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Lind, Anne-Li
Publications (10 of 11) Show all publications
Lind, A.-L. (2017). Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments.

In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments.

Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls.

In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 89
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1342
Keywords
chronic pain, neuropathic pain, lumbar radicular pain, amyotrophic lateral sclerosis, radiculopathy, fibromyalgia, pathophysiology, spinal cord stimulation, mechanism of action, disc herniation, cerebrospinal fluid, plasma, biomarker, human, protein, chemokines, cytokines, inflammation, neuroinflammation, mass spectrometry, proximity ligation assay, proximity extension assay, antibody suspension bead array, protein profiling, molecular medicine, personalized medicine
National Category
Anesthesiology and Intensive Care Clinical Laboratory Medicine Biomedical Laboratory Science/Technology Analytical Chemistry
Research subject
Anaesthesiology and Intensive Care; Biomedical Laboratory Science; Chemistry with specialization in Analytical Chemistry; Medical Science; Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-326180 (URN)978-91-513-0006-1 (ISBN)
Public defence
2017-09-15, Enghoffsalen, Ingång 50, bv, Akademiska sjukhuset, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Projects
Uppsala Berzelii Technology Centre for Neurodiagnostics
Funder
Swedish Research CouncilVINNOVA
Available from: 2017-08-24 Created: 2017-07-03 Last updated: 2017-09-08
Backryd, E., Tanum, L., Lind, A.-L., Larsson, A. & Gordh, T. (2017). Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. Journal of Pain Research, 10
Open this publication in new window or tab >>Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma
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2017 (English)In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 10Article in journal (Refereed) Published
Abstract [en]

In addition to central hyperexcitability and impaired top-down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n= 10) and plasma from blood donor controls (n= 46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

Place, publisher, year, edition, pages
DOVE MEDICAL PRESS LTD, 2017
Keywords
cerebrospinal fluid, chemokines, chronic pain, cytokines, fibromyalgia, inflammation
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-319693 (URN)10.2147/JPR.S128508 (DOI)000396320700001 ()
Funder
VINNOVASwedish Research Council, P29797-1
Note

The two first authors contributed equally to this work

Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2017-11-29Bibliographically approved
Tanum, L., Backryd, E., Lind, A.-L., Larsson, A. & Gordh, T. (2017). Evidence of both Systemic Inflammation and Neuroinflammation in Patients with Chronic Widespread Pain. Paper presented at 72nd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), MAY 18-20, 2017, San Diego, CA. Biological Psychiatry, 81(10), S231-S232
Open this publication in new window or tab >>Evidence of both Systemic Inflammation and Neuroinflammation in Patients with Chronic Widespread Pain
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2017 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 81, no 10, p. S231-S232Article in journal, Meeting abstract (Other academic) Published
Keywords
Cytokines and Chemokines, chronic pain, Neuroinflammation, immunoinflammation, cerebrospinal fluid
National Category
Neurology Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-331810 (URN)10.1016/j.biopsych.2017.02.443 (DOI)000400348700570 ()
Conference
72nd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), MAY 18-20, 2017, San Diego, CA
Funder
Swedish Research Council
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Bäckryd, E., Lind, A.-L., Thulin, M., Larsson, A., Gerdle, B. & Gordh, T. (2017). High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls. Pain, 158(12), 2487-2495
Open this publication in new window or tab >>High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls
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2017 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 12, p. 2487-2495Article in journal (Refereed) Published
Abstract [en]

Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-335278 (URN)10.1097/j.pain.0000000000001061 (DOI)000419133700022 ()28930774 (PubMedID)
Available from: 2017-12-02 Created: 2017-12-02 Last updated: 2018-02-09Bibliographically approved
Lind, A.-L., Yu, D., Freyhult, E., Bodolea, C., Ekegren, T., Larsson, A., . . . Kamali-Moghaddam, M. (2016). A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients. PLoS ONE, 11(2), Article ID e0149821.
Open this publication in new window or tab >>A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0149821Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 μL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest.

National Category
Neurology Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-281233 (URN)10.1371/journal.pone.0149821 (DOI)000371175700030 ()26914813 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research Council, 316929EU, European Research Council, 294409
Available from: 2016-03-21 Created: 2016-03-21 Last updated: 2017-11-30Bibliographically approved
Moen, A., Lind, A.-L., Thulin, M., Kamali-Moghaddam, M., Roe, C., Gjerstad, J. & Gordh, T. (2016). Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation. INTERNATIONAL JOURNAL OF INFLAMMATION, Article ID UNSP 3874964.
Open this publication in new window or tab >>Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation
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2016 (English)In: INTERNATIONAL JOURNAL OF INFLAMMATION, ISSN 2090-8040, article id UNSP 3874964Article in journal (Refereed) Published
Abstract [en]

Earlier studies suggest that lumbar radicular pain following disc herniation may be associated with a local or systemic inflammatory process. In the present study, we investigated the serum inflammatory protein profile of such patients. All 45 patients were recruited from Oslo University Hospital, Ulleval, Norway, during the period 2007-2009. The new multiplex proximity extension assay (PEA) technology was used to analyze the levels of 92 proteins. Interestingly, the present data showed that patients with radicular pain 12 months after disc herniation may be different from other patients with regard to many measurable serum cytokines. Given a false discovery rate (FDR) of 0.10 and 0.05, we identified 41 and 13 proteins, respectively, which were significantly upregulated in the patients with severe pain one year after disc herniation. On the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 (CXCM5; 217% increase), epidermal growth factor (EGF; 142% increase), and monocyte chemotactic protein 4 (MCP-4; 70% increase). Moreover, a clear overall difference in the serum cytokine profile between the chronic and the recovered patients was demonstrated. Thus, the present results may be important for future protein serum profiling of lumbar radicular pain patients with regard to prognosis and choice of treatment. We conclude that serum proteins may be measurable molecular markers of persistent pain after disc herniation.

National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-317717 (URN)10.1155/2016/3874964 (DOI)000394106300001 ()27293953 (PubMedID)
Funder
VINNOVASwedish Research Council, P29797-1
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Larsson, A., Carlsson, L., Lind, A.-L., Gordh, T., Bodolea, C., Kamali-Moghaddam, M. & Thulin, M. (2015). The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid. Cytokine, 76(2), 514-518
Open this publication in new window or tab >>The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid
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2015 (English)In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, no 2, p. 514-518Article in journal (Refereed) Published
Abstract [en]

Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.

Keywords
Age; Body mass index; Cytokine; Human; Proximity extension assay (PEA); Cerebrospinal fluid
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-259347 (URN)10.1016/j.cyto.2015.07.010 (DOI)000364244400051 ()26188367 (PubMedID)
Funder
VINNOVASwedish Research Council
Available from: 2015-07-31 Created: 2015-07-31 Last updated: 2017-12-04Bibliographically approved
Larsson, A., Carlsson, L., Gordh, T., Lind, A.-L., Thulin, M. & Kamali-Moghaddam, M. (2015). The effects of age and gender on plasma levels of 63 cytokines. JIM - Journal of Immunological Methods, 425, 58-61
Open this publication in new window or tab >>The effects of age and gender on plasma levels of 63 cytokines
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2015 (English)In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 425, p. 58-61Article in journal (Refereed) Published
Abstract [en]

Cytokines play important roles as regulators of cell functions, and over the last decades a number of cytokine assays have been developed. The aim of the present study was to investigate the effects of age and gender on a large number of cytokines. Plasma samples were collected from 33 healthy blood donors. The samples were analyzed using the multiplex proximity extension assay (PEA) allowing simultaneous measurement of 92 cytokines and four technical controls. Biomarkers with less than 80% quantitative results were excluded leaving 63 cytokines that were analyzed for the effects of gender and age. The plasma level of three of the investigated biomarkers (DNER, MCP-4 and MMP-10) were found to be significantly different for the two genders (adjusted p-value <0.05), and 15 of the biomarkers (CCL11, CCL25, CDCP1, CSF-1, CXCL11, CXCL9, FGF-23, Flt3L, HGF, IL-10RB, MCP-3, MCP-4, MMP-10, OPG, VEGF-A) were significantly associated with age. This study reveals the effects of age and gender on a large number of cytokine assays. CXCL5 and TNFB were significantly higher in females, while the other markers with significant gender-dependent differences were higher in males. For the markers that were significantly associated with age, only CXCL6 was found to decrease with age, while the other biomarkers increased with age.

Keywords
Age; Gender; Cytokine; Human; Proximity extension assay (PEA); Plasma
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-255952 (URN)10.1016/j.jim.2015.06.009 (DOI)000363819600008 ()26080062 (PubMedID)
Available from: 2015-06-21 Created: 2015-06-21 Last updated: 2017-12-04Bibliographically approved
Gordh, T., Lind, A.-L., Bodolea, C., Hewitt, E. & Larsson, A. (2014). Cathepsin S is increased in cerebrospinal fluid from patients with neuropathic pain: A support of the microglia hypothesis in humans. Scandinavian Journal of Pain, 5(3), 208-209
Open this publication in new window or tab >>Cathepsin S is increased in cerebrospinal fluid from patients with neuropathic pain: A support of the microglia hypothesis in humans
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2014 (English)In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 5, no 3, p. 208-209Article in journal (Refereed) Published
Abstract [en]

Aims: Cathepsin S has been reported to be a biomarker of spinal microglial activation, a process suggested to be involved in the pathophysiology of chronic neuropathic pain. So far this has been shown only in animal experiments. The aim of this study was to investigate the concentrations of cathepsin S in human cerebrospinal fluid (CSF) samples from a well-defined patient cohort suffering from neuropathic pain as compared to controls.

Methods: CSF samples from patients suffering from chronic neuropathic pain (n = 14) were analyzed for cathepsin S levels using commercial sandwich ELISAs (DY1183, R&D Systems, Minneapolis, MN, USA). Control CSF was sampled from patients undergoing minor urological surgical procedures under spinal anaesthesia (n = 70), having no obvious pain suffering.

Results: The neuropathic pain group had significantly higher levels of CSF cathepsin S (median 15189 pg/mL, range 3213–40,040), than the control group (median 5911 pg/mL, range 1909–17,188) (p < 0.005, Mann–Whitney U-test).

Conclusion: The results support the existence of microglial activation in chronic neuropathic pain patients. CSF Cathepsin S may serve as a potential biomarker for this specific mechanism linked to neuropathic pain. In the future, Cathepsin S inhibiting drugs might become a new treatment alternative for neurophatic pain.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-234936 (URN)10.1016/j.sjpain.2014.05.015 (DOI)
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-12-05Bibliographically approved
Miclescu, A., Nordquist, L., Hysing, E.-B., Butler, S., Basu, S., Lind, A.-L. & Gordh, T. (2013). Targeting oxidative injury and citokines activity in the treatment with anti-TNF alpha antibodies against CRPS 1. Pain Practice, 13(8), 641-648
Open this publication in new window or tab >>Targeting oxidative injury and citokines activity in the treatment with anti-TNF alpha antibodies against CRPS 1
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2013 (English)In: Pain Practice, ISSN 1530-7085, E-ISSN 1533-2500, Vol. 13, no 8, p. 641-648Article in journal (Refereed) Published
Abstract [en]

Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F2-isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-189235 (URN)10.1111/papr.12027 (DOI)000330950200007 ()
Available from: 2013-01-02 Created: 2012-12-28 Last updated: 2017-12-06Bibliographically approved
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