Publications by authors named "Måns Thulin"

20 Publications

  • Page 1 of 1

Increased Plasma GDF15 Is Associated with Altered Levels of Soluble VEGF Receptors 1 and 2 in Symptomatic Multiple Myeloma.

Acta Haematol 2021 Nov 24:1-8. Epub 2021 Nov 24.

Department of Medical Science, Uppsala University, Uppsala, Sweden.

Introduction: In multiple myeloma, there is an increase in bone marrow microvascular density and enhanced renal lymphangiogenesis. Increased levels of the proangiogenic protein growth differentiation factor-15 (GDF15) have previously been reported to be associated with poor prognosis in myeloma. A possible association between GDF15 and the soluble forms of vascular endothelial growth factor receptors (sVEGFR) 1 and 2 has not yet been investigated, and a role for these receptors in pathological angiogenesis in myeloma is still to be defined.

Methods: Plasma levels of GDF15 and sVEGFR1 and 2 were determined by ELISA in patients with smouldering multiple myeloma (sMM), patients with symptomatic multiple myeloma (abbreviated as MM), and healthy controls. The levels were compared between the three groups, and correlation coefficients were calculated, as were Kaplan-Meier curves for GDF15 and sVEGFR1 and sVEGFR2.

Results: Levels of GDF15 were significantly higher in MM than in both patients with sMM and controls. A gradual decrease in mean sVEGFR1 concentration was observed, with MM > sMM > controls. Mean sVEGFR2 was lower in patients with MM than in controls. There was a positive correlation between GDF15 and sVEGFR1, and GDF15 correlated negatively with sVEGFR2. High GDF15 (>3 ng/mL) was associated with poor prognosis.

Conclusion: In multiple myeloma, increased expression of GDF15 correlates positively with sVEGFR1 and negatively with sVEGFR2. It is possible that the altered levels of sVEGFR1 and 2 contribute to the increased angio- and lymphangiogenesis observed in myeloma.
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http://dx.doi.org/10.1159/000519888DOI Listing
November 2021

Follow-up after infectious mononucleosis in search of serological similarities with presymptomatic multiple sclerosis.

Mult Scler Relat Disord 2021 Sep 28;56:103288. Epub 2021 Sep 28.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gröna Stråket 11, 3tr, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address:

Background: A two- to three-fold increase in the risk of multiple sclerosis (MS) after infectious mononucleosis (IM) has been observed in cohort and case control studies. However, this association has not been investigated prospectively from IM. It remains to be determined whether long-term immunospecific sequelae with features consistent with presymptomatic MS occur after IM.

Methods: Sera were obtained from individuals with acute IM from 2003-2007 (n = 42) and from the same individuals at a follow-up (FU) study approximately 10 years after IM. These were assayed for antibodies against a variety of Epstein-Barr virus (EBV) antigens, including gp350, a novel recombinant glycoprotein from the EBV envelope. Similarly, single-protein antigens were used to assess measles and varicella-zoster reactivity (Ncore and varicella-zoster glycoprotein E [VZVgE]). The FU study also included cerebrospinal fluid (CSF) samples from 21 of these individuals to test for IgG antibodies against the same viral antigens. As controls, CSF and serum samples were obtained from 15 EBV-seropositive volunteers who denied a history of IM, and serum samples were obtained from 24 EBV-seropositive blood donors. Anti-gp350, anti-Ncore and anti-VZVgE IgG levels were also analysed in sera and CSF samples from 22 persons with MS.

Results: The FU assays showed higher anti-gp350 IgG (p = 0.007, univariate) than among healthy controls, with no difference in serum anti-VCA or anti-EBNA1 IgG levels and no difference in anti-gp350 in the CSF samples. Anti-Ncore IgG and anti-VZVgE were higher in acute IM samples (p < 0.001 and p < 0.0001, respectively) than at FU, although anti-Ncore remained heightened in an age-adjusted analysis at FU (p = 0.014) compared to the control group. In the MS group, the serum anti-gp350 and anti-Ncore IgG levels were significantly higher than among the control group, but the anti-VZVgE levels were not. The CSF anti-gp350 and VZVgE levels were slightly higher among persons with MS than among the control group, whereas anti-Ncore IgG was markedly higher in persons with MS than in the control group.

Conclusion: In the present study IM showed certain similarities with MS. Increased anti-gp350 reactivity persisted more than a decade after IM, reminiscent of the established increased anti-EBV reactivity in presymptomatic MS. Acute IM was associated with increased anti-measles and anti-VZV immunoreactivity, similar to the MRZ reaction in MS, with some evidence suggesting that this measles reactivity persisted after a decade.
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http://dx.doi.org/10.1016/j.msard.2021.103288DOI Listing
September 2021

Strong Associations Between Early Tubular Damage and Urinary Cytokine, Chemokine, and Growth Factor Levels in Elderly Males and Females.

J Interferon Cytokine Res 2021 08;41(8):283-290

Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.

Acute tubular necrosis is associated with high mortality rates and it is important to develop new biomarkers for tubular damage. The aim of this study was to investigate the effect of early tubular damage on a large number of urinary cytokines, chemokines, and growth factors. We selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The tubular damage markers cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were analyzed in the urine samples and urinary cytokine levels were analyzed with 2 multiplex assays (proximity extension assay). After adjustment for sex, body mass index, estimated glomerular filtration rate, smoking, and multiplicity testing using the false discovery rate approach, there remained 26 cytokines that correlated significantly with urine cystatin C, 27 cytokines that correlated with NGAL, and 66 cytokines that correlated with KIM-1. Tubular damage shows a strong association with urinary cytokines, chemokines, and growth factors. Our findings indicate that multiplex proteomics could be a promising new approach to explore the complex effects of tubular damage.
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http://dx.doi.org/10.1089/jir.2021.0065DOI Listing
August 2021

Increased levels of the cardiovascular disease risk biomarkers GDF15 and myostatin in patients with chronic lymphocytic leukemia.

Growth Factors 2020 Jun-Jul;38(3-4):189-196

Department of Medical Sciences, Division of Hematology, University Hospital, Uppsala, Sweden.

Individuals suffering from cancer, including hematological malignancies, are at increased risk of cardiovascular disease (CVD). Elevated levels of several biomarkers in blood are associated with an increased risk of CVD. The aim of this study was to investigate whether a subset of such CVD risk biomarkers was elevated in patients with untreated chronic lymphocytic leukemia (CLL). Blood plasma and serum from 139 CLL patients and 71 healthy age-matched controls were analyzed for 11 proposed CVD risk biomarkers. The CLL cohort displayed a more heterogeneous pattern of biomarker expression compared to controls. The majority, eight out of 11, analyzed CVD risk biomarkers differed significantly in concentrations between CLL patients and controls. Increased levels of the biomarkers GDF15 and myostatin have not previously been reported in CLL. Further prospective studies are warranted to investigate whether these biomarkers predict future cardiovascular events in patients with CLL.
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http://dx.doi.org/10.1080/08977194.2021.1932870DOI Listing
June 2021

Albumin Urinary Excretion Is Associated with Increased Levels of Urinary Chemokines, Cytokines, and Growth Factors Levels in Humans.

Biomolecules 2021 03 8;11(3). Epub 2021 Mar 8.

Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.

The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.
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http://dx.doi.org/10.3390/biom11030396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000571PMC
March 2021

Intrathecal immunoreactivity in people with or without previous infectious mononucleosis.

Acta Neurol Scand 2020 Aug 10;142(2):161-168. Epub 2020 Jun 10.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objectives: The risk of developing multiple sclerosis (MS) increases (OR: 3.1) after infectious mononucleosis (IM). However, the nature of this link is obscure. We tested the hypothesis that IM might incur long-term sequelae, including low-key inflammatory activity, with characteristics of an MS endophenotype (or presymptomatic trait) and that assays of MS-relevant cyto-/chemokines in the cerebrospinal fluid (CSF) post-IM may show a trend in this direction.

Materials And Methods: We selected seven CSF cytokines (IL-1b, IL-6, YKL-40, TNF-alpha) or chemokines (IL-8, CCL2, IP-10), representing pro-inflammatory factors previously associated with MS. We assayed the CSF levels of these seven cyto-/chemokines in healthy individuals with a median follow-up time of 10 years after serologically confirmed IM (post-IM group, n = 22), and in healthy controls without a history of IM (n = 19). A group of MS patients (n = 23) were included as reference.

Results: The CSF levels of IP-10, YKL-40, and CCL-2 were higher in the post-IM group than in our IM unexposed controls (P = .021, .049, .028). Seven of seven cyto-/chemokine assays showed a trend in the predicted direction (P of binomial ratio = .008). However, this trend was non-significant in a multivariate test (P = .22). A power analysis indicated that similar studies including a larger cohort would be numerically realistic.

Conclusions: These results do not reject the hypothesis that the established epidemiological association between IM and MS results from a stepwise inflammatory propagation from IM sequelae to an MS endophenotype (or presymptomatic trait) in a proportion of IM patients, pending confirmation with adequate power.
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http://dx.doi.org/10.1111/ane.13280DOI Listing
August 2020

Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females.

J Interferon Cytokine Res 2020 02 10;40(2):71-74. Epub 2019 Oct 10.

Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.

There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1α, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.
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http://dx.doi.org/10.1089/jir.2019.0074DOI Listing
February 2020

Profiling surface proteins on individual exosomes using a proximity barcoding assay.

Nat Commun 2019 08 26;10(1):3854. Epub 2019 Aug 26.

Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-75 185, Uppsala, Sweden.

Exosomes have been implicated in numerous biological processes, and they may serve as important disease markers. Surface proteins on exosomes carry information about their tissues of origin. Because of the heterogeneity of exosomes it is desirable to investigate them individually, but this has so far remained impractical. Here, we demonstrate a proximity-dependent barcoding assay to profile surface proteins of individual exosomes using antibody-DNA conjugates and next-generation sequencing. We first validate the method using artificial streptavidin-oligonucleotide complexes, followed by analysis of the variable composition of surface proteins on individual exosomes, derived from human body fluids or cell culture media. Exosomes from different sources are characterized by the presence of specific combinations of surface proteins and their abundance, allowing exosomes to be separately quantified in mixed samples to serve as markers for tissue-specific engagement in disease.
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http://dx.doi.org/10.1038/s41467-019-11486-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710248PMC
August 2019

Monitoring of Protein Biomarkers of Inflammation in Human Traumatic Brain Injury Using Microdialysis and Proximity Extension Assay Technology in Neurointensive Care.

J Neurotrauma 2019 10 17;36(20):2872-2885. Epub 2019 Jun 17.

Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala, Sweden.

Traumatic brain injury (TBI) is followed by secondary injury mechanisms strongly involving neuroinflammation. To monitor the complex inflammatory cascade in human TBI, we used cerebral microdialysis (MD) and multiplex proximity extension assay (PEA) technology and simultaneously measured levels of 92 protein biomarkers of inflammation in MD samples every three hours for five days in 10 patients with severe TBI under neurointensive care. One μL MD samples were incubated with paired oligonucleotide-conjugated antibodies binding to each protein, allowing quantification by real-time quantitative polymerase chain reaction. Sixty-nine proteins were suitable for statistical analysis. We found five different patterns with either early (<48 h; e.g., CCL20, IL6, LIF, CCL3), mid (48-96 h; e.g., CCL19, CXCL5, CXCL10, MMP1), late (>96 h; e.g., CD40, MCP2, MCP3), biphasic peaks (e.g., CXCL1, CXCL5, IL8) or stable (e.g., CCL4, DNER, VEGFA)/low trends. High protein levels were observed for e.g., CXCL1, CXCL10, MCP1, MCP2, IL8, while e.g., CCL28 and MCP4 were detected at low levels. Several proteins (CCL8, -19, -20, -23, CXCL1, -5, -6, -9, -11, CST5, DNER, Flt3L, and SIRT2) have not been studied previously in human TBI. Cross-correlation analysis revealed that LIF and CXCL5 may play a central role in the inflammatory cascade. This study provides a unique data set with individual temporal trends for potential inflammatory biomarkers in patients with TBI. We conclude that the combination of MD and PEA is a powerful tool to map the complex inflammatory cascade in the injured human brain. The technique offers new possibilities of protein profiling of complex secondary injury pathways.
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http://dx.doi.org/10.1089/neu.2018.6320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761596PMC
October 2019

Multivariate two-sample permutation tests for trials with multiple time-to-event outcomes.

Pharm Stat 2019 07 26;18(4):476-485. Epub 2019 Mar 26.

Department of Statistics, Uppsala University, Uppsala, Sweden.

Clinical trials involving multiple time-to-event outcomes are increasingly common. In this paper, permutation tests for testing for group differences in multivariate time-to-event data are proposed. Unlike other two-sample tests for multivariate survival data, the proposed tests attain the nominal type I error rate. A simulation study shows that the proposed tests outperform their competitors when the degree of censored observations is sufficiently high. When the degree of censoring is low, it is seen that naive tests such as Hotelling's T outperform tests tailored to survival data. Computational and practical aspects of the proposed tests are discussed, and their use is illustrated by analyses of three publicly available datasets. Implementations of the proposed tests are available in an accompanying R package.
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http://dx.doi.org/10.1002/pst.1938DOI Listing
July 2019

Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program.

Scand J Pain 2019 04;19(2):235-244

Department of Surgical Science, Uppsala University, Uppsala SE-751 85, Sweden.

Background and aims Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP). Methods Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation. Results Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found. Conclusions Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the "sickness-syndrome" and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved. Implications The findings offer a new insight into the complicated biological processes underlying CP. It may have implications for the understanding of symptoms collectively described as the "sickness-syndrome" - frequently seen in this group of patients. The lowering of cytokines after the participation in a PRP indicate a new way to evaluate this treatment; by measuring inflammatory biomarkers.
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http://dx.doi.org/10.1515/sjpain-2018-0340DOI Listing
April 2019

Increased take-off level in automatic milking systems - effects on milk flow, milk yield and milking efficiency at the quarter level.

J Dairy Res 2019 Feb;86(1):85-87

Department of Animal Science,Aarhus University,Blichers Allé 20, P.O. Box 50, DK-8830 Tjele,Denmark.

This research communication describes how different detachment levels (0.48, 0.3 and 0.06 kg milk/min) at the quarter-level affect milk flow profiles and overall milking efficiency in automatic milking systems. We hypothesized a higher detachment level would result in greater mean flow rates without affecting the volume of harvested milk per cow during 24 h compared to lower detachment levels. The data suggest milk flow decreased to a rate below the overmilking limit within the 6-s delay time required for termination in all treatments, but the duration of overmilking was shorter for the greatest detachment level compared to the other treatments. We conclude that setting a detachment level at a greater milk flow rate reduces the duration of overmilking without affecting the amount of milk harvested when applied to cows in mid-lactation during quarter-level milking. We also suggest that the steepness of the decline phase of the milk flow curve might have a larger effect than the actual detachment level on the duration of overmilking.
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http://dx.doi.org/10.1017/S002202991800078XDOI Listing
February 2019

Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [C]-D-deprenyl PET/CT.

Scand J Pain 2017 10 8;17:418-424. Epub 2017 Nov 8.

Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background And Aims: Positron emission tomography (PET) with the radioligand [C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

Methods: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

Results: Acute [C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [C]-D-deprenyl uptake in painful locations.

Conclusions And Implications: The data provide further support that [C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.
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http://dx.doi.org/10.1016/j.sjpain.2017.10.008DOI Listing
October 2017

Identifying characteristics of the most severely impaired chronic pain patients treated at a specialized inpatient pain clinic.

Scand J Pain 2017 10 12;17:178-185. Epub 2017 Oct 12.

Institution of Surgical Science, Uppsala University, SE-751 85 Uppsala, Sweden.

Background And Aims: Patients suffering from chronic nonmalignant pain constitute a heterogeneous population in terms of clinical presentation and treatment results. Few data are available about what distinguishes different groups in this huge population of patients with chronic persistent pain (CPP). A subgroup that is poorly studied, consists of the most severely impaired chronic pain patients. At the Uppsala University Hospital Pain Clinic, there is a specialized department accepting the most complex patients for rehabilitation. In the endeavour to improve and evaluate treatment for this subgroup, a better understanding of the complex nature of the illness is essential. This prospective study aimed to describe the characteristics of this subgroup of patients with CPP.

Methods: Seventy-two consecutive patients enrolled in the Uppsala programme were evaluated. We collected data on demographics, type of pain and experienced symptoms other than pain using a checklist of 41 possible symptoms. Psychiatric comorbidity was assessed by a psychiatrist using a structured clinical interview. Quality of life (QoL), pain rating and medication/drug/alcohol usage were measured by validated questionnaires: SF-36, NRS, DUDIT and AUDIT. Concerning physical functioning and sick leave, a comparison was made with data from the Swedish Quality Register Registry for pain rehabilitation (SQRP).

Results: The cohort consisted of 61% women and the average age was 45 (range 20-70) years. For this cohort, 74% reported being on sick leave or disability-pension. In the SQRP 59% were on sick leave at the time they entered the rehabilitation programmes [1]. On average, the study-population reported 22 symptoms other than pain, to be at a high rate of severity. Patients treated in conventional pain-rehabilitation programmes reported a mean of 10 symptoms in average. Symptoms reported with the highest frequency (>80%), were lethargy, tiredness, headache and difficulties concentrating. Seventy-six percent were diagnosed with a psychiatric disorder. Sixty-nine fulfilled the criteria for depression or depression/anxiety disorder despite that most (65%) were treated with psychotropic medication. Alcohol/drug abuse was minimal. Seventy-one percent were on opioids but the doses were moderate (<100mg) MEq. The pain rating was ≥7 (out of a maximum of 10) for 60% of the patients.

Conclusion: This study describes what makes the subgroup of pain patients most affected by their pain special according to associated factors and comorbidity We found that they were distinguished by a high degree of psychiatric comorbidity, low physical functioning and extreme levels of symptom preoccupation/hypervigilance. Many severe symptoms additional to pain (e.g. depression/anxiety, tiredness, disturbed sleep, lack of concentration, constipation) were reported. The group seems hypervigilant, overwhelmed with a multitude of different symptoms on a high severity level.

Implications: When treating this complex group, the expressions of the illness can act as obstacles to achieve successful treatment outcomes. The study provides evidence based information, for a better understanding of the needs concerning these pain patients. Our result indicates that parallel assessment and treatment of psychiatric comorbidities and sleep disorders combined with traditional rehabilitation, i.e. physical activation and cognitive reorganization are imperative for improved outcomes.
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http://dx.doi.org/10.1016/j.sjpain.2017.09.008DOI Listing
October 2017

High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls.

Pain 2017 Dec;158(12):2487-2495

Department of Surgical Sciences, Anesthesiology and Intensive Care, and Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.

Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.
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http://dx.doi.org/10.1097/j.pain.0000000000001061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690569PMC
December 2017

Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine.

EBioMedicine 2017 Sep 24;23:111-118. Epub 2017 Aug 24.

Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden. Electronic address:

Mecillinam (amdinocillin) is a β-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (Mec) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were Mec due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, MecE. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the Mec mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as Mec in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting MecE. coli strain and thereby increase treatment efficiency.
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http://dx.doi.org/10.1016/j.ebiom.2017.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605379PMC
September 2017

Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation.

Int J Inflam 2016 11;2016:3874964. Epub 2016 May 11.

Department of Surgical Sciences, Uppsala University, 751 85 Uppsala, Sweden.

Earlier studies suggest that lumbar radicular pain following disc herniation may be associated with a local or systemic inflammatory process. In the present study, we investigated the serum inflammatory protein profile of such patients. All 45 patients were recruited from Oslo University Hospital, Ullevål, Norway, during the period 2007-2009. The new multiplex proximity extension assay (PEA) technology was used to analyze the levels of 92 proteins. Interestingly, the present data showed that patients with radicular pain 12 months after disc herniation may be different from other patients with regard to many measurable serum cytokines. Given a false discovery rate (FDR) of 0.10 and 0.05, we identified 41 and 13 proteins, respectively, which were significantly upregulated in the patients with severe pain one year after disc herniation. On the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 (CXCM5; 217% increase), epidermal growth factor (EGF; 142% increase), and monocyte chemotactic protein 4 (MCP-4; 70% increase). Moreover, a clear overall difference in the serum cytokine profile between the chronic and the recovered patients was demonstrated. Thus, the present results may be important for future protein serum profiling of lumbar radicular pain patients with regard to prognosis and choice of treatment. We conclude that serum proteins may be measurable molecular markers of persistent pain after disc herniation.
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http://dx.doi.org/10.1155/2016/3874964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879232PMC
June 2016

The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid.

Cytokine 2015 Dec 15;76(2):514-518. Epub 2015 Jul 15.

Department of Statistics, Uppsala University, SE-751 05 Uppsala, Sweden.

Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.
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http://dx.doi.org/10.1016/j.cyto.2015.07.010DOI Listing
December 2015

The effects of age and gender on plasma levels of 63 cytokines.

J Immunol Methods 2015 Oct 14;425:58-61. Epub 2015 Jun 14.

Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 08 Uppsala, Sweden.

Cytokines play important roles as regulators of cell functions, and over the last decades a number of cytokine assays have been developed. The aim of the present study was to investigate the effects of age and gender on a large number of cytokines. Plasma samples were collected from 33 healthy blood donors. The samples were analyzed using a multiplex proximity extension assay (PEA) allowing simultaneous measurement of 92 cytokines and four technical controls. Biomarkers with less than 80% quantitative results were excluded leaving 63 cytokines that were analyzed for the effects of gender and age. The plasma level of three of the investigated biomarkers (DNER, MCP-4 and MMP-10) were found to be significantly different for the two genders (adjusted p-value<0.05), and 15 of the biomarkers (CCL11, CCL25, CDCP1, CSF-1, CXCL11, CXCL9, FGF-23, Flt3L, HGF, IL-10RB, MCP-3, MCP-4, MMP-10, OPG, VEGF-A) were significantly associated with age. This study reveals the effects of age and gender on a large number of cytokine assays. CXCL5 and TNFB were significantly higher in females, while the other markers with significant gender-dependent differences were higher in males. For the markers that were significantly associated with age, only CXCL6 was found to decrease with age, while the other biomarkers increased with age.
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http://dx.doi.org/10.1016/j.jim.2015.06.009DOI Listing
October 2015

Temperature measurements with two different IR sensors in a continuous-flow microwave heated system.

Beilstein J Org Chem 2013 10;9:2079-87. Epub 2013 Oct 10.

Department of Medicinal Chemistry, Uppsala University, Box 574, 751 23 Uppsala, Sweden.

In a continuous-flow system equipped with a nonresonant microwave applicator we have investigated how to best assess the actual temperature of microwave heated organic solvents with different characteristics. This is non-trivial as the electromagnetic field will influence most traditional methods of temperature measurement. Thus, we used a microwave transparent fiber optic probe, capable of measuring the temperature inside the reactor, and investigated two different IR sensors as non-contact alternatives to the internal probe. IR sensor 1 measures the temperature on the outside of the reactor whilst IR sensor 2 is designed to measure the temperature of the fluid through the borosilicate glass that constitutes the reactor wall. We have also, in addition to the characterization of the before mentioned IR sensors, developed statistical models to correlate the IR sensor reading to a correct value of the inner temperature (as determined by the internal fiber optic probe), thereby providing a non-contact, indirect, temperature assessment of the heated solvent. The accuracy achieved with these models lie well within the range desired for most synthetic chemistry applications.
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http://dx.doi.org/10.3762/bjoc.9.244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817514PMC
November 2013
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