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Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or the 5-LOX-activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli, produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on-target actions, we found that: 1) COX or 15-LOX-1 inhibitors elevate inflammatory leukotriene levels, 2) FLAP and 5-LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3) zileuton blocks resolution-initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4) that the 15-LOX-1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.-Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.
Learn More >To study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH).
Learn More >Previous research has shown that youth with chronic pain who presented for a multidisciplinary evaluation report a history of adverse childhood experiences (ACEs) (eg, abuse, neglect, parent/guardian separation or divorce) at a high rate (over 80%) and that those with pain and ACEs experience increased psychosocial impairment. Outside of chronic pain, evidence also suggests that youth with a history of ACEs experience poorer treatment outcomes. However, no study to date has examined treatment outcomes in youth with chronic pain and a history of ACEs. The current study aimed to examine the role of ACEs in multidisciplinary intensive pain rehabilitation treatment outcomes for youth with chronic pain.
Learn More >To assess national trends in selected prescription opioid risk mitigation practices and associations with prescriber type, state-specific opioid overdose severity, and required pain education.
Learn More >Spinal cord stimulation (SCS) is an established therapy for refractory neuropathic pain. To ascertain the balance between treatment benefits and risks, the French National Authority for Health requested a post-market registry for real-world evaluation of the long-term effectiveness and safety of the therapy.
Learn More >Children of mothers with chronic pain are at increased risk for poor health, but few studies have examined what characteristics of maternal chronic pain may be associated with children's risk. This study identified subgroups of mothers based on patterns of pain, physical function, and emotional function on the 29-item Patient-Reported Outcomes Measurement Information System® (PROMIS-29®) and evaluated associations between maternal subgroups and children's pain and emotional functioning.
Learn More >Visual cortical hyperexcitability is now known to be an underlying factor for aberrant visual experience, including hallucinations, and pattern or light induced visual discomfort. Such factors have also been observed in neurological and non-clinical groups (albeit in attenuated form) – consistent with the notion of a continuum of anomalous experiences. Utilizing an exploratory factor analysis (EFA) approach (n = 300), Study 1 developed a revised proxy screening measure for visual cortical hyperexcitability – the Cortical Hyperexcitability index – II(CHi-II). The EFA revealed a stable 3-factor solution which can be characterised as; (i) Heightened Visual Sensitivity and Discomfort (HVSD); (ii) Aura-like Hallucinatory Experience (AHE); and, (iii) Distorted Visual Perception (DVP). Study 2 tested both a self-reported migraine group and a control group on the CHi-II in conjunction with a computerised pattern-glare task that is known to reflect visual cortical hyperexcitability. The migraine group produced significantly elevated scores on both the AHE and HVSD factors of the CHi-II, relative to controls. Among the non-migraine group, subjects who scored higher in the pattern-glare task also produced significantly elevated scores on the AHE factor compared to those with low pattern-glare task scores. Collectively, these findings support the utility of the CHi-II as an indirect proxy measure for signs of cortical hyperexcitability and reveal new categorical distinctions for the nature of the anomalous perceptions. These perceptions may well reflect diverse neurocognitive underpinnings leading to advancements in our understanding of aberrations in conscious experience.
Learn More >Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB) model is a model for inflammatory pain in which three times the minimal erythema dose (3MED) is typically applied to induce sensitisation. Based on reports of long-lasting postinflammatory hyperpigmentation (PIH) associated with 3MED, it was decided to investigate the prevalence of PIH among subjects who were previously exposed to 3MED at our research centre. In addition, re-evaluation of the UVB inflammation model using a reduced exposure paradigm (2MED) was performed in healthy subjects.
Learn More >Musculoskeletal pain is a prevalent health challenge for all age groups worldwide, but most notably in older adults. Social isolation is the consequence of a decrease in social network size with a reduction in the number of social contacts. Loneliness is the psychological embodiment of social isolation and represents an individual's perception of dissatisfaction in the quality or quantity of their social contacts. This study aims to determine whether a relationship exists between musculoskeletal pain and social isolation and loneliness.
Learn More >Neuropathic pain following surgery could be a useful model for the study of the genetic mechanisms of peripheral neuropathic pain.
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