Rarely,penetrating injuries to the spinal cord result from wooden objects,creating unique challenges to mitigate neurological injury and high rates of infection and foreign body reactions.We report a man who sustained...Rarely,penetrating injuries to the spinal cord result from wooden objects,creating unique challenges to mitigate neurological injury and high rates of infection and foreign body reactions.We report a man who sustained a penetrating cervical spinal cord injury from a sharpened stick.While initially tetraparetic,he rapidly recovered function.The risks of neurological deterioration during surgical removal made the patient reluctant to consent to surgery despite the impalement of the spinal cord.A repeat MRI on day 3 showed an extension of edema indicating progressive inflammation.On the 7~(th)day after injury,fever and paresthesias occurred with a large increase in serum inflammatory indicators,and the patient agreed to undergo surgical removal of the wooden object.We discuss the management nuances related to wood,the longitudinal evolution of MRI findings,infection risk,surgical risk mitigation and technique,an inflammatory marker profile,long-term recovery,and the surprisingly minimal neurological deficits associated with low-velocity midline spinal cord injuries.The patient had an excellent clinical outcome.The main lessons are that a wooden penetrating central nervous system injury has a high risk for infection,and that surgical removal from the spinal cord should be performed soon after injury and under direct visualization.展开更多
For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein th...For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.展开更多
cAMP signaling and the control of Schwann cell fate： The ubiquitous second messenger cyclic adenosine monophosphate （cAMP） controls a variety of cellular responses in a cell type-specific and stimulus-de- pendent m...cAMP signaling and the control of Schwann cell fate： The ubiquitous second messenger cyclic adenosine monophosphate （cAMP） controls a variety of cellular responses in a cell type-specific and stimulus-de- pendent manner through an elaborate network of signaling intermedi- aries that connect stimulation of cell membrane receptors （typically G protein-coupled receptors, GPCRs） to transcription factor activation. Schwann cells （SCs） are highly responsive to cAMP throughout their lifespan, as extensive research has shown that SC survival, lineage spec- ification, proliferation and differentiation into myelin-forming cells require cAMP signaling.展开更多
On September 12 and 13,2019,the National Institute of Neurological Disorders and Stroke(NINDS),Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD),as well as other federal agencies a...On September 12 and 13,2019,the National Institute of Neurological Disorders and Stroke(NINDS),Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD),as well as other federal agencies and several private foundations sponsored a stake holder meeting at the National Institutes of Health(NIH)Bethesda campus with a provocative title:“SCI 2020:Launching a decade for disruption in spinal cord injury research”.Over the past decade,“disruptive”has become a cool buzz word for entrepreneurs to use to market their technology.In this context,disruptive means“innovative,ingenious,and unconventional”(typically definition#2 in online dictionaries).The hope is their new technology or business model is so powerful it will upend current technologies and come to dominate the market place.Uber’s destruction of taxi companies worldwide is a leading example of being“disruptive”.展开更多
Objective To explore the feasibility for therapy of spinal cord injury (SCI) by genetic engineering neural stem cell (NSC) modified by lentiviral vector. Methods Following the construction of the genetic engineering N...Objective To explore the feasibility for therapy of spinal cord injury (SCI) by genetic engineering neural stem cell (NSC) modified by lentiviral vector. Methods Following the construction of the genetic engineering NSC modified by lentivirus to secrete both neurotrophic factor-3 (NT-3) and green fluorescence protein (GFP), hemisection of spinal cord at the level of T_ 10 was performed in 56 adult Wistar rats that were randomly divided into 4 groups (n=14), namely 3 therapeutic groups and 1 control group. The therapeutic groups were dealed with NSC, genetic engineering NSC, and concentrated lentiviral supernatant which carries both GFP and NT-3, respectively. Then used fluorescence microscope to detect the transgenic expression in vitro and in vivo, migration of the grafted cells in vivo, and used the Basso, Beattie, and Bresnahan (BBB) open-field locomotor test to assess the recovery of function. Results The transplanted cells could survive for long time in vivo and migrate for long distance. The stable transgenic expression could be detected in vivo. The hindlimb function of the injured rats in 3 therapeutic groups, especially those dealed with genetic engineering NSC, improved obviously. Conclusion It is feasible to combine NSC with lentivirus for the repair of SCI. NSC modified by lentivirus to deliver NT-3, acting as a source of neurotrophic factors and function cell in vivo, has the potential to participate in spinal cord repair.展开更多
Schwann cell transplantation is a promising therapy for the treatment of spinal cord injury（SCI） and is currently in clinical trials.In our continuing efforts to improve Schwann cell transplantation strategies,we so...Schwann cell transplantation is a promising therapy for the treatment of spinal cord injury（SCI） and is currently in clinical trials.In our continuing efforts to improve Schwann cell transplantation strategies,we sought to determine the combined effects of Schwann cell transplantation with macrophage depletion.Since macrophages are major inflammatory contributors to the acute spinal cord injury,and are the major phagocytic cells,we hypothesized that transplanting Schwann cells after macrophage depletion will improve cell survival and integration with host tissue after SCI.To test this hypothesis,rat models of contusive SCI at thoracic level 8 were randomly subjected to macrophage depletion or not.In rat subjected to macrophage depletion,liposomes filled with clodronate were intraperitoneally injected at 1,3,6,11,and 18 days post injury.Rats not subjected to macrophage depletion were intraperitoneally injected with liposomes filled with phosphate buffered saline.Schwann cells were transplanted 1 week post injury in all rats.Biotinylated dextran amine（BDA） was injected at thoracic level 5 to evalute axon regeneration.The Basso,Beattie,and Bresnahan locomotor test,Gridwalk test,and sensory test using von Frey filaments were performed to assess functional recovery.Immunohistochemistry was used to detect glial fibrillary acidic protein,neurofilament,and green fluorescent protein（GFP）,and also to visulize BDA-labelled axons.The GFP labeled Schwann cell and cyst and lesion volumes were quantified using stained slides.The numbers of BDA-positive axons were also quantified.At 8 weeks after Schwann cell transplantation,there was a significant reduction in cyst and lesion volumes in the combined treatment group compared to Schwann cell transplantation alone.These changes were not associated,however,with improved Schwann cell survival,axon growth,or locomotor recovery.Although combining Schwann cell transplantation with macrophage depletion does improve histopathology of the injury site,the effect on axon growth and behavioral recovery appears no better than what can be achieved with Schwann cell transplants alone.展开更多
It has been controversial whether gender has any effect on recovery following spinal cord injury（SCI）. Past experimental and clinical research aimed at addressing this subject has led to constrasting findings on whe...It has been controversial whether gender has any effect on recovery following spinal cord injury（SCI）. Past experimental and clinical research aimed at addressing this subject has led to constrasting findings on whether females hold any advantage in locomotor recovery. Additionally, for studies supporting the notion of a female gender related advantage, a definite cause has not been explained. In a recent study, using large sample sizes for comparative male and female spinal cord injury cohorts, we reported that a significant gender advantage favoring females existed in both tissue preservation and functional recovery after taking into consideration discrepancies in age and weight of the animals across sexes. Prior animal research frequently used sample sizes that were too small to determine significance with certainty and also did not account for two other factors that influence locomotor performance： age and weight. Our finding is important in light of controversy surrounding the effect of gender on outcome and the fact that SCI affects more than ten thousand new individuals annually, a population that is disproportionately male. By deepening our understanding of why a gender advantage exists, potential new therapeutics can be designed to improve recovery for the male population following the initial trauma or putatively augment the neuroprotective privilege in females for enhanced outcomes.展开更多
Objective: To explore the feasibility to construct genetic engineering human neural stem cells (hNSCs) mediated by lentivirus to express multigene in order to provide a graft source for further studies of spinal cord ...Objective: To explore the feasibility to construct genetic engineering human neural stem cells (hNSCs) mediated by lentivirus to express multigene in order to provide a graft source for further studies of spinal cord injury (SCI). Methods: Human neural stem cells from the brain cortex of human abortus were isolated and cultured, then gene was modified by lentivirus to express both green fluorescence protein (GFP) and rat neurotrophin-3 (NT-3); the transgenic expression was detected by the methods of fluorescence microscope, dorsal root ganglion of fetal rats and slot blot. Results: Genetic engineering hNSCs were successfully constructed. All of the genetic engineering hNSCs which expressed bright green fluorescence were observed under the fluorescence microscope. The conditioned medium of transgenic hNSCs could induce neurite flourishing outgrowth from dorsal root ganglion (DRG). The genetic engineering hNSCs expressed high level NT-3 which could be detected by using slot blot. Conclusions: Genetic engineering hNSCs mediated by lentivirus can be constructed to express multigene successfully.展开更多
Recent studies suggest that cell cycle pathways may contain therapeutic targets important for neurotrauma.An example of this is the finding that the vertebrate cell cycle exploits proteolysis pathways,yet these activi...Recent studies suggest that cell cycle pathways may contain therapeutic targets important for neurotrauma.An example of this is the finding that the vertebrate cell cycle exploits proteolysis pathways,yet these activities persist in fully differentiated cells that have exited the cell cycle such as neurons.We have known for some time that a ubiquitin ligase.展开更多
Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the acti...Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion（DRG） sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model.展开更多
Couples with a spinal cord injured male partner require assisted ejaculation techniques to collect semen that can then be further used in various assisted reproductive technology methods to achieve a pregnancy. The ma...Couples with a spinal cord injured male partner require assisted ejaculation techniques to collect semen that can then be further used in various assisted reproductive technology methods to achieve a pregnancy. The majority of men sustaining a spinal cord injury regardless of the cause or the level of injury cannot ejaculate during sexual intercourse. Only a small minority can ejaculate by masturbation. Penile vibratory stimulation and electroejaculation are the two most common methods used to retrieve sperm. Other techniques such as prostatic massage and the adjunct application of other medications can be used, but the results are inconsistent. Surgical sperm retrieval should be considered as a last resort if all other methods fail. Special attention must be paid to patients with T6 and rostral levels of injury due to the risk of autonomic dysreflexia resulting from stimulation below the level of injury. Bladder preparation should be performed before stimulation if retrograde ejaculation is anticipated. Erectile dysfunction is ubiquitous in the spinal cord injured population but is usually easily managed and does not pose a barrier to semen retrieval in these men. Semen analysis parameters of men with spinal cord injury are unique for this population regardless of the method of retrieval, generally presenting as normal sperm concentration but abnormally low sperm motility and viability. When sperm retrieval is desired in this population, emphasis should be placed on initially trying the simple methods of penile vibratory stimulation or electroejaculation before resorting to more advanced and invasive surgical procedures.展开更多
Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann c...Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.展开更多
文摘Rarely,penetrating injuries to the spinal cord result from wooden objects,creating unique challenges to mitigate neurological injury and high rates of infection and foreign body reactions.We report a man who sustained a penetrating cervical spinal cord injury from a sharpened stick.While initially tetraparetic,he rapidly recovered function.The risks of neurological deterioration during surgical removal made the patient reluctant to consent to surgery despite the impalement of the spinal cord.A repeat MRI on day 3 showed an extension of edema indicating progressive inflammation.On the 7~(th)day after injury,fever and paresthesias occurred with a large increase in serum inflammatory indicators,and the patient agreed to undergo surgical removal of the wooden object.We discuss the management nuances related to wood,the longitudinal evolution of MRI findings,infection risk,surgical risk mitigation and technique,an inflammatory marker profile,long-term recovery,and the surprisingly minimal neurological deficits associated with low-velocity midline spinal cord injuries.The patient had an excellent clinical outcome.The main lessons are that a wooden penetrating central nervous system injury has a high risk for infection,and that surgical removal from the spinal cord should be performed soon after injury and under direct visualization.
基金supported by Hong Kong Spinal Cord Injury Fund (HKSCIF),China (to HZ)。
文摘For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.
基金supported by NIH-NINDS Grants NS009923 and NS084326The Miami Project to Cure Paralysis and The Buoniconti Fund
文摘cAMP signaling and the control of Schwann cell fate： The ubiquitous second messenger cyclic adenosine monophosphate （cAMP） controls a variety of cellular responses in a cell type-specific and stimulus-de- pendent manner through an elaborate network of signaling intermedi- aries that connect stimulation of cell membrane receptors （typically G protein-coupled receptors, GPCRs） to transcription factor activation. Schwann cells （SCs） are highly responsive to cAMP throughout their lifespan, as extensive research has shown that SC survival, lineage spec- ification, proliferation and differentiation into myelin-forming cells require cAMP signaling.
基金Vance Lemmon is listed as an inventor on patents held by the University of Miami relevant to nerve regeneration.He is the co-founder of a drug discovery start-up working in early stage drug discovery relevant to cancer
文摘On September 12 and 13,2019,the National Institute of Neurological Disorders and Stroke(NINDS),Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD),as well as other federal agencies and several private foundations sponsored a stake holder meeting at the National Institutes of Health(NIH)Bethesda campus with a provocative title:“SCI 2020:Launching a decade for disruption in spinal cord injury research”.Over the past decade,“disruptive”has become a cool buzz word for entrepreneurs to use to market their technology.In this context,disruptive means“innovative,ingenious,and unconventional”(typically definition#2 in online dictionaries).The hope is their new technology or business model is so powerful it will upend current technologies and come to dominate the market place.Uber’s destruction of taxi companies worldwide is a leading example of being“disruptive”.
基金Supported by the Natural Science Foundation of Yunnan Province(2002C0070M).
文摘Objective To explore the feasibility for therapy of spinal cord injury (SCI) by genetic engineering neural stem cell (NSC) modified by lentiviral vector. Methods Following the construction of the genetic engineering NSC modified by lentivirus to secrete both neurotrophic factor-3 (NT-3) and green fluorescence protein (GFP), hemisection of spinal cord at the level of T_ 10 was performed in 56 adult Wistar rats that were randomly divided into 4 groups (n=14), namely 3 therapeutic groups and 1 control group. The therapeutic groups were dealed with NSC, genetic engineering NSC, and concentrated lentiviral supernatant which carries both GFP and NT-3, respectively. Then used fluorescence microscope to detect the transgenic expression in vitro and in vivo, migration of the grafted cells in vivo, and used the Basso, Beattie, and Bresnahan (BBB) open-field locomotor test to assess the recovery of function. Results The transplanted cells could survive for long time in vivo and migrate for long distance. The stable transgenic expression could be detected in vivo. The hindlimb function of the injured rats in 3 therapeutic groups, especially those dealed with genetic engineering NSC, improved obviously. Conclusion It is feasible to combine NSC with lentivirus for the repair of SCI. NSC modified by lentivirus to deliver NT-3, acting as a source of neurotrophic factors and function cell in vivo, has the potential to participate in spinal cord repair.
基金NINDS R01NS09923(MBB)R01NS081040(JKL)+1 种基金The Miami Project to Cure Paralysisthe Buoniconti Fund
文摘Schwann cell transplantation is a promising therapy for the treatment of spinal cord injury（SCI） and is currently in clinical trials.In our continuing efforts to improve Schwann cell transplantation strategies,we sought to determine the combined effects of Schwann cell transplantation with macrophage depletion.Since macrophages are major inflammatory contributors to the acute spinal cord injury,and are the major phagocytic cells,we hypothesized that transplanting Schwann cells after macrophage depletion will improve cell survival and integration with host tissue after SCI.To test this hypothesis,rat models of contusive SCI at thoracic level 8 were randomly subjected to macrophage depletion or not.In rat subjected to macrophage depletion,liposomes filled with clodronate were intraperitoneally injected at 1,3,6,11,and 18 days post injury.Rats not subjected to macrophage depletion were intraperitoneally injected with liposomes filled with phosphate buffered saline.Schwann cells were transplanted 1 week post injury in all rats.Biotinylated dextran amine（BDA） was injected at thoracic level 5 to evalute axon regeneration.The Basso,Beattie,and Bresnahan locomotor test,Gridwalk test,and sensory test using von Frey filaments were performed to assess functional recovery.Immunohistochemistry was used to detect glial fibrillary acidic protein,neurofilament,and green fluorescent protein（GFP）,and also to visulize BDA-labelled axons.The GFP labeled Schwann cell and cyst and lesion volumes were quantified using stained slides.The numbers of BDA-positive axons were also quantified.At 8 weeks after Schwann cell transplantation,there was a significant reduction in cyst and lesion volumes in the combined treatment group compared to Schwann cell transplantation alone.These changes were not associated,however,with improved Schwann cell survival,axon growth,or locomotor recovery.Although combining Schwann cell transplantation with macrophage depletion does improve histopathology of the injury site,the effect on axon growth and behavioral recovery appears no better than what can be achieved with Schwann cell transplants alone.
基金supported by CDMRP SCIRP Award No.W81XWH-10-1-0793The Miami Project to Cure Paralysis and The Buoniconti Fund
文摘It has been controversial whether gender has any effect on recovery following spinal cord injury（SCI）. Past experimental and clinical research aimed at addressing this subject has led to constrasting findings on whether females hold any advantage in locomotor recovery. Additionally, for studies supporting the notion of a female gender related advantage, a definite cause has not been explained. In a recent study, using large sample sizes for comparative male and female spinal cord injury cohorts, we reported that a significant gender advantage favoring females existed in both tissue preservation and functional recovery after taking into consideration discrepancies in age and weight of the animals across sexes. Prior animal research frequently used sample sizes that were too small to determine significance with certainty and also did not account for two other factors that influence locomotor performance： age and weight. Our finding is important in light of controversy surrounding the effect of gender on outcome and the fact that SCI affects more than ten thousand new individuals annually, a population that is disproportionately male. By deepening our understanding of why a gender advantage exists, potential new therapeutics can be designed to improve recovery for the male population following the initial trauma or putatively augment the neuroprotective privilege in females for enhanced outcomes.
文摘Objective: To explore the feasibility to construct genetic engineering human neural stem cells (hNSCs) mediated by lentivirus to express multigene in order to provide a graft source for further studies of spinal cord injury (SCI). Methods: Human neural stem cells from the brain cortex of human abortus were isolated and cultured, then gene was modified by lentivirus to express both green fluorescence protein (GFP) and rat neurotrophin-3 (NT-3); the transgenic expression was detected by the methods of fluorescence microscope, dorsal root ganglion of fetal rats and slot blot. Results: Genetic engineering hNSCs were successfully constructed. All of the genetic engineering hNSCs which expressed bright green fluorescence were observed under the fluorescence microscope. The conditioned medium of transgenic hNSCs could induce neurite flourishing outgrowth from dorsal root ganglion (DRG). The genetic engineering hNSCs expressed high level NT-3 which could be detected by using slot blot. Conclusions: Genetic engineering hNSCs mediated by lentivirus can be constructed to express multigene successfully.
文摘Recent studies suggest that cell cycle pathways may contain therapeutic targets important for neurotrauma.An example of this is the finding that the vertebrate cell cycle exploits proteolysis pathways,yet these activities persist in fully differentiated cells that have exited the cell cycle such as neurons.We have known for some time that a ubiquitin ligase.
基金supported by National Institutes of Health HD057632the Buoniconti Fundthe Walter G.Ross Distinguished Chair in Developmental Neuroscience(to VPL)
文摘Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion（DRG） sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model.
文摘Couples with a spinal cord injured male partner require assisted ejaculation techniques to collect semen that can then be further used in various assisted reproductive technology methods to achieve a pregnancy. The majority of men sustaining a spinal cord injury regardless of the cause or the level of injury cannot ejaculate during sexual intercourse. Only a small minority can ejaculate by masturbation. Penile vibratory stimulation and electroejaculation are the two most common methods used to retrieve sperm. Other techniques such as prostatic massage and the adjunct application of other medications can be used, but the results are inconsistent. Surgical sperm retrieval should be considered as a last resort if all other methods fail. Special attention must be paid to patients with T6 and rostral levels of injury due to the risk of autonomic dysreflexia resulting from stimulation below the level of injury. Bladder preparation should be performed before stimulation if retrograde ejaculation is anticipated. Erectile dysfunction is ubiquitous in the spinal cord injured population but is usually easily managed and does not pose a barrier to semen retrieval in these men. Semen analysis parameters of men with spinal cord injury are unique for this population regardless of the method of retrieval, generally presenting as normal sperm concentration but abnormally low sperm motility and viability. When sperm retrieval is desired in this population, emphasis should be placed on initially trying the simple methods of penile vibratory stimulation or electroejaculation before resorting to more advanced and invasive surgical procedures.
基金support from the Miami Project to Cure Paralysis,the Buoniconti Fund,and the Interdisciplinary Stem Cell Institute(to AK,WDD,JDG,and ADL)the unconditional support of Dean Henri Ford of the Leonard M.Miller School of Medicine at the University of Miami.
文摘Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.
