Economic choice between remifentanil and food in squirrel monkeys

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.Subject terms: Addiction, Decision     

Microbiology of the female genital tract

Patients who contract genital tract infections are predominantly young, are otherwise healthy, and generally respond well to treatment for bacterial infections. These infections are most commonly polymicrobial in etiology, with several noteworthy exceptions. Often there is an inciting event such as childbirth, surgical intervention, pregnancy termination or intrauterine contraceptive device insertion. With treatment, prognosis for cure is excellent; however, sequelae such as recurrent infections, infertility, or ectopic pregnancy can be serious. Bacteria encountered in the female genital tract can be divided into aerobic and anaerobic organisms. Among the aerobic gram-positive organisms, several varieties of streptococci such as Group B streptococci and enterococci occur frequently. Staphylococcus aureus is an infrequent but important pathogen. Among the aerobic gram-negative organisms, the most common is Escherichia coli. Klebsiella sp. and Proteus sp. occur in about 5% of genital tract infections. Species that are more resistant to antibiotics, such as Pseudomonas aeruginosa and Enterobacter sp., occur in approximately 1% or 2% of these cases and are more likely to appear in patients who have previously received antibiotic therapy or who have been hospitalized for some time. Among the anaerobic organisms, the most common gram-positive isolates are Peptostreptococci and Peptococci. Clostridia sp. occurs less frequently. Among the anaerobic gram-negative organisms, the Bacteroides sp. most frequently encountered are Bacteroides bivius and Bacteroides disiens. Bacteroides fragilis is still a common problem but appears to be less predominant. Other organisms encountered are Chlamydia trachomatis, the genital mycoplasmas, yeasts, protozoa, and viruses.     

Evaluation of a new Rift Valley fever vaccine: safety and immunogenicity trials

A formalin-inactivated Rift Valley fever vaccine prepared in primary monkey kidney cells has been used to protect laboratory workers from disease since 1967. A similar but improved vaccine was prepared in 1978-1979 using well characterized diploid fetal rhesus lung cells. In initial clinical trials reported here, the new vaccine elicited high levels of plaque neutralizing antibodies and caused only minimal local reactions at the injection site. Significant variability was observed in the geometric mean titre evoked by various vaccine lots. This variability had not been predicted by conventional pre-filtration or pre-inactivation virus infectivity assays, or the results of animal potency tests. These findings emphasize the need for statistically valid human potency testing and the development of accurate predictive preclinical measurements for this and other vaccines.     

Novel Hendra Virus Variant Circulating in Black Flying Foxes and Grey-Headed Flying Foxes,Australia

A novel Hendra virus variant, genotype 2, was recently discovered in a horse that died after acute illness and in Pteropus flying fox tissues in Australia. We detected the variant in flying fox urine, the pathway relevant for spillover, supporting an expanded geographic range of Hendra virus risk to horses and humans.     

Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus–infected rhesus macaques on antiretroviral therapy

Proliferation of latently infected CD4⁺ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4⁺ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA–treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4⁺ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.