Planning Future Strategies for Domestic and International NeuroAIDS Research, July 24–25, 2008

The National Institute of Mental Health in cooperation with the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke organized a meeting on July 24–25, 2008 to develop novel research directions for neuroAIDS research. The deliberations of this meeting are outlined in this brief report. Several critical research areas in neuroAIDS were identified as areas of emphasis. Opportunities for collaborations between large NIH-funded projects were also discussed

Casimir Energies for 6D Supergravities Compactified on T_2/Z_N with Wilson Lines

We compute (as functions of the shape and Wilson-line moduli) the one-loop Casimir energy induced by higher-dimensional supergravities compactified from 6D to 4D on 2-tori, and on some of their Z_N orbifolds. Detailed calculations are given for a 6D scalar field having an arbitrary 6D mass m, and we show how to extend these results to higher-spin fields for supersymmetric 6D theories. Particular attention is paid to regularization issues and to the identification of the divergences of the potential, as well as the dependence of the result on m, including limits for which m^2 A> 1 where A is the volume of the internal 2 dimensions. Our calculation extends those in the literature to very general boundary conditions for fields about the various cycles of these geometries. The results have potential applications towards Supersymmetric Large Extra Dimensions (SLED) as a theory of the Dark Energy. First, they provide an explicit calculation within which to follow the dependence of the result on the mass of the bulk states which travel within the loop, and for heavy masses these results bear out the more general analysis of the UV-sensitivity obtained using heat-kernel methods. Second, because the potentials we find describe the dynamics of the classical flat directions of these compactifications, within SLED they would describe the present-day dynamics of the Dark Energy.Comment: 40 pages, 7 figure

Gauge Theory and the Excision of Repulson Singularities

We study brane configurations that give rise to large-N gauge theories with eight supersymmetries and no hypermultiplets. These configurations include a variety of wrapped, fractional, and stretched branes or strings. The corresponding spacetime geometries which we study have a distinct kind of singularity known as a repulson. We find that this singularity is removed by a distinctive mechanism, leaving a smooth geometry with a core having an enhanced gauge symmetry. The spacetime geometry can be related to large-N Seiberg-Witten theory.Comment: 31 pages LaTeX, 2 figures (v3: references added

Monensin Improves the Effectiveness of meso-Dimercaptosuccinate when Used to Treat Lead Intoxication in Rats

Among divalent cations, the ionophore monensin shows high activity and selectivity for the transport of lead ions (Pb(2+)) across phospholipid membranes. When coadministered to rats that were receiving meso-dimercaptosuccinate for treatment of Pb intoxication, monensin significantly increased the amount of Pb removed from femur, brain, and heart. It showed a tendency to increase Pb removal from liver and kidney but had no effect of this type in skeletal muscle. Tissue levels of several physiologic (calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, zinc) and nonphysiologic (arsenic, cadmium, chromium, nickel, strontium) elements were also determined after the application of these compounds. Among the physiologic elements, a number of significant changes were seen, including both rising and falling values. The size of these changes was typically around 20% compared with control values, with the largest examples seen in femur. These changes often tended to reverse those of similar size that had occurred during Pb administration. Among the nonphysiologic elements, which were present in trace amounts, the changes were smaller in number but larger in size. None of these changes appears likely to be significant in terms of toxicity, and there were no signs of overt toxicity under any of the conditions employed. Monensin may act by cotransporting Pb(2+) and OH(–) ions out of cells, in exchange for external sodium ions. The net effect would be to shuttle intracellular Pb(2+) to extracellular dimercaptosuccinic acid thereby enhancing its effectiveness. Thus, monensin may be useful for the treatment of Pb intoxication when applied in combination with hydrophilic Pb(2+) chelators

Do Tobacco Companies Have an Incentive to Promote “Harm Reduction” Products? The Role of Competition

Background Some cigarette companies have started to talk about replacing cigarettes with less harmful alternatives, which might include nicotine vaping products (NVPs), heated tobacco products (HTPs) and oral nicotine delivery products (ONDPs). We consider market competition as a primary driver of whether cigarette companies follow through on their stated intentions. Methods We focus on the behavior of cigarette companies in the US. We compare competition in the pre- and post-2012 time periods, analyze the impact of the growth in NVPs on smoking prevalence and cigarette company profits, and examine the potential future role of competition. Results Since 2006, consumers have broadened their use of non-combustible nicotine delivery products (NCNDPs) to include, inter alia, NVPs, HTPs and ONDPs. US cigarette companies have acquired major stakes in each of these product categories which corresponds to a period of rapidly declining adult smoking prevalence, especially among younger adults (ages 18-24 years). The shifting dynamics of the nicotine product marketplace are also reflected in cigarette company stock prices. While cigarette companies are likely to promote HTPs and ONDPs over NVPs, their incentives will be directly related to competition from independent firms, which in turn will depend on government regulation. Conclusions While cigarette companies will back alternatives to combusted tobacco when threatened by competition, the prospects for their lasting conversion to NCNDPs will depend on the extent of such competition, which will be influenced by government regulation of tobacco products

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib

Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features

Building Irish families through surrogacy: medical and judicial issues for the advanced reproductive technologies

Surrogacy involves one woman (surrogate mother) carrying a child for another person/s (commissioning person/couple), based on a mutual agreement requiring the child to be handed over to the commissioning person/couple following birth. Reasons for seeking surrogacy include situations where a woman has non-functional or absent reproductive organs, or as a remedy for recurrent pregnancy loss. Additionally, surrogacy may find application in any medical context where pregnancy is contraindicated, or where a couple consisting of two males seek to become parents through oocyte donation. Gestational surrogacy is one of the main issues at the forefront of bioethics and the advanced reproductive technologies, representing an important challenge to medical law. This analysis reviews the history of surrogacy and clinical and legal issues pertaining to this branch of reproductive medicine. Interestingly, the Medical Council of Ireland does not acknowledge surrogacy in its current practice guidelines, nor is there specific legislation addressing surrogacy in Ireland at present. We therefore have developed a contract-based model for surrogacy in which, courts in Ireland may consider when confronted with a surrogacy dispute, and formulated a system to resolve any potential dispute arising from a surrogacy arrangement. While the 2005 report by the Commission on Assisted Human Reproduction (CAHR) is an expert opinion guiding the Oireachtas' development of specific legislation governing assisted human reproduction and surrogacy, our report represents independent scholarship on the contractual elements of surrogacy with particular focus on how Irish courts might decide on surrogacy matters in a modern day Ireland. This joint medico-legal collaborative also reviews the contract for services arrangement between the commissioning person/s and the surrogate, and the extent to which the contract may be enforced