| 1. |
- Brisby, Helena, 1965, et al.
(författare)
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Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica.
- 2002
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Ingår i: 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. - 0940-6719. ; 11:1, s. 62-6
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Tidskriftsartikel (refereegranskat)abstract
- Proinflammatory cytokines have been identified in herniated intervertebral discs in humans, and such cytokines have experimentally been demonstrated to be important in the pathophysiological mechanisms of disc herniation. Cerebrospinal fluid (CSF) and serum concentrations of interleukin (IL)-1beta IL-6, IL-8, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha were investigated using the enzyme-linked immunosorbent assay (ELISA) technique in 39 patients with lumbar disc herniation and sciatica. Pain duration and pain intensity (visual analogue scale, VAS) were recorded at inclusion, and a clinical examination was performed evaluating neurological findings. The extent of disc herniation (protrusion or extrusion/sequestration) was evaluated perioperatively. Normal concentrations of IL-1beta, IL-6, IFN-gamma and TNF-alpha were present in CSF and serum in almost all patients with lumbar disc herniation. The concentrations of IL-8 in CSF were increased in 12 out of 39 patients, and these increased levels of IL-8 correlated to a short duration of pain and to more pronounced herniation (extrusion or sequestration). No relationship between IL-8 concentrations in CSF and pain intensity, positive neurological findings or a positive straight leg-raising (SLR) test was found. The observation of increased concentrations of IL-8 in CSF in patients with a short duration of symptoms supports the concept of the initial involvement of inflammatory mechanisms after a disc herniation. The finding that most of the patients with increased concentrations of IL-8 in CSF had an extrusion or a sequestration may suggest that the increase in IL-8 is related to mechanical nerve root compression, but may also indicate a biochemical effect exerted by the herniated disc on the surrounding tissue. Further studies on the potential role of IL-8 as a biomarker for disc herniation are warranted.
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| 2. |
- Geiss, A., et al.
(författare)
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Autoimmune properties of nucleus pulposus: an experimental study in pigs
- 2007
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Ingår i: Spine. - 1528-1159. ; 32:2, s. 168-73
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: Assessment of activated T and B cells in a subcutaneous chamber filled with autologous nucleus pulposus using flow cytometry and immunohistochemistry. OBJECTIVES: To examine if subcutaneously placed autologous nucleus pulposus may attract activated T and B cells in an animal model. SUMMARY OF BACKGROUND DATA: Nucleus pulposus has been suggested to trigger an autoimmune response if exposed to the immune system, for example, in association with disc herniation. T-cell activation represents a hallmark in the generation of an autoimmune response, subsequently leading to the differentiation of B cells, but a causal association between the exposure of nucleus pulposus to the systemic circulation and T and B cell activation is still lacking. METHODS: Autologous nucleus pulposus was harvested from the intervertebral disc of 9 pigs and placed subcutaneously in perforated titanium chambers. In order to control for the effect of the titanium chamber, an additional empty chamber was placed subcutaneously in each pig. After 7 days, the pigs were killed and the chambers were harvested. Flow cytometry and immunohistochemistry were used for analysis of T-helper cells (CD4+), cytotoxic T cells (CD8+), and B cells (Igkappa) in the chamber exudates and T cells (CD45RC) in the remaining blood clot tissue of the chamber. RESULTS: As compared with the empty chambers, the proportion of activated T cells (CD4+ and CD8+) was significantly higher in the exudate of the nucleus pulposus filled chamber. The proportion of activated B cells expressing immunoglobulin kappa (Igkappa) was also significantly elevated in the exudate of the nucleus pulposus chambers. The analysis of the remaining chamber tissue revealed a significantly higher amount of T cells (CD45RC) in the nucleus pulposus chambers than in the empty chambers. CONCLUSIONS: The present findings indicate that nucleus pulposus attracts activated T and B cells. However, since the cell population in the nucleus pulposus of young pigs may differ from that of adult humans, the obtained data may not be directly transferred to the human situation of a disc herniation. The observations in the present study may nevertheless explain some of the local tissue reactions occurring in association with disc herniation and nerve root involvement, thereby providing further insight into the pathophysiology of sciatica.
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| 3. |
- Geiss, Andrea, et al.
(författare)
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Autologous nucleus pulposus primes T cells to develop into interleukin-4-producing effector cells: an experimental study on the autoimmune properties of nucleus pulposus.
- 2009
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Ingår i: Journal of orthopaedic research : official publication of the Orthopaedic Research Society. - : Wiley. - 1554-527X. ; 27:1, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- An autoimmune response to herniated nucleus pulposus has been proposed to constitute a pathophysiologic mechanism for inducing sciatica based on the fact that nucleus pulposus under normal conditions is excluded from the development of immunological tolerance. The manifestation of an autoimmune response comprises different steps starting with antigen capture, continuing with activation of T helper (T(H)) cells and ending with production of autoantibodies. Activated T(H) cells differentiate into either T(H)1 cells, predominately producing proinflammatory cytokines such as interferon gamma (IFNgamma) or a T(H)2 subset mainly producing anti-inflammatory cytokines such as interleukin-4 (IL-4). The aim of the present study was to examine if exposure of autologous nucleus pulposus (NP) to the immune system for 3 weeks is potent enough to prime T(H) cells to differentiate into T(H)2 cells. The study was performed in a pig model allowing the exposure of NP to the immune system. To assess the polarization of T(H) cells the intracellular production of IFNgamma and IL-4 was measured in T cells by using flow cytometry. The revealed predominant production of IL-4 together with low production of IFNgamma in T cells after NP exposure to the immune system indicates that nucleus pulposus may prime T(H) cells to develop into IL-4-producing T(H)2 cells after being exposed to the immune system, for example, in association with disc herniation.
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| 4. |
- Larsson, Karin, 1955, et al.
(författare)
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Disc related cytokines inhibit axonal outgrowth from dorsal root ganglion cells in vitro
- 2005
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Ingår i: Spine. - 1528-1159. ; 30:6, s. 621-4
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: Application of nucleus pulposus and disc related cytokines in vitro on cultured dorsal root ganglion (DRG) cells. OBJECTIVES: To study if tumor necrosis factor (TNF) and interleukin-1beta (IL-1beta) may induce similar inhibition of axonal outgrowth from cultured DRG cells as application of nucleus pulposus and to compare a new assessment method to previous data. SUMMARY OF BACKGROUND DATA: Pro-inflammatory cytokines related to the intervertebral disc have been suggested to affect adversely neurons following local application, with implications for the nucleus pulposus-induced nerve injury seen in various studies. Nucleus pulposus is known to inhibit axonal outgrowth from cultured DRG cells, thereby indicating a neurotoxic potential. The mechanisms were not understood, but it was suspected that the effect was mediated by pro-inflammatory cytokines produced by the nucleus pulposus. METHODS: DRG were harvested from newborn rats and put in culture. The axonal outgrowth was determined 24 hours after starting the culture. Twenty-four hours after exposing the cultured cells to nucleus pulposus, frozen nucleus pulposus, TNF, or IL-1beta, the axonal outgrowth was reassessed, and the outgrowth during the exposure time was calculated. RESULTS: Nucleus pulposus clearly reduced the axonal outgrowth. Also, application of TNF and IL-1beta reduced the outgrowth but not as pronounced as the nucleus pulposus. Frozen nucleus pulposus had no effects on the outgrowth. Overall, the data were similar regarding frozen and nonfrozen nucleus pulposus compared to a previous study. CONCLUSIONS: It was evident that the 2 studied cytokines inhibited the outgrowth of axons from cultured DRG cells, thus suggesting a neurotoxic potential. However, the inhibition was not as pronounced as for nucleus pulposus. These data may increase our understanding for cytokine induced nerve injury, with implications for future treatment strategies for such conditions.
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| 5. |
- Murata, Y., et al.
(författare)
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Incision of the intervertebral disc induces disintegration and increases permeability of the dorsal root ganglion capsule
- 2005
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Ingår i: Spine. - 1528-1159. ; 30:15, s. 1712-6
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: The origin and the barrier properties of the characteristic reaction at the surface of the dorsal root ganglion (DRG) exposed to the nucleus pulposus was studied using Alcian-Blue staining, van Gieson staining, and the application of Evans Blue Albumin (EBA) complex in rats. OBJECTIVE: To study the origin and the barrier properties of the capsule, including the characteristic reaction, at the surface of the DRG exposed to the nucleus pulposus. SUMMARY OF BACKGROUND DATA: Local application of nucleus pulposus may induce a characteristic reaction at the surface of the DRG. This reaction histologically resembles an acute inflammatory reaction. However, it is not evident if this is a swelling of the DRG capsule, if it is located between the capsule and neurons of the DRG, or if it is only an attached nucleus pulposus. METHODS: Nucleus pulposus from the discs was obtained. The nucleus pulposus was smeared on glass slides. Alcian-Blue with hematoxylin and eosin staining was performed for each smear. Herniation of the nucleus pulposus was made in the L4-L5 disc in rats. The L4 DRGs were resected 3, 24, and 72 hours after surgery, and sectioned. The sections were processed for Alcian-Blue staining, van Gieson staining, and EBA complex infiltration. The sections were observed using light or fluorescent microscopy. RESULTS: Smear of nucleus pulposus was stained bright blue indicating mucins. A characteristic reaction, "inflammatory crescent," was confirmed at the surface of the DRG exposed to the nucleus pulposus. No mucins were observed in the crescent using Alcian-Blue. The results of van Gieson staining showed that the reaction started both inside and outside the elastic fiber layer, the DRG capsule, within 3 hours. The EBA complex was capable of infiltrating into the DRG capsule 24 hours after disc incision. CONCLUSIONS: The disintegrated capsule showed an increased permeability even for a large molecule as albumin, which indicates a possible entrance route for various substances induced by locally applied nucleus pulposus.
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| 6. |
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| 7. |
- Murata, Y., et al.
(författare)
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Production of tumor necrosis factor-alpha from porcine nucleus pulposus cells at various time points in cell culture under conditions of nutritional deficiency
- 2006
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666. ; 34:3-4, s. 206-11
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Tidskriftsartikel (refereegranskat)abstract
- Nucleus pulposus (NP) in the epidural space induces spinal nerve damage not only by mechanical but also chemical mechanism. NP has been shown to be capable of producing tumor necrosis factor-alpha (TNF). TNF may play key roles in the NP-induced chemical damage. One of the main pathways to reach the avascular NP is diffusion from the blood supply of the vertebral body through the cartilage endplate. On disk herniation, when NP moves to the epidural space, the distance from the endplate to the herniated NP are longer in the herniated disk than in the intact disk. That is, it seems more difficult to receive adequate nutritional supply from the endplate in the sequestrated type. However, there have been only a few reports of the appearance of TNF in NP. The present study was performed to investigate TNF production in porcine NP under conditions of nutritional deficiency. NP cells were cultured and processed for immunohistochemistry using antisera to TNF, and for ELISA to measure TNF production. The latter was compared longitudinally. The immunoreactivity increased over time. On the other hand, the results of ELISA showed a peak in TNF production 12h, and lower amounts 1 day and 2 days after application of PBS. These observations may suggest that a nutritional deficit is a possible turn-on switch for TNF up-regulation in the NP.
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| 8. |
- Onda, A., et al.
(författare)
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Infliximab attenuates immunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus
- 2004
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Ingår i: Spine. - 1528-1159. ; 29:17, s. 1857-61
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: The effect of infliximab, a chimeric monoclonal antibody to TNF-alpha, on induction of brain-derived neurotrophic factor (BDNF) was examined using an experimental herniated nucleus pulposus (NP) model. OBJECTIVES: To investigate whether treatment of infliximab could attenuate an induction of BDNF, which functions as a modulator of pain, following NP application to the nerve root. SUMMARY OF BACKGROUND DATA: Evidence from basic scientific studies proposes that TNF-alpha is involved in the development of NP-induced nerve injuries. However, the therapeutic mechanisms of infliximab against pain have not been elucidated experimentally. METHODS: Twenty rats were used in this study. In the test groups, the animals underwent application of NP to the L4 nerve roots and received a single systemic (intraperitoneal) injection of infliximab at the time of surgery (Infli-0 group, n = 5) or at 1 day after operation (Infli-1 group, n = 5). As a control treatment, sterile water was administered intraperitoneally to 5 rats with NP application (NP group) and to 5 sham-operated rats (sham group). On day 3 after surgery, the L4 dorsal root ganglion (DRG) and L4 spinal segment were harvested and assessed regarding BDNF immunoreactivity. RESULTS.: Application of NP induced a marked increase of BDNF immunoreactivity in number in the DRG neurons and within the superficial layer in the dorsal horn compared with the sham group (P < 0.01). Infliximab treatment in the Infli-0 and Infli-1 groups reduced the BDNF induction in both DRG and spinal cord (P < 0.05). CONCLUSION: These findings indicate that infliximab attenuates the elevated BDNF levels induced by NP. The present study therefore further indicates the importance of TNF-alpha in sciatica due to disc herniation and the possible therapeutic use of a TNF-alpha inhibitor for this condition.
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| 9. |
- Onda, A., et al.
(författare)
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Nerve growth factor content in dorsal root ganglion as related to changes in pain behavior in a rat model of experimental lumbar disc herniation
- 2005
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Ingår i: Spine. - 1528-1159. ; 30:2, s. 188-93
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: The time courses of nerve growth factor content and pain-related behavior were examined using experimental disc herniation models. OBJECTIVES: To investigate a relationship between nerve growth factor level and pain behavior. SUMMARY OF BACKGROUND DATA: An induction of nerve growth factor in the periphery is regarded as a major contributor of inflammatory hyperalgesia and neuropathic pain. However, it has not been clarified quantitatively whether disc herniation induces changes in nerve growth factor levels in the dorsal root ganglion in relation to pain-related behavior. METHODS: A total of 140 rats were used in this study. The animals had their left L4 nerve roots and associated dorsal root ganglion exposed and were equally divided into 4 groups: L4-L5 disc puncture, displacement of L4 nerve roots/dorsal root ganglion, the combination of disc puncture and displacement, and sham exposure. The content of nerve growth factor in the affected dorsal root ganglion was assessed by enzyme-linked immunosorbent assay as well as pain behavior during a postoperative 21-day period. RESULTS: Disc puncture resulted in nerve growth factor induction at postoperative day 3, but not apparent behavioral changes. Mechanical displacement induced nerve growth factor at postoperative day 1 and mechanical allodynia at postoperative day 3, respectively (P < 0.05). In the combination model, there were more pronounced changes in nerve growth factor induction and both mechanical and thermal threshold during 7 days after surgery (P < 0.05). CONCLUSIONS: These data suggest the possibilities that elevated nerve growth factor level is partly involved in pain behavior and further the combined model mimicking the clinical situation, which causes the marked neuronal responses, is helpful to advance the understanding of the mechanisms underlying sciatica due to lumbar disc herniation.
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| 10. |
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