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1.
Med Sci Sports Exerc ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32168104

RESUMO

PURPOSE: Physical exercise is increasingly being promoted by healthcare for chronic pain conditions with beneficial outcomes such as: pain and fatigue reduction, and increased quality of life. Nevertheless, knowledge about biochemical consequences of physical exercise in chronic pain is still relatively poor.The endocannabinoid system has been suggested to play a role for acute exercise-induced reward and pain inhibition. The aim of this study is to investigate the chronic outcomes of resistance exercise on levels of endocannabinoids and related lipids in fibromyalgia (FM). METHODS: This study examine the outcomes of a 15-week person-centered resistance exercise program on plasma levels of the lipid mediators; anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) sampled from 37 women with FM and 33 healthy controls. The associations between clinical scorings of pain, depression, anxiety, fatigue, and muscle strength with levels of these lipid mediators before and after the exercise program are also analysed. RESULTS: After the 15 weeks exercise program anandamide levels were significantly increased and SEA levels significantly decreased in FM. Pain intensity and depression scorings decreased and muscle strength increased, and in a multivariate context muscle strength was positively associated with 2-AG levels after the resistance exercise program in FM. CONCLUSIONS: The increased anandamide and decreased SEA in women with fibromyalgia after the 15 weeks program might point to a chronic effect of resistance exercise. Pain and depression scorings decreased in the fibromyalgia group after the program but no associations between pain, depression and lipid level changes were assured.

2.
Neuromodulation ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31755628

RESUMO

OBJECTIVE: Electrical neuromodulation by deep brain stimulation (DBS) is a well-established method for treatment of severe essential tremor (ET). The mechanism behind the tremor relieving effect remains largely unknown. Our aim of this study was to evaluate alterations in proteomics pre- and post-DBS in patients diagnosed with severe ET. MATERIALS AND METHODS: Ten right-handed ET patients were included in this study. Cerebrospinal fluid (CSF) was obtained by lumbar puncture preoperatively (N = 10) and six months postoperatively (N = 7). The samples were analyzed by high sensitive liquid chromatography tandem mass spectrometry. RESULTS: Twenty-two proteins were statistically significantly altered in the CSF of ET patients before and after DBS treatment. Downregulated proteins were involved in regulatory processes of protein activation, complement activation, humoral immune response as well as acute inflammatory response. The upregulated proteins were involved in pathways for cell secretion, adhesion as well as response to axon injury. CONCLUSIONS: DBS in ET patients effects the neurochemical environment in the CSF. These findings further elucidate the mechanisms of DBS and may lead to new biomarkers for evaluating the effect of DBS treatment.

3.
J Pain Res ; 12: 2875-2889, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686904

RESUMO

Objective: Neuropathic pain and fibromyalgia are two common and poorly understood chronic pain conditions that lack satisfactory treatments, cause substantial suffering and societal costs. Today, there are no biological markers on which to base chronic pain diagnoses, treatment choices or to understand the pathophysiology of pain for the individual patient. This study aimed to investigate cerebrospinal fluid (CSF) protein profiles potentially associated with fibromyalgia and neuropathic pain. Methods: CSF samples were collected from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery, and n=11 for verification), 40 patients with fibromyalgia and 134 controls without neurological disease from two different populations. CSF protein profiling of 55 proteins was performed using antibody suspension bead array technology. Results: We found increased levels of apolipoprotein C1 (APOC1) in CSF of neuropathic pain patients compared to controls and there was a trend for increased levels also in fibromyalgia patients. In addition, levels of ectonucleotide pyrophosphatase family member 2 (ENPP2, also referred to as autotaxin) were increased in the CSF of fibromyalgia patients compared to all other groups including patients with neuropathic pain. Conclusion: The increased levels of APOC1 and ENPP2 found in neuropathic pain and fibromyalgia patients may shed light on the underlying mechanisms of these conditions. Further investigation is required to elucidate their role in maintaining pain and other main symptoms of these disorders.

4.
Scand J Pain ; 20(1): 125-138, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31584875

RESUMO

It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.

5.
J Rehabil Med ; 51(10): 779-787, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31544950

RESUMO

BACKGROUND: The pathophysiology of fibromyalgia includes central and peripheral factors. Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, are involved in peripheral and central nervous system development of pain and hyperalgesia. Few studies have examined circulating nerve growth factor and brain-derived neurotrophic factor in fibromyalgia or have investigated whether exercise interventions affect the levels of these peptides. OBJECTIVES: To compare plasma levels of nerve growth factor and brain-derived neurotrophic factor in fibromy-algia and in healthy controls, to investigate correlations between levels of nerve growth factor, brain-derived neurotrophic factor, and cytokines and clinical variables, and to investigate the effect of exercise on these levels. SUBJECTS AND METHODS: A total of 75 women with fibromyalgia participated in blood tests at baseline and after the 15-week intervention, and 25 healthy controls participated at baseline. Patients were randomized to a 15-week progressive resistance exercise intervention or a relaxation intervention. RESULTS: Brain-derived neurotrophic factor level was significantly higher (p < 0.001) and nerve growth factor level was significantly lower (p < 0.001) in fibromyalgia than in healthy controls. Neither resistance exercise nor relaxation interventions affected the levels of brain-derived neurotrophic factor or nerve growth factor. No significant correlations were found between brain-derived neurotrophic factor or nerve growth factor plasma levels in fibromyalgia and cytokine levels or clinical variables. CONCLUSION: Changes in circulating nerve growth factor and brain-derived neurotrophic factor levels may affect nociception/pain in fibromyalgia. Clinical improvements were achieved following the exercise intervention, but the levels of brain-derived neurotrophic factor and nerve growth factor were not normalized.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Fibromialgia , Fator de Crescimento Neural/sangue , Treinamento de Resistência , Feminino , Fibromialgia/sangue , Fibromialgia/terapia , Humanos
6.
Plast Reconstr Surg Glob Open ; 7(5): e2221, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31333952

RESUMO

Background: Hyaluronic acid (HA), a large glycosaminoglycan involved in proliferation, migration, and tissue repair, is suggested to be an important factor for keratinocyte activation and re-epithelialization. The experimental hypothesis of this study was that HA accelerates re-epithelialization, and we aimed to investigate the effect of exogenous intradermal HA during deep dermal, incisional wound healing in vivo in humans, the primary endpoint being re-epithelialization. Methods: A total of 8 standardized deep dermal incisional wounds (depth 1.6 mm, width 1.8 mm) per subject were induced in 10 healthy volunteers. Two of the wound sites per subject were pretreated with injections of HA and 2 with saline solution. At 2 time points (24 hours and 14 days), 2 biopsies for each treatment group (one for histology and one for proteomics) were taken. Skin erythema was measured at 24-hour intervals for 14 days as a surrogate measurement of inflammation. Results: At 24 hours, 8 of 9 wounds pretreated with HA showed complete re-epithelization, whereas none of the wounds pretreated with saline had re-epithelized. Wounds pretreated with HA also showed a 10-fold regulation of 8 identified proteins involved in wound healing compared to wounds treated with saline solution. No difference in inflammation, as measured as erythema, could be seen between any of the groups. Conclusions: We conclude that HA accelerates re-epithelialization and stimulates an altered protein expression in vivo in human deep dermal incisional skin wounds, but has no effect on the inflammation process as measured by erythema.

7.
Sci Rep ; 9(1): 3181, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816204

RESUMO

The secondary injury cascades exacerbating the initial brain injury following intracerebral haemorrhage (ICH) are incompletely understood. We used dual microdialysis (MD) catheters placed in the perihaemorrhagic zone (PHZ) and in seemingly normal cortex (SNX) at time of surgical ICH evacuation in ten patients (range 26-70 years). Routine interstitial MD markers (including glucose and the lactate/pyruvate ratio) were analysed and remaining microdialysate was analysed by two-dimensional gel electrophoresis (2-DE) and nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS). Two time intervals were analysed; median 2-10 hours post-surgery (time A) and median 68-76 hours post-ICH onset (time B). Using 2-DE, we quantified 232 ± 31 different protein spots. Two proteins differed between the MD catheters at time A, and 12 proteins at time B (p < 0.05). Thirteen proteins were significantly altered between time A and time B in the SNX and seven proteins in the PHZ, respectively. Using nLC-MS/MS ca 800 proteins were identified out of which 76 were present in all samples. At time A one protein was upregulated and two downregulated, and at time B, seven proteins were upregulated, and four downregulated in the PHZ compared to the SNX. Microdialysis-based proteomics is feasible for study of secondary injury mechanisms and discovery of biomarkers after ICH.

8.
Biosci Rep ; 39(3)2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30842338

RESUMO

There is a strong association between periodontal disease and atherosclerotic cardiovascular disorders. A key event in the development of atherosclerosis is accumulation of modified lipoproteins within the arterial wall. We hypothesise that patients with periodontitis have an altered lipoprotein profile towards an atherogenic form. Therefore, the present study aims at identifying modifications of plasma lipoproteins in periodontitis. Lipoproteins from ten female patients with periodontitis and gender- and age-matched healthy controls were isolated by density-gradient ultracentrifugation. Proteins were separated by 2D gel-electrophoresis and identified by map-matching or by nano-LC followed by MS. Apolipoprotein (Apo) A-I (ApoA-I) methionine oxidation, Oxyblot, total antioxidant capacity and a multiplex of 71 inflammation-related plasma proteins were assessed. Reduced levels of apoJ, phospholipid transfer protein, apoF, complement C3, paraoxonase 3 and increased levels of α-1-antichymotrypsin, apoA-II, apoC-III were found in high-density lipoprotein (HDL) from the patients. In low-density lipoprotein (LDL)/very LDL (VLDL), the levels of apoL-1 and platelet-activating factor acetylhydrolase (PAF-AH) as well as apo-B fragments were increased. Methionine oxidation of apoA-I was increased in HDL and showed a relationship with periodontal parameters. α-1 antitrypsin and α-2-HS glycoprotein were oxidised in LDL/VLDL and antioxidant capacity was increased in the patient group. A total of 17 inflammation-related proteins were important for group separation with the highest discriminating proteins identified as IL-21, Fractalkine, IL-17F, IL-7, IL-1RA and IL-2. Patients with periodontitis have an altered plasma lipoprotein profile, defined by altered protein levels as well as post-translational and other structural modifications towards an atherogenic form, which supports a role of modified plasma lipoproteins as central in the link between periodontal and cardiovascular disease (CVD).


Assuntos
Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Lipoproteínas/sangue , Periodontite/sangue , Apolipoproteína A-I , Apolipoproteínas B/sangue , Citocinas/sangue , Eletroforese em Gel Bidimensional , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Espectrometria de Massas/métodos , Pessoa de Meia-Idade
9.
BMC Musculoskelet Disord ; 20(1): 51, 2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30711003

RESUMO

BACKGROUND: There is insufficient knowledge of pathophysiological parameters to understand the mechanism behind prolonged whiplash associated disorders (WAD), and it is not known whether or not changes can be restored by rehabilitation. The aims of the projects are to investigate imaging and molecular biomarkers, cervical kinaesthesia, postural sway and the association with pain, disability and other outcomes in individuals with longstanding WAD, before and after a neck-specific exercise intervention. Another aim is to compare individuals with WAD with healthy controls. METHODS: Participants are a sub-group (n = 30) of individuals recruited from an ongoing randomized controlled study (RCT). Measurements in this experimental prospective study will be carried out at baseline (before intervention) and at a three month follow-up (end of physiotherapy intervention), and will include muscle structure and inflammation using magnetic resonance imaging (MRI), brain structure and function related to pain using functional MRI (fMRI), muscle function using ultrasonography, biomarkers using samples of blood and saliva, cervical kinaesthesia using the "butterfly test" and static balance test using an iPhone app. Association with other measures (self-reported and clinical measures) obtained in the RCT (e.g. background data, pain, disability, satisfaction with care, work ability, quality of life) may be investigated. Healthy volunteers matched for age and gender will be recruited as controls (n = 30). DISCUSSION: The study results may contribute to the development of improved diagnostics and improved rehabilitation methods for WAD. TRIAL REGISTRATION: Clinicaltrial.gov Protocol ID: NCT03664934, initial release 09/11/2018.


Assuntos
Vértebras Cervicais/fisiopatologia , Cinestesia , Músculos do Pescoço/fisiopatologia , Equilíbrio Postural , Projetos de Pesquisa , Traumatismos em Chicotada/fisiopatologia , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Vértebras Cervicais/diagnóstico por imagem , Avaliação da Deficiência , Terapia por Exercício , Humanos , Imagem por Ressonância Magnética , Estudos Multicêntricos como Assunto , Músculos do Pescoço/diagnóstico por imagem , Medição da Dor , Estudos Prospectivos , Recuperação de Função Fisiológica , Saliva/metabolismo , Suécia , Resultado do Tratamento , Ultrassonografia , Traumatismos em Chicotada/sangue , Traumatismos em Chicotada/diagnóstico , Traumatismos em Chicotada/reabilitação
10.
Diagnostics (Basel) ; 9(1)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678220

RESUMO

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.

11.
Front Psychol ; 9: 2400, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555396

RESUMO

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.

12.
BMC Neurol ; 18(1): 116, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115020

RESUMO

BACKGROUND: Post-translational modifications (PTMs) generate a tremendous protein diversity from the ~ 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.


Assuntos
Angiotensinogênio/líquido cefalorraquidiano , Proteínas do Olho/líquido cefalorraquidiano , Haptoglobinas/líquido cefalorraquidiano , Fatores de Crescimento Neural/líquido cefalorraquidiano , Neuralgia/líquido cefalorraquidiano , Serpinas/líquido cefalorraquidiano , alfa 1-Antitripsina/líquido cefalorraquidiano , Adulto , Idoso , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Feminino , Glicosilação , Humanos , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/líquido cefalorraquidiano
13.
Heliyon ; 4(8): e00718, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30116793

RESUMO

Objective: The pathophysiology of chronic pain is complex, with most of our knowledge being derived from preclinical studies. The search for biomarkers mirroring the pathophysiology of chronic pain is ongoing, and there is an increasing interest in saliva as a diagnostic tool. Given what is known about salivary substance P and salivary gland innervation, we hypothesized that salivary substance P and/or beta-endorphin might reflect the basal activity of these neuropeptides in the central nervous system, thereby perhaps mirroring a general propensity to chronic pain. Based on this overall hypothesis, our aim was to compare salivary levels of these neuropeptides in chronic neuropathic pain patients with healthy controls. An additional aim was to relate salivary levels to plasma levels. Materials and methods: We compared salivary concentrations of beta-endorphin and substance P in 14 chronic neuropathic pain patients with concentrations in 18 healthy controls using a Luminex technology kit. Salivary-to-plasma quotients were also calculated. Results: We found no significant difference between the groups' salivary concentrations of substance P and beta-endorphin. No correlation was found between salivary and plasma concentrations of each neuropeptide, which we hypothesize might point to local production of beta-endorphin and/or substance P in the salivary glands. Given high substance P salivary-to-plasma quotients, such a local production seems more likely for substance P than for beta-endorphin. Conclusions: Propensity to neuropathic chronic pain was not substantiated by our analysis of salivary levels of substance P and/or beta-endorphin. However, we report salivary-to-plasma quotients that give potentially important physiological insight about these neuropeptides.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30118859

RESUMO

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 naïve 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.


Assuntos
Doenças Desmielinizantes/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Oxilipinas/líquido cefalorraquidiano , Adulto , Biomarcadores/líquido cefalorraquidiano , Cromatografia Líquida , Doenças Desmielinizantes/diagnóstico , Feminino , Humanos , Ácidos Linoleicos/líquido cefalorraquidiano , Ácidos Linoleicos Conjugados/líquido cefalorraquidiano , Estudos Longitudinais , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Estudos Prospectivos , Espectrometria de Massas em Tandem , Adulto Jovem
15.
Mol Psychiatry ; 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120421

RESUMO

Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

16.
J Pain ; 19(11): 1318-1328, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29885369

RESUMO

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.

17.
Sci Rep ; 8(1): 3034, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29445230

RESUMO

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.


Assuntos
Dor Musculoesquelética/fisiopatologia , Limiar da Dor/fisiologia , Músculos Superficiais do Dorso/patologia , Adulto , Biomarcadores/sangue , Velocidade do Fluxo Sanguíneo , Estudos Transversais , Líquido Extracelular/metabolismo , Feminino , Glucose/análise , Ácido Glutâmico/análise , Glicerol/análise , Humanos , Ácido Láctico/análise , Masculino , Microdiálise/métodos , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Dor Musculoesquelética/metabolismo , Medição da Dor , Pressão , Ácido Pirúvico/análise , Músculos Superficiais do Dorso/metabolismo
18.
Sci Rep ; 8(1): 3220, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29459715

RESUMO

Saliva is often neglected as a body fluid of diagnostic or prognostic value, even though generally well accepted by the patients. This is due to lack of a standardized collection procedure. The aim of this study was to identify the ideal saliva collection technique and develop new sensitive methods to detect and analyse markers related to pain in healthy pain-free subjects. Plasma and five different saliva collection approached was evaluated during strictly controlled conditions. Levels of nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and brain derived neurotropic factor (BDNF) were determined using novel western blotting based technology. Glutamate and substance P (SP) was determined using commercial available methods. Several new isoforms were found for NGF, CGRP and BDNF in saliva. The isoform pattern showed significant variation in both expression and chemiluminescence levels between different collection methods. New sensitive methods to study pain related markers in saliva were developed in this study. Furthermore, we are first to demonstrate a correlation between the Glutamate concentration in stimulated whole saliva and blood. However, the fundamental conclusion drawn is the importance of consistency in the collection method.


Assuntos
Biomarcadores/análise , Dor , Saliva/química , Adulto , Western Blotting , Fator Neurotrófico Derivado do Encéfalo/análise , Peptídeo Relacionado com Gene de Calcitonina/análise , Feminino , Expressão Gênica , Ácido Glutâmico/análise , Voluntários Saudáveis , Humanos , Luminescência , Masculino , Fator de Crescimento Neural/análise , Plasma/química , Manejo de Espécimes/métodos , Substância P/análise , Adulto Jovem
20.
Lipids Health Dis ; 16(1): 112, 2017 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-28606089

RESUMO

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-α, IL-1ß, 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.


Assuntos
Dor Crônica/sangue , Endocanabinoides/sangue , Etanolaminas/sangue , Fibromialgia/sangue , Ácidos Oleicos/sangue , Ácidos Palmíticos/sangue , Ácidos Esteáricos/sangue , Adulto , Idoso , Anti-Inflamatórios/sangue , Dor Crônica/patologia , Citocinas/sangue , Citocinas/genética , Endocanabinoides/genética , Feminino , Fibromialgia/genética , Estudos de Associação Genética , Humanos , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Lipídeos/sangue , Lipídeos/genética , Pessoa de Meia-Idade , Ácidos Oleicos/genética
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