Analogues of capsaicin with agonist activity as novel analgesic agents: structure-activity studies. 4. Potent, orally active analgesics

Structural features of three regions of the capsaicin molecule necessary for agonist properties were delineated by a previously reported modular approach. These in vitro agonist effects were shown to correlate with analgesic potency in rodent models. Combination of optimal structural features from each of these regions of the capsaicin molecule have led to highly potent agonists (eg., 1b). Evaluation in vivo established that 1b had analgesic properties but poor oral activity, short duration of action, and excitatory side effects which precluded further development of this compound. Preliminary metabolism studies had shown that the phenol moiety of 1b was rapidly glucuronidated in vivo, providing a possible explanation for the poor pharmacokinetic profile. Subsequent specific modification of the phenol group led to compounds 2a-j, which retained in vitro potency. The in vivo profiles of two representatives of this series, 2a,h, were much improved over the "parent" phenol series, and they are candidates for development as analgesic agents.     

Postural instability induced by virtual reality exposure: development of a certification protocol

Exposure to virtual environments often causes users to experience symptoms of motion sickness. An accessory manifestation of motion sickness symptoms is postural disequilibrium. If the postural disequilibrium that occurs persists beyond the time an individual is within the confines of the laboratory or system site, user safety could be compromised and products liability issues could be forthcoming. In this study, a portable, automated postural assessment system is developed that can be employed before and after exposure to a virtual reality (VR) system in order to certify that a user's balance on exiting the system is at least demonstrably as good as it was on entering. It is argued that if the "coming out" balance performance is sufficiently poorer than the "going in" balance, then the user should be retained until the pretest balance performance is regained. The results from a set of normative and validation experiments on postural equilibrium identified several reliable measures of stance that could serve as a basis for certification. Furthermore, a new automated video-based measure using only head movement showed that performance over sessions is stable and reliable. The head movement changes that occur with stimuli, such as alcohol and simulator exposure, are well behaved, predictable, and significant even with small samples. The implication is that the proposed objective measure of postural stability, in conjunction with procedures for obtaining self-reports of symptoms, can afford some measure of certification that exposure to a given VR system is without harm.     

Sensitivity analysis and optimization of vehicle–bridge systems based on combined PEM–PIM strategy

This paper presents a new optimization method for coupled vehicle–bridge systems subjected to uneven road surface excitation. The vehicle system is simplified as a multiple rigid-body model and the single-span bridge is modeled as a simply supported Bernoulli–Euler beam. The pseudo-excitation method transforms the random surface roughness into the superposition of a series of deterministic pseudo-harmonic excitations, which enables convenient and accurate computation of first and second order sensitivity information. The precise integration method is used to compute the vertical random vibrations for both the vehicle and the bridge. The sensitivities are used to find the optimal solution, with vehicle ride comfort taken as the objective function. Optimization efficiency and computational accuracy are demonstrated numerically.     

Visualising Errors in Animal Pedigree Genotype Data

Genetic analysis of a breeding animal population involves determining the inheritance pattern of genotypes for multiple genetic markers across the individuals in the population pedigree structure. However, experimental pedigree genotype data invariably contains errors in both the pedigree structure and in the associated individual genotypes, introducing inconsistencies into the dataset, rendering them useless for further analysis. The resolution of these errors requires consideration of genotype inheritance patterns in the context of the pedigree structure. Existing pedigree visualisations are typically more suited to human pedigrees and are less suitable for large complex animal pedigrees which may exhibit cross generational inbreeding. Similarly, table‐based viewers of genotype marker data can highlight where errors become apparent but lack the functionality and interactive visual feedback to allow users to locate the origin of errors within the pedigree. In this paper, we detail a design study steered by biologists who work with pedigree data, and describe successive iterations through approaches and prototypes for viewing genotyping errors in the context of a displayed pedigree. We describe how each approach performs with real pedigree genotype data and why eventually we deemed them unsuitable. Finally, a novel prototype visualisation for pedigrees, which we term the ‘sandwich view’, is detailed and we demonstrate how the approach effectively communicates errors in the pedigree context, supporting the biologist in the error identification task.     

Virtual rights? Property in online game objects and characters

The new industry of Massively Multi-Player Online Role-Playing Games (MMORPGs) brings together two sets of fictions: the interactive stories of shared computer games and the legal devices of intellectual property. In these virtual worlds, scarcity need not exist, but players tend to prefer the competition it creates. This leads to the development of property rights within the game world and players trading real money for virtual objects, ‘land’ and characters. This new phenomenon brings with it familiar legal problems such as theft, fraud and ownership disputes. Game creators also challenge the right of the players to claim ownership outside the game world. The volume and value of the items traded make real money trading an important area of current interest for intellectual property lawyers. Something is being traded, but does it fit neatly into existing conceptions of property rights and who owns it? Analysing the novel problems that result from various theoretical perspectives (utilitarianism, labour-desert theory and personality theory) leads to the conclusion that with time, we will see the development of property rights for players in online games. This connects with a growing understanding that the traditional conception of copyright law dealing with creative work generated by the solitary author is becoming less appropriate in the new creative spaces that information and communications technology brings, where individuals are both consumer and producer. In virtual worlds, new forms of intellectual property, and perhaps even new rights, are taking shape.     

Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The hydrophobic side-chain "C-region"

Structural variants of the hydrophobic side chain ("C region") of the capsaicin molecule have been incorporated into a series of vanillylamides and vanillylthioureas. These compounds have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), previously shown to be predictive of analgesic activity. The results of this study have established the requirement for a hydrophobic substituent of limited size (molar refractivity, MR, < 55) in order to obtain high potency. Combination of the information gained here about the "C-region" of the capsaicin molecule with the studies described in the preceding two papers provides a rational basis for the design of compounds of increased potency.     

Development of clinical indicators for performance measurement and improvement: an HMO/purchaser collaborative effort

This article describes a collaborative effort between a major health care purchaser, three area health maintenance organizations, and a state Medicaid agency to develop clinical indicators as the basis for a comparison database. Some of the difficulties in developing a "common yardstick" of quality and value are candidly discussed.     

Application of polymerase chain reaction for the correlation of Salmonella serovars recovered from greyhound feces with their diet

The polymerase chain reaction was employed to correlate Salmonella serovars isolated from fecal material of greyhounds suffering from gastroenteritis with those isolated from the diet fed to the greyhounds prior to onset of diarrhea. Kennels around the Abilene, Kansas, area were contacted and supplied with materials needed to collect a portion of the diet each day. With the onset of diarrhea, the kennels were instructed to ship the fecal material and diet from the previous 10 days to the laboratory for testing. Forty-one fecal samples and corresponding diets were screened for Salmonella, Clostridium perfringens, Campylobacter jejuni, Staphylococcus aureus, Staphylococcus intermedius, and pathogenic (piliated) Escherichia coli by direct culture using standard procedures. The fecal material was also screened for coronavirus and parvovirus using electron microscopy. Thirty-five "normal" fecal samples were screened for all of the above mentioned microorganisms as a control. In addition, the fecal material was screened for E. coli verotoxins I and II and clostridial enterotoxins. A total of 61 Salmonella isolates were recovered from the 41 samples of feces and diet submitted for testing; 31 were recovered from the feces and 30 from the diet. Four Salmonella isolates were recovered from the normal fecal samples. Results obtained by PCR, plasmid profiles, antigenic analysis, and antibiogram profiles indicated that 16 of the 31 isolates recovered from the fecal material were the same strain as that recovered from the diet.