Toxicity and dose-response studies of 1,25-(OH)2-16-ene-23-yne vitamin D3 in transgenic mice.

The vitamin D3 analogue 1,25-(OH)2-16-ene-23-yne vitamin D3 (16,23-D3) in doses with low systemic toxicity has been demonstrated to inhibit retinoblastoma growth in transgenic mice. This study examines the dose-dependent response for inhibition of tumor growth in transgenic mice with retinoblastoma and evaluates the in vivo toxicity of 16,23-D3 in nontransgenic mice. Transgenic 8-10-week-old mice with retinoblastoma (n = 119) were randomly assigned to groups receiving 1.0, 0.75, 0.5, 0.35, 0.2, or 0.05 microg of 16,23-D3 and a vehicle alone (control) group i.p. five times a week for 5 weeks. An additional control group received no injection. Eyes were enucleated one week after the end of treatment, and tumor areas were measured. To determine the toxic dose, transgene-negative littermates received 0.5, 1.0, 1.5, 2.5, 3.5, 4.5, or 5.0 microg of 16,23-D3, and control groups received vehicle alone, 5 days a week for 5 weeks. Serum calcium levels were measured, and necropsies were performed on animals from each group. In the dose-response study, tumor growth inhibition was greatest in the group receiving 0.35 microg (55% inhibition; P = 0.0056) and was also significant in the group receiving 0.5 microg (42% inhibition; P = 0.036). The systemic toxic effects due to hypercalcemia occurred at doses of > or =1.0 microg. 16,23-D3 inhibits tumor growth at doses > or =0.35 microg and shows toxic effects at doses > or =1.0 microg related to hypercalcemia in mice fed an unrestricted diet. No toxicity was observed with lower doses.

Melanocytes and iris color. Light microscopic findings.

OBJECTIVE: To systematically evaluate morphologic differences in iris stroma that contribute to clinically perceptible differences in iris color, using immunohistochemical identification of stromal melanocytes and fluorescence microscopy. METHODS: Paraffin-embedded sections from 51 human irides were stained with S100a and fluorescein isothiocyanate. Cells were counted and scored as melanocytes or other. Melanocyte number, proportion, and density were determined for light-colored (blue), medium-colored (hazel) and dark-colored (brown) irides and compared. RESULTS: No statistically significant difference was observed for mean total cellularity or mean melanocyte number among the three color groups. Mean total stromal cell count was 1177 +/- 259 (mean +/- SEM), and mean melanocyte number was 778 +/- 196 per 5-micrometer section. In human irides, 65.9% of the iris stroma is composed of melanocytes. Melanocyte density (number of cells per square millimeter) is not related to iris color. CONCLUSION: The number of melanocytes, the proportion of melanocytes, and iris stromal cellularity are not major contributors to iris color.

Determination of pulmonary deposition, translocation and clearance using neutron activation techniques.

Neutron activation provides a sensitive technique to estimate pulmonary deposition, translocation and clearance of inhaled particles. Talc and fly ash were irradiated in an integrated neutron flux of or approximately 10(16) n/cm2. Radionuclides were induced by (n, gamma) reactions on major an minor elements in the dusts. Hamsters received a single nose-only exposure to the dusts. Groups of 4 to 6 animals were than serially sacrificed at intervals up to 4 months postexposure. Lungs, other tissues of interest and excreta were collected for gamma-ray analysis. Limit of detection for the isotopes 60Co or 46Sc was or approximately 0.1 dpm, facilitating detection of 10(-11) gram quantities of these elements. Analyzing for more than one radionuclide and comparing their ratios in the bulk dust to those in the tissue or excreta indicated whether a radionuclide leached from the particle or represented particles in the tissue samples. Six to 8% of the inhaled talc were deposited in the alveoli; its biological half-life in the lung was 7 to 10 days. Alveolar clearance was essentially complete 4 months postexposure. No translocation of talc to liver, kidneys, ovaries of other parts of the body was found. Picogram quantities of 60Co found in the urine probably represented leached 60Co, absorbed in the gastrointestinal tract. Two to 3% of the inhaled fly ash were initially retained in the respiratory tract. Estimated biological half-lives were 3 and 35 days for airways and alveoli, respectively. After 99 days the mean lung burden had decreased to about 10% of its initial value; extrapolation suggests near-complete pulmonary clearance at about 200 days postexposure.

Comparison of APACHE II, TRISS, and a proposed 24-hour ICU point system for prediction of outcome in ICU trauma patients.

The APACHE II system for predicting outcomes in critically ill patients is now being used to evaluate quality of care for patients in surgical intensive care units, including trauma patients. The trauma data, however, on which the APACHE outcomes are based, were derived from only 364 ICU trauma patients. We compared the outcome predictions by APACHE II, TRISS, and a proposed 24-hour ICU point system in 1,000 ICU patients. [table: see text] p less than 0.025 by unpaired t test for predictive power of ICU point system versus APACHE II. Values of more than 15.5 represent poor agreement between the outcomes estimated from the model and the observed outcomes; a low value represents good agreement. The APACHE system significantly overestimated the risk of death in the lower ranges of predicted risk and underestimated the deaths in the higher ranges. Although TRISS was not developed for ICU trauma patients, it tended to perform better than APACHE II in our sample. The 24-hour ICU point system performed well, with accurate agreement between the outcomes estimated from the model and the observed outcomes.