Chemokine Expression in Peripheral Tissues from the Monosodium Lodoacetate Model of Chronic Joint Pain

Background Chronic pain arising from degenerative diseases of the joint such as osteoarthritis (OA) has a strong peripheral component which is likely to be mediator driven. Current treatments which reduce the production of such mediators i.e. non-steroidal anti-inflammatory drugs (NSAIDs), can help to lessen pain in OA patients. However, this is not always the case and complete pain relief is rarely achieved, suggesting that additional unidentified mediators play a role. Here we have investigated the notion that chemokines might act as such pain mediators in OA. Results Using the monosodium iodoacetate (MIA) model of chronic joint pain the expression of over 90 different inflammatory mediators, mainly cytokines and chemokines, were measured in tissues taken from the femorotibial joint (cartilage, subchondral bone, fat pad) using custom-made quantitative real-time polymerase chain reaction (qPCR) array cards. At both the day 3 and 14 time points, numerous inflammatory mediators were significantly up-regulated in these tissues, although it was clear that the largest transcriptional dysregulation occurred in the cartilage. Using individual qPCR to measure immune cell markers, a significant infiltration of macrophages was measured in the cartilage and fat pad at day 3. Neutrophil infiltration was also measured in the fat pad at the same time point, but no infiltration was observed at day 14. Combination of mRNA expression data from different time points and tissues identified the chemokines, CCL2, 7 and 9 as being consistently up-regulated. The overall increase in CCL2 expression was also measured at the protein level. Conclusion Chemokines in general and CCL2, 7 and 9 in particular, represent promising targets for further studies into the identification of new pain mediators in chronic joint pain. </jats:sec

A role for pathogenic autoantibodies in small fiber neuropathy?

The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen’s syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients

Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2 ) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability

Social Preferences and the Efficiency of Bilateral Exchange

Under what conditions do social preferences, such as altruism or a concern for fair outcomes, generate efficient trade? I analyze theoretically a simple bilateral exchange game: Each player sequentially takes an action that reduces his own material payoff but increases the other player’s. Each player’s preferences may depend on both his/her own material payoff and the other player’s. I identify necessary conditions and sufficient conditions on the players’ preferences for the outcome of their interaction to be Pareto efficient. The results have implications for interpreting the rotten kid theorem, gift exchange in the laboratory, and gift exchange in the field

Continuation for thin film hydrodynamics and related scalar problems

This chapter illustrates how to apply continuation techniques in the analysis of a particular class of nonlinear kinetic equations that describe the time evolution through transport equations for a single scalar field like a densities or interface profiles of various types. We first systematically introduce these equations as gradient dynamics combining mass-conserving and nonmass-conserving fluxes followed by a discussion of nonvariational amendmends and a brief introduction to their analysis by numerical continuation. The approach is first applied to a number of common examples of variational equations, namely, Allen-Cahn- and Cahn-Hilliard-type equations including certain thin-film equations for partially wetting liquids on homogeneous and heterogeneous substrates as well as Swift-Hohenberg and Phase-Field-Crystal equations. Second we consider nonvariational examples as the Kuramoto-Sivashinsky equation, convective Allen-Cahn and Cahn-Hilliard equations and thin-film equations describing stationary sliding drops and a transversal front instability in a dip-coating. Through the different examples we illustrate how to employ the numerical tools provided by the packages auto07p and pde2path to determine steady, stationary and time-periodic solutions in one and two dimensions and the resulting bifurcation diagrams. The incorporation of boundary conditions and integral side conditions is also discussed as well as problem-specific implementation issues

The meandering instability of a viscous thread

A viscous thread falling from a nozzle onto a surface exhibits the famous rope-coiling effect, in which the thread buckles to form loops. If the surface is replaced by a belt moving with speed $U$, the rotational symmetry of the buckling instability is broken and a wealth of interesting states are observed [See S. Chiu-Webster and J. R. Lister, J. Fluid Mech., {\bf 569}, 89 (2006)]. We experimentally studied this "fluid mechanical sewing machine" in a new, more precise apparatus. As $U$ is reduced, the steady catenary thread bifurcates into a meandering state in which the thread displacements are only transverse to the motion of the belt. We measured the amplitude and frequency $\omega$ of the meandering close to the bifurcation. For smaller $U$, single-frequency meandering bifurcates to a two-frequency "figure eight" state, which contains a significant $2\omega$ component and parallel as well as transverse displacements. This eventually reverts to single-frequency coiling at still smaller $U$. More complex, highly hysteretic states with additional frequencies are observed for larger nozzle heights. We propose to understand this zoology in terms of the generic amplitude equations appropriate for resonant interactions between two oscillatory modes with frequencies $\omega$ and $2\omega$. The form of the amplitude equations captures both the axisymmetry of the U=0 coiling state and the symmetry-breaking effects induced by the moving belt.Comment: 12 pages, 9 figures, revised, resubmitted to Physical Review

A role for pathogenic autoantibodies in small fiber neuropathy?

The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen’s syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients

Does cannabis use predict psychometric schizotypy via aberrant salience?

Cannabis can induce acute psychotic symptoms in healthy individuals and exacerbate pre-existing psychotic symptoms in patients with schizophrenia. Inappropriate salience allocation is hypothesised to be central to the association between dopamine dysregulation and psychotic symptoms. This study examined whether cannabis use is associated with self-reported salience dysfunction and schizotypal symptoms in a non-clinical population. 910 University students completed the following questionnaire battery: the cannabis experience questionnaire modified version (CEQmv); schizotypal personality questionnaire (SPQ); community assessment of psychic experience (CAPE); aberrant salience inventory (ASI). Mediation analysis was used to test whether aberrant salience mediated the relationship between cannabis use and schizotypal traits. Both frequent cannabis consumption during the previous year and ASI score predicted variation across selected positive and disorganised SPQ subscales. However, for the SPQ subscales ‘ideas of reference’ and ‘odd beliefs’, mediation analysis revealed that with the addition of ASI score as a mediating variable, current cannabis use no longer predicted scores on these subscales. Similarly, cannabis use frequency predicted higher total SPQ as well as specific Positive and Disorganised subscale scores, but ASI score as a mediating variable removed the significant predictive relationship between frequent cannabis use and ‘odd beliefs’, ‘ideas of reference’, ‘unusual perceptual experiences’, ‘odd speech’, and total SPQ scores. In summary, cannabis use was associated with increased psychometric schizotypy and aberrant salience. Using self-report measures in a non-clinical population, the cannabis-related increase in selected positive and disorganised SPQ subscale scores was shown to be, at least in part, mediated by disturbance in salience processing mechanisms