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Rationale Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. Objectives The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. Methods To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. Results Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. Conclusions These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.

Context .— A Treatise on Pathological Anatomy , published in 1829 by William E. Horner, is the first American textbook on pathology. Several articles have been written on Horner, but they do not evaluate the role that the knowledge he recorded played on the intellectual origin of the discipline of pathology in America. Only one article, published in 1930, deals in some detail with the content of the Treatise . Because of new historiographic standards, this is an opportunity to expand on, and update, that article. Furthermore, Horner's book is now available free online, and print-on-demand paperback copies can be ordered for a modest cost from online booksellers. Objective .—To describe the organization and structure of the scientific knowledge found in the Treatise with the intent of demonstrating how this material created the intellectual basis for the origin of pathology as a discipline in America. Design .—Using current historiographic standards, the knowledge included in the book is examined and contextualized within the social, professional, and educational conditions existing at the time of publication. The essay also includes biographic data on the author. Results .—The Treatise contains important information on the principles, ideas, and practice of pathology in the nineteenth century and illustrates the influence of French literature on the author. Conclusion .—The contribution of the Treatise as the first formal textbook on the subject in America is seminal and should be the basis for further historic studies on the organization and structure of scientific knowledge in pathology in America.

The growth in computing resources at scientific computing centers has created new challenges for system software. These multi-teraflop systems often exceed the capabilities of the system software and require new approaches to accommodate these large processor counts. The costs associated with development and maintenance of this software are also significant impediments, which are compounded by a lack of interoperability because of site-specific enhancements. The Scalable System Software project seeks to address these issues through a component based approach to system software development. An overview of this design and the benefits of such an approach will be discussed in this paper.

Comparison of the minor and trace element compositions of bullet lead alloys has been used by some forensic examiners to make definitive positive associations between bullets or lead fragments at a crime scene and samples of bullets linked to a suspect(s). Such conclusions have been based on the elemental analysis of isolated groups of bullets with no consideration of the metallurgical processes involved in the production and refining of the bullet lead alloys. An understanding of the metallurgy of lead refining reveals that the elements quantified in the forensic analysis are carefully controlled in the refining process and that there are logical reasons why some elements are more discriminatory than others. Data for lead alloys supplied to two major ammunition manufacturers confirm that multiple indistinguishable shipments of lead alloys from secondary lead refiners to the ammunition manufacturers are made each year and over a period of many years. The data also demonstrate that distinguishable compositions can come from the same melt or “source” of lead alloy. These results clearly indicate that bullets with indistinguishable compositions could have come from different lead “sources” produced in the same or different years. Furthermore, the observation that two bullets have a distinguishable composition does not necessarily mean that they came from a different “source”. Our results show that the forensic examiner using a method of bullet lead alloy elemental analysis, which quantifies up to six elements is restricted to concluding only that indistinguishable bullets might have come from the same “source,” not that they did come from the same “source”. In addition, it is quite possible that multiple bullets with similar but distinguishable compositions could have come from the same “source”. The authors therefore feel that there is no scientific validity to any conclusions more positive than attributing the possible association as to molten source among bullets from different samples. An understanding of the metallurgical principles operative in the melting/casting process as well as the data acquired for this study, indicate that any forensic conclusions which associate unknown bullets with the “same source”, and/or “same box” should fail most or all Daubert criteria.