Compound 48/80 blocks transmission and increases the excitability of ganglion neurons.

Compound 48/80 (5.0-50 micrograms/ml) significantly and reversibly decreased (1) the amplitude, but not the shape of the compound action potential, (2) the amplitude and duration of the acetylcholine potential and (3) the residual fast excitatory postsynaptic potential recorded from neurons of the 9th and 10th paravertebral ganglia of the bullfrog Rana catesbeiana. The excitability of B-type ganglion neurons in the presence of nicotinic and muscarinic receptor antagonists was increased by compound 48/80 without altering the input resistance or membrane potential. In addition, compound 48/80 (10-50 micrograms/ml) significantly decreased the duration of the spike afterhyperpolarization (AHP). The amplitude but not the decay rate of the current underlying the slow component of the spike AHP was decreased by compound 48/80. Compound 48/80 did not, however, alter either the amplitude or the duration of calcium-dependent spikes. Intracellular recordings from dissociated sympathetic neurons also demonstrated a compound 48/80-induced increase in neuronal excitability. These results suggest that compound 48/80 interacts with the nicotinic receptor/channel complex to decrease ganglionic transmission, and also has a direct action to increase neuronal excitability by blocking potassium channels mediating the duration of the spike AHP.     

Low-artifact intravascular devices: MR imaging evaluation

Flow-phantom magnetic resonance (MR) imaging, with use of both spin-echo (SE) and gradient-echo (GRE) techniques at 1.5 T, was performed on the percutaneous Greenfield (beta-III titanium alloy [TMA wire]), Amplatz (MP32-N alloy), and Simon nitinol filters and TMA wire facsimiles of the bird's nest, Gunther, new retrievable, and Amplatz vena caval filters. SE imaging allowed detection of thrombi as small as 5 X 5 mm trapped within the percutaneous Greenfield, Simon nitinol, and TMA-wire facsimile filters; with the MP32-N Amplatz filter, a larger volume of thrombus (10 X 20-mm clots) was necessary for clot detection. GRE imaging allowed detection of intraluminal tilting of the percutaneous Greenfield and facsimile Amplatz (TMA-wire) filters. GRE imaging was useful for demonstrating postfilter turbulence due to clots, which was greatest for the Amplatz filter. Imaging of facsimile vascular devices made of tantalum or TMA wire did not cause the severe "black-hole" MR artifacts typical of the stainless-steel devices. SE and GRE imaging were very useful for determining caval patency in two patients with previously placed Mobin-Uddin filters. Noninvasive MR evaluation of blood vessels in the presence of a variety of low-artifact intravascular devices appears feasible.     

MCF10AT: a model for the evolution of cancer from proliferative breast disease.

A human cell line (MCF10A) originated from spontaneous immortalization of breast epithelial cells obtained from a patient with fibrocystic disease. MCF10A cells do not survive in vivo in immunodeficient mice. However, T24 c-Ha-ras oncogene-transfected MCF10A cells (MCF10AT) form small nodules in nude/beige mice that persist for at least 1 year and sporadically progress to carcinomas. By reestablishing cells in tissue culture from one of the carcinomas, a cell line designated MCF10AT1 was derived that forms simple ducts when transplanted in Matrigel into immunodeficient mice. With time in vivo, the epithelium becomes proliferative and a cribriform pattern develops within the xenografts. A significant number progress to lesions resembling atypical hyperplasia and carcinoma in situ in women, and approximately 25% progress to invasive carcinomas with various types of differentiation including glandular, squamous, and undifferentiated. Cells have been established in culture from lesions representing successive transplant generations. With each generation, cells are somewhat more likely to progress to high risk lesions resembling human proliferative breast disease. Although the incidence of invasive carcinoma remained fairly constant at 20 to 25%, the frequency of nodules showing proliferative breast disease rose from 23% in the first transplant generation to 56% in the fourth transplant generation.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Osteopetrosis: MR characteristics at 1.5 T

Four patients with proved osteopetrosis (three with the infantile malignant form and one with the benign form) were examined with magnetic resonance imaging at 1.5 T. All patients were studied in the coronal and sagittal planes using both short and long repetition time/echo time sequences. The infantile malignant form was characterized by a complete lack of signal from the marrow alternating with a signal intensity equivalent to that of the intervertebral disks, resulting in a "stepladder" appearance. In the benign form or after successful marrow transplantation in the infantile malignant form, intermediate or high signal intensity in the vertebrae was noted, suggesting the presence of some marrow elements.