nerve root avulsions occur.If not tended early,degeneration of motor neurons and loss of axon regeneration can occur,leading to loss of function.Although surgical procedures exist,patients often do not fully recover,and quality of life deteriorates.Peripheral nerves have limited regeneration,and it is usually mediated by Schwann cells and neurotrophic factors,like glial cell line-derived neurotrophic factor,as seen in Wallerian degeneration.Glial cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite outgrowth.Glial cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy,sciatic nerve crush,and compression,thus creating great interest to explore this protein as a potential treatment for peripheral nerve injuries.Exogenous glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve injuries.In this review,we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor,the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries,delivery systems,and complementary treatments(electrical muscle stimulation and exercise).Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients'quality of life.     

Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation

Spinal cord injury is linked to the interruption of neural pathways,which results in irreversible neural dysfunction.Neural repair and neuroregeneration are critical goals and issues for rehabilitation in spinal cord injury,which require neural stem cell repair and multimodal neuromodulation techniques involving personalized rehabilitation strategies.Besides the involvement of endogenous stem cells in neurogenesis and neural repair,exogenous neural stem cell transplantation is an emerging effective method for repairing and replacing damaged tissues in central nervous system diseases.However,to ensure that endogenous or exogenous neural stem cells truly participate in neural repair following spinal cord injury,appropriate interventional measures(e.g.,neuromodulation)should be adopted.Neuromodulation techniques,such as noninvasive magnetic stimulation and electrical stimulation,have been safely applied in many neuropsychiatric diseases.There is increasing evidence to suggest that neuromagnetic/electrical modulation promotes neuroregeneration and neural repair by affecting signaling in the nervous system;namely,by exciting,inhibiting,or regulating neuronal and neural network activities to improve motor function and motor learning following spinal cord injury.Several studies have indicated that fine motor skill rehabilitation training makes use of residual nerve fibers for collateral growth,encourages the formation of new synaptic connections to promote neural plasticity,and improves motor function recovery in patients with spinal cord injury.With the development of biomaterial technology and biomechanical engineering,several emerging treatments have been developed,such as robots,brain-computer interfaces,and nanomaterials.These treatments have the potential to help millions of patients suffering from motor dysfunction caused by spinal cord injury.However,large-scale clinical trials need to be conducted to validate their efficacy.This review evaluated the efficacy of neural stem cells and magnetic or electrical stimulation combined with rehabilitation training and intelligent therapies for spinal cord injury according to existing evidence,to build up a multimodal treatment strategy of spinal cord injury to enhance nerve repair and regeneration.     

Efficacy and safety of transcutaneous auricular vagus nerve stimulation combined with conventional rehabilitation training in acute stroke patients: a randomized controlled trial conducted for 1 year involving 60 patients

Transcutaneous auricular vagus nerve stimulation(ta-VNS)is a novel noninvasive treat-ment for stroke that directly stimulates the peripheral auricular branch of the vagus nerve.There have been recent reports that ta-VNS combined with conventional rehabilitation training promotes the recovery of neurological function of patients with acute stroke.However,these were small-sample-sized studies on the recovery of neurological function in patients after percutaneous vagus nerve stimulation in the subacute and chronic phases after stroke.This double-blinded randomized controlled trial involved 60 acute ischemic or hemorrhagic stroke patients aged 18-80 years who received treatment in the Second Affiliated Hospital of Chongqing Medical University.The subjects were randomly assigned to receive ta-VNS or sham ta-VNS combined with conventional rehabilitation training.The follow-up results over 1 year revealed that ta-VNS combined with conventional rehabilitation training greatly improved the recovery of motor and sensory functions and emotional responses compared with sham ta-VNS combined with conventional rehabilitation training.There were no obvious side effects.These findings suggest that ta-VNS combined with conventional rehabilitation training for the treatment of acute ischemic or hemorrhagic stroke patients is safe and effective.     

Insights into platinum-induced peripheral neuropathy–current perspective

Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.     

Experimental nerve transfer model in the neonatal rat

Clinically,peripheral nerve reconstructions in neonates are most frequently applied in brachial plexus birth injuries.Most surgical concepts,however,have investigated nerve reconstructions in adult animal models.The immature neuromuscular system reacts differently to the effects of nerve lesion and surgery and is poorly investigated due to the lack of reliable experimental models.Here,we describe an experimental forelimb model in the neonatal rat,to study these effects on both the peripheral and central nervous systems.Within 24 hours after birth,three groups were prepared:In the nerve transfer group,a lesion of the musculocutaneous nerve was reconstructed by selectively transferring the ulnar nerve.In the negative control group,the musculocutaneous nerve was divided and not reconstructed and in the positive control group,a sham surgery was performed.The animal's ability to adapt to nerve lesions and progressive improvement over time were depict by the Bertelli test,which observes the development of grooming.Twelve weeks postoperatively,animals were fully matured and the nerve transfer successfully reinnervated their target muscles,which was indicated by muscle force,muscle weight,and cross sectional area evaluation.On the contrary,no spontaneous regeneration was found in the negative control group.In the positive control group,reference values were established.Retrograde labeling indicated that the motoneuron pool of the ulnar nerve was reduced following nerve transfer.Due to this post-axotomy motoneuron death,a diminished amount of motoneurons reinnervated the biceps muscle in the nerve transfer group,when compared to the native motoneuron pool of the musculocutaneous nerve.These findings indicate that the immature neuromuscular system behaves profoundly different than similar lesions in adult rats and explains reduced muscle force.Ultimately,pathophysiologic adaptations are inevitable.The maturing neuromuscular system,however,utilizes neonatal capacity of regeneration and seizes a variety of compensation mechanism to restore a functional extremity.The above described neonatal rat model demonstrates a constant anatomy,suitable for nerve transfers and allows all standard neuromuscular analyses.Hence,detailed investigations on the pathophysiological changes and subsequent effects of trauma on the various levels within the neuromuscular system as well as neural reorganization of the neonatal rat may be elucidated.This study was approved by the Ethics Committee of the Medical University of Vienna and the Austrian Ministry for Research and Science(BMWF-66.009/0187-WF/V/3 b/2015)on March 20,2015.     

Effects of cortical intermittent theta burst stimulation combined with precise root stimulation on motor function after spinal cord injury: a case series study

Activation and reconstruction of the spinal cord circuitry is important for improving motor function following spinal cord injury.We conducted a case series study to investigate motor function improvement in 14 patients with chronic spinal cord injury treated with 4 weeks of unilateral(right only)cortical intermittent theta burst stimulation combined with bilateral magnetic stimulation of L3-L4 nerve roots,five times a week.Bilateral resting motor evoked potential amplitude was increased,central motor conduction time on the side receiving cortical stimulation was significantly decreased,and lower extremity motor score,Berg balance score,spinal cord independence measure-III score,and 10 m-walking speed were all increased after treatment.Right resting motor evoked potential amplitude was positively correlated with lower extremity motor score after 4 weeks of treatment.These findings suggest that cortical intermittent theta burst stimulation combined with precise root stimulation can improve nerve conduction of the corticospinal tract and lower limb motor function recovery in patients with chronic spinal cord injury.     

Korean red ginseng promotes hippocampal neurogenesis in mice

Neurogenesis in the adult hippocampus plays a major role in cognitive ability of animals including learning and memory.Korean red ginseng (KRG) has long been known as a medicinal herb with the potential to improve learning and memory;however,the mechanisms are still elusive.Therefore,we evaluated whether KRG can promote cognitive function and enhance neurogenesis in the hippocampus.Eight-week-old male C57BL/6 mice received 50 mg/kg of 5-bromo-2′-deoxyuridine (BrdU) intraperitoneally and 100 mg/kg of KRG or vehicle orally once a day for 14 days.Pole,Rotarod and Morris water maze tests were performed and the brains were collected after the last behavioral test.Changes in the numbers of BrdU- and BrdU/ doublecortin (DCX;a marker for neuronal precursor cells and immature neurons)-positive cells in the dentate gyrus and the gene expression of proliferating cell nuclear antigen (a marker for cell differentiation),cerebral dopamine neurotrophic factor and ciliary neurotrophic factor in the hippocampus were then investigated.KRG-treated mice came down the pole significantly faster and stood on the rotarod longer than vehicle-treated mice.The Morris water maze test showed that KRG administration enhanced the learning and memory abilities significantly.KRG also significantly increased BrdU- and BrdU/DCX-positive cells in the dentate gyrus as well as the proliferating cell nuclear antigen,cerebral dopamine neurotrophic factor and ciliary neurotrophic factor mRNA expression levels in the hippocampus compared to vehicle.Administration of KRG promotes learning and memory abilities,possibly by enhancing hippocampal neurogenesis.This study was approved by the Pusan National University Institutional Animal Care and Use Committee (approval No.PNU-2016-1071) on January 19,2016.     

Neurorehabilitation using a voluntary driven exoskeletal robot improves trunk function in patients with chronic spinal cord injury: a single-arm study

Body weight-supported treadmill training with the voluntary driven exoskeleton(VDE-BWSTT) has been shown to improve the gait function of patients with chronic spinal cord injury. However, little is known whether VDE-BWSTT can effectively improve the trunk function of patients with chronic spinal cord injury. In this open-label, single-arm study, nine patients with chronic spinal cord injury at the cervical or thoracic level(six males and three females, aged 37.8 ± 15.6 years, and time since injury 51.1 ± 31.8 months) who underwent outpatient VDE-BWSTT training program at Keio University Hospital, Japan from September 2017 to March 2019 were included. All patients underwent twenty 60-minute gait training sessions using VDE. Trunk muscular strength, i.e., the maximum force against which patient could maintain a sitting posture without any support, was evaluated in four directions: anterior, posterior, and lateral(right and left) after 10 and 20 training sessions. After intervention, lateral muscular strength significantly improved. In addition, a significant positive correlation was detected between the change in lateral trunk muscular strength after 20 training sessions relative to baseline and gait speed. The change in trunk muscular strength after 20 training sessions relative to baseline was greatly correlated with patient age. This suggests that older adult patients with chronic spinal cord injury achieved a greater improvement in trunk muscle strength following VDE-BWSTT. All these findings suggest that VDE-BWSTT can improve the trunk function of patients with chronic spinal cord injury and the effect might be greater in older adult patients. The study was approved by the Keio University of Medicine Ethics Committee(IRB No. 20150355-3) on September 26, 2017.     

Nerve growth factor-basic fibroblast growth factor poly-lactide co-glycolid sustained-release microspheres and the small gap sleeve bridging technique to repair peripheral nerve injury

We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique. Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury; as a result, in this study, we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration. First, in an in vitro biomimetic microenvironment, we developed and used a drug screening biomimetic ...     

Mesenchymal stem cell treatment for peripheral nerve injury: a narrative review

Peripheral nerve injuries occur as the result of sudden trauma and lead to reduced quality of life.The peripheral nervous system has an inherent capability to regenerate axons.However,peripheral nerve regeneration following injury is generally slow and incomplete that results in poor functional outcomes such as muscle atrophy.Although conventional surgical procedures for peripheral nerve injuries present many benefits,there are still several limitations including scarring,difficult accessibility to donor nerve,neuroma formation and a need to sacrifice the autologous nerve.For many years,other therapeutic approaches for peripheral nerve injuries have been explored,the most notable being the replacement of Schwann cells,the glial cells responsible for clearing out debris from the site of injury.Introducing cultured Schwann cells to the injured sites showed great benefits in promoting axonal regeneration and functional recovery.However,there are limited sources of Schwann cells for extraction and difficulties in culturing Schwann cells in vitro.Therefore,novel therapeutic avenues that offer maximum benefits for the treatment of peripheral nerve injuries should be investigated.This review focused on strategies using mesenchymal stem cells to promote peripheral nerve regeneration including exosomes of mesenchymal stem cells,nerve engineering using the nerve guidance conduits containing mesenchymal stem cells,and genetically engineered mesenchymal stem cells.We present the current progress of mesenchymal stem cell treatment of peripheral nerve injuries.     

The proteome of distal nerves:implication in delayed repair and poor functional recovery

Chronic denervation is one of the key factors that affect nerve regeneration.Chronic axotomy deteriorates the distal nerve stump,causes protein changes,and renders the microenvironment less permissive for regeneration.Some of these factors/proteins have been individually studied.To better delineate the comprehensive protein expression profiles and identify proteins that contribute to or are associated with this detrimental effect,we carried out a proteomic analysis of the distal nerve using an established delayed rat sciatic nerve repair model.Four rats that received immediate repair after sciatic nerve transection served as control,whereas four rats in the experimental group(chronic denervation)had their sciatic nerve repaired after a 12-week delay.All the rats were sacrificed after 16 weeks to harvest the distal nerves for extracting proteins.Twenty-five micrograms of protein from each sample were fractionated in SDS-PAGE gels.NanoLC-MS/MS analysis was applied to the gels.Protein expression levels of nerves on the surgery side were compared to those on the contralateral side.Any protein with a P value of less than 0.05 and a fold change of 4 or higher was deemed differentially expressed.All the differentially expressed proteins in both groups were further stratified according to the biological processes.A PubMed search was also conducted to identify the differentially expressed proteins that have been reported to be either beneficial or detrimental to nerve regeneration.Ingenuity Pathway Analysis(IPA)software was used for pathway analysis.The results showed that 709 differentially expressed proteins were identified in the delayed repair group,with a bigger proportion of immune and inflammatory process-related proteins and a smaller proportion of proteins related to axon regeneration and lipid metabolism in comparison to the control group where 478 differentially expressed proteins were identified.The experimental group also had more beneficial proteins that were downregulated and more detrimental proteins that were upregulated.IPA revealed that protective pathways such as LXR/RXR,acute phase response,RAC,ERK/MAPK,CNTF,IL-6,and FGF signaling were inhibited in the delayed repair group,whereas three detrimental pathways,including the complement system,PTEN,and apoptosis signaling,were activated.An available database of the adult rodent sciatic nerve was used to assign protein changes to specific cell types.The poor regeneration seen in the delayed repair group could be associated with the down-regulation of beneficial proteins and up-regulation of detrimental proteins.The proteins and pathways identified in this study may offer clues for future studies to identify therapeutic targets.     

Skeletal muscle-derived cells repair peripheral nerve defects in mice

Skeletal muscle-derived cells have strong secretory function,while skeletal muscle-derived stem cells,which are included in muscle-derived cells,can differentiate into Schwann cell-like cells and other cell types.However,the effect of muscle-derived cells on peripheral nerve defects has not been reported.In this study,5-mm-long nerve defects were created in the right sciatic nerves of mice to construct a peripheral nerve defect model.Adult female C57BL/6 mice were randomly divided into four groups.For the muscle-derived cell group,muscle-derived cells were injected into the catheter after the cut nerve ends were bridged with a polyurethane catheter.For external oblique muscle-fabricated nerve conduit and polyurethane groups,an external oblique muscle-fabricated nerve conduit or polyurethane catheter was used to bridge the cut nerve ends,respectively.For the sham group,the sciatic nerves on the right side were separated but not excised.At 8 and 12 weeks post-surgery,distributions of axons and myelin sheaths were observed,and the nerve diameter was calculated using immunofluorescence staining.The number,diameter,and thickness of myelinated nerve fibers were detected by toluidine blue staining and transmission electron microscopy.Muscle fiber area ratios were calculated by Masson’s trichrome staining of gastrocnemius muscle sections.Sciatic functional index was recorded using walking footprint analysis at 4,8,and 12 weeks after operation.The results showed that,at 8 and 12 weeks after surgery,myelin sheaths and axons of regenerating nerves were evenly distributed in the muscle-derived cell group.The number,diameter,and myelin sheath thickness of myelinated nerve fibers,as well as gastrocnemius muscle wet weight and muscle area ratio,were significantly higher in the muscle-derived cell group compared with the polyurethane group.At 4,8,and 12 weeks post-surgery,sciatic functional index was notably increased in the muscle-derived cell group compared with the polyurethane group.These criteria of the muscle-derived cell group were not significantly different from the external oblique muscle-fabricated nerve conduit group.Collectively,these data suggest that muscle-derived cells effectively accelerated peripheral nerve regeneration.This study was approved by the Animal Ethics Committee of Plastic Surgery Hospital,Chinese Academy of Medical Sciences(approval No.040)on September 28,2016.     

Magnet-targeted delivery of bone marrow-derived mesenchymal stem cells improves therapeutic efficacy following hypoxic-ischemic brain injury

hypoxicischemic brain injury;however,the therapeutic efficacy of bone marrow-derived mesenchymal stem cells largely depends on the number of cells that are successfully transferred to the target.Magnet-targeted drug delivery systems can use a specific magnetic field to attract the drug to the target site,increasing the drug concentration.In this study,we found that the double-labeling using superparamagnetic iron oxide nanoparticle and poly-L-lysine(SPIO-PLL)of bone marrow-derived mesenchymal stem cells had no effect on cell survival but decreased cell proliferation 48 hours after labeling.Rat models of hypoxic-ischemic brain injury were established by ligating the left common carotid artery.One day after modeling,intraventricular and caudal vein injections of 1×105 SPIO-PLL-labeled bone marrow-derived mesenchymal stem cells were performed.Twenty-four hours after the intraventricular injection,magnets were fixed to the left side of the rats’heads for 2 hours.Intravoxel incoherent motion magnetic resonance imaging revealed that the perfusion fraction and the diffusion coefficient of rat brain tissue were significantly increased in rats treated with SPIO-PLL-labeled cells through intraventricular injection combined with magnetic guidance,compared with those treated with SPIO-PLL-labeled cells through intraventricular or tail vein injections without magnetic guidance.Hematoxylin-eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining revealed that in rats treated with SPIO-PLL-labeled cells through intraventricular injection under magnetic guidance,cerebral edema was alleviated,and apoptosis was decreased.These findings suggest that targeted magnetic guidance can be used to improve the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation for hypoxic-ischemic brain injury.This study was approved by the Animal Care and Use Committee of The Second Hospital of Dalian Medical University,China(approval No.2016-060)on March 2,2016.     

Repairing whole facial nerve defects with xenogeneic acellular nerve grafts in rhesus monkeys

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.     

Micro-computed tomography utility for estimation of intraparenchymal spinal cord cystic lesions in small animals

Precise assessment of spinal cord cystic lesions is crucial to formulate effective therapeutic strategies,yet histological assessment of the lesion remains the primary method despite numerous studies showing inconsistent results regarding estimation of lesion size via histology.On the other hand,despite numerous advances in micro-computed tomography(micro-CT)imaging and analysis that have allowed precise measurements of lesion size,there is not enough published data on its application to estimate intraspinal lesion size in laboratory animal models.This work attempts to show that micro-CT can be valuable for spinal cord injury research by demonstrating accurate estimation of syrinx size and compares between micro-CT and traditional histological analysis.We used a post-traumatic syringomyelia rat model to compare micro-CT analysis to conventional histological analysis.The study showed that micro-CT can detect lesions within the spinal cord very similar to histology.Importantly,micro-CT appears to provide more accurate estimates of the lesions with more measures(e.g.,surface area),can detect compounds within the cord,and can be done with the tissue of interest(spinal cord)intact.In summary,the experimental work presented here provides one of the first investigations of the use of micro-CT for estimating the size of intraparenchymal cysts and detecting materials within the spinal cord.All animal procedures were approved by the University of Akron Institutional Animal Care and Use Committee(IACUC)(protocol#LRE 16-05-09 approved on May 14,2016).     

Baculoviral inhibitor of apoptosis protein repeat-containing protein 3 delays early Wallerian degeneration after sciatic nerve injury

Wallerian degeneration is a complex biological process that occurs after nerve injury,and involves nerve degeneration and regeneration.Schwann cells play a crucial role in the cellular and molecular events of Wallerian degeneration of the peripheral nervous system.However,Wallerian degeneration regulating nerve injury and repair remains largely unknown,especially the early response.We have previously reported some key regulators of Wallerian degeneration after sciatic nerve injury.Baculoviral inhibitor of apoptosis protein repeat-containing protein 3(BIRC3)is an important factor that regulates apoptosis-inhibiting protein.In this study,we established rat models of right sciatic nerve injury.In vitro Schwann cell models were also established and subjected to gene transfection to inhibit and overexpress BIRC3.The data indicated that BIRC3 expression was significantly up-regulated after sciatic nerve injury.Both BIRC3 upregulation and downregulation affected the migration,proliferation and apoptosis of Schwan cells and affected the expression of related factors through activating c-fos and ERK signal pathway.Inhibition of BIRC3 delayed early Wallerian degeneration through inhibiting the apoptosis of Schwann cells after sciatic nerve injury.These findings suggest that BIRC3 plays an important role in peripheral nerve injury repair and regeneration.The study was approved by the Institutional Animal Care and Use Committee of Nantong University,China(approval No.2019-nsfc004)on March 1,2019.     

Assessment of structural brain changes in patients with type 2 diabetes mellitus using the MRI-based brain atrophy and lesion index

Patients with type 2 diabetes mellitus(T2 DM) often have cognitive impairment and structural brain abnormalities.The magnetic resonance imaging(MRI)-based brain atrophy and lesion index can be used to evaluate common brain changes and their correlation with cognitive function,and can therefore also be used to reflect whole-brain structural changes related to T2 DM.A total of 136 participants(64 men and 72 women,aged 55–86 years) were recruited for our study between January 2014 and December 2016.All participants underwent MRI and Mini-Mental State Examination assessment(including 42 healthy control,38 T2 DM without cognitive impairment,26 with cognitive impairment but without T2 DM,and 30 T2 DM with cognitive impairment participants).The total and sub-category brain atrophy and lesion index scores in patients with T2 DM with cognitive impairment were higher than those in healthy controls.Differences in the brain atrophy and lesion index of gray matter lesions and subcortical dilated perivascular spaces were found between non-T2 DM patients with cognitive impairment and patients with T2 DM and cognitive impairment.After adjusting for age,the brain atrophy and lesion index retained its capacity to identify patients with T2 DM with cognitive impairment.These findings suggest that the brain atrophy and lesion index,based on T1-weighted and T2-weighted imaging,is of clinical value for identifying patients with T2 DM and cognitive impairment.Gray matter lesions and subcortical dilated perivascular spaces may be potential diagnostic markers of T2 DM that is complicated by cognitive impairment.This study was approved by the Medical Ethics Committee of University of South China(approval No.USC20131109003) on November 9,2013,and was retrospectively registered with the Chinese Clinical Trial Registry(registration No.Chi CTR1900024150) on June 27,2019.     

Brain and spinal cord trauma:what we know about the therapeutic potential of insulin growth factor 1 gene therapy

Although little attention has been paid to cognitive and emotional dysfunctions observed in patients after spinal co rd injury,several reports have described impairments in cognitive abilities.Our group also has contributed significantly to the study of cognitive impairments in a rat model of spinal co rd injury.These findings are very significant because they demonstrate that cognitive and mood deficits are not induced by lifestyle changes,drugs of abuse,and combined medication.They are related...     

The anatomical,electrophysiological and histological observations of muscle contraction units in rabbits:a new perspective on nerve injury and regeneration

In the conventional view a muscle is composed of intermediate structures before its further division into microscopic muscle fibers.Our experiments in mice have confirmed this intermediate structure is composed of the lamella cluster formed by motor endplates,the innervating nerve branches and the corresponding muscle fibers,which can be viewed as an independent structural and functional unit.In this study,we verified the presence of these muscle construction units in rabbits.The results showed that the muscular branch of the femoral nerve sent out 4–6 nerve branches into the quadriceps and the tibial nerve sent out 4–7 nerve branches into the gastrocnemius.When each nerve branch of the femoral nerve was stimulated from the most lateral to the medial,the contraction of the lateral muscle,intermediate muscle and medial muscle of the quadriceps could be induced by electrically stimulating at least one nerve branch.When stimulating each nerve branch of the tibial nerve from the lateral to the medial,the muscle contraction of the lateral muscle 1,lateral muscle 2,lateral muscle 3 and medial muscle of the gastrocnemius could be induced by electrically stimulating at least one nerve branch.Electrical stimulation of each nerve branch resulted in different electromyographical waves recorded in different muscle subgroups.Hematoxylin-eosin staining showed most of the nerve branches around the neuromuscular junctions consisted of one individual neural tract,a few consisted of two or more neural tracts.The muscles of the lower limb in the rabbit can be subdivided into different muscle subgroups,each innervated by different nerve branches,thereby allowing much more complex muscle activities than traditionally stated.Together,the nerve branches and the innervated muscle subgroups can be viewed as an independent structural and functional unit.This study was approved by the Animal Ethics Committee of Peking University People’s Hospital(approval No.2019 PHE027)on October 20,2019.     

Diffusion tensor imaging reveals brain structure changes in dogs after spinal cord injury

Based on the Wallerian degeneration in the spinal cord pathways, the changes in synaptic connections, and the spinal cord-related cellular responses that alter the cellular structure of the brain, we presumed that brain diffusion tensor imaging(DTI) parameters may change after spinal cord injury. However, the dynamic changes in DTI parameters remain unclear. We established a Beagle dog model of T10 spinal cord contusion and performed DTI of the injured spinal cord. We found dynamic changes in DT...