Morphine activates neuroinflammation in a manner parallel to endotoxin

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yi

Musculoskeletal modelling of an ostrich (Struthio camelus) pelvic limb: influence of limb orientation on muscular capacity during locomotion

We developed a three-dimensional, biomechanical computer model of the 36 major pelvic limb muscle groups in an ostrich (Struthio camelus) to investigate muscle function in this, the largest of extant birds and model organism for many studies of locomotor mechanics, body size, anatomy and evolution. Combined with experimental data, we use this model to test two main hypotheses. We first query whether ostriches use limb orientations (joint angles) that optimize the moment-generating capacities of their muscles during walking or running. Next, we test whether ostriches use limb orientations at mid-stance that keep their extensor muscles near maximal, and flexor muscles near minimal, moment arms. Our two hypotheses relate to the control priorities that a large bipedal animal might evolve under biomechanical constraints to achieve more effective static weight support. We find that ostriches do not use limb orientations to optimize the moment-generating capacities or moment arms of their muscles. We infer that dynamic properties of muscles or tendons might be better candidates for locomotor optimization. Regardless, general principles explaining why species choose particular joint orientations during locomotion are lacking, raising the question of whether such general principles exist or if clades evolve different patterns (e.g., weighting of muscle force–length or force–velocity properties in selecting postures). This leaves theoretical studies of muscle moment arms estimated for extinct animals at an impasse until studies of extant taxa answer these questions. Finally, we compare our model’s results against those of two prior studies of ostrich limb muscle moment arms, finding general agreement for many muscles. Some flexor and extensor muscles exhibit self-stabilization patterns (posture-dependent switches between flexor/extensor action) that ostriches may use to coordinate their locomotion. However, some conspicuous areas of disagreement in our results illustrate some cautionary principles. Importantly, tendon-travel empirical measurements of muscle moment arms must be carefully designed to preserve 3D muscle geometry lest their accuracy suffer relative to that of anatomically realistic models. The dearth of accurate experimental measurements of 3D moment arms of muscles in birds leaves uncertainty regarding the relative accuracy of different modelling or experimental datasets such as in ostriches. Our model, however, provides a comprehensive set of 3D estimates of muscle actions in ostriches for the first time, emphasizing that avian limb mechanics are highly three-dimensional and complex, and how no muscles act purely in the sagittal plane. A comparative synthesis of experiments and models such as ours could provide powerful synthesis into how anatomy, mechanics and control interact during locomotion and how these interactions evolve. Such a framework could remove obstacles impeding the analysis of muscle function in extinct taxa

Cost-effectiveness of HCV case-finding for people who inject drugs via dried blood spot testing in specialist addiction services and prisons

ObjectivesPeople who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV), but many are unaware of their infection. HCV dried blood spot (DBS) testing increases case-finding in addiction services and prisons. We determine the cost-effectiveness of increasing HCV case-finding among PWID by offering DBS testing in specialist addiction services or prisons as compared to using venepuncture.DesignCost-utility analysis using a dynamic HCV transmission model among PWID, including: disease progression, diagnosis, treatment, injecting status, incarceration and addition services contact.Setting uk interventionDBS testing in specialist addiction services or prisons. Intervention impact was determined by a meta-analysis of primary data.Primary and secondary outcome measuresCosts (in UK £, £1=US$1.60) and utilities (quality-adjusted life years, QALYs) were attached to each state and the incremental cost effectiveness ratio (ICER) determined. Multivariate uncertainty and one-way sensitivity analyses were performed.ResultsFor a £20 000 per QALY gained willingness-to-pay threshold, DBS testing in addiction services is cost-effective (ICER of £14 600 per QALY gained). Under the base-case assumption of no continuity of treatment/care when exiting/entering prison, DBS testing in prisons is not cost-effective (ICER of £59 400 per QALY gained). Results are robust to changes in HCV prevalence; increasing PWID treatment rates to those for ex-PWID considerably reduces ICER (£4500 and £30 000 per QALY gained for addiction services and prison, respectively). If continuity of care is >40%, the prison DBS ICER falls below £20 000 per QALY gained.ConclusionsDespite low PWID treatment rates, increasing case-finding can be cost-effective in specialist addiction services, and in prisons if continuity of treatment/care is ensured

Regional variation in digital cushion pressure in the forefeet of horses and elephants

In this study, we seek to understand how the digital cushion morphologies evident in horse and elephant feet influence internal and external foot pressures. Our novel use of invasive blood pressure monitoring equipment, combined with a pressure pad and force plate, enabled measurements of (ex vivo) digital cushion pressure under increasing axial loads in seven horse and six elephant forefeet. Linear mixed effects models (LMER) revealed that internal digital cushion pressures increase under load and differ depending on region; elephant feet experienced higher magnitudes of medial digital cushion pressure, whereas horse feet experienced higher magnitudes of centralised digital cushion pressure. Direct comparison of digital cushion pressure magnitudes in both species, at equivalent loads relative to body weight, revealed that medial and lateral pressures increased more rapidly with load in elephant limbs. Within the same approximate region, internal pressures exceeded external, palmar pressures (on the sole of the foot), supporting previous Finite Element (FE) predictions. High pressures and large variations in pressure may relate to the development of foot pathology, which is a major concern in horses and elephants in a captive/domestic environment

STEM Careers Awareness Timelines Attitudes and ambitions towards science, technology, engineering and maths (STEM at Key Stage 3)

The importance of science, technology, engineering and maths (STEM) expertise to the UK economy is generally accepted as key to maintaining our international competitiveness. This importance was noted in the 2002 review by Sir Gareth Roberts, ‘Set for Success: The supply of people with science, technology, engineering and mathematics skills’. This report stemmed from the, ‘Government’s concern that the supply of high-quality scientists and engineers should not constrain the UK’s future research and development (R&D) and innovation performance.’ (Roberts, 2002, p.1

STEM Careers Awareness Timelines

The importance of science, technology, engineering and maths (STEM) expertise to the UK economy is generally accepted as key to maintaining our international competitiveness. This importance was noted in the 2002 review by Sir Gareth Roberts, ‘Set for Success: The supply of people with science, technology, engineering and mathematics skills’. This report stemmed from the, ‘Government’s concern that the supply of high-quality scientists and engineers should not constrain the UK’s future research and development (R&D) and innovation performance.’ (Roberts, 2002, p.1) ‘A shortage of graduates in these disciplines is likely to become increasingly serious since the UK economy – with its large financial services sector, strong science base and increasing focus on high-tech and high value-added manufacturing businesses – is likely to need more mathematics and physical science graduates, not fewer’ (Roberts, 2002, p. 49). The report highlighted increasing employer difficulties in the recruitment of suitably qualified scientists and engineers, and corresponding implications for future UK competitiveness. Although recruitment data revealed that employers and universities were not doing enough to attract candidates by offering competitive conditions of employment, the report highlighted ‘poor experiences of science and engineering education among pupils generally, coupled with a negative image of, and inadequate information about careers arising from the study of science and engineering.’ Addressing these issues would require, ‘Action in schools and further and higher education’ (Roberts, 2002, p.3). Recent years have thus seen much emphasis placed on the quality of learning and teaching of STEM subjects in schools, accompanied by adequate IAG provision. However, STEM subjects are being dropped at school by young people in favour of other choices prior to, and following GCSEs, with worrying implications for higher level STEM study, and subsequently careers such as engineering, construction and scientific research. Consequently, the Department for Children, Schools and Families (DCSF) have developed a suite of 11 Action Programmes within a strategic framework to prioritise STEM issues. Action Programme 8 focussed on careers and seeks to achieve two objectives: • For all young people to be made aware of the fulfilling and attractive careers open to them through the continued study of science and mathematics • To provide the knowledge and skills to enable young people to make informed subject choices to achieve qualifications to keep their options open for further study and careers in STEM

Dissipation in nanocrystalline-diamond nanomechanical resonators

We have measured the dissipation and frequency of nanocrystalline-diamond nanomechanical resonators with resonant frequencies between 13.7 MHz and 157.3 MHz, over a temperature range of 1.4–274 K. Using both magnetomotive network analysis and a time-domain ring-down technique, we have found the dissipation in this material to have a temperature dependence roughly following T^(0.2), with Q^(–1) ≈ 10^(–4) at low temperatures. The frequency dependence of a large dissipation feature at ~35–55 K is consistent with thermal activation over a 0.02 eV barrier with an attempt frequency of 10 GHz