Involvement of EphB1 Receptors Signalling in Models of Inflammatory and Neuropathic Pain

EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Is leg lifting in full extension safe following anterior cruciate ligament reconstruction?

There is controversy over whether leg lifting in full extension following anterior cruciate ligament reconstruction (ACLR) will threaten the graft. We reviewed published biomechanical studies of normal knees which suggest that while full passive extension of the knee joint will not strain the graft, an active leg lift will subject the ACL graft to strain. There is, however, evidence that ACL strain is greater at 20-30° flexion than near full extension. We therefore recommend that if ACLR patients lift their recently operated leg, provided there is no limitation of passive extension, they should do so with the knee joint near full extension rather than in 20-30° flexion

Crotoxin, the major toxin from the rattlesnake Crotalus durissus terrificus, inhibits ³H-choline uptake in guinea pig ileum

We examined the effect of crotoxin, the neurotoxic complex from the venom of the South American rattlesnake Crotalus durissus terrificus, on the uptake of ³H-choline in minces of smooth muscle myenteric plexus from guinea pig ileum. In the concentration range used (0.03-1 µM) and up to 10 min of treatment, crotoxin decreased ³H-choline uptake by 50-75% compared to control. This inhibition was time dependent and did not seem to be associated with the disruption of the neuronal membrane, because at least for the first 20 min of tissue exposure to the toxin (up to 1 µM) the levels of lactate dehydrogenase (LDH) released into the supernatant were similar to those of controls. Higher concentrations of crotoxin or more extensive incubation times with this toxin resulted in elevation of LDH activity detected in the assay supernatant. The inhibitory effect of crotoxin on ³H-choline uptake seems to be associated with its phospholipase activity since the equimolar substitution of Sr2+ for Ca2+ in the incubation medium or the modification of the toxin with p-bromophenacyl bromide substantially decreased this effect. Our results show that crotoxin inhibits ³H-choline uptake with high affinity (EC25 = 10 ± 5 nM). We suggest that this inhibition could explain, at least in part, the blocking effect of crotoxin on neurotransmission

Sterile neutrinos in leptonic and semileptonic decays

We address the impact of a modified $W \ell \nu$ coupling on a wide range of observables, such as $\tau$ leptonic and mesonic decays, leptonic decays of pseudoscalar mesons, as well as semileptonic meson decays. In particular, we concentrate on deviations from lepton flavour universality, focusing on the ratios $R_{P} = \Gamma (P \to \ell \nu) / \Gamma (P \to \ell' \nu)$, with $P=K, \pi, D, D_s$, $R(D)={\Gamma (B^+ \to D \tau^+ \nu)}/{\Gamma (B^+ \to D\ell^+ \nu)}$, $R \tau={\Gamma (\tau\to \mu\nu\nu)}/{\Gamma (\tau\to e\nu\nu)}$, $R^{\ell \tau}_P=\Gamma(\tau\to P\nu)/\Gamma(P\to \ell \nu)$, and $\text{BR}(B \to \tau \nu)$. We further consider leptonic gauge boson decays, such as $W\to \ell \nu$ and $Z \to \nu \nu$. For all the above observables, we provide the corresponding complete analytical expressions, derived for the case of massive neutrinos. Working in the framework of the Standard Model extended by additional sterile fermions, which mix with the active (left-handed) neutrinos, we numerically study the impact of active-sterile mixings on the above mentioned observables.Comment: 31 pages, Latex, 22 figures. Published in JHE