The interaction of reduced metronidazole with DNA bases and nucleosides.

The electrochemical behavior of the 1-electron couple for the bioreductive drug metronidazole has been examined in the presence and absence of the biological target molecules, DNA bases, and nucleosides, including uracil and uridine. Using cyclic voltammetry as the investigation technique, the change in return-to-forward peak current ratio, ipr/ipf, from the control, recorded in the absence of target, was measured as a function of scan rate and biological target concentration. All target molecules, except adenosine and guanine, resulted in interaction with RNO2.-, as measured by the decrease in the ipr/ipf ratio in the following order of increasing reactivity: adenine, guanosine, thymine, uracil, uridine, and thymidine (at a metronidazole:target ratio of 1:1). No decrease in ipr/ipf was observed with cytosine or cytidine until ratios of 1:20 and 1:30, respectively, were attained. An approximately linear relationship was found between the percentage change in the CV response and log[target] allowing us to determine the sensitivity of RNO2.- to the concentration of the target species. The implication for the biological action of metronidazole and other nitro-heterocyclic drugs is discussed.     

Complementary components and local variations of the pattern electroretinogram

Pattern electroretinograms have been presumed to arise from a combination of luminance and pattern detection activities. Since the responses at low spatial frequencies are linearly related to contrast and contain negligible pattern specific components, it is proposed that a retinal illuminance response for higher spatial frequencies can be computed from the optical transfer function of the eye. These computed responses are subtracted from pattern electroretinograms to reveal a pattern-specific response with a marked bandpass characteristic. The peak spatial frequency of the bandpass curve declines with increasing peripheral angle. For central vision, the peak amplitude of the pattern-specific response is larger than the retinal illuminance response, but, in the peripheral retina, the two responses are found to be almost equal. The possible origins of these signals are discussed, and it is concluded that the technique provides a method of obtaining separated illuminance and pattern responses from retinal regions having different properties of spatial selectivity.     

Mutual inhibition among neural command systems as a possible mechanism for behavioral choice in crayfish

Mutual inhibition among behavioral command systems frequently has been suggested as a possible mechanism for switching between incompatible behaviors. Several neural circuits in crayfish that mediate incompatible behaviors have been found to interact through inhibition; this accounts for increased stimulus threshold of one behavior (e.g., escape tailflip) during performance of others (eating, walking, defense). To determine whether mutual inhibition between command systems can provide a mechanism that produces adaptive behavior, I developed a model crayfish that uses this mechanism to govern its behavioral choices in a simulated world that contains a predator, a shelter, and a food source. The crayfish uses energy that must be replaced by eating while it avoids capture by the predator. The crayfish has seven command systems (FORAGE, EAT, DEFENSE, RETREAT, ESCAPE, SWIM, HIDE) that compete through mutual inhibition for control of its behavior. The model crayfish was found to respond to changing situations by making adaptive behavioral choices at appropriate times. Choice depends on internal and external stimuli, and on recent history, which determines the pattern of those stimuli. The model's responses are unpredictable: small changes in the initial conditions can produce unexpected patterns of behavior that are appropriate alternate responses to the stimulus conditions. Despite this sensitivity, the model is robust; it functions adaptively over a large range of internal and external parameter values.     

Predicting Survival after Trauma: a Comparison of TRISS and ASCOT in the Netherlands

Background: Evaluating the performance of a trauma system may be attempted by comparing outcome in different trauma populations. Controlling for injury severity is a necessity for such evaluations. We compare two current models for doing so: the “Trauma and Injury Severity Score” (TRISS) and “A Severity Characterization Of Trauma” (ASCOT). Material and Methods: This study of high-energy trauma victims took place in Leiden, the Netherlands, between 1993 and 1998. Using the Hosmer-Lemeshow (HL) test and receiver operator characteristic (ROC) analysis, the TRISS and ASCOT models were compared for calibration and discrimination. Results: 1,024 patients, with an average Injury Severity Score (ISS) of 13.5, were eligible for inclusion. Blunt trauma was the predominant cause of injuries. Both models gave accurate, though pessimistic, results in predicting the actual number of fatalities (n = 71). The HL test indicated a sufficient fit for the ASCOT model (p = 0.28) and an insufficient fit (p = 0.02) for TRISS. The ROC curves were nearly identical (0.97). Including age as a linear variable, instead of using the current age groups, resulted in an improved discriminative power of the models. Conclusions: The ASCOT model proved superior over TRISS in its accuracy to estimate of survival chances. This difference was most evident for victims with an estimated survival chance of 60–90%. Future national trauma researchers should therefore collect ASCOT data. Improved ASCOT models could be developed, with age as a linear variable. Received: April 25, 2002; revision accepted: September 17, 2002 Correspondence Address Prof. Arie B. van Vugt, MD, PhD, Department of General Surgery and Traumatology, Erasmus MC Rotterdam, Dr. Molewaterplein 40, Postbus 2040, 3000 CA Rotterdam, The Netherlands, Phone (+31/10) 463-5735, Fax -4757, e-mail: vanvugt@hlkd.azr.nl     

Reproductive toxicity studies with oxybutynin hydrochloride

Oxybutynin hydrochloride, an anti-cholinergic/anti-spasmodic agent, was examined for its effect on fertility and peri-post natal development in the rat and its embryotoxic potential in the rat and rabbit. In the rat effects on reproductive performance included a slight increase in the incidence of foetal malformations, extended gestation period and impaired post natal performance of offspring. These findings occurred at dosages clearly associated with maternal toxicity. Oxybutynin hydrochloride did not exert an effect on reproductive processes in the rat at lower dosages or on embryonic and foetal development in the rabbit.     

Multiattribute utility assessment of outcomes of treatment for head and neck cancer.

Good clinical practice is dependent on continuous audit. Most audits of head and neck cancer treatment planning have been subjective, with only 5-year survival rates being considered objectively. Improvements in clinical care require not only measurable goals that relate to patients'' perspectives, but also a means of assessing to what extent those goals have been met. In this context, 5-year survival rates are too crude to be useful, although they remain important for other reasons. Because a simple clinical objective measure of outcome applicable to head and neck cancer is not available, multiattribute assessment techniques were used to develop a clinically based scale for outcomes following treatment for head and neck cancer, with domains centred on social function, pain, physical appearance, eating and speech problems, nausea, donor site problems and shoulder function. Domains were weighted relative to each other; pain (mean weight 85) and social function (89) were considered most important followed by physical appearance (76), eating (76) and speech problems (74) A series of graded statements was constructed within each domain and scaled relative to each other. These components were also combined into an overall scale that will enable objective outcome assessment in this important area of medical care.     

Brevetoxins bind to multiple classes of sites in rat brain synaptosomes.

The brevetoxins (PbTx series), neurotoxins produced by the marine dinoflagellate Ptychodiscus brevis, cause dose-dependent activation of the voltage-sensitive sodium channel (VSSC). Saturation binding studies employing adult rat brain synaptosomes suggest the existence of a high affinity/low capacity (HA/LC) and a second, lower affinity/higher capacity (LA/HC) class of binding site. LIGAND analysis of saxitoxin and brevetoxin saturation binding data yields a statistically identical Bmax for the brevetoxin high affinity/low capacity (HA/LC) site (1.9 +/- 0.98 pmol/mg protein) and for saxitoxin (1.72 +/- 0.78 pmol/mg protein; P less than 0.001). The stoichiometry of HA/LC brevetoxin binding and saxitoxin binding approaches 1:1. Covalent modification of synaptosomes with a brevetoxin photoaffinity probe preferentially blocks the HA/LC binding site. Hill plots of saturation binding data yield a coefficient of 1.0 +/- 0.02, demonstrating a lack of cooperativity between brevetoxin binding site classes. Kd and Bmax for toxin binding are independent of membrane polarity, intimating that the observed low affinity/high capacity (LA/HC) binding characteristics are not due to modification of the HA/LC site, and strongly argue for the presence of multiple brevetoxin binding site classes. Half-maximal binding at the LA/HC site, and strongly argue for the presence of multiple brevetoxin binding site classes. Half-maximal binding at the LA/HC site occurs at concentration ranges for which the brevetoxins allosterically modulate binding of other natural toxins to their specific sites.