Not going with the flow : locomotor activity does not constrain immunity in a wild fish

Immunity is a central component of fitness in wild animals, but its determinants are poorly understood. In particular, the importance of locomotory activity as a constraint on immunity is unresolved. Using a piscine model (Gasterosteus aculeatus) we combined a 25-month observational time series for a wild lotic habitat with an open flume experiment to determine the influence of locomotor activity (counter-current swimming) on natural variation in immune function. To maximize the detectability of effects in our flume experiment we set flow velocity and duration (10 cm s-1 for 48 h) just below the point at which exhaustion would ensue. Following this treatment, we measured expression in a set of immune-associated genes and infectious disease resistance through a standard challenge with an ecologically-relevant monogenean infection (Gyrodactylus gasterostei). In the wild, there was a strong association of water flow with the expression of immune-associated genes, but this association became modest and more complex when adjusted for thermal effects. Our flume experiment, although statistically well-powered and based on a scenario near the limits of swimming performance in stickleback, detected no counter-current swimming effect on immune-associated gene expression or infection resistance. The field association between flow rate and immune expression could thus be due to an indirect effect and we tentatively advance hypotheses to explain this. This study clarifies the drivers of immune investment in wild vertebrates; although locomotor activity, within the normal natural range, may not directly influence immunocompetence, it may still correlate with other variables that do

Quantum limits to center-of-mass measurements

We discuss the issue of measuring the mean position (center-of-mass) of a group of bosonic or fermionic quantum particles, including particle number fluctuations. We introduce a standard quantum limit for these measurements at ultra-low temperatures, and discuss this limit in the context of both photons and ultra-cold atoms. In the case of fermions, we present evidence that the Pauli exclusion principle has a strongly beneficial effect, giving rise to a 1/N scaling in the position standard-deviation -- as opposed to a $1/\sqrt{N}$ scaling for bosons. The difference between the actual mean-position fluctuation and this limit is evidence for quantum wave-packet spreading in the center-of-mass. This macroscopic quantum effect cannot be readily observed for non-interacting particles, due to classical pulse broadening. For this reason, we also study the evolution of photonic and matter-wave solitons, where classical dispersion is suppressed. In the photonic case, we show that the intrinsic quantum diffusion of the mean position can contribute significantly to uncertainties in soliton pulse arrival times. We also discuss ways in which the relatively long lifetimes of attractive bosons in matter-wave solitons may be used to demonstrate quantum interference between massive objects composed of thousands of particles.Comment: 12 pages, 6 figures. Submitted to PRA. Revised to include more references as well as a discussion of fermionic center-of-mas

Reversible antibiotic tolerance induced in <i>Staphylococcus aureus</i> by concurrent drug exposure

ABSTRACT   Resistance of Staphylococcus aureus to beta-lactam antibiotics has led to increasing use of the glycopeptide antibiotic vancomycin as a life-saving treatment for major S. aureus infections. Coinfection by an unrelated bacterial species may necessitate concurrent treatment with a second antibiotic that targets the coinfecting pathogen. While investigating factors that affect bacterial antibiotic sensitivity, we discovered that susceptibility of S. aureus to vancomycin is reduced by concurrent exposure to colistin, a cationic peptide antimicrobial employed to treat infections by Gram-negative pathogens. We show that colistin-induced vancomycin tolerance persists only as long as the inducer is present and is accompanied by gene expression changes similar to those resulting from mutations that produce stably inherited reduction of vancomycin sensitivity (vancomycin-intermediate S. aureus [VISA] strains). As colistin-induced vancomycin tolerance is reversible, it may not be detected by routine sensitivity testing and may be responsible for treatment failure at vancomycin doses expected to be clinically effective based on such routine testing. IMPORTANCE   Commonly, antibiotic resistance is associated with permanent genetic changes, such as point mutations or acquisition of resistance genes. We show that phenotypic resistance can arise where changes in gene expression result in tolerance to an antibiotic without any accompanying genetic changes. Specifically, methicillin-resistant Staphylococcus aureus (MRSA) behaves like vancomycin-intermediate S. aureus (VISA) upon exposure to colistin, which is currently used against infections by Gram-negative bacteria. Vancomycin is a last-resort drug for treatment of serious S. aureus infections, and VISA is associated with poor clinical prognosis. Phenotypic and reversible resistance will not be revealed by standard susceptibility testing and may underlie treatment failure

LiST as a catalyst in program planning: experiences from Burkina Faso, Ghana and Malawi

Background African countries are working to achieve rapid reductions in maternal and child mortality and meet their targets for the Millennium Development Goals (MDGs). Partners in the Catalytic Initiative to Save One Million Lives (CI) are assisting them by providing funding and technical assistance to increase and accelerate coverage for proven interventions. Here we describe how the Lives Saved Tool (LiST) was used as part of an early assessment of the expected impact of CI plans in Malawi, Burkina Faso and Ghana

Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose

BACKGROUND: Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. OBJECTIVES: To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. METHODS: The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. RESULTS: A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. CONCLUSIONS: The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily