Critical development periods for inhibition of ornithine decarboxylase by alpha-difluoromethylornithine: effects on ontogeny of sensorimotor behavior.

The roles of ornithine decarboxylase and the polyamines in behavioral development were examined through the use of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase. alpha-Difluoromethylornithine was administered either prenatally during gestation (days 15-17) or postnatally (days 1-20) to examine critical periods of sensitivity. Prenatal alpha-difluoromethylornithine administration resulted in a deficit in early sensorimotor ontogeny: latencies in surface righting reflex (postnatal days 1-5) and negative geotaxis (postnatal days 5-8) were prolonged, and time spent pivoting (postnatal days 7, 9, and 11) was reduced. In contrast, postnatal alpha-difluoromethylornithine primarily influenced later maturing, complex integrative behaviors such as swimming and open field activity. Thus, the behavioral effects of alpha-difluoromethylornithine exposure are highly dependent upon the age at which the drug is administered, a finding in keeping with the participation of the ornithine decarboxylase/polyamine system in cell replication and differentiation during discrete periods of neural development. The behavioral consequences of ornithine decarboxylase inhibition during these critical periods are thus related primarily both to the timetable for cellular maturation in each brain region.

Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature.

Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor "feeding" vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.

Mucocele of the appendix: imaging findings.

Mucocele of the appendix, a cystic mass resulting from a dilated appendiceal lumen caused by abnormal accumulation of mucus, is a rare entity that often is not considered when problems of the right lower quadrant are assessed. Preoperative recognition of mucocele of the appendix is important because of the possibility of rupture at surgery with development of pseudomyxoma peritonei and to predict malignant transformation. The appearances of mucoceles of the appendix on sonography, CT, and barium studies are illustrated.

Soft-tissue sarcomas: detection of metabolic heterogeneity with P-31 MR spectroscopy.

Regional variations in metabolic parameters derived with multivoxel, localized phosphorus-31 magnetic resonance (MR) spectroscopy in spontaneous human-soft-tissue sarcomas were compared with variations in the same parameters in normal human legs. In addition, multivoxel P-31 MR spectroscopy of transplanted rodent sarcomas and microelectrode measurement of pH and PO2 in several locations within them were performed, and, when appropriate, results were compared with the clinical data. Striking voxel-voxel variability in parameters derived with P-31 spectroscopy was found in tumors, with less marked variability seen in normal legs. In the rodent tumors, spatial variations also were found in pH and PO2 measured by means of microelectrodes. These data are consistent with the results of regional measurements in tumors by means of other methods and suggest that clinical MR spectroscopic studies of tumors may need to consider the variability within malignant lesions.

Evaluation of BA1112 rhabdomyosarcoma oxygenation with microelectrodes, optical spectrophotometry, radiosensitivity, and magnetic resonance spectroscopy.

We studied tumor tissue oxygenation in the BA1112 rhabdomyosarcoma using micro-electrode pO2 measurements, optical spectrophotometry, analyses of cell survival after irradiation, and 31P magnetic resonance spectroscopy (MRS). Studies were carried out in WAG/Rij/Y rats breathing normoxic, hypoxic, and hyperoxic gas mixtures with and without iv administration of perfluorochemical. Significant changes in tissue oxygenation and metabolic status were found when pO2 values, optical measurements of hemoglobin saturation and cytochrome a, a3 reduction-oxidation, radiation cell survival determinations, and MRS measurements of phosphometabolite ratios were obtained in rats breathing different gas mixtures. Inhalation of 100% O2 caused increases in tumor pO2, hemoglobin saturation, cytochrome a, a3 oxidation, tumor radiosensitivity, and PCr/Pi, NTP/Pi, and PDE/Pi ratios. Such changes were augmented by pretreatment with iv perfluorochemicals. Inhalation of hypoxic gas mixtures resulted in reductions in the above parameters. These results indicate that tissue oxygenation can be manipulated reproducibly in the BA1112 rhabdomyosarcoma and suggest that 31P MRS can be used to monitor changes in tumor oxygenation in this model system.