The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability.

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly considered, the function of the NMJ is to transduce a nerve action potential into a muscle fiber action potential (MFAP). Efficient information transfer requires both cholinergic signaling, responsible for the generation of endplate potentials (EPPs), and excitation, the activation of postsynaptic voltage-gated sodium channels (Nav1.4) to trigger MFAPs. In contrast to the cholinergic apparatus, the signaling pathways that organize Nav1.4 and muscle fiber excitability are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as an agrin-LRP4 receptor, is also a BMP co-receptor that binds BMPs via its Ig3 domain and shapes BMP-induced signaling and transcriptional output. Here we probed the function of the MuSK-BMP pathway at the NMJ using mice lacking the MuSK Ig3 domain ('ΔIg3-MuSK'). Synapses formed normally in ΔIg3-MuSK animals, but the postsynaptic apparatus was fragmented from the first weeks of life. Anatomical denervation was not observed at any age examined. Moreover, spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable to WT. However, trains of nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal as revealed by increased jitter and blocking in single fiber electromyography. Further, nerve-evoked compound muscle action potentials (CMAPs), as well as twitch and tetanic muscle torque force production, were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK synapses but not at the extrajunctional sarcolemma, indicating that the observed excitability defects are the result of impaired localization of this voltage-gated ion channel at the NMJ. We propose that MuSK plays two distinct roles at the NMJ: as an agrin-LRP4 receptor necessary for establishing and maintaining cholinergic signaling, and as a BMP co-receptor required for maintaining proper Nav1.4 density, nerve-evoked muscle excitability and force production. The MuSK-BMP pathway thus emerges as a target for modulating excitability and functional innervation, which are defective in conditions such as congenital myasthenic syndromes and aging.

Successful treatment of methicillin-resistant Staphylococcus aureus Keratitis with topical ciprofloxacin.

Ciprofloxacin is a new quinolone antibiotic with a broad spectrum of activity against most aerobic gram-positive and gram-negative bacteria. Topical ciprofloxacin (3 mg/ml) was used to treat bacterial keratitis caused by methicillin-resistant strains of Staphylococcus aureus in two patients. Both corneal ulcers had been previously treated with other antibiotics without success. Topical ciprofloxacin was curative in both cases. The authors recommend the use of topical ciprofloxacin for methicillin-resistant S. aureus keratitis.

Transmission of gram-negative bacilli to asthmatic children via home nebulizers.

Home use of nebulizers has increased in recent years, although adequate studies have not been performed to evaluate for possible contamination or transmission of potentially harmful bacteria. This study of 20 asthmatic children demonstrated that transmission of pathogenic bacteria occurs.

Molteno implantation for secondary glaucomas associated with advanced epithelial ingrowth.

Nine patients with advanced epithelial ingrowth underwent Molteno implantation for medically uncontrollable secondary glaucomas. Substantial reductions in intraocular pressures (IOPs) were observed in most patients (preoperative IOPs ranged from 5 to 48 mmHg [mean +/- standard deviation, 33.6 +/- 14.6 mmHg]; postoperative IOPs ranged from 10 to 30 mmHg [mean +/- standard deviation, 16.0 +/- 6.5 mmHg]); follow-up ranged from 9 to 47 months (mean +/- standard deviation, 18.8 +/- 12.1 months). Seven (78%) patients had final postoperative IOPs of less than 22 mmHg, five (56%) retained formed vision (visual acuity of at least 1/200), and six (67%) remained comfortable. Postoperative complications related to Molteno implantation included one case each of: conjunctival wound leak, vitreous-tube block, tube-cornea touch, and iris-tube block (or tube retraction). Complications attributed to epithelial ingrowth included five cases of corneal decompensation with band keratopathy. Molteno implantation is an effective technique for palliative treatment of secondary glaucomas associated with advanced epithelial ingrowth, frequently maintaining modest vision and comfort in eyes in which the intraocular epithelialization is too extensive for surgical removal and/or destruction.

Progressive cranial polyneuropathy caused by primary central nervous system melanoma.

Primary malignant melanoma of the central nervous system (CNS) is exceedingly rare. The earliest description by Virchow in 1859 has been followed by approximately 50 autopsy-proven cases reported in the literature. These tumors are considered to arise from leptomeningeal melanocytes whose embryonic origin is neural crest tissue. Given the rarity of primary CNS melanoma, the diagnosis requires a thorough search to exclude a dermatologic, ocular, or visceral site of tumor origin. We report an unusual case of primary CNS melanoma in a patient with painful, progressive cranial polyneuropathy that eluded antemortem diagnosis despite extensive clinical, radiographical, and laboratory investigations.

Persistence of diurnal fluctuation after radial keratotomy.

Three patients were examined before 8:00 AM and after 7:00 PM to determine diurnal changes in uncorrected visual acuity, refractive error, and average central keratometric power at 3 months, 4 years, and 6 years after radial keratotomy. The average absolute diurnal change in the spherical equivalent refraction increased over time: 0.26 diopters at 3 months, 0.75 D at 4 years, and 1.29 D at 6 years. Diurnal change in the absolute average keratometric values were not progressive: 0.35 D at 3 months, 0.27 D at 4 months, and 0.40 D at 6 years. Computer-assisted corneal topographic analysis demonstrated diurnal changes in the topography that may be subtle and not necessarily reflected in the average keratometry values. These limited data suggest that wound healing over several years may not restore stability to the cornea.

Inhibition of macrophage-induced tumor cell cytostasis and cytolysis by tumor-promoting phorbol diesters.

The effects of 3 tumor-promoting phorbol diesters and the corresponding inactive polyol phorbol on cytostatic and cytolytic activities of activated murine peritoneal macrophages toward target tumor cells derived from skin cells of the same species were examined. In both cases the diesters, without showing concurrent toxicity, considerably suppressed in dose-related fashion, the activity of the macrophages at concentrations active in promotion in vivo, being active even in nanogram quantities. The order of activity among different diesters for cytostasis or cytolysis was the same as that observed toward tumor promotion in mouse skin. The non-promoter phorbol was inactive in all instances. These findings concur with proposals for an important role for abrogation of normal antitumor defense mechanisms in promotion of mouse skin carcinogenesis by active phorbol diesters.

Lactate dehydrogenase isoenzyme levels in collagen disease.

Serum lactate dehydrogenase (LDH) isoenzymes were determined in 27 patients with collagen disease and 88 normal subjects. The mean value for LDH-3 isoenzyme was 20.4 +/- 3% in normal controls, 31.47 +/- 8.9% in patients with collagen disease who showed activity of the disease, and 20 +/- 3.74% in patients in complete remission. Six patients who had positive rheumatoid factor showed higher LDH-3 levels. There was also some correlation between the activity of the disease and serum LDH-3 level in patients with connective tissue disorders.