Pathogenesis of trimethyltin neuronal toxicity. Ultrastructural and cytochemical observations

The ultrastructural cytopathologic and cytochemical effects of trimethyltin (TMT) neurotoxicity were delineated in hippocampal and pyriform neurons of acutely intoxicated adult rats. TMT produced neuronal necrosis that preferentially involved hippocampal formation pyriform cortex. The first subcellular alterations were multifocal collection of dense-cored vesicles and tubules and membrane-delimited vacuoles in the cytoplasm of the perikaryon and proximal dendrite. Ultrastructural cytochemical examination revealed that the vesicles and tubules had acid phosphatase activity analagous to Golgi-associated endoplasmic reticulum (GERL). Shortly after the appearance of the GERL-like vesicles and tubules, autophagic vacuoles and polymorphic dense bodies accumulated in the neuronal cytoplasm. Some dense bodies appeared to arise from the dense-cored tubules. Neuronal necrosis was characterized by increased electron density of the cytoplasm and large, electron-dense intranuclear masses. Alterations of mitochondria and other organelles were not observed in the early stages of cell injury. No light- or electron-microscopic alterations were found in liver or kidney. Comparable subcellular alterations were observed in adult and neonatal rats chronically intoxicated with TMT. A series of other trialkyl and tricyclic tins and dimethyltin did not produce similar pathologic findings. The GERL-like accumulations are unique in neuronal cytopathology. These findings suggests that GERL and autophagy play an important role in the pathogenesis of TMT-induced neuronal injury.     

Detection of amphetamine and methamphetamine-type materials in pharmaceutical and biological fluids by fluorometric labeling

A rapid and sensitive method for detecting amphetamine and methamphetamine in drug preparations and biological fluids has been developed. Amphetamine and methamphetamine in pharmaceutical and clandestine drug preparations can be easily screened from other contaminating drugs and readily identified by their fluorescence, with subsequent separation accomplished by TLC. The same general procedure can also be used to detect amphetamine and methamphetamine in human urine at concentrations of 0.1 mug/ml.     

Kinetic correlates of methotrexate transport and therapeutic responsiveness in murine tumors

Net accumulation of methotrexate by carrier-mediated transport in different murine tumor cells in vitro exhibits a positive correlation with the relative drug pharmacokinetics and therapeutic responsiveness in these tumors in vivo. The transport of methotrexate by Sarcoma 180, Ehrlich carcinoma, P388, P288, and L1210 leukemia cells is qualitatively similar. Influx of drug exhibits saturation kinetics and is highly temperature dependent (Q10, 6.1 to 9.4). Efflux of exchangeable methotrexate from all of the different tumor cells exhibited first-order kinetics and the same high temperature dependence seen for influx (Q10, 6.1 to 8.0). The major kinetic determinant of responsiveness is the Km for influx. Values vary from 3.1 to 11.2 X 10(-6) M and are highest in cells from a nonresponsive Sarcoma 180 tumor, somewhat lower in the poorly responsive Ehrlich tumor, lower in moderately responsive P388 and P288 leukemias, and lowest in the highly responsive L1210 leukemia. Values for the influx Vmax differ to some extent, but in a manner not correlatable with responsiveness. The level of responsiveness of the P388 leukemia in vivo can also be partially attributed to an efflux rate that is lower than that measured for the other tumor cells. Steady-state levels of drug accumulation in vitro reflected influx and efflux rates and were consistently correlatable with therapeutic responsiveness. There was no significant difference in the extent to which folate and reduced 5-substituted folate derivatives compete with methotrexate for uptake in cells from all five tumors. The average value for Ki measured with folate for each tumor cell type was 50- and 80-fold higher than for 5-formyltetrahydrofolate and 5-methyltetrahydrofolate.     

Melatonin induction of testicular recrudescence in hamsters and its subsequent inhibitory action on the antigonadotrophic influence of darkness on the pituitary-gonadal axis

The results of this animal study confirm the induction of delayed hypersensitivity to a halothane metabolite, but the sensitization does not cause hepatic damage on subsequent halothane exposures. Before the hypothesis that hepatic necrosis following halothane has an immunologic basis can be accepted or rejected, more critical studies with different approaches must be made.     

Frontal cortex and response suppression in the rat

Parts of the rat's neocortex were mapped for sites where electrical stimulation, square waves at 10/sec, will suppress a bar-press response for food. Effective sites were found in the frontal pole and over most of the frontal dorsolateral cortex. Within these regions the strongest inhibitory influences were at sites in the frontal pole and adjacent frontal cortex, and at sites along the midline. These data generally agree with results of previous cortical ablation studies, but they suggest that inhibitory processes are more widespread in the dorsolateral cortex than these studies indicated.     

Force and motion analysis of the normal, diseased, and prosthetic ankle joint

A 2-dimensional motion and force study of the ankle joint during gait has been carried out on normal subjects and patients with ankle joint disease, before and 1 year following total ankle replacemetn. The methods employed involved the use of high-speed motion picture film, force plate and foot-switch data. The Achilles and anterior tibial tendon forces, the compressive and tangential (shear) forces across the ankle during stance phase of gait were determined, based on a quasi-static analysis. During stance phase of gait normal subjects used a mean of 24.4 degree of sagittal plane ankle motion. Patients with ankle joint disease showed reduced motion which returned to near normal values 1 year following total ankle replacement. Compressive force across the ankle joint rose to about 5 times body weight during the latter part of stance phase. Backward, or aft, shear forces or nearly full body weight were demonstrated during all but the last 20% of stance phase. Patients with ankle joint disease apparently altered their gait to markedly reduce these forces. Following total ankle replacement, shear forces returned toward more normal values, but compressive forces were not significantly changed.