ROLE OF. AUTOANTIBODIES Next, a closer look will be taken at the pathophysiological effect of the two most frequently found antibodies, i.e., AChR and MuSK antibodies. Serum antibodies to the AChR are usually of the IgG1 or IgG3 subclass. These antibodies can cross- link because they are bivalent and they can activate serum complement to cause complement-dependent damage to the neuromuscular junction (NMJ) [13, 14]. The latter is the most important mechanism in most patients and results in morphologic damage to the NMJ with loss of AChRs [13]. This damage to the normally highly folded NMJ postsynaptic muscle membrane results in a reduction in the number of voltage-gated sodium channels, increasing the threshold for activation of the action potential and further impairing the efficacy of signal transmission [2, 13, 14]. Furthermore, accelerated internalization of the AChRs induced by polyvalent antibody cross-linking further reduces the AChR numbers. Direct blocking of AChR function by a variety of possible mechanisms is rarely a major mechanism [2]. Serum antibodies against MuSK are predominantly of the IgG4 subclass. Antibodies of the IgG4 subclass do not activate complement, and are considered to be monovalent for binding to MuSK, as IgG4 antibodies can “exchange” arms with other IgG4 antibodies. Thus, complement activation and antigenic modulation are not thought to play a major role in the pathogenesis of MuSK MG (compared with AChR MG). IgG4 MuSK antibodies block the agrin-induced binding of LRP4 to MuSK, which activates multiple signaling pathways that lead to aggregation of AChR and transition from the plaque-to-pretzel form of the neuromuscular synapse [14, 15]. Thus, in MuSK MG the disease mechanism leading to clinical weakness is clearly different from that in AChR MG. IMMUNOSUPPRESSIVE MEDICATION A large part of the patients needs long-term immunosuppressive medication, because symptomatic treatment with cholinesterase inhibitors (such as mestinon) is insufficient. Even despite immunosuppressive medication, in 10-15% of the patients full control of the disease is not achieved. This is possibly associated with severe side-effects of the medication [1]. The most frequently used medication is azathioprine combined with prednisolone, followed by mycophenolic mofetil and cyclosporine. The latter two are also frequently combined with prednisolone and are also used to reduce the dosage of prednisolone. Less frequently used medication is rituximab and eculizumab...
ROLE OF. []*. Except as otherwise provided in this Agreement (including without limitation Section 13.2(c)) or agreed by the Parties, []* will have the right to make all decisions with respect to manufacturing of Drug Substance, including without limitation, decisions relating to Manufacturing procedures, work to support quality assurance, improving Manufacturing Costs, Manufacturing efficiency and commercial scale-up Manufacturing, provided that Dyax will Manufacture or have Manufactured Drug Substance in conformity with all Applicable Law in the United States and Europe.
ROLE OF. The shall provide the following;
ROLE OF. LIMITED PARTNERS 6.1.
ROLE OF. (a) will assist APUGBCL in fund mobilization for development of urban greening and beautification in the State of A.P.
