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Dai W, Wen M, Kalso E, Palada V. Circadian disruption upon painful peripheral nerve injury in mice: Temporal effects on transcriptome in pain-regulating sensory tissues. Neurobiol Dis 2025; 211:106934. [PMID: 40324566 DOI: 10.1016/j.nbd.2025.106934] [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: 02/04/2025] [Revised: 03/21/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Neuropathic pain (NP) resulting from nerve damage shows diurnal fluctuation of intensity in patients, indicating circadian regulation. However, mechanisms linking NP and circadian regulation remain unclear. This study aimed to investigate time-dependent transcriptomic changes during a 24-hour period using a spared nerve injury (SNI) mouse model of NP. METHODS Pain-related behaviours were assessed at baseline and on days 7, 14, and 21 after SNI and control sham surgeries in C57BL/6JRJ mice. Spinal cord (SC) and periaqueductal gray (PAG) were collected 4-hourly over 24 h upon completion of behavioural testing. RESULTS RNA sequencing revealed 111 up- and 21 downregulated differentially expressed genes (DEGs) in the SC, and 35 up- and 33 downregulated DEGs in the PAG, across all six time points. The large majority of DEGs, 245 in the SC and 191 in the PAG, are involved in regulation of immunity. Among the top expressed genes, five DEGs in the SC, Atf3, Anxa10, Gpr151, Cxcl10, Sprr1a, and two DEGs in the PAG, Igf2 and Wnt6, were previously reported to regulate pain. Circadian analysis using CircaCompare identified 383 SC transcripts and 261 PAG transcripts with altered rhythmicity. Variability of gene expression during circadian day was increased in the SC and decreased in the PAG from the SNI mice. CONCLUSION These findings suggest that NP disrupts the circadian expression of rhythmic transcripts in the SC and PAG, potentially revealing new targets for chronotherapy of NP.
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Affiliation(s)
- Wenjing Dai
- Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Manqing Wen
- Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Eija Kalso
- SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Finland; Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital, Finland
| | - Vinko Palada
- Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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Sandy-Hindmarch OP, Chang PS, Scheuren PS, De Schoenmacker I, Hubli M, Loizou C, Wirth S, Mahadevan D, Wiberg A, Furniss D, Calvo M, Bennett DL, Denk F, Baskozos G, Schmid AB. The local molecular signature of human peripheral neuropathic pain. Pain 2025; 166:1143-1156. [PMID: 39588776 PMCID: PMC12004989 DOI: 10.1097/j.pain.0000000000003472] [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: 05/15/2024] [Revised: 08/19/2024] [Accepted: 09/10/2024] [Indexed: 11/27/2024]
Abstract
ABSTRACT Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). Immunofluorescent staining revealed demyelination and chronic infiltration of immune cells in Morton's neuroma. RNA bulk sequencing identified 3349 differentially expressed genes between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed higher densities of macrophages and B cells in Morton's neuroma than control samples. Modules associated with defence response, neurogenesis, and muscle system development as well as macrophage cell populations identified by deconvolution correlated with patients' paroxysmal or evoked pain. Of note, we identified a consistently differentially expressed gene signature ( MARCO, CD163, STAB1 ) , indicating the presence of a specific M(GC) subset of macrophages. MARCO gene expression correlated with paroxysmal pain. Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163 + MARCO + macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO + subset implicated.
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Affiliation(s)
- Oliver P. Sandy-Hindmarch
- Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Pao-Sheng Chang
- Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Paulina S. Scheuren
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
- International Collaboration on Repair Discoveries, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Iara De Schoenmacker
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Michèle Hubli
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | | | - Stephan Wirth
- Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | | | - Akira Wiberg
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Dominic Furniss
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Margarita Calvo
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
| | - David L.H. Bennett
- Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Franziska Denk
- Wolfson Sensory, Pain and Regeneration Centre (SPaRC), King's College London, Guy's Campus, London, United Kingdom
| | - Georgios Baskozos
- Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Annina B. Schmid
- Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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Cai M, Yin J, Jin Y, Liu H. A Nomogram Model Integrating Inflammation Markers for Predicting the Risk of Recurrent Sciatica After Selective Nerve Root Blocks. Risk Manag Healthc Policy 2025; 18:1279-1289. [PMID: 40242298 PMCID: PMC12002072 DOI: 10.2147/rmhp.s503360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
Background Lumbar disc herniation (LDH) usually c auses sciatica. Although selective nerve root block (SNRB) is an effective, highly target-oriented interventional procedure for patients with LDH, accurately predicting the risk of sciatica recurrence in such patients after SNRB remains a major challenge. Objective We aimed to construct a nomogram model by integrating clinical data, imaging features and inflammation markers that could predict recurrent sciatica following SNRB in LDH patients, which fill the inflammation data gaps during model construction. Methods In total, 121 sciatica patients were enrolled and assigned to the recurrence group (n = 41) and non-recurrence group (n = 80). By performing the logistic regression analyses, we identified risk factors serving as independent predictors and constructed the nomogram prediction model. Then, the performance and clinical practicality of the nomogram model were validated by performing the receiver operating characteristic curve (ROC) analysis, calibration curve analysis, and decision curve analysis (DCA). The bootstrap method was applied for the internal validation of the nomogram model. Results Preoperative sensory symptoms (odds ratio [OR] [95% confidence interval (CI)]: 2.933 [1.211-7.353]), type of herniation (OR [95% CI]: 2.712 [1.261-6.109]), and systemic inflammation response index (OR [95% CI]: 2.447 [1.065-6.271]) were included in the nomogram for predicting unfavorable outcomes following sciatica. The nomogram AUC was 0.764, and the prognostic precision, validated using the bootstrap method, reached 0.756. The ROC and calibration curve analyses, and DCA also produced excellent results, exhibiting favorable predictive performance and clinical benefit. Conclusion This study thus identified risk factors that predict unfavorable outcomes after sciatica and developed a risk prediction model based on clinical, radiologic, and inflammatory factors, thereby facilitating early predictions by clinicians and offering an individualized medical interventions for patients with recurrent sciatica in early stages.
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Affiliation(s)
- Meng Cai
- Department of Pain Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - Jing Yin
- Department of Pain Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - Yi Jin
- Department of Pain Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - HongJun Liu
- Department of Pain Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
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McLachlan H, Maher CG, Lin CWC, Billot L, Day RO, Ivers R, Underwood M, McLachlan AJ, Richards B, Finnerup NB, Ferreira GE. DREAM: an adaptive, randomised, placebo-controlled trial of duloxetine for reducing leg pain in people with chronic sciatica-trial protocol. BMJ Open 2024; 14:e096796. [PMID: 39740937 PMCID: PMC11749743 DOI: 10.1136/bmjopen-2024-096796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 12/03/2024] [Indexed: 01/02/2025] Open
Abstract
INTRODUCTION Sciatica is a debilitating condition that often becomes chronic, and for which there are few effective treatment options. Treatments such as the anti-depressant duloxetine have shown promise, but the evidence is inconclusive. We are describing a high quality, definitive trial to investigate the efficacy, safety and cost-effectiveness of duloxetine in chronic sciatica. METHODS AND ANALYSIS The duloxetine for chronic sciatica (DREAM) trial is a randomised, superiority, parallel-group, placebo-controlled, triple-blinded (participant, clinician, assessor) trial with an adaptive group sequential design investigating the efficacy and safety of duloxetine in participants with chronic sciatica of at least 3 months duration. Participants will be randomised at a 1:1 ratio to duloxetine or placebo. 332 participants will be recruited on presentation to general practices, specialist clinics and hospital emergency departments or from hospital in-patient wards and from the community. In the active treatment group, participants will receive duloxetine 60 mg per day for 12 weeks, including 1 week of titration at 30 mg/day. The treatment phase will be followed by a 2-week tapering phase where they will receive duloxetine 30 mg/day. Participants will be followed-up for 1 year, with outcomes being measured 4, 8, 12, 16, 26, and 52 weeks post-randomisation. The primary outcome is leg pain intensity at 12 weeks post-randomisation. Secondary outcomes include back pain intensity, disability, time to recovery, quality of life, depressive and anxiety symptoms, and sleep disturbance. Adverse events will be recorded, and a cost-effectiveness analysis will be conducted. ETHICS AND DISSEMINATION Ethical approval has been granted by the University of Sydney Human Research Ethics Committee. Trial results will be disseminated by publications, conference presentations and via the media. TRIAL REGISTRATION NUMBER ACTRN12624000919516.
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Affiliation(s)
- Hanan McLachlan
- Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, New South Wales, Australia
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Christopher G Maher
- Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, New South Wales, Australia
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Chung-Wei Christine Lin
- Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, New South Wales, Australia
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Laurent Billot
- The George Institute for Global Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Richard O Day
- Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital Sydney, Sydney, New South Wales, Australia
- St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Rowena Ivers
- Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia
| | - Martin Underwood
- Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Andrew J McLachlan
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Bethan Richards
- Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, New South Wales, Australia
- Rheumatology Department, Institute of Rheumatology and Orthopaedics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Nanna B Finnerup
- Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Giovanni E Ferreira
- Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, New South Wales, Australia
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
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Scheuren PS, Calvo M. Exploring neuroinflammation: A key driver in neuropathic pain disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 179:311-338. [PMID: 39580216 DOI: 10.1016/bs.irn.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2024]
Abstract
Inflammation is a fundamental part of the body's natural defense mechanism, involving immune cells and inflammatory mediators to promote healing and protect against harm. In the event of a lesion or disease of the somatosensory nervous system, inflammation, however, triggers a cascade of changes in both the peripheral and central nervous systems, ultimately contributing to chronic neuropathic pain. Substantial evidence links neuroinflammation to various conditions associated with neuropathic pain. This chapter will explore the role of neuroinflammation in the initiation, maintenance, and resolution of peripheral and central neuropathic pain. Additionally, biomarkers of neuroinflammation in humans will be examined, emphasizing their relevance in different neuropathic pain disorders.
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Affiliation(s)
- Paulina S Scheuren
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
| | - Margarita Calvo
- Physiology Department, Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago, Chile
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Yamahata H, Ijiri K, Tanabe F, Murasumi K, Nagano Y, Makino R, Higa N, Hanaya R. Cerebrospinal fluid protein concentration in patients with lumbar spinal stenosis. Surg Neurol Int 2024; 15:303. [PMID: 39246796 PMCID: PMC11380900 DOI: 10.25259/sni_610_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 08/01/2024] [Indexed: 09/10/2024] Open
Abstract
Background In this study, we examined the impact and degree of lumbar stenosis on cerebrospinal fluid (CSF) protein concentration. Methods In this retrospective study, we analyzed protein concentrations in CSF samples of 61 patients with lumbar spinal stenosis (LSS) obtained during pre-operative myelography. Patients were divided into two groups: those showing no block to contrast (Group A) versus those showing medium block to contrast below the lumbar puncture level (Group B). Results The CSF protein concentration in Group B (104.3 ± 59 g/dL) patients with medium block was significantly greater than that in Group A (65.1 ± 33 g/dL) patients without medium block. Conclusion A higher average CSF protein concentration was seen in Group B patients with significant lumbar stenosis versus Group A patients without significant lumbar stenosis. Theoretically, damage to the cauda equina in patients with LSS may cause these elevated CSF protein levels.
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Affiliation(s)
- Hitoshi Yamahata
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kirishima, Kagoshima, Japan
| | - Kosei Ijiri
- Department of Orthopaedics, Kirishima Orthopaedics, Kirishima, Kagoshima, Japan
| | - Fumito Tanabe
- Department of Orthopaedics, Kirishima Orthopaedics, Kirishima, Kagoshima, Japan
| | - Kyoichi Murasumi
- Department of Orthopaedics, Kirishima Orthopaedics, Kirishima, Kagoshima, Japan
| | - Yushi Nagano
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kirishima, Kagoshima, Japan
| | - Ryutaro Makino
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kirishima, Kagoshima, Japan
| | - Nayuta Higa
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kirishima, Kagoshima, Japan
| | - Ryosuke Hanaya
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kirishima, Kagoshima, Japan
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Wu Y, Lin Y, Zhang M, He K, Tian G. Causal association between circulating inflammatory markers and sciatica development: a Mendelian randomization study. Front Neurol 2024; 15:1380719. [PMID: 39015317 PMCID: PMC11250389 DOI: 10.3389/fneur.2024.1380719] [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: 02/13/2024] [Accepted: 06/03/2024] [Indexed: 07/18/2024] Open
Abstract
Background This research explores the causal association between circulating inflammatory markers and the development of sciatica, a common and debilitating condition. While previous studies have indicated that inflammation may be a factor in sciatica, but a thorough genetic investigation to determine a cause-and-effect relationship has not yet been carried out. Gaining insight into these interactions may uncover novel treatment targets. Methods We utilized data from the OpenGWAS database, incorporating a large European cohort of 484,598 individuals, including 4,549 sciatica patients. Our study focused on 91 distinct circulating inflammatory markers. Genetic variations were employed as instrumental variables (IVs) for these markers. The analysis was conducted using inverse variance weighting (IVW) as the primary method, supplemented by weighted median-based estimation. Validation of the findings was conducted by sensitivity studies, utilizing the R software for statistical computations. Results The analysis revealed that 52 out of the 91 inflammatory markers studied showed a significant causal association with the risk of developing sciatica. Key markers like CCL2, monocyte chemotactic protein-4, and protein S100-A12 demonstrated a positive correlation. In addition, there was no heterogeneity or horizontal pleiotropy in these results. Interestingly, a reverse Mendelian randomization analysis also indicated potential causative effects of sciatica on certain inflammatory markers, notably Fms-related tyrosine kinase 3 ligands. Discussion The study provides robust evidence linking specific circulating inflammatory markers with the risk of sciatica, highlighting the role of inflammation in its pathogenesis. These findings could inform future research into targeted treatments and enhance our understanding of the biological mechanisms underlying sciatica.
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Affiliation(s)
- Yang Wu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yi Lin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mengpei Zhang
- School of Computer Science and Technology, Beijing Institute of Technology, Beijing, China
| | - Ke He
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guihua Tian
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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Zvonickova K, Rhee A, Sandy-Hindmarch O, Furniss D, Wiberg A, Schmid AB. Systemic low-grade C-reactive protein is associated with proximal symptom spread in carpal tunnel syndrome. Pain Rep 2024; 9:e1156. [PMID: 38606315 PMCID: PMC11008662 DOI: 10.1097/pr9.0000000000001156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/13/2024] [Accepted: 02/20/2024] [Indexed: 04/13/2024] Open
Abstract
Introduction Neuropathic pain is a highly prevalent condition associated with persistent disability. Some patients with neuropathic pain experience symptom spread outside neuroanatomical boundaries; these patients report more severe sensory symptoms and greater disability. However, the mechanisms behind such symptom spread are not fully understood. Objective We used pre-surgical carpal tunnel syndrome (CTS) as a human model system of neuropathic pain to identify differences in the concentration of serologic inflammatory mediators between patients with CTS with territorial symptoms and those with proximal symptom spread to either the elbow or shoulder/neck. Methods We performed a post-hoc analysis, comparing levels of serologic inflammatory mediators in a discovery cohort among 3 symptoms spread profiles (n = 55; n = 25 no spread, n = 21 spread to elbow, n = 9 spread to shoulder/neck). We then de-novo analysed the significantly dysregulated mediators in an independent validation cohort (n = 72; n = 34 no spread, n = 16 spread to elbow, n = 22 spread to shoulder/neck). Results The discovery cohort revealed higher serum concentrations of C-reactive protein (CRP) and interleukin-6 in patients with any symptom spread proximal to the wrist; interferon-γ was higher in patients with symptom spread to the elbow compared with those without proximal spread. The validation study replicated the association of higher CRP concentrations in patients with proximal spread to the elbow (no spread: median [interquartile range] 2.5 [5.4]; spread to elbow 6.2 [4.6]; spread to shoulder/neck 2.6 [3.7], P = 0.006). No other markers replicated in the validation cohort. Conclusions Our findings suggest that proximal symptom spread in the context of neuropathic symptoms is associated with low-grade inflammation.
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Affiliation(s)
- Karolina Zvonickova
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Amber Rhee
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Oliver Sandy-Hindmarch
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Dominic Furniss
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Akira Wiberg
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Annina B. Schmid
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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Bielewicz J, Daniluk B, Kamieniak P. Altered serum cytokines in patients with symptomatic disk herniation and depressive symptoms. Front Neurosci 2024; 18:1366559. [PMID: 38646609 PMCID: PMC11026593 DOI: 10.3389/fnins.2024.1366559] [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: 01/06/2024] [Accepted: 03/25/2024] [Indexed: 04/23/2024] Open
Abstract
Purpose An increasing number of studies have indicated the important role of cytokines in the development of depressive disturbances (DD). In medically ill patients, cytokines can provoked sickness behavior, the signs of which resemble DD. This results in alterations in behavior to limit energy expenditure and redirect it to cope with particular diseases. The aim of our study was to investigate the role of pro-inflammatory IL-6, TNF-α, and IL-1β and anti-inflammatory IL-10 and TGF-β in DD observed in patients suffering from pain caused by disk herniation (DH) qualified for surgery. Patients and methods The intensity of DD assessed by using Beck Depression Inventory, pain intensity, and functional impairment were evaluated in 70 patients with DH who were qualified for surgery. Pro-inflammatory serum levels of TNF-α, IL-1, IL-6, anti-inflammatory TGF-β, and IL-10 were measured. Results Elevated serum levels of TGF-β, IL-10, and IL-6 were found in the group with moderate and severe depressive symptoms (SD) compared with the groups with mild (MD) or no depressive symptoms (ND). TGF-β levels were negatively correlated with pain intensity, as assessed using the Present Pain Intensity scale in SD. Functional impairment measured using the Oswestry Disability Index was the most advanced in SD group. Conclusion Results of our study can suggest association between depressive disturbances and anti-inflammatory cytokines TGF-β and IL-10. Functional impairment of SD group is more severe but serum levels of TGF-β and IL-10, which are involved in the healing processes, are increased.
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Affiliation(s)
- Joanna Bielewicz
- Department of Neurology, Medical University of Lublin, Lublin, Poland
| | - Beata Daniluk
- Institute of Psychology, Maria Curie-Skłodowska University, Lublin, Poland
| | - Piotr Kamieniak
- Department of Neurosurgery, Medical University of Lublin, Lublin, Poland
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Chen L, Jiang C, Xu Q, Jin J, A S, Wang X, Li X, Hu Y, Sun H, Lu X, Duan S, Gao Z, Wang W, Wang Y. Biphasic release of betamethasone from an injectable HA hydrogel implant for alleviating lumbar disc herniation induced sciatica. Acta Biomater 2024; 176:173-189. [PMID: 38244658 DOI: 10.1016/j.actbio.2024.01.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 12/17/2023] [Accepted: 01/11/2024] [Indexed: 01/22/2024]
Abstract
Epidural steroid injection (ESI) is a common therapeutic approach for managing sciatica caused by lumbar disc herniation (LDH). However, the short duration of therapeutic efficacy and the need for repeated injections pose challenges in LDH treatment. The development of a controlled delivery system capable of prolonging the effectiveness of ESI and reducing the frequency of injections, is highly significant in LDH clinical practice. In this study, we utilized a thiol-ene click chemistry to create a series of injectable hyaluronic acid (HA) based release systems loaded with diphasic betamethasone, including betamethasone dipropionate (BD) and betamethasone 21-phosphate disodium (BP) (BD/BP@HA). BD/BP@HA hydrogel implants demonstrated biocompatibility and biodegradability to matched neuronal tissues, avoiding artificial compression following injection. The sustained release of betamethasone from BD/BP@HA hydrogels effectively inhibited both acute and chronic neuroinflammation by suppressing the nuclear factor kappa-B (NF-κB) pathway. In a mouse model of LDH, the epidural administration of BD/BP@HA efficiently alleviated LDH-induced sciatica for at least 10 days by inhibiting the activation of macrophages and microglia in dorsal root ganglion and spinal dorsal horn, respectively. The newly developed HA hydrogels represent a valuable platform for achieving sustained drug release. Additionally, we provide a simple paradigm for fabricating BD/BP@HA for epidural injection, demonstrating greater and sustained efficiency in alleviating LDH-induced sciatica compared to traditional ESI and displaying potentials for clinical translation. This system has the potential to revolutionize drug delivery for co-delivery of both soluble and insoluble drugs, thereby making a significant impact in the pharmaceutical industry. STATEMENT OF SIGNIFICANCE: Lumbar disc herniation (LDH) is a common degenerative disorder leading to sciatica and spine surgery. Although epidural steroid injection (ESI) is routinely used to alleviate sciatica, the efficacy is short and repeated injections are required. There remains challenging to prolong the efficacy of ESI. Herein, an injectable hyaluronic acid (HA) hydrogel implant by crosslinking acrylated-modified HA (HA-A) with thiol-modified HA (HA-SH) was designed to achieve a biphasic release of betamethasone. The hydrogel showed biocompatibility and biodegradability to match neuronal tissues. Notably, compared to traditional ESI, the hydrogel better alleviated sciatica in vivo by synergistically inhibiting the neuroinflammation in central and peripheral nervous systems. We anticipate the injectable HA hydrogel implant has the potential for clinical translation in treating LDH-induced sciatica.
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Affiliation(s)
- Lunhao Chen
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Chao Jiang
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qian Xu
- The Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin D04V1W8, Ireland; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Jiale Jin
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Sigen A
- School of Medicine, Anhui University of Science and Technology, Huainan, China; The Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin D04V1W8, Ireland
| | - Xi Wang
- The Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin D04V1W8, Ireland
| | - Xiaolin Li
- The Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin D04V1W8, Ireland
| | - Yaling Hu
- Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Pancreatic Diseases, The First Affiliated Hospital, University School of Medicine, Hangzhou 310003, China
| | - Huankun Sun
- Zhejiang Provincial Key Laboratory of Pancreatic Diseases, The First Affiliated Hospital, University School of Medicine, Hangzhou 310003, China
| | - Xuan Lu
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shumin Duan
- Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Zhihua Gao
- Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
| | - Wenxin Wang
- Research and Clinical Translation Center of Gene Medicine and Tissue Engineering, School of Public Health, Anhui University of Science and Technology, Huainan, China; School of Medicine, Anhui University of Science and Technology, Huainan, China; The Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin D04V1W8, Ireland.
| | - Yue Wang
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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11
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Lu G, Zhang C, Li K, Gao K, Fu M, Lyu C, Quan Z. Sinomenine Ameliorates IL-1β-Induced Intervertebral Disc Degeneration in Rats Through Suppressing Inflammation and Oxidative Stress via Keap1/Nrf2/NF-κB Signaling Pathways. J Inflamm Res 2023; 16:4777-4791. [PMID: 37881650 PMCID: PMC10596063 DOI: 10.2147/jir.s430423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/17/2023] [Indexed: 10/27/2023] Open
Abstract
Purpose To investigate the molecular mechanism underlying the inhibitory effect of sinomenine (SN) on interleukin-1β (IL-1β)-induced apoptosis in nucleus pulposus cells (NPCs), and to evaluate the potential role of SN in preventing intervertebral disk degeneration (IDD). Methods The Rat NPCs were cultured in vitro and identified using Hematoxylin-Eosin (HE) staining, toluidine blue staining, and immunofluorescence analysis. NPCs were pretreated with or without SN, then induced with IL-1β to assess cell viability, ROS levels, apoptotic rates, and wound healing ability. Relevant protein expression was detected using Elisa, qPCR and Western Blot techniques. NPCs were pretreated with SN, either alone or in combination with Nrf2-IN-1 or SC, before being induced to undergo apoptosis by IL-1β. Apoptosis was detected using Hoechst staining, while qPCR and Western Blot techniques assessed protein expression. Rat caudal intervertebral discs were induced with IDD, with or without SN injection, and then co-injected with IL-1β. The levels of IDD were evaluated using HE staining and modified saffron-O-fix green cartilage staining. Relevant protein expression was detected using Elisa, qPCR, and Western Blot techniques. Results IL-1β significantly reduced NPC activity, induced ROS accumulation and apoptosis, decreased cell healing rate, promoted the expression and secretion of inflammatory factors, and inhibited extracellular matrix synthesis. However, pretreatment with SN effectively reversed these effects. Inhibition of the Keap1/Nrf2 signaling pathway or activation of the NF-κB signaling pathway significantly attenuated the cytoprotective effects of SN and increased apoptosis. Acupuncture combined with IL-1β injection markedly induced intervertebral disc degeneration in rat caudal spine, upregulated inflammatory factors expression and secretion, and downregulated extracellular matrix synthesis. SN intervention notably enhanced antioxidant enzyme expression and reversed these outcomes. Conclusion SN can prevent IL-1β-induced apoptosis of NPCs and ameliorate IDD by activating the Keap1/Nrf2 pathway and inhibiting the NF-κB signaling pathway.
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Affiliation(s)
- Gongbiao Lu
- Department of Spine Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, People’s Republic of China
- Department of Spine Surgery, Jining No.1 People’s Hospital, Jining, 272011, People’s Republic of China
| | - Cunxin Zhang
- Department of Spine Surgery, Jining No.1 People’s Hospital, Jining, 272011, People’s Republic of China
| | - Kang Li
- Department of Spine Surgery, Jining No.1 People’s Hospital, Jining, 272011, People’s Republic of China
| | - Kai Gao
- Department of Orthopaedics, Jining No.1 People’s Hospital, Jining, 272011, People’s Republic of China
| | - Maoqing Fu
- Department of Spine Surgery, Jining No.1 People’s Hospital, Jining, 272011, People’s Republic of China
| | - Chaoliang Lyu
- Department of Spine Surgery, Jining No.1 People’s Hospital, Jining, 272011, People’s Republic of China
| | - Zhengxue Quan
- Department of Spine Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, People’s Republic of China
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12
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Bhattacharya S, Munshi C. Biological significance of C-reactive protein, the ancient acute phase functionary. Front Immunol 2023; 14:1238411. [PMID: 37860004 PMCID: PMC10582692 DOI: 10.3389/fimmu.2023.1238411] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 09/05/2023] [Indexed: 10/21/2023] Open
Abstract
C-reactive protein (CRP) is one of the major members of the family of acute phase proteins (APP). Interest in this CRP was the result of a seminal discovery of its pattern of response to pneumococcal infection in humans. CRP has the unique property of reacting with phosphocholine-containing substances, such as pneumococcal C-polysaccharide, in the presence of Ca2+. The attention regarding the origin of CRP and its multifunctionality has gripped researchers for several decades. The reason can be traced to the integrated evolution of CRP in the animal kingdom. CRP has been unequivocally listed as a key indicator of infectious and inflammatory diseases including autoimmune diseases. The first occurrence of CRP in the evolutionary ladder appeared in arthropods followed by molluscs and much later in the chordates. The biological significance of CRP has been established in the animal kingdom starting from invertebrates. Interestingly, the site of synthesis of CRP is mainly the liver in vertebrates, while in invertebrates it is located in diverse tissues. CRP is a multifunctional player in the scenario of innate immunity. CRP acts as an opsonin in the area of complement activation and phagocytosis. Interestingly, CRP upregulates and downregulates both cytokine production and chemotaxis. Considering various studies of CRP in humans and non-human animals, it has been logically proposed that CRP plays a common role in animals. CRP also interacts with Fcγ receptors and triggers the inflammatory response of macrophages. CRP in other animals such as primates, fish, echinoderms, arthropods, and molluscs has also been studied in some detail which establishes the evolutionary significance of CRP. In mammals, the increase in CRP levels is an induced response to inflammation or trauma; interestingly, in arthropods and molluscs, CRP is constitutively expressed and represents a major component of their hemolymph. Investigations into the primary structure of CRP from various species revealed the overall relatedness between vertebrate and invertebrate CRP. Invertebrates lack an acquired immune response; they are therefore dependent on the multifunctional role of CRP leading to the evolutionary success of the invertebrate phyla.
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Affiliation(s)
| | - Chayan Munshi
- Ethophilia (An Autonomous Research Group), Santiniketan, India
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13
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Abdul Khaleq MA. Evaluation of the effect of Remdesivir on some biomarkers in Iraqi patients with coronavirus 2019 (COVID-19): A cross-sectional study. J Med Life 2023; 16:1231-1234. [PMID: 38024833 PMCID: PMC10652683 DOI: 10.25122/jml-2023-0209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 07/26/2023] [Indexed: 12/01/2023] Open
Abstract
COVID-19 is a new virus spreading worldwide that can cause mild to severe illness, multi-organ failure, and even death. Injectable antiviral Remdesivir is effective in treating patients with moderate-to-severe COVID-19. Biomarkers linked to clinical outcomes have been found for COVID-19, although only a few antiviral therapies have been studied. This study aimed to assess how Remdesivir affects several biomarkers in patients with COVID-19 and how those changes impact the severity of the illness. According to Chinese care guidelines for COVID-19, 80 patients with COVID-19 were separated into two groups: group 1 did not receive Remdesivir (RDV) medication and Group 2 received it after 5 days. Injectable antiviral Remdesivir has recently been tested in high-risk, individuals with confirmed SARS-CoV-2 infection who were not hospitalized, and it successfully delayed the onset of the illness. From February 2022 to October 2023, blood samples were taken from study participants to evaluate ferritin, Lactate Dehydrogenase (LDH), and C-reactive protein. The results of this investigation showed that various COVID-19 severity biomarkers, including ferritin, C-reactive protein, and lactate dehydrogenase, may improve more quickly with RDV treatment. These biomarkers are linked to better clinical outcomes during infection. These discoveries enhance the understanding of the COVID-19 antiviral treatment's function. In conclusion, there is a clear association between the levels of biomarkers before and after Remdesivir treatment in COVID-19 cases ranging from moderate to severe. This suggests that the COVID-19 infection might lead to the elevation of several biomarkers.
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14
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Nagington A, Foster NE, Snell K, Konstantinou K, Stynes S. Prognostic factors associated with outcome following an epidural steroid injection for disc-related sciatica: a systematic review and narrative synthesis. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2023; 32:1029-1053. [PMID: 36680619 DOI: 10.1007/s00586-023-07528-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/28/2022] [Accepted: 01/07/2023] [Indexed: 01/22/2023]
Abstract
PURPOSE Clinical guidelines recommend epidural steroid injection (ESI) as a treatment option for severe disc-related sciatica, but there is considerable uncertainty about its effectiveness. Currently, we know very little about factors that might be associated with good or poor outcomes from ESI. The aim of this systematic review was to synthesise and appraise the evidence investigating prognostic factors associated with outcomes following ESI for patients with imaging confirmed disc-related sciatica. METHODS The search strategy involved the electronic databases Medline, Embase, CINAHL Plus, PsycINFO and reference lists of eligible studies. Selected papers were quality appraised independently by two reviewers using the Quality in Prognosis Studies tool. Between-study heterogeneity precluded statistical pooling of results. RESULTS 3094 citations were identified; 15 studies were eligible. Overall study quality was low with all judged to have moderate or high risk of bias. Forty-two prognostic factors were identified but were measured inconsistently. The most commonly assessed prognostic factors were related to pain and function (n = 10 studies), imaging features (n = 8 studies), patient socio-demographics (n = 7 studies), health and lifestyle (n = 6 studies), clinical assessment findings (n = 4 studies) and injection level (n = 4 studies). No prognostic factor was found to be consistently associated with outcomes following ESI. Most studies found no association or results that conflicted with other studies. CONCLUSIONS There is little, and low quality, evidence to guide practice in terms of factors that predict outcomes in patients following ESI for disc-related sciatica. The results can help inform some of the decisions about potential prognostic factors that should be assessed in future well-designed prospective cohort studies.
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Affiliation(s)
- Alan Nagington
- Midlands Partnership NHS Foundation Trust, Haywood Hospital, Stoke On Trent, Staffordshire, UK
| | - Nadine E Foster
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Staffordshire, UK.,Surgical Treatment and Rehabilitation Service (STARS), Education and Research Alliance, The University of Queensland and Metro North Hospital and Health Service, Herston, QLD, Australia
| | - Kym Snell
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Staffordshire, UK
| | - Kika Konstantinou
- Midlands Partnership NHS Foundation Trust, Haywood Hospital, Stoke On Trent, Staffordshire, UK.,Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Staffordshire, UK
| | - Siobhán Stynes
- Midlands Partnership NHS Foundation Trust, Haywood Hospital, Stoke On Trent, Staffordshire, UK. .,Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Staffordshire, UK.
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15
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Singh G. Is Chronic Pain as an Autoimmune Disease? Can J Pain 2023. [DOI: 10.1080/24740527.2023.2175205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Affiliation(s)
- Gurmit Singh
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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16
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Hassan A, Jabbar N. C-reactive Protein as a Predictor of Severity in Chronic Obstructive Pulmonary Disease: An Experience From a Tertiary Care Hospital. Cureus 2022; 14:e28229. [PMID: 36017482 PMCID: PMC9393023 DOI: 10.7759/cureus.28229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2022] [Indexed: 12/02/2022] Open
Abstract
Background In this study, we aimed to determine the frequency of raised C-reactive protein (CRP) levels and their association with the severity of the disease. Methodology This descriptive cross-sectional study was conducted at the Shifa International Hospital, Islamabad, from June 2018 to December 2018 in the Department of Medicine. Patients attending the respiratory outpatient clinic in the Department of Medicine, Shifa International Hospital, Islamabad, with chronic obstructive pulmonary disease, meeting the sample selection criteria, were included in our study. A total of 104 patients were enrolled. All patients had plasma CRP levels measured, and forced expiratory volume in one second to forced vital capacity ratio was calculated to quantify the severity of the disease. We used SPSS version 26.0 (IBM Corp., Armonk, NY, USA) for data analysis. Results All patients with levels of hs-CRP greater than 3 mg/L had stage 3 or 4 chronic obstructive pulmonary disease (COPD) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, which accounted for 16.4% of the sample, while 81.7% of all patients suffering from COPD had levels greater than 1 mg/L. Only a small minority of patients, 1.9%, had normal high-sensitivity (hs)-CRP levels. The relationship between high levels of hs-CRP levels and advanced stages of COPD was statistically significant (p < 0.001). Conclusions The severity of COPD is directly related to the raised CRP levels, which can help in identifying these patients and managing them subsequently. It can be a useful indicator and a basis for high suspicion index and close follow-up for patients with high levels.
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17
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Romano A, Del Vescovo E, Rivetti S, Triarico S, Attinà G, Mastrangelo S, Maurizi P, Ruggiero A. Biomarkers Predictive of Metabolic Syndrome and Cardiovascular Disease in Childhood Cancer Survivors. J Pers Med 2022; 12:880. [PMID: 35743665 PMCID: PMC9225298 DOI: 10.3390/jpm12060880] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 05/23/2022] [Accepted: 05/25/2022] [Indexed: 11/16/2022] Open
Abstract
The improvement in childhood cancer treatments resulted in a marked improvement in the survival of pediatric cancer patients. However, as survival increased, it was also possible to observe the long-term side effects of cancer therapies. Among these, metabolic syndrome is one of the most frequent long-term side effects, and causes high mortality and morbidity. Consequently, it is necessary to identify strategies that allow for early diagnosis. In this review, the pathogenetic mechanisms of metabolic syndrome and the potential new biomarkers that can facilitate its diagnosis in survivors of pediatric tumors are analyzed.
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Affiliation(s)
| | | | | | | | | | | | | | - Antonio Ruggiero
- Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, 00168 Rome, Italy; (A.R.); (E.D.V.); (S.R.); (S.T.); (G.A.); (S.M.); (P.M.)
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18
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Lutke Schipholt IJ, Scholten-Peeters G, Bontkes H, Coppieters MW. Neuroimmune responses following joint mobilisation and manipulation in people with persistent neck pain: a protocol for a randomised placebo-controlled trial. BMJ Open 2022; 12:e055748. [PMID: 35260459 PMCID: PMC8905979 DOI: 10.1136/bmjopen-2021-055748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Joint mobilisation and manipulation often results in immediate pain relief in people with neck pain. However, the biological mechanisms behind pain relief are largely unknown. There is preliminary evidence that joint mobilisation and manipulation lessens the upregulated neuroimmune responses in people with persistent neck pain. METHODS AND ANALYSIS This study protocol describes a randomised placebo-controlled trial to investigate whether joint mobilisation and manipulation influence neuroimmune responses in people with persistent neck pain. People with persistent neck pain (N=100) will be allocated, in a randomised and concealed manner, to the experimental or control group (ratio 3:1). Short-term (ie, baseline, immediately after and 2 hours after the intervention) neuroimmune responses will be assessed, such as inflammatory marker concentration following in vitro stimulation of whole blood cells, systemic inflammatory marker concentrations directly from blood samples, phenotypic analysis of peripheral blood mononuclear cells and serum cortisol. Participants assigned to the experimental group (N=75) will receive cervical mobilisations targeting the painful and/or restricted cervical segments and a distraction manipulation of the cervicothoracic junction. Participants assigned to the control group (N=25) will receive a placebo mobilisation and placebo manipulation. Using linear mixed models, the short-term neuroimmune responses will be compared (1) between people in the experimental and control group and (2) within the experimental group, between people who experience a good outcome and those with a poor outcome. Furthermore, the association between the short-term neuroimmune responses and pain relief following joint mobilisation and manipulation will be tested in the experimental group. ETHICS AND DISSEMINATION This trial is approved by the Medical Ethics Committee of Amsterdam University Medical Centre, location VUmc (Approval number: 2018.181). TRIAL REGISTRATION NUMBER NL6575 (trialregister.nl.
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Affiliation(s)
- Ivo J Lutke Schipholt
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Clinical Chemistry, Laboratory Medical Immunology, Amsterdam UMC, Location VU Medical Centre, Amsterdam, Netherlands
| | - Gwendolyne Scholten-Peeters
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Hetty Bontkes
- Department of Clinical Chemistry, Laboratory Medical Immunology, Amsterdam UMC, Location VU Medical Centre, Amsterdam, Netherlands
| | - Michel W Coppieters
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Menzies Health Institute Queensland, Griffith University, Brisbane & Gold Coast, Queensland, Australia
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Sandy-Hindmarch O, Bennett DL, Wiberg A, Furniss D, Baskozos G, Schmid AB. Systemic inflammatory markers in neuropathic pain, nerve injury, and recovery. Pain 2022; 163:526-537. [PMID: 34224495 PMCID: PMC7612369 DOI: 10.1097/j.pain.0000000000002386] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/15/2021] [Indexed: 11/28/2022]
Abstract
ABSTRACT The role that inflammation plays in human nerve injury and neuropathic pain is incompletely understood. Previous studies highlight the role of inflammation in the generation and maintenance of neuropathic pain, but the emerging evidence from the preclinical literature for its role in the resolution of neuropathic pain remains to be explored in humans. Here, we use carpal tunnel syndrome (CTS) as a human model system of nerve injury and neuropathic pain to determine changes in serum cytokine protein levels and gene expression levels before (active stage of disease) and after carpal tunnel decompression surgery (recovery). Fifty-five patients with CTS were studied, and 21 healthy age-matched and gender-matched participants served as controls. In the active stage of the disease (CTS before surgery vs healthy controls), PTGES2 mRNA was decreased in patients (adjusted P = 0.013), while transforming growth factor-β and C-C motif chemokine ligand 5 protein levels were increased (adjusted P = 0.016 and P = 0.047, respectively). In the resolution phase (CTS before surgery vs after surgery), IL-9 mRNA was increased after surgery (adjusted P = 0.014) and expression of IL-6 mRNA and IL-4 protein levels were increased before surgery (adjusted P = 0.034 and P = 0.002, respectively). IL-9 mRNA expression negatively correlated with several (neuropathic) pain scores. By contrast, protein levels of IL-4 positively correlated with pain scores. In conclusion, we demonstrate specific dysregulation of systemic cytokine expression in both the active and resolution phases of nerve injury and neuropathic pain. IL-9 represents an interesting candidate associated with resolution of nerve injury and neuropathic pain.
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Affiliation(s)
- Oliver Sandy-Hindmarch
- Nuffield Department for Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - David L Bennett
- Nuffield Department for Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Akira Wiberg
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Dominic Furniss
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Georgios Baskozos
- Nuffield Department for Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Annina B Schmid
- Nuffield Department for Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
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Oxidative Stress and Inflammation Are Associated with Coexistent Severe Multivessel Coronary Artery Stenosis and Right Carotid Artery Severe Stenosis in Elderly Patients. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2021:2976447. [PMID: 34976297 PMCID: PMC8716240 DOI: 10.1155/2021/2976447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/29/2021] [Accepted: 12/01/2021] [Indexed: 11/18/2022]
Abstract
Oxidative stress and inflammatory response are the main pathogenic pathways in atherosclerosis stenosis. This study is aimed at evaluating the roles of oxidative stress and inflammatory response in coexistent right carotid artery severe stenosis and severe multivessel coronary artery stenosis in elderly patients. Circulating levels of total oxidant status (TOS), lipid hydroperoxide (LHP), 8-isoprostane (8-IP), malondialdehyde (MDA), monocyte chemotactic protein-4 (MCP-4), amyloid A (AA), high-sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor-α (TNF-α) were measured by standardised laboratory test methods. Markers of oxidative stress and inflammatory response: levels of TOS, LHP, 8-IP, MDA, MCP-4, AA, hs-CRP, and TNF-α, were increased (P < 0.001) in elderly patient. These results suggested that oxidative stress and inflammatory response may be involved in carotid artery severe stenosis and severe multivessel coronary artery stenosis and measuring oxidative stress and inflammation biomarkers may also be a promising step in the development of an effective method for monitoring the severity of right carotid artery stenosis and multivessel coronary artery stenosis in elderly patients.
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Ekram S, Khalid S, Salim A, Khan I. Regulating the fate of stem cells for regenerating the intervertebral disc degeneration. World J Stem Cells 2021; 13:1881-1904. [PMID: 35069988 PMCID: PMC8727226 DOI: 10.4252/wjsc.v13.i12.1881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/12/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden. The etiology of intervertebral disc (IVD) degeneration is complicated, and its mechanism is still not completely understood. Factors such as aging, systemic inflammation, biochemical mediators, toxic environmental factors, physical injuries, and genetic factors are involved in the progression of its pathophysiology. Currently, no therapy for restoring degenerated IVD is available except pain management, reduced physical activities, and surgical intervention. Therefore, it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc, repopulate the cell types to retain water content, synthesize extracellular matrix, and strengthen the disc to restore normal spine flexion. Cellular therapy has gained attention for IVD management as an alternative therapeutic option. In this review, we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD. Modern therapeutic approaches, including proteins and growth factors, cellular and gene therapy, and cell fate regulators are reviewed. Similarly, small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.
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Affiliation(s)
- Sobia Ekram
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Shumaila Khalid
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan.
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22
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Wilson SH, Hellman KM, James D, Adler AC, Chandrakantan A. Mechanisms, Diagnosis, and Medical Management of Hyperalgesia: an Educational Review. CURRENT ANESTHESIOLOGY REPORTS 2021. [DOI: 10.1007/s40140-021-00485-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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23
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Koop MA, Lutke Schipholt IJ, Scholten-Peeters GGM, Coppieters MW. Identifying the most important confounders when assessing the association between low-grade systemic inflammation and musculoskeletal pain: A modified Delphi study. PAIN MEDICINE 2021; 22:2661-2669. [PMID: 34343332 PMCID: PMC8633774 DOI: 10.1093/pm/pnab243] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Objective The association between low-grade systemic inflammation and musculoskeletal pain may be influenced by multiple factors. However, little is known about the relative importance of these factors, and few studies account for them. This Delphi study aimed to reach consensus on the most important confounders which influence the association between low-grade systemic inflammation and musculoskeletal pain. Methods The panel consisted of 48 experts. In Round 1, the experts proposed what they believed were important confounders. In Round 2, the experts indicated for each confounder whether they believed it was important (yes/no). At least 50% of experts had to indicate the confounder was important to be considered in the final round. In Round 3, the experts rated the importance of each confounder on a 7-point Likert scale. Consensus was reached if ≥75% of the experts considered the factor either extremely or moderately important. Results In Round 1, 120 confounders were proposed, which were synthesized into 38 distinct factors. In Round 2, 33 confounders met the criterion to be considered important. In Round 3, consensus was reached for 14 confounders: acute illness/trauma, immune disease, medication use, endocrine, nutritional, or metabolic disease, other musculoskeletal conditions, age, handling of blood samples, sex, cancer, body composition, pregnancy, cardiovascular disease, physical activity, and pain characteristics. Conclusions These findings provide insight in the complexity of the association between low-grade systemic inflammation and musculoskeletal pain. Some factors currently listed as confounders may be re-classified as moderators or mediators as insights progress.
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Affiliation(s)
- Meghan A Koop
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Van der Boechorststraat 7 1081 BT Amsterdam, The Netherlands
| | - Ivo J Lutke Schipholt
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Van der Boechorststraat 7 1081 BT Amsterdam, The Netherlands.,Department of Clinical Chemistry, Laboratory Medical Immunology, Amsterdam UMC, Location VU Medical Centre, De Boelelaan 1117 1081 HV Amsterdam, The Netherlands
| | - Gwendolyne G M Scholten-Peeters
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Van der Boechorststraat 7 1081 BT Amsterdam, The Netherlands
| | - Michel W Coppieters
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Van der Boechorststraat 7 1081 BT Amsterdam, The Netherlands.,Menzies Health Institute Queensland, Griffith University, Gold Coast Campus (G40; LVL 8.82), Parklands Drive, Southport, QLD 4215, Australia
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24
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"Shooting pain" in lumbar radiculopathy and trigeminal neuralgia, and ideas concerning its neural substrates. Pain 2021; 161:308-318. [PMID: 31651576 DOI: 10.1097/j.pain.0000000000001729] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with radicular low back pain (radicular LBP, sciatica) frequently describe their pain as "shooting" or "radiating." The dictionary meaning of these words implies rapid movement, and indeed, many sufferers report feeling pain moving rapidly from the lower back or buttock into the leg. But, others do not. Moreover, the sensation of movement is paradoxical; it is neither predicted nor accounted for by current ideas about the pathophysiology of radicular LBP. We have used a structured questionnaire to evaluate the sensory qualities associated with "shooting" and "radiating" in 155 patients, 98 with radicular LBP and 57 with trigeminal neuralgia, a second chronic pain condition in which shooting/radiating are experienced. Results indicated a spectrum of different sensations in different people. Although many sciatica patients reported rapid downward movement of their pain, even more reported downward expansion of the area of pain, some reported upward movement, and for some, there was no spatial dynamic at all. The velocity of movement or expansion was also variable. By cross-referencing sensations experienced in the sciatica and trigeminal neuralgia cohorts with known signal processing modes in the somatosensory system, we propose testable hypotheses concerning the pathophysiology of the various vectorial sensations reported, their direction and velocity, and the structures in which they are generated. Systematic evaluation of qualitative features of "shooting" and "radiating" pain at the time of diagnosis can shed light on the pain mechanism in the individual patient and perhaps contribute to a better therapeutic outcomes.
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25
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Verheijen EJA, Munts AG, van Haagen OBHAM, de Vries D, Vleggeert-Lankamp CLA. The Outcome of Epidural Injections in Lumbar Radiculopathy Is Not Dependent on the Presence of Disc Herniation on Magnetic Resonance Imaging: Assessment of Short-Term and Long-Term Efficacy. World Neurosurg 2021; 148:e643-e649. [PMID: 33497827 DOI: 10.1016/j.wneu.2021.01.051] [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: 10/15/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 10/22/2022]
Abstract
OBJECTIVE Lumbar radiculopathy is a condition with major physical, social, and economic consequences. Despite its favorable prognosis, the burden can be significant. In this study, we aimed to determine the value of magnetic resonance imaging (MRI) and the efficacy of transforaminal epidural injections (TEIs) in patients with lumbar radiculopathy secondary to lumbar disc herniation (LDH) and other causes (non-LDH). METHODS Patients with lumbar radiculopathy were reviewed for radiologic diagnosis based on MRI. For patients receiving TEI therapy, response after 6-8 weeks (short-term) and 16 weeks (long-term), number of injections, subsequent surgery, and patient outcome were evaluated. Treatment response was assessed by patient-reported symptom relief and numeric rating scale pain scores. RESULTS Overall, 66% of MRI examinations showed a clinically relevant LDH. A total of 486 of 1824 patients received TEI, of whom one third did not show LDH. Of patients, 70% reported a short-term effect with significant pain reduction and 44% reported a long-term effect. No significant differences were observed between the LDH and non-LDH groups. Of patients, 59% required multiple injections and reported similar efficacy compared with patients treated with a single injection. CONCLUSIONS A considerable part of MRI examinations in patients with lumbar radiculopathy do not show a clinically relevant LDH. Regardless of the radiologic diagnosis, most patients treated with TEI benefit in both the short-term and the long-term after a single-injection or multiple-injection regime. Subsequent injections are advisable if the effect from the first injection is unsatisfactory or wears off. MRI examination before TEI therapy may be redundant, which allows for expedition of this treatment.
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Affiliation(s)
- Eduard J A Verheijen
- Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands.
| | | | | | - Dirk de Vries
- Department of Anaesthesiology, Spaarne Gasthuis, Haarlem, The Netherlands
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26
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Linher-Melville K, Shah A, Singh G. Sex differences in neuro(auto)immunity and chronic sciatic nerve pain. Biol Sex Differ 2020; 11:62. [PMID: 33183347 PMCID: PMC7661171 DOI: 10.1186/s13293-020-00339-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/20/2020] [Indexed: 01/13/2023] Open
Abstract
Chronic pain occurs with greater frequency in women, with a parallel sexually dimorphic trend reported in sufferers of many autoimmune diseases. There is a need to continue examining neuro-immune-endocrine crosstalk in the context of sexual dimorphisms in chronic pain. Several phenomena in particular need to be further explored. In patients, autoantibodies to neural antigens have been associated with sensory pathway hyper-excitability, and the role of self-antigens released by damaged nerves remains to be defined. In addition, specific immune cells release pro-nociceptive cytokines that directly influence neural firing, while T lymphocytes activated by specific antigens secrete factors that either support nerve repair or exacerbate the damage. Modulating specific immune cell populations could therefore be a means to promote nerve recovery, with sex-specific outcomes. Understanding biological sex differences that maintain, or fail to maintain, neuroimmune homeostasis may inform the selection of sex-specific treatment regimens, improving chronic pain management by rebalancing neuroimmune feedback. Given the significance of interactions between nerves and immune cells in the generation and maintenance of neuropathic pain, this review focuses on sex differences and possible links with persistent autoimmune activity using sciatica as an example.
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Affiliation(s)
- Katja Linher-Melville
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
| | - Anita Shah
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Gurmit Singh
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada.
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27
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van Helmond N, Aarts HM, Timmerman H, Olesen SS, Drewes AM, Wilder-Smith OH, Steegers MA, Vissers KC. Is Preoperative Quantitative Sensory Testing Related to Persistent Postsurgical Pain? A Systematic Literature Review. Anesth Analg 2020; 131:1146-1155. [PMID: 32925335 DOI: 10.1213/ane.0000000000004871] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Persistent postsurgical pain (PPSP) is a common complication of surgery that significantly affects quality of life. A better understanding of which patients are likely to develop PPSP would help to identify when perioperative and postoperative pain management may require specific attention. Quantitative sensory testing (QST) of a patient's preoperative pain perception is associated with acute postoperative pain, and acute postoperative pain is a risk factor for PPSP. The direct association between preoperative QST and PPSP has not been reviewed to date. In this systematic review, we assessed the relationship of preoperative QST to PPSP. We searched databases with components related to (1) preoperative QST; (2) association testing; and (3) PPSP. Two authors reviewed all titles and abstracts for inclusion. Inclusion criteria were as follows: (1) QST performed before surgery; (2) PPSP assessed ≥3 months postoperatively; and (3) the association between QST measures and PPSP is investigated. The search retrieved 905 articles; 24 studies with 2732 subjects met inclusion criteria. Most studies (22/24) had moderate to high risk of bias in multiple quality domains. Fourteen (58%) studies reported a significant association between preoperative QST and PPSP. Preoperative temporal summation of pain (4 studies), conditioned pain modulation (3 studies), and pressure pain threshold (3 studies) showed the most frequent association with PPSP. The strength of the association between preoperative QST and PPSP varied from weak to strong. Preoperative QST is variably associated with PPSP. Measurements related to central processing of pain may be most consistently associated with PPSP.
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Affiliation(s)
- Noud van Helmond
- From the Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Anesthesiology, Cooper Medical School of Rowan University, Cooper University Hospital, Camden, New Jersey
| | - Hugo M Aarts
- Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands
| | - Hans Timmerman
- From the Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Søren S Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjørn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Oliver H Wilder-Smith
- From the Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Monique A Steegers
- From the Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Anesthesiology, Vrije Universiteit (VU) Medical Center, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Kris C Vissers
- From the Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
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28
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Linher-Melville K, Zhu YF, Sidhu J, Parzei N, Shahid A, Seesankar G, Ma D, Wang Z, Zacal N, Sharma M, Parihar V, Zacharias R, Singh G. Evaluation of the preclinical analgesic efficacy of naturally derived, orally administered oil forms of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their 1:1 combination. PLoS One 2020; 15:e0234176. [PMID: 32497151 PMCID: PMC7272035 DOI: 10.1371/journal.pone.0234176] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/20/2020] [Indexed: 01/17/2023] Open
Abstract
Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aβ mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.
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Affiliation(s)
- Katja Linher-Melville
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Yong Fang Zhu
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Jesse Sidhu
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Natalka Parzei
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Ayesha Shahid
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Gireesh Seesankar
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Danny Ma
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Zhi Wang
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Natalie Zacal
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Manu Sharma
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Vikas Parihar
- Michael G. DeGroote Pain Clinic, McMaster University Medical Centre, Hamilton, Ontario, Canada
| | - Ramesh Zacharias
- Michael G. DeGroote Pain Clinic, McMaster University Medical Centre, Hamilton, Ontario, Canada
| | - Gurmit Singh
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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Affiliation(s)
- Raymond Wjg Ostelo
- Department of Health Sciences, Faculty of Science, Vrije University Amsterdam, the Netherlands; Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences Research Institute, the Netherlands.
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30
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Ovejero T, Sadones O, Sánchez-Fito T, Almenar-Pérez E, Espejo JA, Martín-Martínez E, Nathanson L, Oltra E. Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients. Int J Mol Sci 2020; 21:1366. [PMID: 32085571 PMCID: PMC7072917 DOI: 10.3390/ijms21041366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 02/06/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Advancements in nucleic acid sequencing technology combined with an unprecedented availability of metadata have revealed that 45% of the human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically necessary. Dysregulation of TEs, including human retroviral endogenous sequences (HERVs) has been shown to associate with several neurologic and autoimmune diseases, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no study has yet addressed whether abnormal expression of these sequences correlates with fibromyalgia (FM), a disease frequently comorbid with ME/CFS. The work presented here shows, for the first time, that, in fact, HERVs of the H, K and W types are overexpressed in immune cells of FM patients with or without comorbid ME/CFS. Patients with increased HERV expression (N = 14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. The findings reported in this study could explain the flu-like symptoms FM patients present with in clinical practice, in the absence of concomitant infections. Future work aimed at identifying specific genomic loci differentially affected in FM and/or ME/CFS is warranted.
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Affiliation(s)
- Tamara Ovejero
- School of Medicine, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain;
| | | | - Teresa Sánchez-Fito
- Escuela de Doctorado, Universidad Católica de Valencia San Vicente Mártir, 46008 Valencia, Spain; (T.S.-F.); (E.A.-P.)
| | - Eloy Almenar-Pérez
- Escuela de Doctorado, Universidad Católica de Valencia San Vicente Mártir, 46008 Valencia, Spain; (T.S.-F.); (E.A.-P.)
| | - José Andrés Espejo
- School of Biotechnology, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain;
| | | | - Lubov Nathanson
- Institute for Neuro Immune Medicine, Nova Southeastern University, Ft Lauderdale, FL 33314, USA;
| | - Elisa Oltra
- School of Medicine, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain;
- Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain
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31
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Demetriades AK. Insights into the inflammatory process of lumbar discopathy. Acta Neurochir (Wien) 2020; 162:87-88. [PMID: 31713700 DOI: 10.1007/s00701-019-04120-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 10/23/2019] [Indexed: 11/26/2022]
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32
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Hao J, Pircher A, Miller NR, Hsieh J, Remonda L, Killer HE. Cerebrospinal fluid and optic nerve sheath compartment syndrome: A common pathophysiological mechanism in five different cases? Clin Exp Ophthalmol 2019; 48:212-219. [DOI: 10.1111/ceo.13663] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/02/2019] [Accepted: 10/08/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Jie Hao
- Department of Biomedicine, University Hospital BaselUniversity of Basel Basel Switzerland
- Beijing Institute of Ophthalmology, Beijing Tongren HospitalCapital Medical University Beijing China
| | - Achmed Pircher
- Department of OphthalmologyKantonsspital Aarau Aarau Switzerland
- Department of Neuroscience/OphthalmologyUppsala University Uppsala Sweden
| | - Neil R. Miller
- Wilmer Ophthalmological InstituteJohns Hopkins Hospital Baltimore Maryland
| | - Jiemei Hsieh
- Department of Ophthalmology, University Hospital BaselUniversity of Basel Basel Switzerland
| | - Luca Remonda
- Department of NeuroradiologyKantonsspital Aarau Aarau Switzerland
| | - Hanspeter E. Killer
- Department of Biomedicine, University Hospital BaselUniversity of Basel Basel Switzerland
- Department of OphthalmologyKantonsspital Aarau Aarau Switzerland
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Authors' Reply: Confounding and mediation to reveal the true association between systemic inflammation and musculoskeletal pain. Spine J 2019; 19:1901. [PMID: 31668334 DOI: 10.1016/j.spinee.2019.06.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 02/03/2023]
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