Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in myasthenia gravis (MG) patients through complement pathway-mediated destruction of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies against muscle-specific kinase (MuSK), which constitute a major subclass of antibodies found in MG patients, do not activate the complement pathway. To investigate the pathophysiology of MuSK-MG and establish an experimental autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in complement component five (C5). MuSK-injected mice simultaneously developed severe muscle weakness, accompanied by an electromyographic pattern such as is typically observed in MG patients. In addition, we observed morphological and functional defects in the NMJs of EAMG mice, demonstrating that complement activation is not necessary for the onset of MuSK-MG. Furthermore, MuSK-injected mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE and the AChE-anchoring protein collagen Q at postsynaptic membranes. These findings suggest that MuSK is indispensable for the maintenance of NMJ structure and function, and that disruption of MuSK activity by autoantibodies causes MG. This mouse model of EAMG could be used to develop appropriate medications for the treatment of MuSK-MG in humans.
There are significant age-related changes in autonomic nervous system function that are responsible for an impaired ability to adapt to environmental or intrinsic visceral stimuli in the elderly. We review data on changes in autonomic nervous system regulation of cardiovascular and urinary function, as well as data on strategies to improve function. There are data showing alterations in peripheral and central autonomic nerve activity, and decreases in neurotransmitter receptor action that lead to diminished autonomic reactivity (e.g. blood pressure and cerebral blood flow regulation) and poorly coordinated autonomic discharge (e.g. bladder function). Simple strategies for autonomic function improvement and increasing cortical blood flow include walking and somatic afferent stimulation (e.g. stroking skin or acupuncture) to increase sympathetic, parasympathetic and central cholinergic activity. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S127-S136.
1. Electrophysiological techniques were used to characterize responses of afferent fibers in pelvic nerve of adult, virgin female rats to mechanical or chemical stimulation of internal reproductive organs and to mechanical stimulation of other pelvic organs. 2. In an in vivo barbiturate-anesthetized preparation, pelvic nerve afferent fibers responded to a wide variety of mechanical stimulation applied to restricted regions of the vaginal canal, caudal uterus (body and cervix), bladder, ureter, colon, or anus. 3. Single-fiber mechanoreceptive fields were invariably confined to a single organ. Notably, responses could be evoked not only by gentle stimulation of the unit's receptive field directly on the organ itself, but also by stimulating the field indirectly with intense stimulation through the appropriate part of a contiguous organ. This innervation feature is consistent with the separability of pelvic organ functions under innocuous conditions but their confusion under noxious ones. 4. Receptive fields on the reproductive organs extended from the caudal edge of the vagina to the uterine body (including the cervix) but were most often located in the fornix (vaginocervical junction). Most units had no or low levels of spontaneous activity. Their responses to mechanical stimuli were usually slowly or moderately adapting and time-locked to the stimulus. 5. Fibers with vaginal receptive fields (including the fornix) responded best either to vaginal distension with a balloon or, more often, to a probe moving along the internal vaginal surface in a direction toward the cervix. They were observed most frequently during the proestrus stage of the rat's estrous cycle. These fibers, therefore, seem particularly suited for relaying information about stimuli that occur during mating. 6. Fibers with receptive fields on the uterine cervix and body responded best to static pressure and were observed less frequently than those with vaginal fields, regardless of estrous stage. They were, however, sensitized by hypoxia. In addition, irritation of the uterus increased the probability of observing them. These fibers, therefore, may exert their primary function during reproductive conditions different from those of virgin rats, such as parturition. 7. Response activity of most of the mechanoreceptive afferent fibers supplying reproductive organs increased as the stimulus intensity increased into the noxious range; i.e., into a range in which the stimulus momentarily produced ischemia at the stimulus site. In addition, in an in vitro preparation, pelvic nerve fibers responded in a dose-dependent manner to injections through the uterine artery of bradykinin (BRAD) as well as to other algesic chemicals, 5-hydroxytryptamine (5-HT) and KCl.(ABSTRACT TRUNCATED AT 400 WORDS)
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