Parachloroamphetamine toxicity in mice: influence of body weight, sex and dose

Five doses of d,l-para-chloroamphetamine (0.0, 15,0, 30.0, 45.0 and 60.0 mg/kg) were used to challenge 10 groups of 16 male and 10 groups of 16 female CF-1 mice weighing either 16 to 25 g or 40 to 55 g. Twenty-four hours after intraperitoneal injection, rates of lethal toxicity were assessed. Effects for body weight and dose were found. In addition, a sex by dose interaction was demonstrated. It was hypothesized that the influence of weight might be related to thermoregulatory processes, since as weight rises, surface-to-volume ratios decline, and with them the efficiency of heat exchange. Caution is suggested in the interpretation of ontological studies of drug response.     

Telemetry system to record force and EMG from cat ankle extensor and tibialis anterior muscles

The purpose of this technical note is to present the design of an eight-channel telemetry system of dimensions and weight small enough to record muscular forces and EMGs simultaneously from gastrocnemius, soleus, plantaris and tibialis anterior muscles of a freely moving cat. All schematics for constructing the telemetry device are shown in detail. Using this system, we were successful in measuring force and EMG data of all four instrumented muscles in freely moving animals. The telemetry system presented here has the advantage over a conventional cable system that recordings may be obtained at any time in the freely moving animal without interference by an experimenter.     

Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway

The protection against apoptosis provided by growth factors in several cell lines is due to stimulation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, which results in activation of protein kinase B (PKB; also known as c-Akt and Rac) and phosphorylation and sequestration to protein 14-3-3 of the proapoptotic Bcl-2-family member BAD. A modest increase in intracellular Ca2+ concentration also promotes survival of some cultured neurons through a pathway that requires calmodulin but is independent of PI(3)K and the MAP kinases. Here we report that Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK) activates PKB directly, resulting in phosphorylation of BAD on serine residue 136 and the interaction of BAD with protein 14-3-3. Serum withdrawal induced a three- to fourfold increase in cell death of NG108 neuroblastoma cells, and this apoptosis was largely blocked by increasing the intracellular Ca2+ concentration with NMDA (N-methyl-D-aspartate) or KCl or by transfection with constitutively active CaM-KK. The effect of NMDA on cell survival was blocked by transfection with dominant-negative forms of CaM-KK or PKB. These results identify a Ca2+-triggered signalling cascade in which CaM-KK activates PKB, which in turn phosphorylates BAD and protects cells from apoptosis.     

Lipid-lowering therapy for patients with or at risk of coronary artery disease

Several studies have shown that effective lipid-lowering therapy slows the progression of atherosclerotic lesions in the coronary and carotid arteries. Recent clinical trials have confirmed and extended previous work showing that lowering cholesterol reduces the risk of coronary events. A clear reduction in major coronary events during treatment for 5 years with the hydroxymethylglutaryl-coenzyme A reductase inhibitor pravastatin was observed in the West of Scotland study and in the preliminary results of the Cholesterol and Recurrent Events study. The Scandinavian Simvastatin Survival Study has provided the first unequivocal demonstration of improved survival as a result of lipid-lowering therapy. These three trials, which together included over 15,000 patients studied for 5 years, have provided good evidence that noncardiovascular mortality is not affected by substantial reductions in blood cholesterol.     

Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice

We previously demonstrated that mice deficient in inhibin develop gonadal sex cord-stromal tumors with nearly 100% penetrance. These ovarian and testicular tumors develop as early as 4 weeks of age and eventually cause cachexia-like symptoms and death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice initially do not develop this wasting syndrome, but eventually will develop adrenal cortical tumors with similar penetrance. These studies have demonstrated that inhibin is a secreted type of tumor suppressor in the gonads and adrenal glands. Gonadotropins are implicated to influence gonadal tumor development in humans as well as experimental animals, and in inhibin-deficient mice, serum FSH levels are elevated. To determine whether gonadotropins influence the development and/or progression of the tumors in the inhibin-deficient mice, we took advantage of a naturally occurring mutant mouse, hypogonadal (hpg); hpg/hpg mice lack a functional GnRH gene and, therefore, have suppressed FSH and LH levels. Heterozygous hpg/+mice were crossed to heterozygous inhibin mutant mice to generate compound homozygous mutant mice that lack both inhibin and GnRH. These compound homozygous mutant mice do not develop a wasting syndrome, do not exhibit gonadal or adrenal tumors, and can survive for more than 1 yr. These results demonstrate that gonadotropins are essential modifier factors for tumor development in inhibin-deficient mice.     

Who is driving when unrestrained children and teenagers are hurt?

This paper examines driver characteristics in crashes where child and teenage motor vehicle crash victims were injured, in particular factors that determine whether or not the victim was restrained. Analyzing the data on children and teenagers who are injured revealed that the presence of a second adult in a vehicle increased the likelihood that these passengers were unrestrained. Other findings are more predictable: victim restraint use generally mirrored driver restraint use; a male driver, a young driver, a drinking driver, a speeding or reckless driver, an unlicenced or suspended driver, and a night-time trip each independently raised the odds that child and teenage passengers were not restrained when they were injured.     

Empirical scoring functions. II. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model

This paper tests the performance of a simple empirical scoring function on a set of candidate designs produced by a de novo design package. The scoring function calculates approximate ligand-receptor binding affinities given a putative binding geometry. To our knowledge this is the first substantial test of an empirical scoring function of this type on a set of molecular designs which were then subsequently synthesised and assayed. The performance illustrates that the methods used to construct the scoring function and the reliance on plausible, yet potentially false, binding modes can lead to significant over-prediction of binding affinity in bad cases. This is anticipated on theoretical grounds and provides caveats on the reliance which can be placed when using the scoring function as a screen in the choice of molecular designs. To improve the predictability of the scoring function and to understand experimental results, it is important to perform subsequent Quantitative Structure-Activity Relationship (QSAR) studies. In this paper, Bayesian regression is performed to improve the predictability of the scoring function in the light of the assay results. Bayesian regression provides a rigorous mathematical framework for the incorporation of prior information, in this case information from the original training set, into a regression on the assay results of the candidate molecular designs. The results indicate that Bayesian regression is a useful and practical technique when relevant prior knowledge is available and that the constraints embodied in the prior information can be used to improve the robustness and accuracy of regression models. We believe this to be the first application of Bayesian regression to QSAR analysis in chemistry.