Suppression of peripheral pain by blockade of voltage-gated calcium 2.2 channels in nociceptors induces RANKL and impairs recovery from inflammatory arthritis in a mouse model

Objective: A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies the inflammation and joint deformation. Patients with RA rate pain relief with highest priority, however, few studies have addressed the efficacy and safety of therapies directed specifically towards pain pathways. The conotoxin MVIIA (Prialt/Ziconotide) is used in humans to alleviate persistent pain syndromes because it specifically blocks the CaV 2.2 voltage-gated calcium channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The purpose of this study was to investigate whether block of CaV 2.2 can suppress arthritic pain, and to examine the progression of induced arthritis during persistent CaV 2.2 blockade. Methods: Transgenic mice (Tg-MVIIA) expressing a membrane-tethered form of the {Omega}-conotoxin MVIIA, under the control of a nociceptor-specific gene, were employed. These mice were subjected to unilateral induction of joint inflammation using the Antigen- and Collagen-Induced Arthritis (ACIA) model. Results: We observed that CaV 2.2-blockade mediated by t-MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsides, Tg-MVIIA mice showed continued inflammation with an up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. Conclusion: Altogether, our results indicate that alleviation of peripheral pain by blockade of CaV 2.2- mediated calcium influx and signaling in nociceptor sensory neurons, impairs recovery from induced arthritis and point to the potentially devastating effects of using CaV 2.2 channel blockers as analgesics during inflammation

Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta

Background: Osteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL1A1 or COL1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships. Methods: Mutation analysis was performed using a next-generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES). Results: Patients offspring of nonconsanguineous parents were mostly identified with COL1A1 or COL1A2 heterozygous changes, although there were also a few cases with IFITM5 and WNT1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, TMEM38B, and WNT1. In addition, two patients born to consanguineous parents were found to have de novo COL1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants in SCN9A, NTRK1, and SLC2A2, which are associated with congenital indifference to pain (CIP) and Fanconi–Bickel syndrome (FBS). Conclusion: This work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role of SCN9A and NTRK1 in bone development

Lex Mercatoria: scope and application of the law merchant in arbitration

Magister Legum - LLMArbitration is the preferred method of dispute resolution in international trade. Naturally, a set of rules is necessary to govern the conflict’s resolution. For cultural, political, economical or other reasons the parties’ national laws may not serve the individual interests and needs of that particular contract well. If one wants to avoid the application of both parties’ national laws, one can choose that the contract be governed by an a-national legal standard, e.g. general principles of International Trade Law or the general usages of a particular trade. These internationally accepted principles of law governing contractual relations are called lex mercatoria (law merchant). Lex mercatoria already existed in the Middle Ages and can even be dated back to antiquity. Later it disappeared through the nationalization of International Trade Law and was rediscovered in the 1950s, when international traders were again creating their own law and disputes were increasingly resolved outside of the national jurisdictions and applying a-national law. Lex mercatoria is being applied more and more by arbitrators and is therefore becoming increasingly important for dispute resolution in International Trade. Numerous different concepts and theories of lex mercatoria have been developed. Its being an autonomous legal system is questioned by some authors and the doctrine in favour of it called unfounded. The critics also argue that the authority to apply lex mercatoria may be a recipe for amateurism and the substitution of the arbitrator’s private preferences for the parties’ intentions, for itis easy to proclaim common principles on the basis of limited knowledge. The lex mercatoria is said only to exist because scholars talk about it. However, these and other allegations can be refuted by critically analyzing the arguments that are supposed to underline those assumptions. Applying lex mercatoria to solve international trade disputes has many advantages. By choosing lex mercatoria the parties avoid rules which are unfit for international contracts, e.g. peculiar formalities, brief cut-off periods and special difficulties created by domestic laws. In addition to that, neither of the parties has the advantage of having the dispute governed by his own law. Since one of the central rules is the principle of good faith and fair dealing, lex mercatoria neither leads to arbitrary results nor does it favour the rich. Is it possible for the arbitrators to apply lex mercatoria if no law has been chosen by the parties? The failure of the parties to indicate a choice could well mean that they did not wish to have their contract governed by any of their national laws. In some awards arbitrators applied lex mercatoria as they considered the community of international merchants to be autonomous and to exist beyond national legislation. However, it cannot be deduced from the absence of such a choice that the parties have impliedly chosen lex mercatoria to be the law governing the conflict. Lex mercatoria is applicable only as a subsidiary law in cases where no national law has been chosen and seems apt.South Afric

A chronic model of arthritis supported by a strain-specific periarticular lymph node in BALB/c mice

Current animal models of arthritis only partially reflect the complexity of rheumatoid arthritis and typically lack either chronicity or autoantibody formation. Here we describe a model that combines features of antigen-induced arthritis and collagen-induced arthritis, which can be efficiently induced in BALB/c and C57BL/6 mice. However, BALB/c mice generate significantly higher titres of anticollagen and anticitrullinated peptide antibodies, show a stronger progressive joint destruction, and in the chronic phase the disease spreads between joints. Concomitant to the observation of a more severe pathology, we discovered a previously undescribed small periarticular lymph node in close proximity to the knee joint of BALB/c mice, which acts as the primary draining lymph node for the synovial cavity. Our model more closely reflects the pathology of rheumatoid arthritis than classical models of arthritis and is hence particularly suitable for further studies of disease pathogenesis

Suppression of Peripheral Pain by Blockade of Voltage-Gated Calcium 2.2 Channels in Nociceptors Induces RANKL and Impairs Recovery From Inflammatory Arthritis in a Mouse Model

OBJECTIVE: A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies the inflammation and joint deformation. Patients with RA rate pain relief with highest priority, however, few studies have addressed the efficacy and safety of therapies directed specifically towards pain pathways. The conotoxin MVIIA (Prialt/Ziconotide) is used in humans to alleviate persistent pain syndromes because it specifically blocks the Ca(V)2.2 voltage-gated calcium channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The purpose of this study was to investigate whether block of Ca(V)2.2 can suppress arthritic pain, and to examine the progression of induced arthritis during persistent Ca(V)2.2 blockade. METHODS: Transgenic mice (Tg-MVIIA) expressing a membrane-tethered form of the ω-conotoxin MVIIA, under the control of a nociceptor-specific gene, were employed. These mice were subjected to unilateral induction of joint inflammation using the Antigen- and Collagen-Induced Arthritis (ACIA) model. RESULTS: We observed that Ca(V)2.2-blockade mediated by t-MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsides, Tg-MVIIA mice showed continued inflammation with an up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. CONCLUSION: Altogether, our results indicate that alleviation of peripheral pain by blockade of Ca(V)2.2- mediated calcium influx and signaling in nociceptor sensory neurons, impairs recovery from induced arthritis and point to the potentially devastating effects of using Ca(V)2.2 channel blockers as analgesics during inflammation

Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis

BACKGROUND: This study examined the development of chronic pain, a cardinal symptom of rheumatoid arthritis (RA), in mice with antigen- and collagen-induced arthritis (ACIA). Since the role of CD8(+) T cells in arthritis is controversial, we investigated the consequences of CD8-depletion on arthritis development and opioid modulation of pain in this novel model of chronic autoimmune arthritis. METHODS: Disease severity in control and CD8-depleted animals was determined by histological assessment of knee-joint sections and measurement of autoantibody formation. Pain was evaluated by measuring mechanical allodynia and thermal hyperalgesia in von Frey and Hargreaves tests, respectively. The production and release of endogenous opioids and inflammatory cytokines was assessed in immunoassays. RESULTS: In ACIA, mice display persistent mechanical allodynia and thermal hyperalgesia for more than 2 months after induction of arthritis. The blockade of peripheral opioid receptors with naloxone-methiodide (NLXM) transiently increased thermal hyperalgesia, indicating that endogenous opioid peptides were released in the arthritic joint to inhibit pain. CD8(+) T cell depletion did not affect autoantibody formation or severity of joint inflammation, but serum levels of the pro-inflammatory cytokines TNFα and IL-17 were increased. The release of opioid peptides from explanted arthritic knee cells and the NLXM effect were significantly reduced in the absence of CD8(+) T cells. CONCLUSIONS: We have successfully modeled the development of chronic pain, a hallmark of RA, in ACIA. Furthermore, we detected a yet unknown protective role of CD8(+) T cells in chronic ACIA since pro-inflammatory cytokines rose and opioid peptide release decreased in the absence of these cells