ABSTRACT
An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice but not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dose-dependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess on-target activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.
Subject(s)
Antidepressive Agents/therapeutic use , Depression/drug therapy , Drug Evaluation, Preclinical , Excitatory Amino Acid Agents/therapeutic use , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/metabolism , Analysis of Variance , Animals , Conditioning, Operant/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Excitatory Amino Acid Agents/chemistry , Excitatory Amino Acid Agents/pharmacology , Exploratory Behavior/drug effects , In Vitro Techniques , Male , Mice , Mice, Knockout , Movement/drug effects , Rats , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/deficiencyABSTRACT
Conversion factors, which relate the kerma-area product to effective dose, have been estimated for paediatric cardiac x-ray angiography. Monte Carlo techniques have been used to calculate the conversion factors for a wide range of projection angles for children of five ages and for adults. Correction factors are provided so that the conversion factors can be adjusted for different tube potentials and filtrations.
Subject(s)
Angiography/methods , Radiometry/methods , Adolescent , Adult , Algorithms , Child , Child, Preschool , Computer Simulation , Female , Humans , Infant , Infant, Newborn , Male , Models, Anatomic , Monte Carlo Method , Phantoms, Imaging , Reference Values , Reproducibility of Results , X-RaysABSTRACT
The need for test objects in mammography quality control programmes to provide an objective measure of image quality pertinent to clinical problems is well documented. However, interobserver variations may be greater than the fluctuations in image quality that the quality control programme is seeking to detect. We have developed a computer algorithm to score a number of features in the Leeds TOR(MAX) mammography phantom. Threshold scoring techniques have been applied in the first instance; scoring schemes which utilize measures such as signal-to-noise ratio and modulation have also been formulated. This fully automatic algorithm has been applied to a set of 10 films which have been digitized at 25 microns resolution using a Joyce-Loebl scanning microdensitometer. The films were chosen retrospectively from quality control test films to demonstrate: (a) a range of optimized imaging systems, and (b) variation from the optimum. The performance of the algorithm has been compared with that of five experienced observers, and has been shown to be as consistent as individual observers, but more consistent than a pool of observers. Problems have been encountered with the detection of small details, indicating that a more sophisticated localization technique is desirable. The computer performs more successfully with the scoring scheme which utilizes the full imaging information available, rather than with the threshold-determined one. However, both the observers and the computer algorithm failed to identify the non-optimum films, suggesting that the sensitivity of the TOR(MAX) test object may not be adequate for modern mammography imaging systems.
Subject(s)
Image Processing, Computer-Assisted/methods , Mammography/instrumentation , Phantoms, Imaging , Algorithms , Feasibility Studies , Female , Humans , Observer Variation , Quality Control , Retrospective Studies , X-Ray FilmABSTRACT
The sparse fur (spf/Y) mouse was evaluated as a model for studying gene therapy in ornithine carbamoyltransferase deficiency (OCTD), the most common inborn error of urea synthesis. Previous studies have defined a number of biochemical characteristics of this animal model that are analogous to the human disease: OCTD in liver, elevated ammonium and glutamine, low citrulline and arginine in plasma, elevated urinary orotic acid excretion, neurochemical alterations and responsiveness to alternative pathway therapy. In this study, metabolic flux, survival, behavior and learning of these animals were examined in preparation for a trial of gene therapy. We found that, as has been previously reported, OCT activity in liver ranged from 10 to 20% of control. Yet, stable isotope studies using 15N ammonium chloride to follow ureagenesis in vivo showed 55% of normal urea synthetic capacity. This suggests that partial correction with gene therapy may be sufficient to normalize urea synthesis. Although it has been suggested that liver OCTD and its consequent metabolic effects normalize without treatment by adulthood in the spf/Y mouse, we did not find this to be the case. We documented that the spf/Y mouse had a markedly decreased lifespan (< 10% of normal) and remained runted throughout life. In terms of behavior, the spf/Y mice had evidence of decreased learning in a passive avoidance task that was not attributable to alterations in activity. These clearly definable metabolic and behavioral abnormalities suggest that the spf/Y mouse should prove a useful model for studying the efficacy of gene therapy in OCTD.
Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , Genetic Therapy , Hair , Ornithine Carbamoyltransferase Deficiency Disease , Ornithine Carbamoyltransferase/genetics , Amino Acid Metabolism, Inborn Errors/metabolism , Amino Acid Metabolism, Inborn Errors/physiopathology , Amino Acids/blood , Ammonia/blood , Animals , Avoidance Learning , Crosses, Genetic , Disease Models, Animal , Female , Fertility , Humans , Male , Mice , Mice, Mutant Strains , Ornithine Carbamoyltransferase/biosynthesis , Orotic Acid/blood , PregnancyABSTRACT
Theoretical reactivity indices have been used to examine the metabolic reactions presumed, on the basis of recent biochemical evidence, to be responsible for the transformation of polycyclic aromatic hydrocarbon precarcinogens to ultimate carcinogens. Of a large number of indices examined, several show strong correlations with carcinogenic activity in a set of 25 representative compounds. The results support the belief that specific transformations involving dihydrodiol, "bay-region" epoxide, and carbonium ion intermediates are responsible for the carcinogenic activity of these compounds. Additional implications of the results are discussed, including the suggestion that this type of analysis might provide a rapid and simple means for prescreening compounds for potential carcinogens.
