Development and validation of a rabbit model of Pseudomonas aeruginosa non-ventilated pneumonia for preclinical drug development

BackgroundNew drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa, have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections.MethodsWe report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression.ResultsIn a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5 h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits (P<0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24 h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved Cmax/MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had Cmax/MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects.ConclusionThe rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia

Gene selection heuristic algorithm for nutrigenomics studies

Large datasets from -omics studies need to be deeply investigated. The aim of this paper is to provide a new method (LEM method) for the search of transcriptome and metabolome connections. The heuristic algorithm here described extends the classical canonical correlation analysis (CCA) to a high number of variables (without regularization) and combines well-conditioning and fast-computing in “R.” Reduced CCA models are summarized in PageRank matrices, the product of which gives a stochastic matrix that resumes the self-avoiding walk covered by the algorithm. Then, a homogeneous Markov process applied to this stochastic matrix converges the probabilities of interconnection between genes, providing a selection of disjointed subsets of genes. This is an alternative to regularized generalized CCA for the determination of blocks within the structure matrix. Each gene subset is thus linked to the whole metabolic or clinical dataset that represents the biological phenotype of interest. Moreover, this selection process reaches the aim of biologists who often need small sets of genes for further validation or extended phenotyping. The algorithm is shown to work efficiently on three published datasets, resulting in meaningfully broadened gene networks. </jats:p

The influence of ageing on the force-velocity-power characteristics of human elbow flexor muscles

The purpose of this study was to quantify the effects of ageing on the maximal power (Pmax) of the elbow flexor muscles and to determine the impact of velocity on the loss of power in older people. Sixteen elderly subjects (7 men and 9 women, age range 61–78 years) and 17 young subjects (11 men and 6 women, age range 18–27 years) participated in this study. Maximal elbow flexions were performed against increasing inertia. The maximal force (Fmax), maximal shortening velocity (Vmax), Pmax, dynamic constants (a, b and a/Fmax), optimal force (Fopt), optimal velocity (Vopt) and Vopt/Vmax were determined from Hill's equation. Myoelectrical activity (EMG) of the biceps and triceps muscles was quantified as an root mean square (RMS) value. Fmax, Vmax, Pmax, Fopt, and Vopt were significantly lower in elderly than in young subjects (28, 31, 45, 24 and 28% lower, respectively; p&lt;0.05), whereas a/Fmax and Vopt/Vmax were not different between the two age groups. In women, the greater decrease in Pmax appears to be more dependent on Vopt than Fopt. In addition, Vmax decreased with age in women but not in men. The absence of significant differences between age groups in normalised RMS values indicates that Pmax and Vmax loss with increasing age could result more from changes in the properties of contractile element than from changes in muscular activity

Development of a new encapsulation method for vaginal delivery of Lactobacillus sp.

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Microencapsulation of an industrial pressure sensitive adhesive by spray-cooling

International audienc

Microencapsulation d\textquoterightun adhésif sensible à la pression

International audienc