In previously healthy adults with otherwise unexplained disseminated/extrapulmonary Nocardia infections, anti-GM-CSF autoantibodies should be considered. Their presence may suggest that these patients may be at risk for later development of pulmonary alveolar proteinosis or other opportunistic infections, and that patients may benefit from therapeutic GM-CSF administration.

Damage to white matter occurs in the brains of patients with Alzheimer s disease (AD), but it is not known if and how oligodendrocytes are affected in AD, nor whether white matter alterations contribute to the cognitive dysfunction in this disease. Mutations in the gene encoding presenilin-1 (PS1) cause some cases of early-onset inherited AD. These mutations may promote neuronal degeneration by increasing the production of neurotoxic forms of amyloid beta-peptide and by perturbing cellular calcium homeostasis. Damage to oligodendrocytes induced by a demyelinating agent is enhanced, and spatial learning is impaired in PS1 mutant knockin mice. Oligodendrocytes from PS1 mutant knockin mice are more vulnerable to being killed by glutamate and amyloid beta-peptide, and exhibit an abnormality in calcium regulation which is responsible for their death. These findings demonstrate an adverse effect of a disease-causing PS1 mutation in oligodendrocytes, and suggest a mechanism responsible for white matter damage in AD and a contribution of such damage to cognitive impairment.

We investigated whether M(2) muscarinic receptor activation opposes isoproterenol-induced relaxation in mouse urinary bladder and whether endogenous acetylcholine acts through a similar M(2) mechanism. When measured in urinary bladder from M(3) receptor knockout mice, the muscarinic agonist oxotremorine-M elicited only very weak contractions. In the presence of alpha,beta-methylene ATP (30 microM) and isoproterenol (1 microM), however, oxotremorine-M elicited a robust contractile response. This response was completely absent in bladder from M(2)/M(3) double knockout mice, indicating that activation of the M(2) receptor inhibits the relaxant effect of isoproterenol on the contraction to alpha,beta-methylene ATP. Similar results were obtained when prostaglandin F(2alpha) (5 microM) was used as the contractile agent but not when serotonin was used. Electrical field stimulation of the urinary bladder from wild-type mouse elicited contractions that were inhibited 20% by atropine and 40% by desensitization with alpha,beta-methylene ATP. When measured in the presence of alpha,beta-methylene ATP to desensitize the purinergic component of contraction, isoproterenol exhibited moderately greater relaxant activity in field-stimulated bladder from the M(2) knockout mouse compared with that observed in wild-type bladder. This differential relaxant effect of isoproterenol was greatly increased in the presence of physostigmine. In contrast, no differential effects were noted for isoproterenol in similar experiments on bladders from M(3) knockout and M(2)/M(3) double knockout mice in the presence of physostigmine. Our results suggest that neuronally released acetylcholine acts on the M(2) muscarinic receptor to inhibit the relaxant effect of isoproterenol on the minor, cholinergic component of contraction in the field-stimulated mouse urinary bladder.

No abstract

Muscarinic agonists and antagonists are used to treat a handful of gastrointestinal (GI) conditions associated with impaired salivary secretion or altered motility of GI smooth muscle. With regard to exocrine secretion, the major muscarinic receptor expressed in salivary, gastric, and pancreatic glands is the M₃ with a small contribution of the M₁ receptor. In GI smooth muscle, the major muscarinic receptors expressed are the M₂ and M₃ with the M₂ outnumbering the M₃ by a ratio of at least four to one. The antagonism of both smooth muscle contraction and exocrine secretion is usually consistent with an M₃ receptor mechanism despite the major presence of the M₂ receptor in smooth muscle. These results are consistent with the conditional role of the M₂ receptor in smooth muscle. That is, the contractile role of the M₂ receptor depends on that of the M₃ so that antagonism of the M₃ receptor eliminates the response of the M₂. The physiological roles of muscarinic receptors in the GI tract are consistent with their known signaling mechanisms. Some so-called tissue-selective M₃ antagonists may owe their selectivity to a highly potent interaction with a nonmuscarinic receptor target.