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Mershon JP, Ballinger J, Heh V, Sciuva J, Charleton M, Colachis S, Schwab J, Crescenze I. Predictors of catheter-free voiding after spinal cord injury. J Spinal Cord Med 2025; 48:518-526. [PMID: 38088774 PMCID: PMC12035921 DOI: 10.1080/10790268.2023.2279271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2025] Open
Abstract
CONTEXT Despite a high prevalence of neurogenic bladder (NGB) in patients with spinal cord injury (SCI), clinicians are unable to predict long-term bladder outcomes due to variable phenotypes of bladder dysfunction. This study investigates if early bladder events, infections, and spinal cord injury characteristics during rehabilitation admission affect bladder outcomes one year after SCI. METHODS This retrospective study included patients with SCI admitted to a tertiary rehabilitation center between 1 January 2016 and 1 January 2020. Data was collected on early bladder management, comorbidities, infections and injury characteristics; level of injury, American Spinal Injury Association Impairment Scale (AIS) classification, and International Standards for Neurological Classification of Spinal Cord Injury lower extremity motor score (LEMS). RESULTS Seventy-two patients met inclusion criteria; 63% (45/72) patients had cervical SCI and 31% (22/72) were complete injuries. Twenty-two percent (16/72) did not use an internal catheter to empty the bladder, improving to 41% (29/72) at one year. On multivariate logistic regression accounting for age, sex, Charlson comorbidity index, LEMS, and infections during admission, higher LEMS (OR 1.104, 95%, CI 1.037-1.176, P = 0.002) associated with catheter-free voiding (CFV) at one year while male sex (OR 0.091, 95% CI 0.012-0.713, P = 0.0225), and non-urologic infections (OR 0.088, 95% CI 0.010-0.768, P = 0.0279) were negatively associated. CONCLUSIONS Preserved LEMS early after SCI associates with CFV at one year while male sex and early non-urologic infections such as pneumonia are associated with persistent urinary retention. This can be used to counsel SCI patients on expected bladder recovery and outcomes.
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Affiliation(s)
- J. Patrick Mershon
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Jennifer Ballinger
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Victor Heh
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Jessica Sciuva
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Mary Charleton
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sam Colachis
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Jan Schwab
- The Belford Center for Spinal Cord Injury, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- Departments of Neurology, Physical Medicine and Rehabilitation, and Neurosciences, The Ohio State University, Columbus, Ohio, USA
| | - Iryna Crescenze
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Buchl SC, Kim HN, Hur B, Simon WL, Langley MR, Sung J, Scarisbrick IA. Delayed atorvastatin delivery promotes recovery after experimental spinal cord injury. Neurotherapeutics 2025; 22:e00517. [PMID: 39755500 PMCID: PMC12014417 DOI: 10.1016/j.neurot.2024.e00517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/04/2024] [Accepted: 12/13/2024] [Indexed: 01/06/2025] Open
Abstract
Spinal cord injury (SCI) significantly alters gene expression, potentially impeding functional recovery. This study investigated the effects of atorvastatin, a widely prescribed cholesterol-lowering drug, on gene expression and functional recovery in a chronic murine SCI model. Female C57BL/6J mice underwent moderate 0.25 mm lateral compression SCI and received daily atorvastatin (10 mg/kg) or vehicle-only injections from two weeks post-injury for four weeks. Sensorimotor functions were assessed using the Basso Mouse Scale (BMS), its subscore, and the inclined plane test. RNA sequencing of spinal cord tissues identified robust transcriptomic changes from SCI and a smaller subset from atorvastatin treatment. Atorvastatin enhanced sensorimotor recovery within two weeks of treatment initiation, with effects persisting to the experimental endpoint. Pathway analysis showed atorvastatin enriched neural regeneration processes including Fatty Acid Transport, Axon Guidance, and the Endocannabinoid Developing Neuron Pathway; improved mitochondrial function via increased TCA Cycle II and reduced Mitochondrial Dysfunction; and decreased Inhibition of Matrix Metalloproteases. Key gene drivers included Fabp7, Unc5c, Rest, and Klf4. Together, these results indicate atorvastatin's potential in chronic SCI recovery, especially where already indicated for cardiovascular protection.
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Affiliation(s)
- Samuel C Buchl
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA
| | - Ha Neui Kim
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA
| | - Benjamin Hur
- Microbiomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Whitney L Simon
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Monica R Langley
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Jaeyun Sung
- Microbiomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA; Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Isobel A Scarisbrick
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
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Craven BC, Souza WH, Jaglal S, Gibbs J, Wiest MJ, Sweet SN, Athanasopoulos P, Lamontagne ME, Boag L, Patsakos E, Wolfe D, Hicks A, Maltais DB, Best KL, Gagnon D. Reducing endocrine metabolic disease risk in adults with chronic spinal cord injury: strategic activities conducted by the Ontario-Quebec RIISC team. Disabil Rehabil 2024; 46:4835-4847. [PMID: 38018518 DOI: 10.1080/09638288.2023.2284223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/17/2023] [Accepted: 11/10/2023] [Indexed: 11/30/2023]
Abstract
PURPOSE The Rehabilitation Interventions for Individuals with a Spinal Cord Injury in the Community (RIISC) team aimed to develop and evaluate innovative rehabilitation interventions to identify endocrine metabolic disease (EMD) risk, intending to reduce the frequency and severity of EMD related morbidity and mortality among adults living with chronic spinal cord injury or disease (SCI/D). MATERIALS AND METHODS An interprovincial team from Ontario and Quebec reviewed available EMD literature and evidence syntheses and completed an inventory of health services, policies and practices in SCI/D care. The review outcomes were combined with expert opinion to create an EMD risk model to inform health service transformation. RESULTS EMD risk and mortality are highly prevalent among adults with chronic SCI/D. In stark contrast, few rehabilitation interventions target EMD outcomes. The modelled solution proposes: 1) abandoning single-disease paradigms and examining a holistic perspective of the individual's EMD risk, and 2) developing and disseminating practice-based research approaches in outpatient community settings. CONCLUSIONS RIISC model adoption could accelerate EMD care optimization, and ultimately inform the design of large-scale longitudinal pragmatic trials likely to improve health outcomes. Linking the RIISC team activities to economic evaluations and policy deliverables will strengthen the relevance and impact among policymakers, health care providers and patients.
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Affiliation(s)
- Beverley Catharine Craven
- Toronto Rehabilitation Institute, Lyndhurst Centre, University Health Network, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - Wagner Henrique Souza
- Kite Research Institute, University Health Network, Lyndhurst Centre, Toronto, Canada
| | - Susan Jaglal
- Department of Physical Therapy, University of Toronto, Toronto, Canada
| | - Jenna Gibbs
- Department of Kinesiology and Physical Education, McGill University, Montreal, Canada
| | | | - Shane N Sweet
- Department of Kinesiology & Physical Education, McGill University, Montreal, Canada
| | - Peter Athanasopoulos
- Senior Manager Public Policy and Government Relations, Spinal Cord Injury Ontario, Toronto, Canada
| | | | - Lynn Boag
- University of Guelph, Guelph, Canada
| | - Eleni Patsakos
- Rehabilitation Sciences Institute, University of Toronto, Toronto, Canada
| | - Dalton Wolfe
- Department of Physical Medicine and Rehabilitation, Western University, Parkwood Institute Research, London, Canada
| | - Audrey Hicks
- Department of Kinesiology, McMaster University, Hamilton, Canada
| | - Désirée B Maltais
- Department of Rehabilitation, Physiotherapy Program, Laval University, Quebec City, Canada
| | - Krista Lynn Best
- Department of Rehabilitation, Faculty of Medicine, Université Laval, Quebec City, Canada
| | - Dany Gagnon
- School of Rehabilitation, Université de Montréal, Montréal, Canada
- Centre for Interdisciplinary Research in Rehabilitation, Institut Universitaire sur la Réadaptation en Déficience Physique de Montréal (IURDPM), Montréal, Canada
- Rehabilitation, Université de Montréal, École de Réadaptation, Montréal, Canada
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Wyndaele M, Charrua A, Hervé F, Aronsson P, Grundy L, Khullar V, Wein A, Abrams P, Cruz F, Cruz CD. Beyond the urothelium: Interplay between autonomic nervous system and bladder inflammation in urinary tract infection, bladder pain syndrome with interstitial cystitis and neurogenic lower urinary tract dysfunction in spinal cord injury-ICI-RS 2023. Neurourol Urodyn 2024; 43:1283-1292. [PMID: 37876314 DOI: 10.1002/nau.25310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 10/11/2023] [Indexed: 10/26/2023]
Abstract
INTRODUCTION Inflammation and neuronal hypersensitivity are reactive protective mechanisms after urothelial injury. In lower urinary tract dysfunctions (LUTD), such as urinary tract infection (UTI), bladder pain syndrome with interstitial cystitis (BPS/IC) and neurogenic LUTD after spinal cord injury (SCI), chronic inflammation can develop. It is unclear how the protective reactionary inflammation escalates into chronic disease in some patients. METHODS During its 2023 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the urothelial and inflammatory changes after UTI, BPS/IC and SCI. Potential factors contributing to the evolution into chronic disease were explored in a think-tank. RESULTS Five topics were discussed. (1) Visceral fat metabolism participates in the systemic pro-inflammatory effect of noradrenalin in BPS/IC and SCI. Sympathetic nervous system-adipocyte-bladder crosstalk needs further investigation. (2) Sympathetic hyperactivity also potentiates immune depression in SCI and needs to be investigated in BPS/IC. Gabapentin and tumor necrosis factor-α are promising research targets. (3) The exact peripheral neurons involved in the integrative protective unit formed by nervous and immune systems need to be further identified. (4) Neurotransmitter changes in SCI and BPS/IC: Neurotransmitter crosstalk needs to be considered in identifying new therapeutic targets. (5) The change from eubiosis to dysbiosis in SCI can contribute to UTI susceptibility and needs to be unraveled. CONCLUSIONS The think-tank discussed whether visceral fat metabolism, immune depression through sympathetic hyperactivity, peripheral nerves and neurotransmitter crosstalk, and the change in microbiome could provide explanations in the heterogenic development of chronic inflammation in LUTD. High-priority research questions were identified.
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Affiliation(s)
- Michel Wyndaele
- Department of Urology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ana Charrua
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, Porto, Portugal
- Translational Neurourology, Instituto de Investigação e Inovação em Saúde-i3S and IBMC University of Porto, Porto, Portugal
| | - François Hervé
- Department of Urology, Ghent University Hospital, Ghent, Belgium
| | - Patrik Aronsson
- Department Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Luke Grundy
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute (FHMRI), Flinders University, Bedford Park, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
- Discipline of Medicine, University of Adelaide, Adelaide, Australia
| | - Vik Khullar
- Department of Urogynaecology, St Mary's Hospital, Imperial College, London, UK
| | - Alan Wein
- Department of Surgery, Division of Urology, Perelman School of Medicine, Penn Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Urology, Desai Sethi Institute of Urology, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Paul Abrams
- Bristol Urological Institute, North Bristol NHS Trust, Southmead Hospital, Bristol, UK
| | - Francisco Cruz
- Translational Neurourology, Instituto de Investigação e Inovação em Saúde-i3S and IBMC University of Porto, Porto, Portugal
- Department of Surgery and Physiology, Faculty of Medicine of Porto, University of Porto, Porto, Portugal
- Department of Urology, Hospital São João, Porto, Portugal
| | - Célia Duarte Cruz
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, Porto, Portugal
- Translational Neurourology, Instituto de Investigação e Inovação em Saúde-i3S and IBMC University of Porto, Porto, Portugal
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Tamburella F, Lena E, Mascanzoni M, Iosa M, Scivoletto G. Harnessing Artificial Neural Networks for Spinal Cord Injury Prognosis. J Clin Med 2024; 13:4503. [PMID: 39124769 PMCID: PMC11313443 DOI: 10.3390/jcm13154503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Background: Prediction of neurorehabilitation outcomes after a Spinal Cord Injury (SCI) is crucial for healthcare resource management and improving prognosis and rehabilitation strategies. Artificial neural networks (ANNs) have emerged as a promising alternative to conventional statistical approaches for identifying complex prognostic factors in SCI patients. Materials: a database of 1256 SCI patients admitted for rehabilitation was analyzed. Clinical and demographic data and SCI characteristics were used to predict functional outcomes using both ANN and linear regression models. The former was structured with input, hidden, and output layers, while the linear regression identified significant variables affecting outcomes. Both approaches aimed to evaluate and compare their accuracy for rehabilitation outcomes measured by the Spinal Cord Independence Measure (SCIM) score. Results: Both ANN and linear regression models identified key predictors of functional outcomes, such as age, injury level, and initial SCIM scores (correlation with actual outcome: R = 0.75 and 0.73, respectively). When also alimented with parameters recorded during hospitalization, the ANN highlighted the importance of these additional factors, like motor completeness and complications during hospitalization, showing an improvement in its accuracy (R = 0.87). Conclusions: ANN seemed to be not widely superior to classical statistics in general, but, taking into account complex and non-linear relationships among variables, emphasized the impact of complications during the hospitalization on recovery, particularly respiratory issues, deep vein thrombosis, and urological complications. These results suggested that the management of complications is crucial for improving functional recovery in SCI patients.
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Affiliation(s)
- Federica Tamburella
- Department of Life Sciences, Health and Health Professions, Link Campus University, 00165 Rome, Italy;
- Spinal Center, Spinal Rehabilitation Laboratory, IRCCS Fondazione S. Lucia, 00179 Rome, Italy; (E.L.); (M.M.); (G.S.)
| | - Emanuela Lena
- Spinal Center, Spinal Rehabilitation Laboratory, IRCCS Fondazione S. Lucia, 00179 Rome, Italy; (E.L.); (M.M.); (G.S.)
| | - Marta Mascanzoni
- Spinal Center, Spinal Rehabilitation Laboratory, IRCCS Fondazione S. Lucia, 00179 Rome, Italy; (E.L.); (M.M.); (G.S.)
| | - Marco Iosa
- Department of Psychology, Sapienza University of Rome, 00183 Rome, Italy
- Smart Lab, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy
| | - Giorgio Scivoletto
- Spinal Center, Spinal Rehabilitation Laboratory, IRCCS Fondazione S. Lucia, 00179 Rome, Italy; (E.L.); (M.M.); (G.S.)
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Portela Hara AC, Aching NC, Marques LM, Barbosa SP, Souza DR, Fregni F, Battistella LR, Simis M. The role of clinical and demographic predictors for understanding the cognitive impairment in Spinal Cord Injury (SCI) patients. Spinal Cord 2024; 62:336-342. [PMID: 38609569 DOI: 10.1038/s41393-024-00986-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 03/14/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024]
Abstract
STUDY DESIGN Using a cross-sectional design, we extracted sociodemographic and clinical data from 488 Spinal Cord Injury (SCI) patients during their initial assessment before receiving intensive rehabilitation treatment. OBJECTIVES The primary objectives of this study were to ascertain the prevalence of cognitive impairment in the study sample and specify the key clinical and demographic predictors of cognitive functioning in SCI patients. SETTING Lucy Montoro Rehabilitation Institute (LMRI), University of Sao Paulo, Sao Paulo, Brazil. METHODS We utilized independent univariate and multivariate regression models with the Montreal Cognitive Assessment (MoCA) scale, adapted for individuals with visual impairment. Moreover, we consider scores from the execution tasks (visuospatial/executive) as the dependent variable. RESULTS Our findings demonstrate that approximately 80% of the evaluated study sample exhibited cognitive impairment. Through the multivariate regression models, we show that several factors, including age, education, depression levels, and the use of analgesics and/or opioids, are significant predictors of total cognitive scores. These factors are independent of the clinical features associated with SCI, such as age, sex, education, and time since the injury. CONCLUSIONS The results indicate a high prevalence of significant cognitive impairment within the sample, with age, education, depression levels, and the use of analgesics and/or opioids emerging as the primary predictors of total cognitive scores, independent of the clinical features correlated to SCI. These findings hold significant implications for both clinical research and practice, offering valuable guidance for comprehensive management throughout hospitalization and rehabilitation.
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Affiliation(s)
- Ana Clara Portela Hara
- Instituto de Medicina Física e Reabilitação, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Nicole C Aching
- Instituto de Medicina Física e Reabilitação, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Lucas M Marques
- Mental Health Department, Santa Casa of Sao Paulo Medical Science School, São Paulo, SP, Brazil
| | - Sara P Barbosa
- Instituto de Medicina Física e Reabilitação, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Daniel R Souza
- Instituto de Medicina Física e Reabilitação, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Felipe Fregni
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Linamara R Battistella
- Instituto de Medicina Física e Reabilitação, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
- Departamento de Medicina Legal, Bioética, Medicina do Trabalho e Medicina Física e Reabilitação, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Marcel Simis
- Instituto de Medicina Física e Reabilitação, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
- Departamento de Medicina Legal, Bioética, Medicina do Trabalho e Medicina Física e Reabilitação, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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Graves LY, Keane KF, Taylor JY, Wang TF, Saligan L, Bogie KM. Subacute and Chronic Spinal Cord Injury: A Scoping Review of Epigenetics and Secondary Health Conditions. Epigenet Insights 2023; 16:25168657231205679. [PMID: 37900668 PMCID: PMC10612389 DOI: 10.1177/25168657231205679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 09/11/2023] [Indexed: 10/31/2023] Open
Abstract
Background Epigenetics studies the impact of environmental and behavioral factors on stable phenotypic changes; however, the state of the science examining epigenomic mechanisms of regulation related to secondary health conditions (SHCs) and neuroepigenetics in chronic spinal cord injury (SCI) remain markedly underdeveloped. Objective This scoping review seeks to understand the state of the science in epigenetics and secondary complications following SCI. Methods A literature search was conducted, yielding 277 articles. The inclusion criteria were articles (1) investigating SCI and (2) examining epigenetic regulation as part of the study methodology. A total of 23 articles were selected for final inclusion. Results Of the 23 articles 52% focused on histone modification, while 26% focused on DNA methylation. One study had a human sample, while the majority sampled rats and mice. Primarily, studies examined regeneration, with only one study looking at clinically relevant SHC, such as neuropathic pain. Discussion The findings of this scoping review offer exciting insights into epigenetic and neuroepigenetic application in SCI research. Several key genes, proteins, and pathways emerged across studies, suggesting the critical role of epigenetic regulation in biological processes. This review reinforced the dearth of studies that leverage epigenetic methods to identify prognostic biomarkers in SHCs. Preclinical models of SCI were genotypically and phenotypically similar, which is not reflective of the heterogeneity found in the clinical population of persons with SCI. There is a need to develop better preclinical models and more studies that examine the role of genomics and epigenomics in understanding the diverse health outcomes associated with traumatic SCI.
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Affiliation(s)
- Letitia Y Graves
- School of Nursing, University of Texas Medical Branch, Galveston, TX, USA
- Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA
| | - Kayla F Keane
- National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA
| | - Jacquelyn Y Taylor
- Columbia School of Nursing and Center for Research on People of Color, New York, NY, USA
| | - Tzu-fang Wang
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Leorey Saligan
- National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA
| | - Kath M Bogie
- Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA
- Case Western Reserve University, Cleveland, OH, USA
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Zhong Y, Xin Y, Liu X, Xiao X, Guo F, Yao H. Transoropharyngeal closed reduction for traumatic atlantoaxial dislocation: a novel technique for fast and precise reduction. INTERNATIONAL ORTHOPAEDICS 2023:10.1007/s00264-023-05817-7. [PMID: 37166469 PMCID: PMC10267008 DOI: 10.1007/s00264-023-05817-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 04/14/2023] [Indexed: 05/12/2023]
Abstract
PURPOSE The aim of this study is to introduce a new technique for the rapid and accurate reduction of traumatic atlantoaxial dislocation (TAAD) and to investigate its radiological and clinical outcomes. METHODS The clinical outcomes of 18 patients who were diagnosed with acute TAAD and underwent rapid transoropharyngeal closed reduction in our hospital were retrospectively analyzed from January 2015 to December 2020. Following general anaesthesia, all patients were immediately treated with oropharyngeal reduction under somatosensory evoked potential monitoring. The Japanese Orthopedic Association score, neck disability index and visual analog scale score for neck pain were used to evaluate clinical efficacy. Atlantodental distance, posterior atlantodental interval, and the clivus-canal angle were used to assess reduction and spinal cord compression. RESULTS The mean follow-up time was 23.3 months, with a range of 13-38 months. No neurovascular injury occurred during the operations. For all patients, the closed reduction method through the oropharynx under general anaesthesia was successful, and the success rate of reduction was 100%. All patients recovered uneventfully with marked improvement in clinical outcomes and imaging parameters (P < 0.01). Two patients developed mild postoperative dysphagia. One patient developed postoperative fever and pulmonary infection. CONCLUSION Rapid trans-oropharyngeal closed reduction can safely, effectively, and rapidly reduce acute TAAD. This method provides a new strategy for treatment of the condition.
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Affiliation(s)
- Yanlong Zhong
- The Orthopedic Hospital, The First Affiliated Hospital of Nanchang University, 1519 Dongyue Avenue, Nanchang, 330209, Jiangxi, China
| | - Yu Xin
- Department of Orthopedics, The People's Hospital of Yi Chun City, Yi Chun, Jiangxi, China
| | - Xuqiang Liu
- The Orthopedic Hospital, The First Affiliated Hospital of Nanchang University, 1519 Dongyue Avenue, Nanchang, 330209, Jiangxi, China
| | - Xinmao Xiao
- The Orthopedic Hospital, The First Affiliated Hospital of Nanchang University, 1519 Dongyue Avenue, Nanchang, 330209, Jiangxi, China
| | - Fengfen Guo
- The Orthopedic Hospital, The First Affiliated Hospital of Nanchang University, 1519 Dongyue Avenue, Nanchang, 330209, Jiangxi, China
| | - Haoqun Yao
- The Orthopedic Hospital, The First Affiliated Hospital of Nanchang University, 1519 Dongyue Avenue, Nanchang, 330209, Jiangxi, China.
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Fasolino I, Carvalho ED, Raucci MG, Bonadies I, Soriente A, Pezzella A, Pêgo AP, Ambrosio L. Eumelanin decorated poly(lactic acid) electrospun substrates as a new strategy for spinal cord injury treatment. BIOMATERIALS ADVANCES 2023; 146:213312. [PMID: 36736264 DOI: 10.1016/j.bioadv.2023.213312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/13/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023]
Abstract
Spinal cord injury (SCI) is characterized by neuroinflammatory processes that are marked by an uncontrolled activation of microglia, which directly damages neurons. Natural and synthetic melanins represent an effective tool to treat neuroinflammation because they possess immunomodulatory properties. Here, the main objective was to evaluate the effect of eumelanin-coated poly(lactic acid) (EU@PLA) aligned microfibers on in vitro model of neuroinflammation related to spinal cord injury in terms of inflammatory mediators' modulation. Aligned fibers were chosen to provide physical cues to guide axonal growth in a specific direction thus restoring the synaptic connection. Eumelanin decorated PLA electrospun substrates were produced combining electrospinning, spin coating and solid-state polymerization processes (oxidative coupling under oxygen atmosphere). Biological response in terms of antioxidant and anti-inflammatory activity was analyzed on an in vitro model of neuroinflammation [microglial cells stimulated with lipopolysaccharide (LPS)]. Cell morphology and EU@PLA mechanism of action, in terms of toll-like receptor-4 (TLR-4) involvement were assessed. The results show that EU@PLA fibers were able to decrease reactive oxygen species, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) expression >50 % compared to PLA + LPS and interleukin 6 (IL-6) secretion about 20 %. Finally, the mechanism of action of EU@PLA in microglia was found to be dependent on the TLR-4 signaling. Protein expression analysis revealed a decreased in TLR-4 production induced by LPS stimulation in presence of EU@PLA. Overall, our results show that EU@PLA represents an innovative and effective strategy for the control of inflammatory response in central nervous system.
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Affiliation(s)
- Ines Fasolino
- Institute of Polymers, Composites and Biomaterials - National Research Council (IPCB-CNR), Naples, Italy.
| | - Eva Daniela Carvalho
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; Faculdade de Engenharia da Universidade do Porto, Porto, Portugal
| | - Maria Grazia Raucci
- Institute of Polymers, Composites and Biomaterials - National Research Council (IPCB-CNR), Naples, Italy; Bioelectronics Task Force at University of Naples "Federico II", Italy.
| | - Irene Bonadies
- Institute of Polymers, Composites and Biomaterials - National Research Council (IPCB-CNR), Naples, Italy
| | - Alessandra Soriente
- Institute of Polymers, Composites and Biomaterials - National Research Council (IPCB-CNR), Naples, Italy
| | - Alessandro Pezzella
- Institute of Polymers, Composites and Biomaterials - National Research Council (IPCB-CNR), Naples, Italy; University of Naples "Federico II" Department of Physics "Ettore Pancini" Complesso Universitario Monte S. Angelo, Italy; Bioelectronics Task Force at University of Naples "Federico II", Italy
| | - Ana Paula Pêgo
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; Faculdade de Engenharia da Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Luigi Ambrosio
- Institute of Polymers, Composites and Biomaterials - National Research Council (IPCB-CNR), Naples, Italy
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10
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Bigford GE, Garshick E. Systemic inflammation after spinal cord injury: A review of biological evidence, related health risks, and potential therapies. Curr Opin Pharmacol 2022; 67:102303. [PMID: 36206621 PMCID: PMC9929918 DOI: 10.1016/j.coph.2022.102303] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 09/06/2022] [Indexed: 01/25/2023]
Abstract
Individuals with chronic traumatic spinal cord injury (SCI) develop progressive multi-system health problems that result in clinical illness and disability. Systemic inflammation is associated with many of the common medical complications and acquired diseases that accompany chronic SCI, suggesting that it contributes to a number of comorbid pathological conditions. However, many of the mechanisms that promote persistent systemic inflammation and its consequences remain ill-defined. This review describes the significant biological factors that contribute to systemic inflammation, major organ systems affected, health risks, and the potential treatment strategies. We aim to highlight the need for a better understanding of inflammatory processes, and to establish appropriate strategies to address inflammation in SCI.
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Affiliation(s)
- Gregory E Bigford
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Eric Garshick
- Pulmonary, Allergy, Sleep, and Critical Care Medicine Section, VA Boston Healthcare System, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
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11
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Panisset MG, El-Ansary D, Dunlop SA, Marshall R, Clark J, Churilov L, Galea MP. Factors influencing thigh muscle volume change with cycling exercises in acute spinal cord injury - a secondary analysis of a randomized controlled trial. J Spinal Cord Med 2022; 45:510-521. [PMID: 32970970 PMCID: PMC9246176 DOI: 10.1080/10790268.2020.1815480] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Objective: To conduct a per-protocol analysis on thigh muscle volume outcomes from the Spinal Cord Injury and Physical Activity (SCIPA) Switch-On Trial.Design: Secondary analysis from an assessor-blind randomized, controlled trial.Setting: Four acute/sub-acute hospitals in Australia and New Zealand.Participants: 24 adults (1 female) within four weeks of motor complete or incomplete spinal cord injury (SCI)Intervention: Functional electrical stimulation-assisted cycling (FESC) or passive cycling (PC) 4x/week for 12 weeks.Outcome Measures: Whole thigh and muscle group volumes calculated from manually segmented MR images.Results: 19/24 participants completed ≥ twelve weeks of the intervention. Five participants experienced hypertrophy (4 FESC; 1 PC) and eight attenuation of atrophy (<20% volume loss) (3 FESC; 5 PC) in thigh muscle volume. Six participants were non-responders, exhibiting atrophy >20% (3 FESC; 3 PC). Mean (SD) change for FESC was -2.3% (25.3%) and PC was -14.0% (12.3%). After controlling for baseline muscle volumes, a strong significant correlation was found between mean weekly exercise frequency and quadriceps and hamstring volumes (r=6.25, P=0.006), regardless of mode. Average watts was highly correlated to quadriceps volumes only (r=5.92, P=0.01), while total number of sessions was strongly correlated with hamstring volumes only (r=5.91, P=0.01).Conclusion: This per-protocol analysis of FESC and PC early after SCI reports a partial response in 42% and a beneficial response in 25% of patients who completed 12 weeks intervention, regardless of mode. Strong correlations show a dose-response according to exercise frequency. Characteristics of non-responders are discussed to inform clinical decision-making.
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Affiliation(s)
- Maya G. Panisset
- Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Parkville, Australia,Correspondence to: Maya G. Panisset, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC3052, Australia; Ph: (+61) 0405 027 127.
| | - Doa El-Ansary
- Department of Nursing and Allied Health, Swinburne University of Technology, Hawthorne, Australia,Department of Physiotherapy, The University of Melbourne, Parkville, Australia
| | - Sarah Alison Dunlop
- School of Biological Sciences, The University of Western Australia, Perth, Australia
| | - Ruth Marshall
- Hampstead Rehabilitation Centre, Northfield, Australia
| | - Jillian Clark
- Hampstead Rehabilitation Centre, Lightsview, Australia
| | | | - Mary P. Galea
- Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Parkville, Australia
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12
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Rosales-Antequera C, Viscor G, Araneda OF. Inflammation and Oxidative Stress as Common Mechanisms of Pulmonary, Autonomic and Musculoskeletal Dysfunction after Spinal Cord Injury. BIOLOGY 2022; 11:biology11040550. [PMID: 35453749 PMCID: PMC9032591 DOI: 10.3390/biology11040550] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/19/2022] [Accepted: 03/28/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary When a spinal cord injury occurs, the neurons that regulate our voluntary movements, those involved in environment and somatic perception and those that regulate vegetative functions are affected. Once neuronal damage is established, the cells of other tissues are also affected in their functions, altering the interaction between organs and altering the proper functioning of the organism. Multiple studies in animal models, as well as in humans, have recognized as factors involved in organ damage the imbalance between the formation of highly reactive molecules called pro-oxidants and defensive mechanisms called antioxidants. Closely associated with this phenomenon, the inflammatory response is also pathologically activated. In this narrative review, we have analyzed the information involving these pathological processes at the level of the lung, the autonomic nervous system and the skeletal musculature after spinal cord injury. Knowing the abnormal functioning mechanisms that occur after a spinal cord injury not only offers a better understanding of the organic events but also offers future possibilities for therapeutic interventions that may benefit the thousands of patients suffering this pathology. Abstract One of the etiopathogenic factors frequently associated with generalized organ damage after spinal cord injury corresponds to the imbalance of the redox state and inflammation, particularly of the respiratory, autonomic and musculoskeletal systems. Our goal in this review was to gain a better understanding of this phenomenon by reviewing both animal and human studies. At the respiratory level, the presence of tissue damage is notable in situations that require increased ventilation due to lower thoracic distensibility and alveolar inflammation caused by higher levels of leptin as a result of increased fatty tissue. Increased airway reactivity, due to loss of sympathetic innervation, and levels of nitric oxide in exhaled air that are similar to those seen in asthmatic patients have also been reported. In addition, the loss of autonomic control efficiency leads to an uncontrolled release of catecholamines and glucocorticoids that induce immunosuppression, as well as a predisposition to autoimmune reactions. Simultaneously, blood pressure regulation is altered with vascular damage and atherogenesis associated with oxidative damage. At the muscular level, chronically elevated levels of prooxidants and lipoperoxidation associated with myofibrillar atrophy are described, with no reduction or reversibility of this process through antioxidant supplementation.
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Affiliation(s)
- Cristián Rosales-Antequera
- Physical Medicine and Rehabilitation Unit, Clínica Universidad de los Andes, Santiago 8320000, Chile;
- Integrative Laboratory of Biomechanics and Physiology of Effort, LIBFE, School of Kinesiology, Faculty of Medicine, Universidad de los Andes, Santiago 8320000, Chile
| | - Ginés Viscor
- Physiology Section, Department of Cell Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain;
| | - Oscar F. Araneda
- Integrative Laboratory of Biomechanics and Physiology of Effort, LIBFE, School of Kinesiology, Faculty of Medicine, Universidad de los Andes, Santiago 8320000, Chile
- Correspondence:
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13
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Solinsky R, Betancourt L, Schmidt-Read M, Kupfer M, Owens M, Schwab JM, Dusseau NB, Szlachcic Y, Sutherland L, Taylor JA, Nash MS. Acute Spinal Cord Injury Is Associated With Prevalent Cardiometabolic Risk Factors. Arch Phys Med Rehabil 2022; 103:696-701. [PMID: 34062117 DOI: 10.1016/j.apmr.2021.04.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/29/2021] [Accepted: 04/26/2021] [Indexed: 12/21/2022]
Abstract
OBJECTIVES To (1) describe the prevalence of cardiometabolic disease (CMD) at spinal cord injury (SCI) rehabilitation discharge; (2) compare this with controls without SCI; and (3) identify factors associated with increased CMD. DESIGN Multicenter, prospective observational study. SETTING Five National Institute on Disability, Independent Living, and Rehabilitation Research Model SCI Rehabilitation Centers. PARTICIPANTS SCI (n=95): patients aged 18-70 years, with SCI (neurologic levels of injury C2-L2, American Spinal Injury Association Impairment Scale grades A-D), and enrolled within 2 months of initial rehabilitation discharge. Control group (n=1609): age/sex/body mass index-matched entries in the National Health and Nutrition Examination Education Survey (2016-2019) (N=1704). INTERVENTIONS None MAIN OUTCOME MEASURES: Percentage of participants with SCI with CMD diagnosis, prevalence of CMD determinants within 2 months of rehabilitation discharge, and other significant early risk associations were analyzed using age, sex, body mass index, insulin resistance (IR) by fasting glucose and Homeostasis Model Assessment (v.2), fasting triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, total cholesterol, and resting blood pressure (systolic and diastolic). RESULTS Participants with SCI had significantly higher diastolic blood pressure and triglycerides than those without SCI, with lower fasting glucose and HDL-C. A total of 74.0% of participants with SCI vs 38.5% of those without SCI were obese when applying population-specific criteria (P<.05). Low HDL-C was measured in 54.2% of participants with SCI vs 15.4% of those without (P<.05). IR was not significantly different between groups. A total of 31.6% of participants with SCI had ≥3 CMD determinants, which was 40.7% higher than those without SCI (P<.05). Interplay of lipids and lipoproteins (ie, total cholesterol:HDL-C ratio and triglyceride:HDL-C ratio) were associated with elevated risk in participants with SCI for myocardial infarction and stroke. The only significant variable associated with CMD was age (P<.05). CONCLUSIONS Individuals with SCI have an increased CMD risk compared with the general population; obesity, IR, and low HDL-C are the most common CMD risk determinants; age is significantly associated with early CMD.
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Affiliation(s)
| | - Luisa Betancourt
- The Miami Project to Cure Paralysis-University of Miami Miller School of Medicine, Miami, FL
| | - Mary Schmidt-Read
- Thomas Jefferson University Hospital and Magee Rehabilitation Hospital, Philadelphia PA
| | - Mendel Kupfer
- Thomas Jefferson University Hospital and Magee Rehabilitation Hospital, Philadelphia PA
| | - Marilyn Owens
- Thomas Jefferson University Hospital and Magee Rehabilitation Hospital, Philadelphia PA
| | - Jan M Schwab
- Belford Center for Spinal Cord Injury, The Ohio State University, Wexner Medical Center, Columbus, OH; Spinal Cord Injury Medicine, Department of Neurology, The Ohio State University, Wexner Medical Center, Columbus, OH; Department of Physical Medicine and Rehabilitation, The Ohio State University, Wexner Medical Center, Columbus, OH
| | - Nathaniel B Dusseau
- Department of Physical Medicine and Rehabilitation, The Ohio State University, Wexner Medical Center, Columbus, OH
| | - Yaga Szlachcic
- Southern California Spinal Cord Injury Model System, Downey, CA; Rancho Research Institute at Rancho Los Amigos National Rehabilitation Center, Downey, CA
| | - Linda Sutherland
- Rancho Research Institute at Rancho Los Amigos National Rehabilitation Center, Downey, CA
| | | | - Mark S Nash
- The Miami Project to Cure Paralysis-University of Miami Miller School of Medicine, Miami, FL.
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14
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Analysis of the long non-coding RNA and mRNA expression profiles associated with lidocaine-induced neurotoxicity in the spinal cord of a rat model. Neurotoxicology 2022; 90:88-101. [DOI: 10.1016/j.neuro.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/19/2022] [Accepted: 03/06/2022] [Indexed: 11/21/2022]
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15
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Spinal cord injury-mediated changes in electrophysiological properties of rat gastric nodose ganglion neurons. Exp Neurol 2022; 348:113927. [PMID: 34798136 PMCID: PMC8727501 DOI: 10.1016/j.expneurol.2021.113927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 10/30/2021] [Accepted: 11/11/2021] [Indexed: 02/03/2023]
Abstract
In preclinical rodent models, spinal cord injury (SCI) manifests as gastric vagal afferent dysfunction both acutely and chronically. However, the mechanism that underlies this dysfunction remains unknown. In the current study, we examined the effect of SCI on gastric nodose ganglia (NG) neuron excitability and on voltage-gated Na+ (NaV) channels expression and function in rats after an acute (i.e. 3-days) and chronic (i.e. 3-weeks) period. Rats randomly received either T3-SCI or sham control surgery 3-days or 3-weeks prior to experimentation as well as injections of 3% DiI solution into the stomach to identify gastric NG neurons. Single cell qRT-PCR was performed on acutely dissociated DiI-labeled NG neurons to measure NaV1.7, NaV1.8 and NaV1.9 expression levels. The results indicate that all 3 channel subtypes decreased. Current- and voltage-clamp whole-cell patch-clamp recordings were performed on acutely dissociated DiI-labeled NG neurons to measure active and passive properties of C- and A-fibers as well as the biophysical characteristics of NaV1.8 channels in gastric NG neurons. Acute and chronic SCI did not demonstrate deleterious effects on either passive properties of dissociated gastric NG neurons or biophysical properties of NaV1.8. These findings suggest that although NaV gene expression levels change following SCI, NaV1.8 function is not altered. The disruption throughout the entirety of the vagal afferent neuron has yet to be investigated.
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16
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Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury. BIOLOGY 2021; 10:biology10090928. [PMID: 34571804 PMCID: PMC8470244 DOI: 10.3390/biology10090928] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/03/2021] [Accepted: 09/10/2021] [Indexed: 12/19/2022]
Abstract
Simple Summary Spinal cord injury can result in an increased vulnerability to infections, but until recently the biological mechanisms behind this observation were not well defined. Immunosuppression and concurrent sustained peripheral inflammation after spinal cord injury have been observed in preclinical and clinical studies, now termed spinal cord injury-induced immune depression syndrome. Recent research indicates a key instigator of this immune dysfunction is altered sympathetic input to lymphoid organs, such as the spleen, resulting in a wide array of secondary effects that can, in turn, exacerbate immune pathology. In this review, we discuss what we know about immune dysfunction after spinal cord injury, why it occurs, and how we might treat it. Abstract Individuals with spinal cord injuries (SCI) exhibit increased susceptibility to infection, with pneumonia consistently ranking as a leading cause of death. Despite this statistic, chronic inflammation and concurrent immune suppression have only recently begun to be explored mechanistically. Investigators have now identified numerous changes that occur in the peripheral immune system post-SCI, including splenic atrophy, reduced circulating lymphocytes, and impaired lymphocyte function. These effects stem from maladaptive changes in the spinal cord after injury, including plasticity within the spinal sympathetic reflex circuit that results in exaggerated sympathetic output in response to peripheral stimulation below injury level. Such pathological activity is particularly evident after a severe high-level injury above thoracic spinal cord segment 6, greatly increasing the risk of the development of sympathetic hyperreflexia and subsequent disrupted regulation of lymphoid organs. Encouragingly, studies have presented evidence for promising therapies, such as modulation of neuroimmune activity, to improve regulation of peripheral immune function. In this review, we summarize recent publications examining (1) how various immune functions and populations are affected, (2) mechanisms behind SCI-induced immune dysfunction, and (3) potential interventions to improve SCI individuals’ immunological function to strengthen resistance to potentially deadly infections.
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17
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Lin M, Huang W, Kabbani N, Theiss MM, Hamilton JF, Ecklund JM, Conley YP, Vodovotz Y, Brienza D, Wagner AK, Robbins E, Sowa GA, Lipsky RH. Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury. PLoS One 2021; 16:e0251110. [PMID: 33956875 PMCID: PMC8101719 DOI: 10.1371/journal.pone.0251110] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/20/2021] [Indexed: 11/18/2022] Open
Abstract
The α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are essential for anti-inflammatory responses. The human-specific CHRFAM7A gene and its 2bp deletion polymorphism (Δ2bp variant) encodes a structurally-deficient α7nAChRs that may impact the anti-inflammatory function. We studied 45 spinal cord injury (SCI) patients for up to six weeks post SCI to investigate the role of the Δ2bp variant on multiple circulating inflammatory mediators and two outcome measures (neuropathic pain and risk of pressure ulcers). The patient's SCI were classified as either severe or mild. Missing values were imputed. Overall genetic effect was conducted with independent sample t-test and corrected with false discovery rate (FDR). Univariate analysis and regression analysis were applied to evaluate the Δ2bp effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the Δ2bp carriers showed higher levels of circulating inflammatory mediators than the Δ2bp non-carriers in TNF-α (FDR = 9.6x10-4), IFN-γ (FDR = 1.3x10-3), IL-13 (FDR = 1.6x10-3), CCL11 (FDR = 2.1x10-3), IL-12p70 (FDR = 2.2x10-3), IL-8 (FDR = 2.2x10-3), CXCL10 (FDR = 3.1x10-3), CCL4 (FDR = 5.7x10-3), IL-12p40 (FDR = 7.1x10-3), IL-1b (FDR = 0.014), IL-15 (FDR = 0.024), and IL-2 (FDR = 0.037). IL-8 and CCL2 were negatively associated with days post injury (DPI) for the Δ2bp carriers (P = 2x10-7 and P = 2x10-8, respectively) and IL-5 was positively associated with DPI for the Δ2bp non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the Δ2bp carriers (P = 0.056). In mild SCI, the Δ2bp carriers had lower circulating levels of IL-15 (FDR = 0.04) than the Δ2bp non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the Δ2bp variant. For the mild SCI Δ2bp carriers, risk of pressure ulcers was positively associated with circulating levels of IFN-γ, CXCL10, and CCL4 and negatively associated with circulating levels of IL-12p70. These findings support an important role for the human-specific CHRFAM7A Δ2bp gene variant in modifying anti-inflammatory function of α7nAChRs following SCI.
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Affiliation(s)
- Mingkuan Lin
- School of Systems Biology, George Mason University, Fairfax, Virginia, United States of America
- Inova Neuroscience and Spine Institute, Inova Health System, Falls Church, Virginia, United States of America
- * E-mail:
| | - Wan Huang
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Nadine Kabbani
- School of Systems Biology, George Mason University, Fairfax, Virginia, United States of America
| | - Mark M. Theiss
- Department of Orthopedic Services, Inova Health System, Falls Church, Virginia, United States of America
| | - John F. Hamilton
- Inova Neuroscience and Spine Institute, Inova Health System, Falls Church, Virginia, United States of America
| | - James M. Ecklund
- Inova Neuroscience and Spine Institute, Inova Health System, Falls Church, Virginia, United States of America
| | - Yvette P. Conley
- School of Nursing and Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Yoram Vodovotz
- Department of Surgery, Center for Inflammation & Regenerative Modeling in McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - David Brienza
- Rehabilitation Science &Technology, Bioengineering, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Amy K. Wagner
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Emily Robbins
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Gwendolyn A. Sowa
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Robert H. Lipsky
- School of Systems Biology, George Mason University, Fairfax, Virginia, United States of America
- Inova Neuroscience and Spine Institute, Inova Health System, Falls Church, Virginia, United States of America
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18
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Ueno M. Restoring neuro-immune circuitry after brain and spinal cord injuries. Int Immunol 2021; 33:311-325. [PMID: 33851981 DOI: 10.1093/intimm/dxab017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 04/13/2021] [Indexed: 12/17/2022] Open
Abstract
Neuro-immune interactions are essential for our body's defense and homeostasis. Anatomical and physiological analyses have shown that the nervous system comprises multiple pathways that regulate the dynamics and functions of immune cells, which are mainly mediated by the autonomic nervous system and adrenal signals. These are disturbed when the neurons and circuits are damaged by diseases of the central nervous system (CNS). Injuries caused by stroke or trauma often cause immune dysfunction by abrogation of the immune-regulating neural pathways, which leads to an increased risk of infections. Here, I review the structures and functions of the neural pathways connecting the brain and the immune system, and the neurogenic mechanisms of immune dysfunction that emerge after CNS injuries. Recent technological advances in manipulating specific neural circuits have added mechanistic aspects of neuro-immune interactions and their dysfunctions. Understanding the neural bases of immune control and their pathological processes will deepen our knowledge of homeostasis and lead to the development of strategies to cure immune deficiencies observed in various CNS disorders.
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Affiliation(s)
- Masaki Ueno
- Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan
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19
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Studies on the Regulatory Roles and Related Mechanisms of lncRNAs in the Nervous System. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6657944. [PMID: 33791072 PMCID: PMC7984887 DOI: 10.1155/2021/6657944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/19/2020] [Accepted: 02/15/2021] [Indexed: 11/25/2022]
Abstract
Long noncoding RNAs (lncRNAs) have attracted extensive attention due to their regulatory role in various cellular processes. Emerging studies have indicated that lncRNAs are expressed to varying degrees after the growth and development of the nervous system as well as injury and degeneration, thus affecting various physiological processes of the nervous system. In this review, we have compiled various reported lncRNAs related to the growth and development of central and peripheral nerves and pathophysiology (including advanced nerve centers, spinal cord, and peripheral nervous system) and explained how these lncRNAs play regulatory roles through their interactions with target-coding genes. We believe that a full understanding of the regulatory function of lncRNAs in the nervous system will contribute to understand the molecular mechanism of changes after nerve injury and will contribute to discover new diagnostic markers and therapeutic targets for nerve injury diseases.
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20
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Felix ER, Gater DR. Interrelationship of Neurogenic Obesity and Chronic Neuropathic Pain in Persons With Spinal Cord Injury. Top Spinal Cord Inj Rehabil 2021; 27:75-83. [PMID: 33814885 PMCID: PMC7983640 DOI: 10.46292/sci20-00062] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The prevalence of obesity and of neuropathic pain are both estimated at above 50% in the population of people with chronic spinal cord injury (SCI). These secondary consequences of SCI have significant negative impact on physical functioning, activities of daily living, and quality of life. Investigations of relationships between weight or body composition and chronic neuropathic pain in people with SCI are lacking, but investigations in non-SCI cohorts suggest an association between obesity and the presence and severity of neuropathic pain conditions. In the present article, we present a review of the literature linking obesity and neuropathic pain and summarize findings suggesting that metabolic syndrome and chronic, systemic inflammation due to excess adiposity increase the risk for neuropathic pain after an SCI.
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Affiliation(s)
- Elizabeth R. Felix
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida
- Research Service, Miami Veterans Affairs (VA) Healthcare System, Miami, Florida
| | - David R. Gater
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida
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21
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Li X, Lou X, Xu S, Du J, Wu J. Hypoxia inducible factor-1 (HIF-1α) reduced inflammation in spinal cord injury via miR-380-3p/ NLRP3 by Circ 0001723. Biol Res 2020; 53:35. [PMID: 32819442 PMCID: PMC7439692 DOI: 10.1186/s40659-020-00302-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a severe central nervous system trauma. The present study aimed to evaluate the effect of HIF-1α on inflammation in spinal cord injury (SCI) to uncover the molecular mechanisms of anti-inflammation. RESULTS HIF-1α was reduced in SCI model rats and HIF-1α activation reduced TNF-α, IL-1β, IL-6 and IL-18 levels in SCI model rats. Meanwhile, Circ 0001723 expression was down-regulated and miR-380-3p expression was up-regulated in SCI model rats. In vitro model, down-regulation of Circ 0001723 promoted TNF-α, IL-1β, IL-6 and IL-18 levels, compared with control negative group. However, over-expression of Circ 0001723 reduced TNF-α, IL-1β, IL-6 and IL-18 levels in vitro model. Down-regulation of Circ 0001723 suppressed HIF-1α protein expressions and induced NLRP3 and Caspase-1 protein expressions in vitro model by up-regulation of miR-380-3p. Next, inactivation of HIF-1α reduced the pro-inflammation effects of Circ 0001723 in vitro model. Then, si-NLRP3 also inhibited the pro-inflammation effects of Circ 0001723 in vitro model via promotion of autophagy. CONCLUSIONS We concluded that HIF-1α reduced inflammation in spinal cord injury via miR-380-3p/ NLRP3 by Circ 0001723.
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Affiliation(s)
- Xigong Li
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
| | - Xianfeng Lou
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
| | - Sanzhong Xu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China.
| | - Junhua Du
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
| | - Junsong Wu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
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Impact of complications at admission to rehabilitation on the functional status of patients with spinal cord lesion. Spinal Cord 2020; 58:1282-1290. [PMID: 32533044 DOI: 10.1038/s41393-020-0501-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/28/2020] [Accepted: 05/28/2020] [Indexed: 11/08/2022]
Abstract
STUDY DESIGN Retrospective cohort study. OBJECTIVE Aim of the study is to evaluate the impact of complications at admission on the functional status of spinal cord lesions patients. SETTING Rehabilitation hospital in Italy. METHODS Two hundred and seven patients with complications (mostly pressure ulcers) at admission to rehabilitation were matched for neurological level of injury and AIS grade with 207 patients without complications. MEASURES International Standards for Neurological Classification of Spinal Cord Injury, Spinal Cord Independence Measure, Rivermead Mobility Index, and Walking Index for Spinal Cord Injury. These measures were recorded at admission to rehabilitation and at discharge. We also recorded length of acute and rehabilitation stay and discharge destination. STATISTICS Student's T test for paired samples, McNemar's chi-square test. RESULTS Patients with complications at admission suffered more often from a traumatic lesions. The functional status at admission and discharge of the patients without complications was significantly better than the functional status of patients with complications (Spinal Cord Independence Measure mean difference between the two groups 5.7 (CI 2.8-8.5) at admission, and 10 (CI 5.3-14.7) at discharge). Length of stay was significantly higher in patients with complications. Patients with complications were more often institutionalized than their counterparts (46/161 vs. 20/187, odds ratio 0.4 (CI 0.2-0.7)). CONCLUSIONS Complications seem to be more frequent in patients with traumatic lesions. The presence of complications has a negative effect on patients' functional status at discharge and length of stay, and it determines a higher risk of being institutionalized.
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Bernardi M, Fedullo AL, Bernardi E, Munzi D, Peluso I, Myers J, Lista FR, Sciarra T. Diet in neurogenic bowel management: A viewpoint on spinal cord injury. World J Gastroenterol 2020; 26:2479-2497. [PMID: 32523306 PMCID: PMC7265150 DOI: 10.3748/wjg.v26.i20.2479] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/14/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to offer dietary advice for individuals with spinal cord injury (SCI) and neurogenic bowel dysfunction. With this in mind, we consider health conditions that are dependent on the level of lesion including skeletal muscle atrophy, autonomic dysreflexia and neurogenic bladder. In addition, SCI is often associated with a sedentary lifestyle, which increases risk for osteoporosis and diseases associated with chronic low-grade inflammation, including cardiovascular and chronic kidney diseases. The Mediterranean diet, along with exercise and dietary supplements, has been suggested as an anti-inflammatory intervention in individuals with SCI. However, individuals with chronic SCI have a daily intake of whole fruit, vegetables and whole grains lower than the recommended dietary allowance for the general population. Some studies have reported an increase in neurogenic bowel dysfunction symptoms after high fiber intake; therefore, this finding could explain the low consumption of plant foods. Low consumption of fibre induces dysbiosis, which is associated with both endotoxemia and inflammation. Dysbiosis can be reduced by exercise and diet in individuals with SCI. Therefore, to summarize our viewpoint, we developed a Mediterranean diet-based diet and exercise pyramid to integrate nutritional recommendations and exercise guidelines. Nutritional guidelines come from previously suggested recommendations for military veterans with disabilities and individuals with SCI, chronic kidney diseases, chronic pain and irritable bowel syndrome. We also considered the recent exercise guidelines and position stands for adults with SCI to improve muscle strength, flexibility and cardiorespiratory fitness and to obtain cardiometabolic benefits. Finally, dietary advice for Paralympic athletes is suggested.
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Affiliation(s)
- Marco Bernardi
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome 00185, Italy
- Italian Paralympic Committee, Rome 00191, Italy
- Federazione Italiana Pallacanestro In Carrozzina (FIPIC), Rome 00188, Italy
| | - Anna Lucia Fedullo
- Federazione Italiana Pallacanestro In Carrozzina (FIPIC), Rome 00188, Italy
| | - Elisabetta Bernardi
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", Bari 70121, Italy
| | - Diego Munzi
- Joint Veteran Center, Scientific Department, Army Medical Center, Rome 00184, Italy
| | - Ilaria Peluso
- Research Centre for Food and Nutrition, Council for Agricultural Research and Economics (CREA-AN), Rome 00178, Italy
| | - Jonathan Myers
- VA Palo Alto Health Care System and Stanford University, Cardiology Division, Palo Alto, CA 94025, United States
| | | | - Tommaso Sciarra
- Joint Veteran Center, Scientific Department, Army Medical Center, Rome 00184, Italy
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24
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Systemic inflammation in traumatic spinal cord injury. Exp Neurol 2019; 325:113143. [PMID: 31843491 DOI: 10.1016/j.expneurol.2019.113143] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 12/06/2019] [Accepted: 12/10/2019] [Indexed: 01/08/2023]
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25
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Holmes GM, Blanke EN. Gastrointestinal dysfunction after spinal cord injury. Exp Neurol 2019; 320:113009. [PMID: 31299180 PMCID: PMC6716787 DOI: 10.1016/j.expneurol.2019.113009] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/13/2019] [Accepted: 07/07/2019] [Indexed: 12/12/2022]
Abstract
The gastrointestinal tract of vertebrates is a heterogeneous organ system innervated to varying degrees by a local enteric neural network as well as extrinsic parasympathetic and sympathetic neural circuits located along the brainstem and spinal axis. This diverse organ system serves to regulate the secretory and propulsive reflexes integral to the digestion and absorption of nutrients. The quasi-segmental distribution of the neural circuits innervating the gastrointestinal (GI) tract produces varying degrees of dysfunction depending upon the level of spinal cord injury (SCI). At all levels of SCI, GI dysfunction frequently presents life-long challenges to individuals coping with injury. Growing attention to the profound changes that occur across the entire physiology of individuals with SCI reveals profound knowledge gaps in our understanding of the temporal dimensions and magnitude of organ-specific co-morbidities following SCI. It is essential to understand and identify these broad pathophysiological changes in order to develop appropriate evidence-based strategies for management by clinicians, caregivers and individuals living with SCI. This review summarizes the neurophysiology of the GI tract in the uninjured state and the pathophysiology associated with the systemic effects of SCI.
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Affiliation(s)
- Gregory M Holmes
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA 17033, United states of America.
| | - Emily N Blanke
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA 17033, United states of America
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26
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Wiest MJ, West C, Ditor D, Furlan JC, Miyatani M, Farahani F, Alavinia SM, Oh PI, Bayley MT, Craven BC. Development of Cardiometabolic Health indicators to advance the quality of spinal cord injury rehabilitation: SCI-High Project. J Spinal Cord Med 2019; 42:166-175. [PMID: 31573456 PMCID: PMC6781462 DOI: 10.1080/10790268.2019.1613322] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Context: Spinal cord injury or disease (SCI/D) leads to unchanged low-density lipoprotein and cholesterol, very low high-density lipoprotein a form of dyslipidemia and physical inactivity which combine to increase risk of morbidity and mortality from cardiometabolic disease. Herein, we describe the selection of structure, process and outcome indicators for adults in the first 18 months post-SCI/D rehabilitation admission. Methods: A Pan-Canadian Cardiometabolic Health Working Group was formed to develop a construct definition. Cardiometabolic risk factors were summarized in a Driver diagram. Release of the Paralyzed Veterans of America "Identification and Management of Cardiometabolic Risk after Spinal Cord Injury" and the International Scientific Exercise Guidelines: "Evidence-based scientific exercise guidelines for adults with spinal cord injury", informed the group's focus on prevention strategies to advance this Domain of rehabilitation admission. Results: The structure indicator identifies during rehabilitation the presence of appropriate time and resources for physical exercise prescription. Process indicators are lipid profile assessment at rehabilitation admission and documented exercise prescriptions prior to discharge. The outcome indicators track patient's knowledge retention regarding exercise prescription at discharge, current exercise adherence and lipid status 18 months after rehabilitation discharge. Conclusion: Routine national implementation of these indicators at the specified time points will enhance efforts to detect dyslipidemia and assure routine participation in endurance exercise. These indicators align with international initiatives to improve cardiometabolic health through interventions targeting modifiable risk factors specifically endurance exercising and optimal lipid profiles, crucial to augmenting cardiometabolic health after SCI/D.
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Affiliation(s)
- Matheus J. Wiest
- KITE, Toronto Rehab – University Health Network, Toronto, Ontario, Canada
| | - Christopher West
- Cell & Physiological Sciences, Southern Medical Program, University of British Columbia, Kelowna, British Columbia, Canada,ICORD, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - David Ditor
- Faculty of Applied Health Science, Brock University, St. Catharines, Ontario, Canada
| | - Julio C. Furlan
- KITE, Toronto Rehab – University Health Network, Toronto, Ontario, Canada,Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Toronto, Toronto, Ontario, Canada,Brain and Spinal Cord Rehabilitation Program, Toronto Rehabilitation Institute – University Health Network, Toronto, Ontario, Canada
| | - Masae Miyatani
- KITE, Toronto Rehab – University Health Network, Toronto, Ontario, Canada
| | - Farnoosh Farahani
- KITE, Toronto Rehab – University Health Network, Toronto, Ontario, Canada
| | - S. Mohammad Alavinia
- KITE, Toronto Rehab – University Health Network, Toronto, Ontario, Canada,Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Paul I. Oh
- Cardiac Prevention and Rehabilitation Program, Toronto Rehabilitation Institute – University Health Network, Toronto, Ontario, Canada
| | - Mark T. Bayley
- KITE, Toronto Rehab – University Health Network, Toronto, Ontario, Canada,Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Toronto, Toronto, Ontario, Canada,Brain and Spinal Cord Rehabilitation Program, Toronto Rehabilitation Institute – University Health Network, Toronto, Ontario, Canada
| | - B. Catharine Craven
- KITE, Toronto Rehab – University Health Network, Toronto, Ontario, Canada,Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Toronto, Toronto, Ontario, Canada,Brain and Spinal Cord Rehabilitation Program, Toronto Rehabilitation Institute – University Health Network, Toronto, Ontario, Canada,Correspondence to: B. Catharine Craven, Neural Engineering & Therapeutic Team, KITE Toronto Rehabilitation Institute, University Health Network 520 Sutherland Drive, Toronto, ON M4G 3V9, Canada; Ph: (416) 597-3422 (ext: 6122).
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Hyperbaric oxygen improves functional recovery of rats after spinal cord injury via activating stromal cell-derived factor-1/CXC chemokine receptor 4 axis and promoting brain-derived neurothrophic factor expression. Chin Med J (Engl) 2019; 132:699-706. [PMID: 30855350 PMCID: PMC6416102 DOI: 10.1097/cm9.0000000000000115] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background: Spinal cord injury (SCI) is a worldwide medical concern. This study aimed to elucidate the mechanism underlying the protective effect of hyperbaric oxygen (HBO) against SCI-induced neurologic defects in rats via exploring the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis and expression of brain-derived neurotrophic factor (BDNF). Methods: An acute SCI rat model was established in Sprague-Dawley rats using the Allen method. Sixty rats were divided into four groups (n = 15 in each group): sham-operated, SCI, SCI treated with HBO (SCI + HBO), and SCI treated with both HBO and AMD3100 (an antagonist of CXCR4; SCI + HBO + AMD) groups. The rats were treated with HBO twice a day for 3 days and thereafter once a day after the surgery for up to 28 days. Following the surgery, neurologic assessments were performed with the Basso-Bettie-Bresnahan (BBB) scoring system on postoperative day (POD) 7, 14, 21, and 28. Spinal cord tissues were harvested to assess the expression of SDF-1, CXCR4, and BDNF at mRNA and protein levels, using quantitative real-time polymerase chain reaction, Western blot analysis, and histopathologic analysis. Results: HBO treatment recovered SCI-induced descent of BBB scores on POD 14, (1.25 ± 0.75 vs. 1.03 ± 0.66, P < 0.05), 21 (5.27 ± 0.89 vs. 2.56 ± 1.24, P < 0.05), and 28 (11.35 ± 0.56 vs. 4.23 ± 1.20, P < 0.05) compared with the SCI group. Significant differences were found in the mRNA levels of SDF-1 (mRNA: day 21, SCI + HBO vs. SCI + HBO + AMD, 2.89 ± 1.60 vs. 1.56 ± 0.98, P < 0.05), CXCR4 (mRNA: day 7, SCI + HBO vs. SCI, 2.99 ± 1.60 vs.1.31 ± 0.98, P < 0.05; day 14, SCI + HBO vs. SCI + HBO + AMD, 4.18 ± 1.60 vs. 0.80 ± 0.34, P < 0.05; day 21, SCI + HBO vs. SCI, 2.10 ± 1.01 vs.1.15 ± 0.03, P < 0.05), and BDNF (mRNA: day 7, SCI + HBO vs. SCI, 3.04 ± 0.41 vs. 2.75 ± 0.31, P < 0.05; day 14, SCI + HBO vs. SCI, 3.88 ± 1.59 vs. 1.11 ± 0.40, P < 0.05), indicating the involvement of SDF-1/CXCR4 axis in the protective effect of HBO. Conclusions: HBO might promote the recovery of neurologic function after SCI in rats via activating the SDF-1/CXCR4 axis and promoting BDNF expression.
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Li Y, Chen Y, Li X, Wu J, Pan JY, Cai RX, Yang RY, Wang XD. RNA sequencing screening of differentially expressed genes after spinal cord injury. Neural Regen Res 2019; 14:1583-1593. [PMID: 31089057 PMCID: PMC6557110 DOI: 10.4103/1673-5374.255994] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In the search for a therapeutic schedule for spinal cord injury, it is necessary to understand key genes and their corresponding regulatory networks involved in the spinal cord injury process. However, ad hoc selection and analysis of one or two genes cannot fully reveal the complex molecular biological mechanisms of spinal cord injury. The emergence of second-generation sequencing technology (RNA sequencing) has provided a better method. In this study, RNA sequencing technology was used to analyze differentially expressed genes at different time points after spinal cord injury in rat models established by contusion of the eighth thoracic segment. The numbers of genes that changed significantly were 944, 1362 and 1421 at 1, 4 and 7 days after spinal cord injury respectively. After gene ontology analysis and temporal expression analysis of the differentially expressed genes, C5ar1, Socs3 and CCL6 genes were then selected and identified by real-time polymerase chain reaction and western blot assay. The mRNA expression trends of C5ar1, Socs3 and CCL6 genes were consistent with the RNA sequencing results. Further verification and analysis of C5ar1 indicate that the level of protein expression of C5ar1 was consistent with its nucleic acid level after spinal cord injury. C5ar1 was mainly expressed in neurons and astrocytes. Finally, the gene Itgb2, which may be related to C5ar1, was found by Chilibot database and literature search. Immunofluorescence histochemical results showed that the expression of Itgb2 was highly consistent with that of C5ar1. Itgb2 was expressed in astrocytes. RNA sequencing technology can screen differentially expressed genes at different time points after spinal cord injury. Through analysis and verification, genes strongly associated with spinal cord injury can be screened. This can provide experimental data for further determining the molecular mechanism of spinal cord injury, and also provide possible targets for the treatment of spinal cord injury. This study was approved ethically by the Laboratory Animal Ethics Committee of Jiangsu Province, China (approval No. 2018-0306-001) on March 6, 2018.
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Affiliation(s)
- Yi Li
- School of Biology & Basic Medical Sciences, Soochow University, Suzhou; Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China
| | - Ying Chen
- Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China
| | - Xiang Li
- Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China
| | - Jian Wu
- Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China
| | - Jing-Ying Pan
- Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China
| | - Ri-Xin Cai
- Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China
| | - Ri-Yun Yang
- Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China
| | - Xiao-Dong Wang
- Department of Histology and Embryology, Medical College, Nantong University; Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
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