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  • A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch


    http://stke.sciencemag.org/content/10/493/eaal5241.full


    Deriving itch and pain from a fatty acid


    Linoleic acid is a polyunsaturated ω−6 fatty acid that is consumed in high amounts in a typical Western diet and whose derivatives are associated with chronic inflammation and pain. Ramsden et al. identified several derivatives of linoleic acid in inflamed psoriatic lesions. One of these derivatives [9-keto-12,13-trans-epoxy-(10E)-octadecenoate] was much more abundant in itchy psoriatic lesions than in non-itchy psoriatic lesions or normal skin, and it induced scratching when injected into mice. Injection of another linoleic acid derivative [11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate] caused rats to become more sensitive to thermal pain. Furthermore, chronic headache sufferers reported shorter headaches and more headache-free days when they reduced their dietary intake of linoleic acid, which was associated with decreased plasma concentrations of 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate. Identifying the receptor for these linoleic acid derivatives could reveal a potential pharmacological target to reduce pain and itch.

    Abstract



    Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene–related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-Z-pentenyl-E-epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate elicited C-fiber–mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies to manage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13-trans-epoxy-(10E)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch.
    ​​​​​​​


    INTRODUCTION


    Chronic pain and itch are common sources of personal suffering, disability, and societal expense (13). Current treatments often provide only partial or transient relief and have substantial side effects (48). The discovery of previously unknown endogenous mediators and mechanisms underlying pain and itch is needed to facilitate the development of targeted, effective, and safer interventions.

    As the largest sensory organ, the skin is richly innervated by cutaneous nerve endings that can sense the microenvironment (4). Linoleic acid, the most abundant polyunsaturated fatty acid in the skin (5), is an “essential fatty acid” because a small amount (about 0.5% of energy) is needed in the diet to form the outer waxy epidermal barrier that prevents transepidermal water loss (68). Because itch and pain are common manifestations of cutaneous inflammatory conditions (3, 9) and linoleic acid is an endogenous substrate for conversion to bioactive lipid mediators (10), linoleic acid–derived mediators could be used to modulate cutaneous itch and pain.
    Jo Bowyer
    Chartered Physiotherapist Registered Osteopath.
    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

    Comment


    • Accuracy of clinical neurological examination in diagnosing lumbo-sacral radiculopathy: a systematic literature review


      https://bmcmusculoskeletdisord.biome...891-016-1383-2

      Abstract

      Background


      Lumbar radiculopathy remains a clinical challenge among primary care clinicians in both assessment and diagnosis. This often leads to misdiagnosis and inappropriate treatment of patients resulting in poor health outcomes, exacerbating this already debilitating condition. This review evaluated 12 primary diagnostic accuracy studies that specifically assessed the performance of various individual and grouped clinical neurological tests in detecting nerve root impingement, as established in the current literature.

      Methods


      Eight electronic data bases were searched for relevant articles from inception until July 2016. All primary diagnostic studies which investigated the accuracy of clinical neurological test (s) in diagnosing lumbar radiculopathy among patients with low back and referred leg symptoms were screened for inclusion. Qualifying studies were retrieved and independently assessed for methodological quality using the ‘Quality Assessment of Diagnostic tests Accuracy Studies’ criteria.

      Results


      A total of 12 studies which investigated standard components of clinical neurological examination of (sensory, motor, tendon reflex and neuro-dynamics) of the lumbo-sacral spine were included. The mean inter-observer agreement on quality assessment by two independent reviewers was fair (k = 0.3 – 0.7).

      The diagnostic performance of sensory testing using MR imaging as a reference standard demonstrated a sensitivity (confidence interval 95%) 0.61 (0.47-0.73) and a specificity of 0.63 (0.38-0.84). Motor tests sensitivity was poor to moderate, ranging from 0.13 (0.04-0.31) to 0.61 (0.36-0.83). Generally, the diagnostic performance of reflex testing was notably good with specificity ranging from (confidence interval 95%) 0.60 (0.51-0.69) to 0.93 (0.87-0.97) and sensitivity ranging from 0.14 (0.09-0.21) to 0.67 (0.21-0.94). Femoral nerve stretch test had a high sensitivity of (confidence interval 95%) 1.00 (0.40-1.00) and specificity of 0.83 (0.52-0.98) while SLR test recorded a mean sensitivity of 0.84 (0.72-0.92) and specificity of 0.78 (0.67-0.87).

      Conclusions


      There is a scarcity of studies on the diagnostic accuracy of clinical neurological examination testing. Furthermore there seem to be a disconnect among researchers regarding the diagnostic utility of lower limb neuro-dynamic tests which include the Straight Leg Raise and Femoral Nerve tests for sciatic and femoral nerve respectively. Whether these tests are able to detect the presence of disc herniation and subsequent nerve root compression or hyper-sensitivity of the sacral and femoral plexus due to mechanical irritation still remains debatable.
      Keywords

      Lumbar radiculopathy Diagnostic accuracy Clinical neurological examination
      Jo Bowyer
      Chartered Physiotherapist Registered Osteopath.
      "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

      Comment


      • Measuring and managing bias

        http://science.sciencemag.org/content/357/6354/849.full

        We all carry a range of biases that are products of our culture and experiences or, in some cases, of outcomes that we desire. Fortunately, many such biases can be measured and, in some cases, effectively managed. A key is to first acknowledge their presence and then to take steps to minimize their influence on important decisions and results.
        Jo Bowyer
        Chartered Physiotherapist Registered Osteopath.
        "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

        Comment


        • Effectiveness of a specific manual approach to the suboccipital region in patients with chronic mechanical neck pain and rotation deficit in the upper cervical spine: study protocol for a randomized controlled trial


          https://bmcmusculoskeletdisord.biome...891-017-1744-5

          Abstract

          Background


          Mechanical neck pain is a highly prevalent problem in primary healthcare settings. Many of these patients have restricted mobility of the cervical spine. Several manual techniques have been recommended for restoring cervical mobility, but their effectiveness in these patients is unknown. The aim of the present study is to compare the effectiveness of two types of specific techniques of the upper neck region: the pressure maintained suboccipital inhibition technique (PMSIT) and the translatory dorsal glide mobilization (TDGM) C0-C1 technique, as adjuncts to a protocolized physiotherapy treatment of the neck region in subjects with chronic mechanical neck pain and rotation deficit in the upper cervical spine.

          Methods


          A randomized, prospective, double-blind (patient and evaluator) clinical trial. The participants (n = 78) will be randomly distributed into three groups. The Control Group will receive a protocolized treatment for 3 weeks, the Mobilization Group will receive the same protocolized treatment and 6 sessions (2 per week) of the TDGM C0-C1 technique, and the Pressure Group will receive the same protocolized treatment and 6 sessions (2 per week) of the PMSIT technique. The intensity of pain (VAS), neck disability (NDI), the cervical range of motion (CROM), headache intensity (HIT-6) and the rating of clinical change (GROC scale) will be measured. The measurements will be performed at baseline, post-treatment and 3 months after the end of treatment, by the same physiotherapist blinded to the group assigned to the subject.

          Discussion


          We believe that an approach including manual treatment to upper cervical dysfunction will be more effective in these patients. Furthermore, the PMSIT technique acts mostly on the musculature, while the TDGM technique acts on the joint. We expect to clarify which component is more effective in improving the upper cervical mobility.
          Trial registration


          ClinicalTrials.gov NCT02832232. Registered on July 13th, 2016.

          Keywords

          Range of motion Cervical vertebrae Atlantoaxial joint Suboccipital muscle inhibition
          Jo Bowyer
          Chartered Physiotherapist Registered Osteopath.
          "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

          Comment


          • Effects of hyaluronic acid combined with anti-inflammatory drugs compared with hyaluronic acid alone, in clinical trials and experiments in osteoarthritis: a systematic review and meta-analysis

            https://bmcmusculoskeletdisord.biome...891-017-1743-6


            Abstract

            Background


            The objectives are to compare the efficacy of intra-articular hyaluronic acid (IA-HA) alone and in combination with anti-inflammatory drugs (IA-HA + AI), corticosteroids (CS) or non-steroidal anti-inflammatory drugs (NSAIDs) in clinical trials and in vivo and in vitro studies of osteoarthritis (OA).

            Methods


            Data in the BIOSIS, CINAHL, Cochrane Library, EMBASE and Medline databases were collected and analyzed. Random effects models were used to compute the effect size (ES) of the mean difference in pain reduction scores from baseline and the relative risk (RR) of adverse events. The ES of histological scores in vivo and cartilage metabolism in vitro were also calculated. We conducted sensitivity analysis of blinding and intention-to-treat (ITT), compared IA-HA combined with CS vs. IA-HA alone in trials, and compared the effects of HA + AI vs. AI alone in vitro, including anabolic and catabolic gene expression.

            Results


            Thirteen out of 382 papers were included for data analysis. In clinical trials, the ES of pain reduction scores within the 1st month was −4.24 (−6.19, −2.29); 2nd–12th month, −1.39 (−1.95, −0.82); and within one year, −1.63 (−2.19, −1.08), favoring IA-HA + AI (P < 0.001). The ES of RR was 1.08 (0.59, 1.98), and histological scores was 1.38 (−0.55, 3.31). The ES of anabolic gene expression was 1.22 (0.18, 2.25), favoring HA alone (P < 0.05); catabolic gene expression was 0.74 (−0.44, 1.53), favoring HA alone; and glycosaminoglycans remaining was −2.45 (−5.94, 1.03).

            Conclusions


            IA-HA + AI had greater efficacy for pain relief than IA-HA alone within a one-year period. However, HA + AI down-regulated the ACAN gene when compared with HA alone in vitro.
            Keywords

            Anti-inflammatory drugs Cartilage Hyaluronic acid Osteoarthritis Systematic review
            Jo Bowyer
            Chartered Physiotherapist Registered Osteopath.
            "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

            Comment


            • Transparency in peer review

              https://phys.org/news/2017-09-transparency-peer.html

              It wasn't until the dawn of the 21st Century that publishers (such as BMC, BMJ and PLoS) started to seriously experiment with open peer review.
              Why is this? The first reason is the politicisation of science. A good example is climate change—when scientists from the University of East Anglia were bombarded with freedom of information requests by climate sceptics, it became clear there was a lack of transparency and this was used to undermine the veracity of the research. Policy based on published research is under increased scrutiny.

              The second reason stems from the open science and open access agenda. Much research is funded by the public purse and it is argued that the published output from this research should be available to all. It follows that the evidence—data, peer review—on which claims are made should be made open too.

              Finally, transparency has the potential to improve the quality of research and reduce research misconduct. Traditional peer review is confidential, with research papers scrutinised by a small number of anonymous experts. Although publishers are vigilant, this secrecy provides the opportunity for fraud.

              In 2014, the Royal Society launched the journal Royal Society Open Science which offers optional open peer review where reports are published along with articles. This has proved popular with the majority of authors opting for publication of peer review reports and half of reviewers signing their reports. The uptake varies by scientific discipline.
              Since then, open peer review has been introduced on two further Royal Society journals, Proceedings A and Open Biology.

              Benefits of transparency in peer review

              There are several benefits to open peer review.
              1. Readers can see the comments by reviewers and reach their own conclusions about the rigour and fairness of the process. They can also see how the authors have responded to the criticism and if any errors or shortcomings in the article have been missed. Readers have more information on which to base any comments they may wish to make after publication. In this way, the published science can be improved.
              2. Reviewers' suggestions to improve the paper are available to everyone as examples of what makes a good review. This is particularly useful for early career scientists who may have limited experience of reviewing articles themselves.
              3. Reviewers tend to write better and more balanced reviews if they know they will be made public.
              4. By signing their reports reviewers can get recognition for this vital contribution to the research process. Peer review recognition services are becoming more common, with examples including Publons and ORCID.

              Overall, the whole peer review process gains more trust and accountability when everything is transparent.

              Is open peer review just a passing fad (like in 1832)?

              Back in 1832, science wasn't ready for transparency – producing detailed written reports for public judgement on the value of a paper was just too much work for the small number of referees, and publicly criticising peers was socially very difficult.

              Today, because science is funded largely by the public purse and informs so much public policy, transparency is essential. In recent decades many believe that impact and citations have played far too prominent a role in determining what is published. Transparency is important in helping journals focus on the quality and rigour of the research process rather than its likely impact, originality and even fashion. A vital part of this opening up of peer review is recognising the value of such work as an essential 'output' in assessments for grants and tenure. There is cause for optimism that the abandonment of open peer review in 1832 will not be repeated.



              Jo Bowyer
              Chartered Physiotherapist Registered Osteopath.
              "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

              Comment


              • Bad Timing

                http://coopersquarereview.org/post/bad-timing/

                I stayed hidden for as long as I could, listening to people come and go outside. The thought of telling them that it was all a mistake and the results were not accurate made me ill. We would have to start over from scratch. I was already worried that I had over-sold myself to win this fellowship. And the results were too good to be true. Now they’ll know.

                But…do I have to tell them? Couldn’t I just quietly fix the bug and go on collecting data? Surely the timing of button presses is correlated with the timing of button releases. The general pattern would be the same, and that’s what matters. Right?

                In my brief, delirious dance with the devil of scientific dishonesty, I couldn’t decide whether the possibly inconsequential nature of the mistake was more or less of a reason to hide it.

                I suddenly snapped out of it and jogged down to my professor’s office. “I have some bad news,” I began, before he even looked up from the papers on his desk. He was grave at first, but then he managed to laugh at the panic in my eyes and calmly instructed me to fix the code and start collecting new data right away.
                Jo Bowyer
                Chartered Physiotherapist Registered Osteopath.
                "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                Comment

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