THIP analgesia: cross tolerance with morphine

THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridone-3-ol), a direct acting GABA receptor agonist, has been shown to have antinociceptive properties. To determine whether tolerance develops to the analgesic response, mice received multiple injections of THIP for up to 21 days after which analgesia was tested using both tail immersion and hot-plate methods. Both tests indicated a significant reduction in the antinociceptive response to THIP, as well as other GABA agonists, beginning between days 3 and 5 of chronic administration. Moreover, these animals demonstrated a decreased analgesic response to morphine, and morphine tolerant animals were also less responsive to THIP. These data indicate that opiates and GABA agonists induce analgesia by acting through separate but related pathways in the central nervous system.     

Development and evaluation of a multi-applicator system of endocavitary radiothermotherapy of gynecologic tumors

An applicator system for the radiothermotherapy of gynecological tumors has been developed. The concept is based on combining high-dose rate afterloading therapy with local hyperthermia (27.12 MHz). The main applicator, the rf-gamma applicator consists of a guide tube for the gamma source, an electrode system and a cooling system. Isodoses and isotherms can be adapted to the individual anatomical-pathological situation presenting. For therapy planning the interaction between the applicators and the perfused tissue was investigated in a theoretical FEM model. In the first step, the SAR-function in the vicinity of the rf-applicator was determined by means of a 2D FEM calculation. In a second step, the 3D temperature fields was determined using linear shape functions. The results of these calculations showed that in every case the hot spots shifted from the applicator surface into the depths of the tissue. With the aid of an infrared camera and a split phantom the calculations were examined in a homogeneous non-perfused tissue model. Thermometry confirmed the accuracy of the results obtained. The radiothermotherapy system described here was tested in animal experiments, and is presently being used in a clinical pilot study.     

Evidence for a change in the structure of glutamate dehydrogenase during its catalytic cycle under cryogenic conditions

Glutamate dehydrogenase binds alpha-ketoglutarate and NADPH to form a ternary complex whose ultraviolet difference spectrum exhibits a blue-shifted coenzyme absorption band and a distinctive aromatic amino acid perturbation. When ammonia is added to this complex at -42 degrees C in 50% methanol, initiating the enzymatic reaction, these two spectral features disappear at different rates. The kinetic independence of these two features is especially evident in the presence of excess L-glutamate. We propose that, under cryogenic conditions at least, there are two forms of the enzyme. The blue shift of the coenzyme absorption band reflects only the physical presence of an alpha-ketoglutarate molecule at the active site, while the distinctive aromatic amino acid perturbation reflects a change in enzyme structure caused by alpha-ketoglutarate binding which may persist in the absence of any bound alpha-ketoglutarate molecule. Simple red and blue shifts of model tyrosine and tryptophan compounds cannot be used to simulate the observed aromatic amino acid perturbation.     

Altered cellular immune response following peer separation

Lymphocyte response to phytohemagglutinin (PHA) and concanavalin A (Con A) mitogen stimulation was measured in a pair of pigtailed ($\text{M. nemestrina}$) monkey infants that had been raised together as peers since early infancy. at the age of 27 weeks, and following 3 baseline weekly blood samples, the infants were separated from each other for an 11 day period, and then reunited. A depression of lymphocyte stimulation by both PHA and Con A was noted during the latter part of separation and early reunion in both infants. The data support the notion that the disruption of an attachment bond produced by peer separation may impair these measurements of cellular immune function, and may be related to the increase in morbidity and mortality seen after bereavement.