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1.
  • Gerdle, Björn, et al. (författare)
  • Chronic Widespread Pain : Increased Glutamate and Lactate Concentrations in the Trapezius Muscle and Plasma
  • 2014
  • Ingår i: The Clinical Journal of Pain. - : Lippincott Williams & Wilkins. - 0749-8047 .- 1536-5409. ; 30:5, s. 409-420
  • Forskningsöversikt (refereegranskat)abstract
    • BACKGROUND:: Chronic widespread pain (CWP), including fibromyalgia syndrome (FM), is associated with prominent negative consequences. CWP has been associated with alterations in the central processing of nociception. Whereas some researchers consider CWP/FM as a central hyperexcitability pain condition, others suggest that the central alterations are maintained by peripheral nociceptive input. Microdialysis can be used in vivo to study muscle alterations in chronic myalgia. AIM:: The aim of the study was to investigate the plasma and interstitial concentrations of metabolites and algesics in the trapezius muscle of women with CWP and in pain-free women (CON).MATERIALS AND METHODS:: Seventeen women with CWP and 24 CON went through a clinical examination and completed a questionnaire; the pressure pain thresholds in the upper and lower extremities were registered. Microdialysis was conducted in the trapezius muscle, and a blood sample was drawn. Muscle blood flow, interstitial muscle concentrations, and plasma concentrations of lactate, pyruvate, glutamate, glucose, and glycerol (not in the plasma) were determined.RESULTS:: CWP patients had significantly increased interstitial muscle (P=0.02 to 0.001) and plasma (P=0.026 to 0.017) concentrations of lactate and glutamate. No significant differences existed in blood flow between CWP and CON. The interstitial concentrations-but not the plasma levels-of glutamate and lactate correlated significantly with aspects of pain such as pressure pain thresholds of the trapezius (R=0.22) and tibialis anterior (R=0.18) and the mean pain intensity (R=0.10) in CWP but not in CON.CONCLUSIONS:: The present study supports the suggestion that aspects of pain and central alterations in CWP/FM are influenced by peripheral tissue alterations.
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2.
  • Gerdle, Björn, et al. (författare)
  • Signs of ongoing inflammation in female patients with chronic widespread pain A multivariate, explorative, cross-sectional study of blood samples
  • 2017
  • Ingår i: Medicine. - : LIPPINCOTT WILLIAMS & WILKINS. - 0025-7974 .- 1536-5964. ; 96:9
  • Tidskriftsartikel (refereegranskat)abstract
    • This cross-sectional study investigates the plasma inflammatory profile of chronic widespread pain CWP) patients compared to healthy controls CON). Rather than analyzing a relatively few substances at a time, we used a new multiplex proximity extension assay PEA) panel that enabled the simultaneous analysis of 92 inflammation-related proteins, mainly cytokines and chemokines. Seventeen women with CWP and 21 female CON participated and a venous blood sample was drawn from all subjects. Pain intensity and pain thresholds for pressure, heat, and cold were registered. A PEA panel 92 proteins) was used to analyze the blood samples. Multivariate data analysis by projection was used in the statistical analyses. Eleven proteins significantly differentiated the CON and CWP subjects R-2=0.58, Q(2)=0.37, analysis of variance of cross-validated predictive residuals P=0.006). It was not possible to significantly regress pain thresholds within each group CON or CWP). Positive significant correlations existed between several proteins and pain intensities in CWP, but the model reliability of the regression was poor. CWP was associated with systemic low-grade inflammation. Larger studies are needed to confirm the results and to investigate which alterations are condition-specific and which are common across chronic pain conditions. The presence of inflammation could promote the spreading of pain, a hallmark sign of CWP. As it has been suggested that prevalent comorbidities to pain (e.g., depression and anxiety, poor sleep, and tiredness) also are associated with inflammation, it will be important to determine whether inflammation may be a common mediator.
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3.
  • Ghafouri, Nazdar, et al. (författare)
  • Effects of two different specific neck exercise interventions on palmitoylethanolamide and stearoylethanolamide concentrations in the interstitium of the trapezius muscle in women with chronic neck shoulder pain
  • 2014
  • Ingår i: Pain medicine (Malden, Mass.). - : Oxford University Press (OUP). - 1526-2375 .- 1526-4637. ; 15:8, s. 1379-1389
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose. Chronic neck/shoulder pain (CNSP) is one of the most common pain conditions. The understanding of mechanisms, including the peripheral balance between nociceptive and antinociceptive processes, is incomplete. N-acylethanolamines (NAEs) are a class of endogenous compounds that regulate inflammation and pain. The aim of this study was to investigate the levels of two NAEs: the peroxisome proliferator-activated receptor type-a ligand palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) in the muscle interstitium of the trapezius muscle in women with CNSP randomized to two different neck specific training programs and in a healthy pain-free control group (CON). Materials and Methods. Fifty-seven women with CNSP were randomized to strength + stretch or stretch alone exercise programs. Twenty-nine subjects underwent microdialysis procedure before and after 4-6 months of exercise. Twenty-four CON subjects underwent microdialysis procedure before and after 4-6 months without any intervention in between. Microdialysate samples were collected from the trapezius muscle and analyzed by mass spectrometry for PEA and SEA levels. Results. PEA and SEA levels were significantly higher in CNSP patients compared with CON. PEA was significantly higher in CNSP than in CON after both training programs. SEA was significantly higher in CNSP than in CON after stretch alone but not after strength + stretch training. A significant positive correlation was found between changes in pain intensity and in SEA levels in the strength + stretch group, but not in the stretch alone group. Conclusion. Our results indicate that exercise interventions differentially affect the levels of the bioactive lipids PEA and SEA in the interstitium of the trapezius muscle in women with CNSP.
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5.
  • Ghafouri, Nazdar, et al. (författare)
  • High Levels of N-Palmitoylethanolamide and N-Stearoylethanolamide in Microdialysate Samples from Myalgic Trapezius Muscle in Women
  • 2011
  • Ingår i: PLOS ONE. - San Fransisco : Public Library of Science. - 1932-6203. ; 6:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: N-acylethanolamines (NAEs) are endogenous compounds that regulate inflammation and pain. These include the cannabinoid ligand anandamide (AEA) and the peroxisome proliferator-activated receptor-a ligand palmitoylethanolamide (PEA). Little is known as to the levels of NAEs in pain states in human, particularly in the skeletal muscle. The aim of this study was to investigate the levels of these lipid mediators in muscle dialysate from women with chronic neck-/shoulder pain compared to healthy controls. Methods: Eleven women with chronic neck-/shoulder pain and eleven healthy women participated in this study. All participants went through microdialysis procedures in the trapezius muscle. Muscle dialysate samples were collected during four hours and analysed by nano liquid chromatography tandem mass spectrometry (nLC-MS/MS). Results: We were able to detect AEA, PEA, N-stearoylethanolamine (SEA) and 2-arachidonoylglycerol (2-AG) in a single chromatographic run. Of the NAEs studied, PEA and SEA were clearly detectable in the muscle microdialysate samples. The muscle dialysate levels of PEA and SEA were significantly higher in myalgic subjects compared to healthy controls. Conclusion: This study demonstrates that microdialysis in combination with mass spectrometry can be used for analysing NAEs in human muscle tissue regularly over time. Furthermore the significant group differences in the concentration of PEA and SEA in this study might fill an important gap in our knowledge of mechanisms in chronic myalgia in humans. In the long run this expanded understanding of nociceptive and anitinociceptive processes in the muscle may provide a base for ameliorating treatment and rehabilitation of pain.
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7.
  • Ghafouri, Nazdar, et al. (författare)
  • Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity
  • 2013
  • Ingår i: Pain. - : Elsevier. - 0304-3959 .- 1872-6623. ; 154:9, s. 1649-1658
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic widespread pain (CWP) is a complex condition characterized by central hyperexcitability and altered descending control of nociception. However, nociceptive input from deep tissues is suggested to be an important drive. N-Acylethanolamines (NAEs) are endogenous lipid mediators involved in regulation of inflammation and pain. Previously we have reported elevated levels of the 2 NAEs, the peroxisome proliferator-activated receptor type-alpha ligand N-palmitoylethanolamine (PEA) and N-stearoylethanolamine (SEA) in chronic neck/shoulder pain (CNSP). In the present study, the levels of PEA and SEA in women with CWP (n = 18), CNSP (n = 34) and healthy controls (CON, n = 24) were investigated. All subjects went through clinical examination, pressure pain threshold measurements and induction of experimental pain in the tibialis anterior muscle. Microdialysis dialysate of the trapezius was collected before and after subjects performed a repetitive low-force exercise and analyzed by mass spectrometry. The levels of PEA and SEA in CNSP were significantly higher post exercise compared with CWP, and both pre and post exercise compared with CON. Levels of both NAEs decreased significantly pre to post exercise in CWP. Intercorrelations existed between aspects of pain intensity and sensitivity and the level of the 2 NAEs in CWP and CNSP. This is the first study demonstrating that CNSP and CWP differ in levels of NAEs in response to a low-force exercise which induces pain. Increases in pain intensity as a consequence of low-force exercise were associated with low levels of PEA and SEA in CNSP and CWP. These results indicate that PEA and SEA have antinociceptive roles in humans.
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8.
  • Håkansson, Irene, et al. (författare)
  • Oxylipins in cerebrospinal fluid in clinically isolated syndrome and relapsing remitting multiple sclerosis
  • 2018
  • Ingår i: Prostaglandins & other lipid mediators. - : Elsevier. - 1098-8823 .- 2212-196X. ; 138, s. 41-47
  • Tidskriftsartikel (refereegranskat)abstract
    • Although oxylipins are involved in inflammation, data on these lipid mediators in multiple sclerosis are sparse. In this study, a panel of oxylipins were analysed swith liquid chromatography tandem mass spectrometry in cerebrospinal fluid (CSF) from 41 treatment naive patients with clinically isolated syndrome (CIS) or relapsing remitting MS (RRMS) and 22 healthy controls. CSF levels of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE) were significantly higher in patients than in healthy controls (9-HODE median 380 nM (interquartile range 330-450 nM) in patients and 290 nM (interquartile range 250-340 nM) in controls, 13-HODE median 930 nM (interquartile range 810-1080 nM) in patients and 690 nM (interquartile range 570-760 nM) in controls, p < 0.001 in Mann-Whitney U tests). 9-HODE and 13-HODE performed well for separation of patients and healthy controls (AUC 0.85 and 0.88, respectively, in ROC curve analysis). However, baseline CSF levels of the oxylipins did not differ between patients with signs of disease activity during one, two and four years of follow-up and patients without. In conclusion, this study indicates that 9-HODE and 13-HODE levels are increased in CSF from CIS and RRMS patients compared with healthy controls, but does not support 9-HODE or 13-HODE as prognostic biomarkers of disease activity in patients during follow-up.
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9.
  • Karlsson, Linn, et al. (författare)
  • Intramuscular pain modulatory substances before and after exercise in women with chronic neck pain
  • 2015
  • Ingår i: European Journal of Pain. - : WILEY-BLACKWELL. - 1090-3801 .- 1532-2149. ; 19:8, s. 1075-1085
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundIn peripheral tissue, several substances influence pain and pain modulation. Exercise has been found to decrease pain and improve function for chronic pain conditions, but how and why exercise produces beneficial effects remains unclear. This study investigates whether aspects of pain and concentrations of substances with algesic, analgesic and metabolic functions differ between women with chronic neck shoulder pain (CNSP) and healthy women (CON) and whether changes are found after an exercise intervention for CNSP. MethodsForty-one women with CNSP and 24 CON subjects were included. The participants attended two microdialysis sessions with 4-6 months between the experiments. During this period, the CNSP subjects underwent an exercise intervention. Expression levels of substance P, beta-endorphin, cortisol, glutamate, lactate and pyruvate as well as pain intensity and pressure pain thresholds were analysed. ResultsAt baseline, higher concentrations of glutamate and beta-endorphin and lower concentrations of cortisol in CNSP than CON were found. After exercise, decreased levels of substance P and possibly of glutamate, increased levels of beta-endorphin and cortisol as well as decreased pain intensity and increased pain pressure thresholds were found for CNSP. ConclusionsThe findings at baseline indicated algesic and analgesic alterations in the painful trapezius muscles. The findings for CNSP after the exercise intervention, with changes in peripheral substances and decreased pain intensity and sensitivity, could reflect a long-term physiological effect of the exercise.
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10.
  • Olausson, Patrik, et al. (författare)
  • Identification of Proteins from Interstitium of Trapezius Muscle in Women with Chronic Myalgia Using Microdialysis in Combination with Proteomics
  • 2012
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Microdialysis (MD) of the trapezius muscle has been an attractive technique to investigating small molecules and metabolites in chronic musculoskeletal pain in human. Large biomolecules such as proteins also cross the dialysis membrane of the catheters. In this study we have applied in vivo MD in combination with two dimensional gel electrophoresis (2-DE) and mass spectrometry to identify proteins in the extracellular fluid of the trapezius muscle. Materials and Methods: Dialysate from women with chronic trapezius myalgia (TM; n = 37), women with chronic wide spread pain (CWP; n = 18) and healthy controls (CON; n = 22) was collected from the trapezius muscle using a catheter with a cut-off point of 100 kDa. Proteins were separated by two-dimensional gel electrophoresis and visualized by silver staining. Detected proteins were identified by nano liquid chromatography in combination with tandem mass spectrometry. Results: Ninety-seven protein spots were identified from the interstitial fluid of the trapezius muscle; 48 proteins in TM and 30 proteins in CWP had concentrations at least two-fold higher or lower than in CON. The identified proteins pertain to several functional classes, e.g., proteins involved in inflammatory responses. Several of the identified proteins are known to be involved in processes of pain such as: creatine kinase, nerve growth factor, carbonic anhydrase, myoglobin, fatty acid binding protein and actin aortic smooth muscle. Conclusions: In this study, by using in vivo microdialysis in combination with proteomics a large number of proteins in muscle interstitium have been identified. Several of the identified proteins were at least two-fold higher or lower in chronic pain patients. The applied techniques open up for the possibility of investigating protein changes associated with nociceptive processes of chronic myalgia. © 2012 Olausson et al.
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11.
  • Olausson, Patrik, et al. (författare)
  • Protein alterations in women with chronic widespread pain : An explorative proteomic study of the trapezius muscle
  • 2015
  • Ingår i: Scientific Reports. - : Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group. - 2045-2322. ; 5:11894
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic widespread pain (CWP) has a high prevalence in the population and is associated with prominent negative individual and societal consequences. There is no clear consensus concerning the etiology behind CWP although alterations in the central processing of nociception maintained by peripheral nociceptive input has been suggested. Here, we use proteomics to study protein changes in trapezius muscle from 18 female patients diagnosed with CWP compared to 19 healthy female subjects. The 2-dimensional gel electrophoresis (2-DE) in combination with multivariate statistical analyses revealed 17 proteins to be differently expressed between the two groups. Proteins were identified by mass spectrometry. Many of the proteins are important enzymes in metabolic pathways like the glycolysis and gluconeogenesis. Other proteins are associated with muscle damage, muscle recovery, stress and inflammation. The altered expressed levels of these proteins suggest abnormalities and metabolic changes in the myalgic trapezius muscle in CWP. Taken together, this study gives further support that peripheral factors may be of importance in maintaining CWP.
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12.
  • Olausson, Patrik, et al. (författare)
  • Relative recovery over time – an in vivo microdialysisstudy of human skeletal muscle
  • 2013
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa Healthcare. - 0036-5513 .- 1502-7686. ; 73:1, s. 10-16
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:The microdialysis technique is a method for sampling endogenous molecules from the interstitial compartments of varying tissues and relies on diffusion of molecules between the tissue and a perfusate via a membrane. Such samples do not allow determination of the true interstitial concentration but only a certain percentage. This gives rise to one of the most crucial parameter that needs to be considered for a dependable microdialysis; the relative recovery. Relative recovery states the efficiency of which an analyte is extracted from its external medium. Aim. To investigate the relative recovery of small molecules (< 20 kDa) such as lactate, fluid recovery and the reproducibility of the relative recovery at group and individual level of the microdialysis technique applied in muscle.MATERIALS AND METHODS:Using in vivo microdialysis of the trapezius muscle of 65 women from two separate occasions 4-6 months apart. Relative recovery of small molecules was measured from samples collected every 20 min during a period of 220 min.RESULTS:Good reproducibility at group level of catheters with cut-offs 100 and 20kDa were found. Furthermore, there was a high and steady relative recovery with an overall good fluid recovery. Poor reproducibility was found at the individual level for both catheters.CONCLUSIONS:This study demonstrates that when using microdialysis in skeletal muscle relative recovery is stable over time and is not affected by low-force exercise. Although there is a good reproducibility at group level this is not the case at the individual level. Thus in vivo, the relative recovery should be determined for each test subject and at each test occasion.
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13.
  • Olausson, Patrik, et al. (författare)
  • Specific proteins of the trapezius muscle correlate with pain intensity and sensitivity - an explorative multivariate proteomic study of the trapezius muscle in women with chronic widespread pain
  • 2016
  • Ingår i: Journal of Pain Research. - : DOVE MEDICAL PRESS LTD. - 1178-7090. ; 9, s. 345-356
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic widespread pain (CWP) including fibromyalgia syndrome (FMS) has a high prevalence and is associated with prominent negative consequences. CWP/FMS exhibits morphological and functional alterations in the central nervous system. The importance of peripheral factors for maintaining the central alterations are under debate. In this study, the proteins from biopsies of the trapezius muscle from 18 female CWP/FMS patients and 19 healthy female controls were analyzed. Pain intensity and pressure pain thresholds (PPT) over the trapezius muscles were registered. Twelve proteins representing five different groups of proteins were important regressors of pain intensity in CWP/FMS (R-2=0.99; P amp;lt; 0.001). In the regression of PPT in CWP/FMS, it was found that 16 proteins representing six groups of proteins were significant regressors (R-2=0.95, P amp;lt; 0.05). Many of the important proteins were stress and inflammation proteins, enzymes involved in metabolic pathways, and proteins associated with muscle damage, myopathies, and muscle recovery. The altered expression of these proteins may reflect both direct and indirect nociceptive/inflammatory processes as well as secondary changes. The relative importance of the identified proteins and central alterations in CWP need to be investigated in future research. Data from this and the previous study concerning the same cohorts give support to the suggestion that peripheral factors are of importance for maintaining pain aspects in CWP/FMS.
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14.
  • Sorensen, Line Bay, et al. (författare)
  • Investigation of biomarkers alterations after an acute tissue trauma in human trapezius muscle, using microdialysis
  • 2018
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Alterations in muscle milieu are suggested as important activity of peripheral drive in patients with chronic musculoskeletal pain (CMP). Microdialysis (MD) has been used in monitoring altered metabolic response pattern in muscles. However, the insertion of MD probe causes a local tissue trauma. Whether and how metabolites in trapezius muscle are affected by acute tissue trauma is unknown. Hence, this study investigated the metabolic response and nociceptive reaction of the tissue following MD probe insertion in patients with CMP and healthy individuals. Fifty-nine patients and forty pain-free volunteers were recruited. Pressure pain thresholds (PPTs) were obtained at the trapezius and tibialis muscles. Pain questionnaires determined the levels of pain related aspects. MD (20 kDa cut-off) was performed in the trapezius and samples were collected within 40 min. Interstitial concentration of the metabolites was analyzed by a two-way-mixed-ANOVA. The metabolic response pattern changed over time and alterations in the level of metabolites could be seen in both CMP and healthy controls. Pain questionnaires and pain intensities manifested clinical aspects of pain closely to what CMP patients describe. Analyzing metabolites due to acute tissue trauma by aid of MD may be a useful model to investigate altered metabolic response effect in CMP.
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15.
  • Stensson, Niclas, 1974-, et al. (författare)
  • Alterations of anti-inflammatory lipids in plasma from women with chronic widespread pain - a case control study
  • 2017
  • Ingår i: Lipids in Health and Disease. - : BIOMED CENTRAL LTD. - 1476-511X. ; 16
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Chronic widespread pain conditions (CWP) such as the pain associated with fibromyalgia syndrome (FMS) are significant health problems with unclear aetiology. Although CWP and FMS can alter both central and peripheral pain mechanisms, there are no validated markers for such alterations. Pro-and anti-inflammatory components of the immune system such as cytokines and endogenous lipid mediators could serve as systemic markers of alterations in chronic pain. Lipid mediators associated with anti-inflammatory qualities - e.g., oleoylethanolamide (OEA), palmitoylethanolamide ( PEA), and stearoylethanolamide ( SEA) - belong to N-acylethanolamines (NAEs). Previous studies have concluded that these lipid mediators may modulate pain and inflammation via the activation of peroxisome proliferator activating receptors (PPARs) and the activation of PPARs may regulate gene transcriptional factors that control the expression of distinct cytokines. Methods: This study investigates NAEs and cytokines in 17 women with CWP and 21 healthy controls. Plasma levels of the anti-inflammatory lipids OEA, PEA, and SEA, the pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 were investigated. T-test of independent samples was used for group comparisons. Bivariate correlation analyses, and multivariate regression analysis were performed between lipids, cytokines, and pain intensity of the participants. Results: Significantly higher levels of OEA and PEA in plasma were found in CWP. No alterations in the levels of cytokines existed and no correlations between levels of lipids and cytokines were found. Conclusions: We conclude that altered levels of OEA and PEA might indicate the presence of systemic inflammation in CWP. In addition, we believe our findings contribute to the understanding of the biochemical mechanisms involved in chronic musculoskeletal pain.
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16.
  • Stensson, Niclas, 1974- (författare)
  • Endocannabinoids and Related Lipids in Chronic Pain : Analytical and Clinical Aspects
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • In Europe, approximately one in five adults experience chronic pain, pain that lasts more than three months. Chronic pain is a significant problem not only for those people suffering from chronic pain but also for society. The prevalence of chronic pain is higher in women and lower socioeconomic groups. Although chronic pain often originates in a specific site, it may eventually spread to several sites, transforming into chronic widespread pain (CWP), a condition evident in about 10% of the adult population. Approximately 1.2-5.4% are classified with fibromyalgia (FM). In addition to CWP, common symptoms of FM include, stiffness, fatigue, sleep disturbances, and cognitive dysfunction and common co-morbidities include depression and anxiety. Although FM/CWP has been reported to alter both central and peripheral nociceptive mechanisms, no objective biomarkers have been found that correlate with CWP/FM and no standard examinations such as blood test, X-ray or computed tomography can provide support for a diagnosis. Because there are no objective biomarkers that correlate with the pathophysiological processes associated with CWP/FM, this debilitating disease is difficult to diagnose and ultimately treat. However, there are some promising therapeutic targets for chronic pain with inter alia analgesic, anti-inflammatory, and stress modulating properties: the endocannabinoids (ECs) arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) and their related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA).This thesis investigates whether ECs and the related N-acylethanolamines (NAEs) can be used as potential biomarkers for CWP/FM. Specifically, the studies compared the peripheral and systemic levels of ECs and NAEs in 121 women with CWP/FM and in 137 healthy controls in two different cohorts. In addition, the correlation between lipid levels and common pain characteristics such as intensity, sensitivity, and duration were investigated. The EC and related lipid levels were measured using liquid chromatography in combination with tandem mass spectrometry. Multivariate data analysis was used for biomarker evaluation.Compared to the healthy controls, the CWP/FM patients had significantly higher concentrations of OEA, PEA, and SEA in muscle and plasma (p ≤ 0.05) and significantly higher 2-AG in plasma (p ≤ 0.01). These results may indicate that NAEs, are mobilized differently in painful muscles compared with pain free muscles. Moreover, increased systemic levels of NAEs and 2-AG in patients might be signs of ongoing low-grade inflammation inCWP/FM. These findings contribute to a better understanding of how peripheral and systemic factors maintain and activate chronic pain. Although the investigated lipids have statistically significant effects but biologically uncertain role in the clinical manifestations of CWP/FM. Thus plasma lipids are not a good biomarker for CWP/FM. Nevertheless, increased lipid levels indicate a metabolic asymmetry in CWP/FM, a finding that could serve as a basis for more research on pain management.
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17.
  • Stensson, Niclas, et al. (författare)
  • High levels of endogenous lipid mediators (N-acylethanolamines) in women with chronic widespread pain during acute tissue trauma
  • 2016
  • Ingår i: Molecular Pain. - : SAGE PUBLICATIONS INC. - 1744-8069. ; 12:1744806916662886
  • Tidskriftsartikel (refereegranskat)abstract
    • Although chronic widespread musculoskeletal pain is a significant health problem, the molecular mechanisms involved in developing and maintaining chronic widespread musculoskeletal pain are poorly understood. Central sensitization mechanisms maintained by stimuli from peripheral tissues such as muscle have been suggested. Lipid mediators with anti-inflammatory characteristics such as endogenous ligands of peroxisome proliferator activating receptor-alpha, oleoylethanolamide, and palmitoylethanolamide are suggested to regulate nociceptive transmission from peripheral locations on route towards the central nervous system. This case-control study investigates the levels of anti-inflammatory lipids in microdialysis samples collected during the first 2 h after microdialysis probe insertion and explores the association of these lipids with different pain characteristics in women with chronic widespread musculoskeletal pain (n = 17) and female healthy controls (n = 19). The levels of oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide were determined. During sampling of dialysate, pain ratings were conducted using a numeric rating scale. Pain thresholds were registered from upper and lower parts of the body. Oleoylethanolamide and stearoylethanolamide levels were significantly higher (p amp;lt;= 0.05) in chronic widespread musculoskeletal pain at all time points. Numeric rating scale correlated with levels of stearoylethanolamide in chronic widespread musculoskeletal pain. Higher levels of lipid mediators could reflect an altered tissue reactivity in response to microdialysis probe insertion in chronic widespread musculoskeletal pain.
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18.
  • Stensson, Niclas, et al. (författare)
  • Identification of Lipid Mediators in Peripheral Human Tissues Using an Integrative In Vivo Microdialysis Approach
  • 2016
  • Ingår i: Journal of analytical and bioanalytical techniques. - : Omics. - 2155-9872. ; 7:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Endocannabinoids and related N-acylethanolamines (NAEs) are lipid mediators involved in a number of physiological and pathological mechanisms in peripheral tissues. Microdialysis (MD) technique allows continues sampling of endogenous substances in the interstitial fluids of the tissues. The main limitation of MD sampling of lipophilic compounds is low recovery due to adsorption to the MD system and particularly to the catheter membranes. In this in vivo study microdialysate samples were collected from human trapezius muscle and forearm skin. The levels of arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) were analyzed in both microdialysate and in catheter membrane samples using liquid chromatography tandem mass spectrometry.OEA, PEA and SEA were identified in all microdialysate and catheter membrane samples from trapezius and skin. 2-AG was found in all catheter membrane samples from both tissues but not in the actual microdialysate.In conclusion sampling of OEA, PEA and SEA was achievable from trapezius and skin with the presented MD set-up. 2-AG is present in both trapezius muscle and skin tissue but adsorbs to the membranes in a higher extent than the NAEs. Furthermore, consideration of data conserved in the membrane during an MD experiment could be a relevant and more broadly applicable extension of MD sampling methodology which could fill an "information gap" and enhance an adequate interpretation of microdialysate data outcomes.
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19.
  • Stensson, Niclas, 1974-, et al. (författare)
  • The Relationship of Endocannabinoidome Lipid Mediators With Pain and Psychological Stress in Women With Fibromyalgia: A Case-Control Study
  • 2018
  • Ingår i: Journal of Pain. - : Elsevier BV. - 1526-5900 .- 1528-8447. ; 19:11, s. 1318-1328
  • Tidskriftsartikel (refereegranskat)abstract
    • Characterized by chronic widespread pain, generalized hyperalgesia, and psychological stress, fibromyalgia (FM) is difficult to diagnose and lacks effective treatments. Endocannabinoids arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), and the related oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are endogenous lipid mediators with analgesic and anti-inflammatory characteristics, in company with psychological modulating properties (eg, stress and anxiety), and are included in a new emerging "ome," the endocannabinoidome. This case-control study compared the concentration differences of AEA, OEA, PEA, SEA, and 2 AG in 104 women with FM and 116 healthy control subjects. All participants rated their pain, anxiety, depression, and current health status. The relationships between the lipid concentrations and the clinical assessments were investigated using powerful multivariate data analysis and traditional bivariate statistics. The concentrations of OEA, PEA, SEA, and 2-AG were significantly higher in women with FM than in healthy control subjects; significance remained for OEA and SEA after controlling for body mass index and age. 2-AG correlated positively with FM duration and body mass index, and to some extent negatively with pain, anxiety, depression, and health status. In FM, AEA correlated positively with depression ratings. The elevated circulating levels of endocannabinoidome lipids suggest that these lipids play a role in the complex pathophysiology of FM and might be signs of ongoing low-grade inflammation in FM. Although the investigated lipids are significantly altered in FM, their biological roles are uncertain with respect to the clinical manifestations of FM. Thus plasma lipids alone are not good biomarkers for FM. Perspective: This study reports about elevated plasma levels of endocannabinoidome lipid mediators in FM. The lipids' suitability to work as biomarkers for FM in the clinic were low; however, their altered levels indicate that a metabolic asymmetry is ongoing in FM, which could serve as a baseline during explorative FM pain management. (C) 2018 by the American Pain Society
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20.
  • Turkina, Maria V, 1973-, et al. (författare)
  • Evaluation of dynamic changes in interstitial fluid proteome following microdialysis probe insertion trauma in trapezius muscle of healthy women
  • 2017
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Microdialysis ( MD) has been shown to be a promising technique for sampling of biomarkers. Implantation of MD probe causes an acute tissue trauma and provokes innate response cascades. In order to normalize tissue a two hours equilibration period for analysis of small molecules has been reported previously. However, how the proteome profile changes due to this acute trauma has yet to be fully understood. To characterize the early proteome events induced by this trauma we compared proteome in muscle dialysate collected during the equilibration period with two hours later in "post-trauma". Samples were collected from healthy females using a 100 kDa MW cut off membrane and analyzed by high sensitive liquid chromatography tandem mass spectrometry. Proteins involved in stress response, immune system processes, inflammatory responses and nociception from extracellular and intracellular fluid spaces were identified. Sixteen proteins were found to be differentially abundant in samples collected during first two hours in comparison to "post-trauma". Our data suggests that microdialysis in combination with mass spectrometry may provide potentially new insights into the interstitial proteome of trapezius muscle, yet should be further adjusted for biomarker discovery and diagnostics. Moreover, MD proteome alterations in response to catheter injury may reflect individual innate reactivity.
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21.
  • Wåhlén, Karin, et al. (författare)
  • Plasma Protein Pattern Correlates With Pain Intensity and Psychological Distress in Women With Chronic Widespread Pain
  • 2018
  • Ingår i: Frontiers in Psychology. - : FRONTIERS MEDIA SA. - 1664-1078. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Although generalized muscle pain, tiredness, anxiety, and depression are commonly present among chronic widespread pain (CWP) patients, the molecular mechanisms behind CWP are not fully elucidated. Moreover, the lack of biomarkers often makes diagnosis and treatment problematic. In this study, we investigated the correlation between pain intensity, psychological distress, and plasma proteins among CWP patients and controls (CON). Methods: The plasma proteome of CWP (n = 15) and CON (n = 23) was analyzed using two-dimensional gel electrophoresis. Orthogonal Partial Least Square analysis (OPLS) was used to determine proteins associated with pain intensity (numeric rating scale) in CWP and psychological distress (Hospital and Depression Scale, HADS) in CWP and CON. Significant proteins were identified by MALDI-TOF and tandem MS. Results: In CWP, pain intensity was associated with plasma proteins mostly involved in metabolic and immunity processes (e.g., kininogen-1, fibrinogen gamma chain, and ceruloplasmin), and psychological distress was associated with plasma proteins related to immunity response, iron ion, and lipid metabolism (e.g., complement factor B, complement C1r subcomponent, hemopexin, and clusterin). Discussion: This study suggests that different plasma protein patterns are associated with different pain intensity and psychological distress in CWP. Proteins belonging to the coagulation cascade and immunity processes showed strong associations to each clinical outcome. Using the plasma proteome profile of CWP to study potential biomarker candidates provides a snapshot of ongoing systemic mechanisms in CWP.
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22.
  • Wåhlén, Karin, et al. (författare)
  • Systemic alterations in plasma proteins from women with chronic widespread pain compared to healthy controls: a proteomic study
  • 2017
  • Ingår i: Journal of Pain Research. - : DOVE MEDICAL PRESS LTD. - 1178-7090. ; 10, s. 797-809
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic widespread pain (CWP) is a complex pain condition that is difficult to treat. The prevalence of CWP approximates similar to 10% of the general population, with higher prevalence in women. Lack of understanding of molecular mechanisms has been a challenge for diagnosis and treatment of chronic pain. The aim of this study was to explore the systemic protein changes in CWP compared to those in healthy controls (CON). By applying 2-dimensional gel electrophoresis, we analyzed the protein pattern of plasma samples from women with CWP (n=16) and healthy women (n=23). The proteomic data were analyzed using multivariate statistical models, and altered proteins were identified using mass spectrometry. The proteome analysis was further validated by gel-free Western blot. Multivariate statistical data analysis of quantified proteins revealed 22 altered proteins in women with CWP, compared to CON group. Many of the identified proteins are previously known to be involved in different parts of the complement system and metabolic and inflammatory processes, e.g., complement factor B, vitamin D-binding protein, ceruloplasmin, transthyretin and alpha-2-HS-glycoprotein. These results indicate that important systemic protein differences exist between women with CWP and healthy women. Further, this study illustrates the potential use of proteomics to detect biomarkers that may provide new insights into the molecular mechanism(s) of chronic pain. However, further larger investigations are required in order to confirm these findings before it will be possible to identify proteins as potential pain biomarkers for clinical use.
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23.
  • Assenhöj, Maria, et al. (författare)
  • Metal exposure from additive manufacturing and its effect on the nasal lavage fluid proteome - a pilot study
  • 2021
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The use of metal additive manufacturing (AM) is steadily increasing and is an emerging concern regarding occupational exposure. In this study, non-invasive sampled nasal lavage fluid (NLF) from the upper airways was collected from metal AM operators at the beginning and end of a workweek during two consecutive years with preventive interventions in the occupational setting in-between (n = 5 year 1, n = 9 year 2). During year one, NLF was also collected from welders (n = 6) from the same company to get a comparison with a traditional manufacturing technique with known exposure and health risks. The samples were investigated using untargeted proteomics, as well as using multi-immunoassay to analyze a panel of 71 inflammatory protein markers. NLF in AM operators from year 1 showed decreased levels of Immunoglobulin J and WAP four-disulfide core domain protein 2 and increased levels of Golgi membrane protein 1, Uteroglobin and Protein S100-A6 at the end of the workweek. At year two, after preventive interventions, there were no significant differences at the end of the workweek. In welders, Annexin A1 and Protein S100-A6 were increased at the end of the workweek. The analysis of 71 inflammatory biomarkers showed no significant differences between the beginning and the end of workweek year 1 in AM operators. We identified several proteins of interest in the AM operators that could serve as possible markers for exposure in future studies with a larger cohort for validation.
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24.
  • Bajramaj, Ermira, et al. (författare)
  • The Effect of Microdialysis Catheter Insertion on Glutamate and Serotonin Levels in Masseter Muscle in Patients with Myofascial Temporomandibular Disorders and Healthy Controls
  • 2019
  • Ingår i: Diagnostics. - : MDPI. - 2075-4418. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Myofascial temporomandibular disorders (TMD) are the most common cause of chronic pain in the orofacial region. Microdialysis has been used to study metabolic changes in the human masseter muscle. The insertion of the microdialysis probe causes acute tissue trauma that could affect the metabolic milieu and thereby influence the results when comparing healthy subjects to those with TMD. This study aimed to investigate the levels of serotonin and glutamate during the acute tissue trauma period in healthy subjects and in patients with TMD. Microdialysis was carried out in 15 patients with TMD and 15 controls, and samples were collected every 20 min during a period of 140 min. No significant alterations of serotonin or glutamate were observed over the 2 h period for the healthy subjects. For the TMD group, a significant decrease in serotonin was observed over time (p < 0.001), followed by a significant increase between 120 and 140 min (p < 0.001). For glutamate, a significant reduction was observed at 40 min compared to baseline. The results showed that there was a spontaneous increase of serotonin 2 h after the insertion of the catheter in patients with TMD. In conclusion, the results showed that there are differences in the masseter muscle levels of serotonin and glutamate during acute nociception in patients with myofascial TMD compared to healthy subjects.
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25.
  • Bäckryd, Emmanuel, et al. (författare)
  • Cerebrospinal Fluid Metabolomics Identified Ongoing Analgesic Medication in Neuropathic Pain Patients
  • 2023
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain (n = 16) to healthy controls (n = 12). Methods: Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. Results: The significant OPLS-DA model identified 26 features out of 215 as important for group separation (R2 = 0.70, Q2 = 0.42, p = 0.017 by CV-ANOVA; 2 components). Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. Conclusion: CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen.
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26.
  • Bäckryd, Emmanuel, et al. (författare)
  • Do fragments and glycosylated isoforms of alpha-1-antitrypsin in CSF mirror spinal pathophysiological mechanisms in chronic peripheral neuropathic pain? An exploratory, discovery phase study
  • 2018
  • Ingår i: BMC Neurology. - : BMC. - 1471-2377. ; 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Post-translational modifications (PTMs) generate a tremendous protein diversity from the similar to 20,000 protein-coding genes of the human genome. In chronic pain conditions, exposure to pathological processes in the central nervous system could lead to disease-specific PTMs detectable in the cerebrospinal fluid (CSF). In a previous hypothesis-generating study, we reported that seven out of 260 CSF proteins highly discriminated between neuropathic pain patients and healthy controls: one isoform of angiotensinogen (AG), two isoforms of alpha-1-antitrypsin (AT), three isoforms of haptoglobin (HG), and one isoform of pigment epithelium-derived factor (PEDF). The present study had three aims: (1) To examine the multivariate inter-correlations between all identified isoforms of these seven proteins; (2) Based on the results of the first aim, to characterize PTMs in a subset of interesting proteins; (3) To regress clinical pain data using the 260 proteins as predictors, thereby testing the hypothesis that the above-mentioned seven discriminating proteins and/or the characterized isoforms/fragments of aim (2) would be among the proteins having the highest predictive power for clinical pain data. Methods: CSF samples from 11 neuropathic pain patients and 11 healthy controls were used for biochemical analysis of protein isoforms. PTM characterization was performed using enzymatic reaction assay and mass spectrometry. Multivariate data analysis (principal component analysis and orthogonal partial least square regression) was applied on the quantified protein isoforms. Results: We identified 5 isoforms of AG, 18 isoforms of AT, 5 isoforms of HG, and 5 isoforms of PEDF. Fragments and glycosylated isoforms of AT were studied in depth. When regressing the pain intensity data of patients, three isoforms of AT, two isoforms of PEDF, and one isoform of angiotensinogen "reappeared" as major results, i.e., they were major findings both when comparing patients with healthy controls and when regressing pain intensity in patients. Conclusions: Altered levels of fragments and/or glycosylated isoforms of alpha-1-antitrypsin might mirror pathophysiological processes in the spinal cord of neuropathic pain patients. In particular, we suggest that a putative disease-specific combination of the levels of two different N-truncated fragments of alpha-1-antitrypsin might be interesting for future CSF and/or plasma biomarker investigations in chronic neuropathic pain.
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27.
  • Bäckryd, Emmanuel, et al. (författare)
  • Do low levels of Beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study
  • 2014
  • Ingår i: Pain medicine (Malden, Mass.). - : Wiley-Blackwell. - 1526-2375 .- 1526-4637. ; 15:1, s. 111-119
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectivePain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF).DesignCross-sectional, comparative, observational study.SubjectsPatients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included.MethodsSamples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit.ResultsWe found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs rs = 0.574, P = 0.032).ConclusionsPatients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.
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28.
  • Bäckryd, Emmanuel, et al. (författare)
  • Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls : a hypothesis-generating pilot study
  • 2015
  • Ingår i: Journal of Pain Research. - : Dovepress. - 1178-7090. ; 8, s. 321-333
  • Tidskriftsartikel (refereegranskat)abstract
    • Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin–angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin–angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.
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29.
  • Bäckryd, Emmanuel, et al. (författare)
  • Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study
  • 2016
  • Ingår i: Scandinavian Journal of Pain. - : Walter de Gruyter GmbH. - 1877-8860 .- 1877-8879. ; :10, s. 1-5
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Caused by a lesion or disease of the somatosensory system, neuropathic pain is notoriously difficult to treat with conventional analgesics. It has been suggested that inflammatory cytokines play a role in the development and maintenance of neuropathic pain. But human studies of these substances are relatively few and partly contradictory. Objectives: To simultaneously investigate the plasma levels of chemokine interleukin 8 (IL-8) and the cytokines IL-6, IL-1, and Granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with peripheral neuropathic pain (most of whom due to failed back surgery syndrome) (n = 14) compared to controls (n = 17). Results: IL-6 was significantly higher in patients than in controls (0.92 ± 0.12 pg/ml vs. 0.57 ± 0.08 pg/ml, p = 0.012). IL-1, IL-8, and GM-CSF levels did not differ between the two groups. A multivariate analysis showed a tendency for patients also to have higher GM-CSF plasma levels than controls. Conclusions: This study found an increased level of IL-6 in plasma in patients with neuropathic pain, but not for the other pro-inflammatory substances investigated. There are several possible confounders not registered or controlled for in this and other studies of neuropathic pain. Implications: Larger studies that take several possible confounders into consideration are needed to further investigate the levels of plasma cytokines in different pain conditions. © 2015 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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30.
  • Bäckryd, Emmanuel, et al. (författare)
  • Serum levels of endocannabinoids and related lipids in painful vs painless diabetic neuropathy: results from the Pain in Neuropathy Study
  • 2024
  • Ingår i: Pain. - : LIPPINCOTT WILLIAMS & WILKINS. - 0304-3959 .- 1872-6623. ; 165:1, s. 225-232
  • Tidskriftsartikel (refereegranskat)abstract
    • N-arachidonoylethanolamine (also known as anandamide) and 2-arachidonoylglycerol are activators of the cannabinoid receptors. The endocannabinoid system also includes structurally and functionally related lipid mediators that do not target cannabinoid receptors, such as oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide. These bioactive lipids are involved in various physiological processes, including regulation of pain. The primary aim of the study was to analyze associations between serum levels of these lipids and pain in participants in the Pain in Neuropathy Study, an observational, cross-sectional, multicentre, research project in which diabetic patients with painless or painful neuropathy underwent deep phenotyping. Our hypothesis was that painful neuropathy would be associated with higher levels of the 5 lipids compared with painless neuropathy. Secondary aims were to analyze other patient-reported outcome measures and clinical data in relationship to lipid levels. The lipid mediators were analyzed in serum samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Serum levels of anandamide were significantly higher in the painful group, but the effect size was small (Cohen d = 0.31). Using cluster analysis of lipid data, patients were dichotomized into a "high-level" endocannabinoid group and a "low-level" group. In the high-level group, 61% of patients had painful neuropathy, compared with 45% in the low-level group (P = 0.039). This work is of a correlative nature only, and the relevance of these findings to the search for analgesics targeting the endocannabinoid system needs to be determined in future studies.
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31.
  • Bäckryd, Emmanuel, 1974- (författare)
  • The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain.In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question.In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor.In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses.
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32.
  • Christidis, Nikolaos, et al. (författare)
  • Comparison of the Levels of Pro-Inflammatory Cytokines Released in the Vastus Lateralis Muscle of Patients with Fibromyalgia and Healthy Controls during Contractions of the Quadriceps Muscle – A Microdialysis Study
  • 2015
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:12
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Fibromyalgia is associated with central hyperexcitability, but it is suggested that peripheral input is important to maintain central hyperexcitability. The primary aim was to investigate the levels of pro-inflammatory cytokines released in the vastus lateralis muscle during repetitive dynamic contractions of the quadriceps muscle in patients with fibromyalgia and healthy controls. Secondarily, to investigate if the levels of pro-inflammatory cytokines were correlated with pain or fatigue during these repetitive dynamic contractions. MATERIAL AND METHODS: 32 women with fibromyalgia and 32 healthy women (controls) participated in a 4 hour microdialysis session, to sample IL-1β, IL-6, IL-8, and TNF from the most painful point of the vastus lateralis muscle before, during and after 20 minutes of repeated dynamic contractions. Pain (visual analogue scale; 0-100) and fatigue Borg's Rating of Perceived Exertion Scale; 6-20) were assessed before and during the entire microdialysis session. RESULTS: The repetitive dynamic contractions increased pain in the patients with fibromyalgia (P < .001) and induced fatigue in both groups (P < .001). Perceived fatigue was significantly higher among patients with fibromyalgia than controls (P < .001). The levels of IL-1β did not change during contractions in either group. The levels of TNF did not change during contractions in patients with fibromyalgia, but increased in controls (P < .001) and were significantly higher compared to patients with fibromyalgia (P = .033). The levels of IL-6 and IL-8 increased in both groups alike during and after contractions (P's < .001). There were no correlations between pain or fatigue and cytokine levels after contractions. CONCLUSION: There were no differences between patients with fibromyalgia and controls in release of pro-inflammatory cytokines, and no correlations between levels of pro-inflammatory cytokines and pain or fatigue. Thus, this study indicates that IL-1β, IL-6, IL-8, and TNF do not seem to play an important role in maintenance of muscle pain in fibromyalgia.
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33.
  • Dawson, Andreas, et al. (författare)
  • Dopamine in plasma : a biomarker for myofascial TMD pain?
  • 2016
  • Ingår i: Journal of Headache and Pain. - : Springer. - 1129-2369 .- 1129-2377. ; 17:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Dopaminergic pathways could be involved in the pathophysiology of myofascial temporomandibular disorders (M-TMD). This study investigated plasma levels of dopamine and serotonin (5-HT) in patients with M-TMD and in healthy subjects. METHODS: Fifteen patients with M-TMD and 15 age- and sex-matched healthy subjects participated. The patients had received an M-TMD diagnosis according to the Research Diagnostic Criteria for TMD. Perceived mental stress, pain intensity (0-100-mm visual analogue scale), and pressure pain thresholds (PPT, kPa) over the masseter muscles were assessed; a venous blood sample was taken. RESULTS: Dopamine in plasma differed significantly between patients with M-TMD (4.98 ± 2.55 nM) and healthy controls (2.73 ± 1.24 nM; P < 0.01). No significant difference in plasma 5-HT was observed between the groups (P = 0.75). Patients reported significantly higher pain intensities (P < 0.001) and had lower PPTs (P < 0.01) compared with the healthy controls. Importantly, dopamine in plasma correlated significantly with present pain intensity (r = 0.53, n = 14, P < 0.05) and perceived mental stress (r = 0.34, n = 28, P < 0.05). CONCLUSIONS: The results suggest that peripheral dopamine might be involved in modulating peripheral pain. This finding, in addition to reports in other studies, suggests that dopaminergic pathways could be implicated in the pathophysiology of M-TMD but also in other chronic pain conditions. More research is warranted to elucidate the role of peripheral dopamine in the pathophysiology of chronic pain.
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34.
  • Dawson, Andreas, et al. (författare)
  • Effects of Experimental Tooth Clenching on Pain and Intramuscular Release of 5-HT and Glutamate in Patients With Myofascial TMD
  • 2015
  • Ingår i: The Clinical Journal of Pain. - : Lippincott, Williams andamp; Wilkins. - 0749-8047 .- 1536-5409. ; 31:8, s. 740-749
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: It has been suggested that tooth clenching may be associated with local metabolic changes, and is a risk factor for myofascial temporomandibular disorders (M-TMD). This study investigated the effects of experimental tooth clenching on the levels of 5-HT, glutamate, pyruvate, and lactate, as well as on blood flow and pain intensity, in the masseter muscles of M-TMD patients. Methods: Fifteen patients with M-TMD and 15 pain-free controls participated. Intramuscular microdialysis was performed to collect 5-HT, glutamate, pyruvate, and lactate and to assess blood flow. Two hours after the insertion of a microdialysis catheter, participants performed a 20-minute repetitive tooth clenching task (50% of maximal voluntary contraction). Pain intensity was measured throughout. Results: A significant effect of group (P less than 0.01), but not of time, was observed on 5-HT levels and blood flow. No significant effects of time or group occurred on glutamate, pyruvate, or lactate levels. Time and group had significant main effects on pain intensity (P less than 0.05 and less than 0.001). No significant correlations were identified between: (1) 5-HT, glutamate, and pain intensity; or between (2) pyruvate, lactate, and blood flow. Discussion: This experimental tooth clenching model increased jaw muscle pain levels in M-TMD patients and evoked low levels of jaw muscle pain in controls. M-TMD patients had significantly higher levels of 5-HT than controls and significantly lower blood flow. These 2 factors may facilitate the release of other algesic substances that may cause pain.
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35.
  • Dawson, Andreas, et al. (författare)
  • Pain and intramuscular release of algesic substances in the masseter muscle after experimental tooth-clenching exercises in healthy subjects
  • 2013
  • Ingår i: Journal of Orofacial Pain. - : Quintessence Publishing. - 1064-6655 .- 1945-3396 .- 2333-0384. ; 27:4, s. 350-360
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS:To investigate whether experimental tooth clenching leads to a release of algesic substances in the masseter muscle.METHODS:Thirty healthy subjects (16 females, 14 males) participated. During two sessions, separated by at least 1 week, intramuscular microdialysis was performed to collect masseter muscle 5-hydroxytryptamine (5-HT) and glutamate as well as the metabolic markers pyruvate and lactate. Two hours after the start of microdialysis, participants were randomized to a 20-min repetitive experimental tooth-clenching task (50% of maximal voluntary contraction) or a control session (no clenching). Pain and fatigue were measured throughout. The Friedman and Wilcoxon tests were used for statistical analyses.RESULTS:No alterations were observed in the concentrations of 5-HT, glutamate, pyruvate, and lactate over time in the clenching or control session, or between sessions at various time points. Pain (P < .01) and fatigue (P < .01) increased significantly over time in the clenching session and were significantly higher after clenching than in the control session (P < .01).CONCLUSION:Low levels of pain and fatigue developed with this experimental tooth-clenching model, but they were not associated with an altered release of 5-HT, glutamate, lactate, or pyruvate. More research is required to elucidate the peripheral release of algesic substances in response to tooth clenching.
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36.
  • Dimitrijevic Carlsson, Alexandra, 1966-, et al. (författare)
  • Parotid saliva and blood biomarkers in juvenile idiopathic arthritis in relation to temporomandibular joint magnetic resonance imaging findings
  • 2024
  • Ingår i: Journal of Oral Rehabilitation. - : John Wiley & Sons. - 0305-182X.
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundJuvenile idiopathic arthritis (JIA) often affects the temporomandibular joint (TMJ) caused by an abnormal immune system that includes overactive inflammatory processes. Salivary biomarkers may be a powerful tool that can help establishing diagnosis, prognosis and monitor disease progress.ObjectiveThe objective was to investigate biomarkers in parotid saliva and blood plasma in relation to temporomandibular joint (TMJ) magnetic resonance imaging (MRI) findings in patients with JIA and healthy individuals.MethodsForty-five children aged 6 to 16 years with JIA and 16 healthy age- and sex-matched controls were included. Unstimulated parotid saliva samples and venous blood were collected. Biochemical analyses were performed for the cytokine biomarkers. The participants underwent MR imaging of the TMJs, where changes in the inflammatory and the damage domains were assessed.ResultsIn the JIA patients, lower concentrations of IL-6R and gp130 were found in parotid saliva than in plasma. Higher concentrations of IL-6 were found in parotid saliva than in plasma. IL-6, IL-6R and gp130 in parotid saliva explained the presence of bone marrow oedema and effusion in the JIA patients.ConclusionsThis study suggests that the IL-6 family in parotid saliva is associated with TMJ bone marrow oedema and effusion in patients with JIA, suggesting that IL-6 has promising properties as a parotid saliva biomarker for TMJ inflammatory activity. image
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37.
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38.
  • Dimitrijevic Carlsson, Alexandra, 1966- (författare)
  • The Temporomandibular Joint in Juvenile Idiopathic Arthritis : Psychosocial, clinical, imaging and parotid saliva biomarkers
  • 2024
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. The disease can affect the temporomandibular joint (TMJ) and cause orofacial growth disturbances, pain, and jaw dysfunction. TMJ arthritis is often asymptomatic and therefore a challenging joint to diagnose. Clinical assessment of the TMJ is hampered by the low sensitivity and specificity of joint pain and the absence of physical findings early in the disease process. More specific methods are therefore needed for diagnosing TMJ arthritis. Saliva and blood are promising as diagnostic fluids for various diseases. Also, adolescents with chronic pain report high rates of psychosocial stress. Psychosocial stress may also be involved in JIA as a trigger and maintaining factor of the disease. Aim: The main aim of this thesis research was to investigate the relation between clinical variables, psychosocial factors, MRI findings, and inflammatory biomarkers in saliva and blood in relation to TMJ involvement in JIA. The secondary aim was to investigate the relation between stress and change in stress over time in comparison with orofacial pain, psychosocial factors, and jaw function in JIA patients. Methods: This was a cross-sectional case-control study and a longitudinal cohort study. Forty-five patients (6-16 years old) with JIA and 16 healthy age- and sex-matched healthy individuals were examined according to the diagnostic criteria for temporomandibular disorders (DC/TMD). The study subjects completed questionnaires regarding psychosocial factors and underwent bilateral MRI of their TMJs. Unstimulated parotid saliva and venous blood samples were collected. Biochemical analyses were performed using a multiplex platform electrochemiluminescence assay from Meso Scale Discovery (MSD) for measuring cytokine concentrations in saliva and blood. A two-year prospective follow-up study was performed in 40 JIA patients from our original baseline study. The JIA patients underwent the same clinical examination and completed the same questionnaires regarding psychosocial factors as in the baseline studies. Results: The JIA patients with orofacial pain had higher degrees of stress, depression, catastrophizing, and jaw dysfunction than did those JIA patients without such pain. These factors were also associated with orofacial pain intensity. Additionally, patients with orofacial pain had higher systemic inflammatory activity. In the two-year follow-up study, we observed that change in stress was associated with changes in catastrophizing, psychological distress, as well as limitations in both general and jaw functions. Regarding TMJ MRI findings, there were no significant differences between JIA patients and healthy individuals in either the inflammatory or damage domain. Moderate/severe TMJ changes in the inflammatory and damage domains were, however, only found in the JIA patients. Among JIA patients, orofacial pain intensity was correlated to TMJ bone marrow edema, and pain in jaw muscles during jaw function was related to both TMJ bone marrow edema and erosion. JIA patients had lower concentrations of interleukin receptor 6 (IL-6R) and glycoprotein 130 (gp130) in parotid saliva than in plasma. Higher concentrations of IL-6 were found in parotid saliva than in plasma. The members of the interleukin-6 family (i.e., IL-6, IL-6R, and gp130) in parotid saliva were found to be explanatory factors for the presence of bone marrow edema and effusion in the JIA patients. Conclusions: Orofacial pain in patients with JIA is associated with stress, psychological distress, jaw dysfunction, and loss of daily living activities. Pain intensity seems to be the major aspect related to these factors. Increased disease activity with more joint involvement seems to be an important factor contributing to orofacial pain in JIA. Myalgia, in addition to arthritis, seems to be an important source of orofacial pain in these patients. Maintaining a low stress level in JIA patients seems to be crucial, as an increase in stress level over a two-year period appears to negatively impact both jaw function as well as psychosocial distress and catastrophizing. There was an overlap of TMJ MRI findings regarding signs of inflammatory and bone tissue changes between JIA patients and healthy individuals. Among, JIA patients, the presence of inflammatory MRI signs, and bone marrow edema seems to worsen orofacial pain intensity. The IL-6 family in parotid saliva is associated with TMJ bone marrow edema and effusion in patients with JIA, suggesting that IL-6 has promising properties as a parotid saliva biomarker of TMJ inflammatory activity. In addition there seems to be local production of the IL-6 family in the parotid gland in JIA patients and healthy individuals. However, parotid saliva does not seem to reflect the plasma content in terms of the investigated biomarkers in JIA.
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39.
  • Dimitrijevic Carlsson, Alexandra, 1966-, et al. (författare)
  • Unstimulated Parotid Saliva Sampling in Juvenile Idiopathic Arthritis and Healthy Controls : A Proof-of-Concept Study on Biomarkers
  • 2020
  • Ingår i: Diagnostics (Basel). - : MDPI. - 2075-4418. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • The aims of this proof-of-concept study were to develop a collecting method for unstimulated parotid saliva in juvenile idiopathic arthritis (JIA) patients and healthy children and to investigate if inflammatory biomarkers could be detected in these samples. Forty-five children with JIA (median age of 12 years and 25th-75th percentile of 10-15 years; 33 girls and 12 boys) and 16 healthy children as controls (median age of 13 years and 25-75th percentile of 10-13 years; 11 girls and 5 boys) were enrolled in this study. Unstimulated parotid saliva was collected with a modified Carlson-Crittenden collector. The salivary flow rate and salivary concentrations of total protein and inflammatory mediators were assessed. The Meso Scale Discovery electrochemiluminescence immunoassay was used for analyzing protein concentrations and the inflammatory biomarkers. Sufficient parotid saliva volumes to be analyzed could be collected with the collection device. JIA patients had a lower sampling saliva volume (p = 0.008) and saliva flow rate (p = 0.039) than controls. The total protein concentrations and inflammatory biomarkers were measured in the last six healthy subjects. The median protein concentration was 1312 mu g/mL (25th percentile: 844 mu g/mL and 75th percentile: 2062 mu g/mL; n = 6) and quantifiable concentrations of 39 inflammatory proteins could be assessed in these samples. In conclusion, this study indicates that the saliva sampling method, as used in the present study, is able to collect sufficient sample volumes in children, and that it is possible to analyze various inflammatory biomarkers in the collected saliva.
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40.
  • Djerf Svenningsson, Emelie, et al. (författare)
  • Resistance to gefitinib in malignant melanoma cells is related to increased expression of Met and the insulin receptor and sustained Akt signaling
  • 2012
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Acquired resistance to cancer therapy, including targeted therapies such as epidermal growth factor receptor (ErbB) tyrosine kinase inhibitors (TKIs), constitutes a major clinical problem in treating patients with malignant disease. Several drug resistance mechanisms for ErbB1 TKIs involving abnormal activation of growth factor receptors or activation of intracellular signaling pathways have been discovered. ErbB TKIs have recently been shown to inhibit growth in melanoma cells. This study was undertaken to develop a gefitinib-resistant melanoma cell line in order to find any resistance mechanism to gefitinib in melanoma cells lacking activating mutation in BRAF or NRAS.Material and methods: A malignant melanoma cell line (RaH5) was made resistant to the ErbB1 TKI gefitinib by continuous culture with stepwise increasing concentrations of the drug up to 10 μM. The phosphorylation status of 42 different human receptor tyrosine kinases was screened in a protein array in resistant (RaH5ZDR) and wild-type RaH5 cells treated with or without gefitinib. The PI3K, MAPK and Stat3 signaling pathways were studied in an analogous way by Western blot analysis; 2-D gel electrophoresis was performed to determine other potential proteins involved in gefitinib resistance in RaH5 cells. In addition, the effect of the pan-ErbB TKI canertinib on gefitinib-resistant cells was investigated.Results: Protein array experiments showed that only Met and the insulin receptor (IR) exhibited substantially increased activation in RaH5ZDR cells as compared to their nonresistant counterparts. Interestingly, following gefitinib treatment ErbB2 and ErbB3 receptor signaling in resistant cells were equally well suppressed as in non-resistant cells. However, downstream Akt and Erk1/2 phosphorylation was inhibited to a greater extent in non-resistant RaH5 cells.Conclusion: Resistance to gefitinib in RaH5 cells appears to be related to an increased expression of Met and IR and linked to a more persistent signaling through Akt and Erk1/2. However, additional studies are required to further elucidate the resistance to gefitinib in our experimental system.
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41.
  • Dong, Huan-Ji, et al. (författare)
  • Eating habits and the desire to eat healthier among patients with chronic pain: a registry-based study
  • 2024
  • Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Healthcare professionals often meet pain patients with a poor nutritional status such as obesity, unhealthy dietary behaviors, and a suboptimal dietary intake. A poor nutritional status may play a significant role in the occurrence, development, and prognosis of chronic pain. This study investigated eating habits in a specialized pain rehabilitation center using data (N = 2152) from the Swedish quality registry for pain rehabilitation during the period 2016-2021. Patients answered a lifestyle questionnaire regarding their eating habits and desire to modify their lifestyle. The mean (SD) patient age was 46.1 (14.6) years, with 24.8% classified as obese. Suboptimal eating habits included irregular mealtimes (27.2%), weekly consumption of fast-food (20.3%) and nearly daily consumption of confectionery (33.3%). Approximately 20% (n = 426) reported a desire to eat healthier. Frequent confectionery intake (Odds ratio [OR] 1.23, 95% Confidence Interval (CI) 1.04-1.47) and fast-food consumption (OR 1.58, 95% CI 1.24-2.02) increased the likelihood to desire healthier eating. Younger patients (18-29 years), those classified as obese, and those with more extended spatial pain were more likely to express a desire to eat healthier. Eating habits should be addressed in pain management and interdisciplinary pain rehabilitation teams are encouraged to provide nutritional care tailored to the patient's needs.
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42.
  • Ernberg, Malin, et al. (författare)
  • Altered Plasma Proteins in Myogenous Temporomandibular Disorders
  • 2022
  • Ingår i: Journal of Clinical Medicine. - Basel, Switzerland : MDPI. - 2077-0383. ; 11:10
  • Tidskriftsartikel (refereegranskat)abstract
    • The aims of this study were (1) to compare the levels and interactions of several plasma proteins in patients with myogenous temporomandibular disorders (TMDM) compared to healthy and pain-free controls, (2) to compare the levels and interactions in two TMDM subgroups, myalgia (MYA) and myofascial pain (MFP), and (3) to explore associations between the proteins and clinical data. Thirty-nine patients with TMDM (MFP, n = 25, MYA, n = 14), diagnosed according to the diagnostic criteria for TMD (DC/TMD), aged 38 years, and sex-matched pain-free controls completed an extended DC/TMD Axis II questionnaire and the plasma concentration of 87 biomarkers were analyzed. Nine proteins separated TMDM from controls (p = 0.0174) and 12 proteins separated MYA from MFP (p = 0.019). Pain duration, characteristic pain intensity, pain catastrophizing, perceived stress, and insomnia severity were significantly associated with protein markers (p < 0.001 to p < 0.022). In conclusion, several plasma proteins were upregulated in TMDM and either upregulated or downregulated in MYA compared to MFP. Some proteins in TMDM were associated with pain variables, sleep disturbance, and emotional function. These results show that systemic differences in protein expression exist in patients with TMDM and that altered levels of specific plasma proteins are associated with different clinical variables.
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43.
  • Ernberg, M., et al. (författare)
  • Effects of 15 weeks of resistance exercise on pro-inflammatory cytokine levels in the vastus lateralis muscle of patients with fibromyalgia
  • 2016
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: This study aimed at investigating the effect of a resistance exercise intervention on the interstitial muscle levels of pro-inflammatory cytokines in fibromyalgia (FMS) and healthy controls (CON). Methods: Twenty-four female patients with FMS (54 +/- 8 years) and 27 female CON (54 +/- 9 years) were subjected to intramuscular microdialysis of the most painful vastus lateralis muscle before and after 15 weeks of progressive resistance exercise twice per week. Baseline dialysates were sampled in the resting muscle 140 min after insertion of the microdialysis catheter. The participants then performed repetitive dynamic contractions (knee extension) for 20 min, followed by 60 min rest. Pain intensity was assessed with a 0-100 mm visual analogue scale (VAS), and fatigue was assessed with Borg's RPE throughout microdialysis. Dialysates were sampled every 20 min and analyzed with Luminex for interleukin (IL)-1 beta, tumor necrosis factor (TNF) alpha, IL-6, and IL-8. Results: At both sessions and for both groups the dynamic contractions increased pain (P < 0.012) and fatigue (P < 0.001). The levels of TNF were lower in the FMS group than the CON group at both sessions (P < 0.05), but none of the other cytokines differed between the groups. IL-6 and IL-8 increased after the dynamic contractions in both groups (P < 0.010), while TNF increased only in CON (P < 0.05) and IL-1 beta did not change. Overall pain intensity was reduced after the 15 weeks of resistance exercise in FMS (P < 0.05), but there was no changes in fatigue or cytokine levels. Conclusion: Progressive resistance exercise for 15 weeks did not affect the interstitial levels of IL-1 beta, TNF, IL-6, and IL-8 in the vastus lateralis muscle of FMS patients or CON.
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44.
  • Ernberg, M., et al. (författare)
  • Experimental myalgia induced by repeated infusion of acidicsaline into the human masseter muscle does not cause the release of algesic substances
  • 2013
  • Ingår i: European Journal of Pain. - : John Wiley & Sons. - 1090-3801 .- 1532-2149. ; 17:4, s. 539-550
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:Animal studies have shown that two repeated intramuscular injections of acidic saline induce mechanical allodynia that lasts for 4 weeks with spread to the contralateral side. In this study, we tested the hypothesis that two repeated intramuscular infusions of acidic saline into the human masseter muscle is associated with pain, mechanical allodynia and release of algesic substances. Eighteen healthy volunteers participated. On day 1, 2.5 mL of acidic saline (pH 3.3) was infused into one of the masseter muscles and isotonic saline (pH 6.0) into the other (randomized and single-blind). Two days later, intramuscular microdialysis was performed to sample serotonin, glutamate, pyruvate, lactate and glucose, during which the saline infusions were repeated. Pain and pressure pain thresholds (PPTs) were recorded before and after infusions on both days.RESULTS:Pain intensity induced by the infusions was higher after acidic than that after isotonic saline (p < 0.05). PPTs were decreased on both sides after microdialysis compared with baseline day 1 (p's < 0.05), but there were no differences in PPTs between sides at any time point. The levels of serotonin, glutamate, pyruvate, lactate or glucose did not change significantly during microdialysis.CONCLUSION:Infusion of acidic saline caused low levels of muscle pain, but no mechanical allodynia and no increased release of algesic substances. The value of this model appears modest, but future studies could be performed with larger sample size and higher flow rate before definite conclusions about the validity of the model for craniofacial myalgia can be drawn.
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45.
  • Ernberg, M, et al. (författare)
  • Plasma Cytokine Levels in Fibromyalgia and Their Response to 15 Weeks of Progressive Resistance Exercise or Relaxation Therapy.
  • 2018
  • Ingår i: Mediators of inflammation. - : Hindawi Limited. - 1466-1861 .- 0962-9351. ; 2018
  • Tidskriftsartikel (refereegranskat)abstract
    • The aims of this study were to compare circulating cytokines between FM and healthy controls and to investigate the effect on cytokine levels by 15 weeks of progressive resistance exercise or relaxation therapy in FM. Baseline plasma cytokine levels and clinical data were analyzed in 125 women with FM and 130 age-matched healthy women. The FM women were then randomized to progressive resistance exercise (n = 49) or relaxation (n = 43). Baseline IL-2, IL-6, TNF-α, IP-10, and eotaxin were higher in FM than in healthy controls (P < 0.041), whereas IL-1β was lower (P < 0.001). There were weak correlations between cytokine levels and clinical variables. After both interventions, IL-1ra had increased (P = 0.004), while IL-1β had increased in the relaxation group (P = 0.002). Changes of IFN-γ, IL-2, IL-4, IL-6, IL-8, and IL-17A were weakly correlated with changes of PPT, but there were no significant correlations between changes of cytokine and changes in other clinical variables. The elevated plasma levels of several cytokines supports the hypothesis that chronic systemic inflammation may underlie the pathophysiology of FM even if the relation to clinical variables was weak. However, 15 weeks of resistance exercise, as performed in this study, did not show any anti-inflammatory effect on neither FM symptoms nor clinical and functional variables. This trial is registered with ClinicalTrials.gov NCT01226784, registered October 21, 2010. The first patient was recruited October 28, 2010.
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46.
  • Farnebo, Simon, et al. (författare)
  • Differentially Expressed Proteins in Intra Synovial Compared to Extra Synovial Flexor Tendon Grafts in a Rabbit Tendon Transplantation Model
  • 2020
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 8:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Uncomplicated healing of grafts for tendon reconstruction remains an unsolved problem in hand surgery. Results are limited by adhesion formation and decreased strength properties, especially within the tight fibro-osseous sheath of the digits. This is especially problematic when an extra synovial tendon graft is used to replace an intra synovial flexor tendon. Compositional differences are likely to play an important role in these processes. The aim of this study was, therefore, to compare protein expression in pair-matched intra synovial tendon grafts with extra synovial tendon grafts, using a rabbit tendon injury model. We hypothesized that there would be significant differences in proteins critical for response to tensile loading and adhesion formation between the two groups. Using mass spectrometry and multivariate statistical data analysis, we found tissue-specific differences in 22 proteins, where 7 explained 93% (R2) of the variation, with a prediction of 81% (Q2). Among the highest discriminating proteins were Galectin, Histone H2A, and Periostin, which were found in a substantially larger amount in the extra synovial tendons compared to the intra synovial tendons. These findings may contribute to improved understanding of the differences in outcome seen after tendon reconstruction using tendon grafts with intra synovial and extra synovial grafts.
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47.
  • Fornander, Louise, et al. (författare)
  • Airway irritation among indoor swimming pool personnel : trichloramine exposure, exhaled NO and protein profiling of nasal lavage fluids
  • 2013
  • Ingår i: International Archives of Occupational and Environmental Health. - : Springer. - 0340-0131 .- 1432-1246. ; 86:5, s. 571-580
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeOccurrence of airway irritation among indoor swimming pool personnel was investigated. The aims of this study were to assess trichloramine exposure levels and exhaled nitric oxide in relation to the prevalence of airway symptoms in swimming pool facilities and to determine protein effects in the upper respiratory tract.MethodsThe presence of airway symptoms related to work was examined in 146 individuals working at 46 indoor swimming pool facilities. Levels of trichloramine, as well as exhaled nitric oxide, were measured in five facilities with high prevalence of airway irritation and four facilities with no airway irritation among the personnel. Nasal lavage fluid was collected, and protein profiles were determined by a proteomic approach.Results17 % of the swimming pool personnel reported airway symptoms related to work. The levels of trichloramine in the swimming pool facilities ranged from 0.04 to 0.36 mg/m3. There was no covariance between trichloramine levels, exhaled nitric oxide and prevalence of airway symptoms. Protein profiling of the nasal lavage fluid showed that the levels alpha-1-antitrypsin and lactoferrin were significantly higher, and S100-A8 was significantly lower in swimming pool personnel.ConclusionsThis study confirms the occurrence of airway irritation among indoor swimming pool personnel. Our results indicate altered levels of innate immunity proteins in the upper airways that may pose as potential biomarkers. However, swimming pool facilities with high prevalence of airway irritation could not be explained by higher trichloramine exposure levels. Further studies are needed to clarify the environmental factors in indoor swimming pools that cause airway problems and affect the immune system.
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48.
  • Fornander, Louise, et al. (författare)
  • Airway symptoms and biological markers in nasal lavage fluid in subjects exposed to metalworking fluids
  • 2013
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12, s. e83089-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUNDS: Occurrence of airway irritation among industrial metal workers was investigated. The aims were to study the association between exposures from water-based metal working fluids (MWF) and the health outcome among the personnel, to assess potential effects on the proteome in nasal mucous membranes, and evaluate preventive actions.METHODS: The prevalence of airway symptoms related to work were examined among 271 metalworkers exposed to MWF and 24 metal workers not exposed to MWF at the same factory. At the same time, air levels of potentially harmful substances (oil mist, morpholine, monoethanolamine, formaldehyde) generated from MWF was measured. Nasal lavage fluid was collected from 13 workers and 15 controls and protein profiles were determined by a proteomic approach.RESULTS: Airway symptoms were reported in 39% of the workers exposed to MWF although the measured levels of MWF substances in the work place air were low. Highest prevalence was found among workers handling the MWF machines but also those working in the same hall were affected. Improvement of the ventilation to reduce MWF exposure lowered the prevalence of airway problems. Protein profiling showed significantly higher levels of S100-A9 and lower levels of SPLUNC1, cystatin SN, Ig J and β2-microglobulin among workers with airway symptoms.CONCLUSIONS: This study confirms that upper airway symptoms among metal workers are a common problem and despite low levels of MWF-generated substances, effects on airway immune proteins are found. Further studies to clarify the role of specific MWF components in connection to airway inflammation and the identified biological markers are warranted.
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49.
  • Fornander, Louise, et al. (författare)
  • Innate immunity proteins and a new truncated form of SPLUNC1 in nasopharyngeal aspirates from infants with respiratory syncytial virus infection
  • 2011
  • Ingår i: PROTEOMICS CLINICAL APPLICATIONS. - : Wiley-VCH Verlag Berlin. - 1862-8346. ; 5:9-10, s. 513-522
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Respiratory syncytial virus (RSV) is the most common cause of severe respiratory tract infection in infants. The aim was to identify host defence components in nasopharyngeal aspirate (NPA) from infants with RSV infection and to study the expression of the novel 25 kDa innate immunity protein SPLUNC1. less thanbrgreater than less thanbrgreater thanExperimental design: NPAs from infants were analyzed with 2-DE and MS in a pilot study. The levels of SPLUNC1 were analyzed with immunoblotting in 47 NPAs, admitted for RSV diagnosis. less thanbrgreater than less thanbrgreater thanResults: Totally, 35 proteins were identified in NPA, including several innate immunity proteins such as group X phospholipase A(2), different S100 proteins and SPLUNC1. In addition, a new truncated 15 kDa form of SPLUNC1 was identified that was detected in about 50% of the aspirates admitted for RSV diagnosis. RSV-positive boys had significantly less 25 kDa SPLUNC1 than RSV-negative boys while there were no significant differences among girls. less thanbrgreater than less thanbrgreater thanConclusions and clinical relevance: Several important innate immunity proteins were identified in NPA. Notably, a new truncated form of the newly suggested anti-bacterial protein SPLUNC1 was found. It is possible that a decrease in SPLUNC1 in the upper airways may increase the risk for severe pneumonia in boys.
  •  
50.
  • Fornander, Louise, 1983- (författare)
  • Upper Airway Mucosal Inflammation : Proteomic Studies after Exposure to Irritants and Microbial Agents
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • People are, in their daily lives, exposed to a number of airborne foreign compounds that do not normally affect the body. However, depending on the nature of these compounds, dose and duration of exposure, various airway symptoms may arise. Early symptoms are often manifested as upper airway mucosal inflammation which generates changes in protein composition in the airway lining fluid.This thesis aims at identifying, understanding mechanisms and characterizing protein alterations in the upper airway mucosa that can be used as potential new biomarkers for inflammation in the mucosa. The protein composition in the mucosa was studied by sampling of nasal lavage fluid that was further analyzed with a proteomic approach using twodimensional gel electrophoresis and mass spectrometry. Additionally, by studying factors on site through environmental examination, health questionnaires and biological analyses, we have tried to understand the background to these protein alterations and their impact on health.Respiratory symptoms from the upper airways are common among people who are exposed to irritative and microbial agents. This thesis have focused on personnel in swimming pool facilities exposed to trichloramine, metal industry workers exposed to metalworking fluids, employees working in damp and moldy buildings and infants diagnosed with respiratory syncytial virus infection. The common denominator in these four studies is that the subjects experience upper airway mucosal inflammation, which is manifested as cough, rhinitis, phlegm etc. In the three occupational studies, the symptoms were work related. Notably, a high prevalence of perceived mucosal symptoms was shown despite the relatively low levels of airborne irritants revealed by the environmental examination. Protein profiling verified an ongoing inflammatory response by identification of several proteins that displayed altered levels. Interestingly, innate immune proteins dominated and four protein alterations occurred in most of the studies; SPLUNC1, protein S100A8 and S100A9 and alpha-1-antitrypsin. Similarly, these proteins were also found in nasal fluid from children with virus infection and in addition a truncated form of SPLUNC1 and two other S100 proteins (S100A7-like 2 and S100A16), not previously found in nasal secretion, were identified.Altogether, the results indicate the potential use of a proteomic approach for identifying new biomarkers for the upper respiratory tract at an early stage in the disease process after exposure to irritant and microbial agents. The results indicate an effect on the innate immunity system and the proteins; SPLUNC1, protein S100A8 and S100A9 and alpha-1-antitrypsin are especially promising new biomarkers. Moreover, further studies of these proteins may help us to understand the molecular mechanisms involved in irritant-induced airway inflammation.
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