Population dynamics of a salmonella lytic phage and its host : implications of the host bacterial growth rate in modelling

The prevalence and impact of bacteriophages in the ecology of bacterial communities coupled with their ability to control pathogens turn essential to understand and predict the dynamics between phage and bacteria populations. To achieve this knowledge it is essential to develop mathematical models able to explain and simulate the population dynamics of phage and bacteria. We have developed an unstructured mathematical model using delay-differential equations to predict the interactions between a broad-host-range Salmonella phage and its pathogenic host. The model takes into consideration the main biological parameters that rule phage-bacteria interactions likewise the adsorption rate, latent period, burst size, bacterial growth rate, and substrate uptake rate, among others. The experimental validation of the model was performed with data from phage-interaction studies in a 5 L bioreactor. The key and innovative aspect of the model was the introduction of variations in the latent period and adsorption rate values that are considered as constants in previous developed models. By modelling the latent period as a normal distribution of values and the adsorption rate as a function of the bacterial growth rate it was possible to accurately predict the behaviour of the phage-bacteria population. The model was shown to predict simulated data with a good agreement with the experimental observations and explains how a lytic phage and its host bacteria are able to coexist.Financial support was received through the Strategic Project PEst-OE/EQB/LA0023/2013 from the FCT-Fundacao para a Ciencia e Tecnologia (http://www.fct.pt) and the projects "BioHealth - Biotechnology and Bioengineering approaches to improve health quality'', Ref. NORTE-07-0124 FEDER-000027, co-funded by the Programa Operacional Regional do Norte (ON.2 - O Novo Norte), QREN, FEDER and "Consolidating Research Expertise and Resources on Cellular and Molecular Biotechnology at CEB/IBB'', Ref. FCOMP-01-0124-FEDER-027462. Silvio B. Santos was supported by the grant SFRH/BPD/75311/2010 and Carla Carvalho was supported by the grant SFRH/BPD/79365/2011 both from the FCT-Fundacao para a Ciencia e Tecnologia (http://www.fct.pt). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Experience with different botulinum toxins for the treatment of refractory neurogenic detrusor overactivity

PURPOSE: To report our experience with the use of the botulinum toxin-A (BoNT/A) formulations Botox® and Prosigne® in the treatment of neurogenic detrusor overactivity (NDO). MATERIALS AND METHODS: At a single institution, 45 consecutive patients with refractory urinary incontinence due to NDO received a single intradetrusor (excluding the trigone) treatment with botulinum toxin type A 200 or 300 units. Botox was used for the first 22 patients, and Prosigne for the subsequent 23 patients. Evaluations at baseline and week 12 included assessment of continence and urodynamics. Safety evaluations included monitoring of vital signs, hematuria during the procedure, hospital stay, and spontaneous adverse event reports. RESULTS: A total of 42 patients were evaluated (74% male; mean age, 34.8 years). Significant improvements from baseline in maximum cystometric capacity (MCC), maximum detrusor pressure during bladder contraction, and compliance were observed in both groups (P < 0.05). Improvement in MCC was significantly greater with Botox versus Prosigne (+103.3% vs. +42.2%; P = 0.019). Continence was achieved by week 12 in 16 Botox recipients (76.2%) and 10 Prosigne recipients (47.6%; P = 0.057). No severe adverse events were observed. Mild adverse events included 2 cases of transient hematuria on the first postoperative day (no specific treatment required), and 3 cases of afebrile urinary tract infection. CONCLUSIONS: Botox and Prosigne produce distinct effects in patients with NDO, with a greater increase in MCC with Botox. Further evaluation will be required to assess differences between these formulations

Quantitative models of in vitro bacteriophage-host dynamics and their application to phage therapy

Phage therapy is the use of bacteriophages as antimicrobial agents for the control of pathogenic and other problem bacteria. It has previously been argued that successful application of phage therapy requires a good understanding of the non-linear kinetics of phage-bacteria interactions. Here we combine experimental and modelling approaches to make a detailed examination of such kinetics for the important food-borne pathogen Campylobacter jejuni and a suitable virulent phage in an in vitro system. Phage-insensitive populations of C. jejuni arise readily, and as far as we are aware this is the first phage therapy study to test, against in vitro data, models for phage-bacteria interactions incorporating phage-insensitive or resistant bacteria. We find that even an apparently simplistic model fits the data surprisingly well, and we confirm that the so-called inundation and proliferation thresholds are likely to be of considerable practical importance to phage therapy. We fit the model to time series data in order to estimate thresholds and rate constants directly. A comparison of the fit for each culture reveals density-dependent features of phage infectivity that are worthy of further investigation. Our results illustrate how insight from empirical studies can be greatly enhanced by the use of kinetic models: such combined studies of in vitro systems are likely to be an essential precursor to building a meaningful picture of the kinetic properties of in vivo phage therapy