Evaluation and localization of an artificial drainage network by 3D time-lapse electrical resistivity tomography.

In France, 10 % of total arable land is equipped with subsurface drainage systems, to control winter and spring waterlogging due to a temporary perched water table. Most of these systems were installed in the1980s and have aged since then and may now need maintenance. Sometimes, the location of the systems is known, but the standard situation in France is that the original as-built master sketches are no longer available. Performance assessment of drainage systems and curative actions are complicated since drain location is unknown. In this article, the authors test the application of a non-destructive drain detection method which consists in water injection at the outfall of the drainage network combined with time-lapse electrical resistivity tomography (ERT) monitoring. To assess the performance of this methodology, which consists in measuring electrical resistivity from electrodes placed at the nodes of a 1.2-m regular mesh, the authors interpreted the signal using a two-step approach. The first step is based on 3D ERT numerical modelling during a scenario of surface infiltration processes (forward modelling followed by geophysical inversion); this step optimizes the ERT method for locating the infiltration at depths below 1 m. The second step is the validation of the results obtained by numerical modelling with an experimental data set, using water injection into the drainage network combined with time-lapse ERT monitoring on an experimental field site. The results showed the relevance of time-lapse ERT monitoring on a small agricultural plot for locating the drainage network. The numerical results also showed several limitations of the combined methodology: (i) it is necessary to use an electrode spacing unit less than 1.20 m, which does not facilitate investigation on large agriculture plots, (ii) measurements must be taken when resistivity contrast is the strongest between the infiltration area and the soil and (iii) the volume of water needed for injection can limit the extension of the method.

BCL2 protein signalling determines acute responses to neoadjuvant chemoradiotherapy in rectal cancer.

UNLABELLED: In locally advanced rectal cancer, neoadjuvant chemoradiotherapy is performed prior to surgery to downstage the tumour. Thirty to 40 % of patients do not respond. Defects in apoptotic machinery lead to therapy resistance; however, to date, no study quantitatively assessed whether B cell lymphoma 2 (BCL2)-dependent regulation of mitochondrial apoptosis, effector caspase activation downstream of mitochondria or a combination of both predicts patient responses. In a cohort of 20 rectal cancer patients, we performed protein profiling of tumour tissue and employed validated ordinary differential equation-based systems models of apoptosis signalling to calculate the ability of cancer cells to undergo apoptosis. Model outputs were compared to clinical responses. Systems modelling of BCL2-signalling predicted patients in the poor response group (p = 0.0049). Systems modelling also demonstrated that rectal cancers depended on BCL2 rather than B cell lymphoma-extra large (BCL(X)L) or myeloid cell leukemia 1 (MCL1) for survival, suggesting that poor responders may benefit from therapy with selective BCL2 antagonists. Dynamic modelling of effector caspase activation could not stratify patients with poor response and did not further improve predictive power. We deliver a powerful patient stratification tool identifying patients who will likely not benefit from neoadjuvant chemoradiotherapy and should be prioritised for surgical resection or treatment with BCL2 antagonists. KEY MESSAGES: Modelling BCL2-family proteins identifies patients unresponsive to therapy. Caspase activation downstream of mitochondria cannot identify these patients. Rectal tumours of poor responders are BCL2- but not BCL-XL-dependent. DR_MOMP allows clinicians to identify patients who would not benefit from therapy. DR_MOMP is also a useful patient stratification tool for BCL2 antagonists.

Comparison of the pharmacokinetics of miconazole after administration via a bioadhesive slow release tablet and an oral gel to healthy male and female subjects.

AIMS: The aim of this study was to compare salivary miconazole pharmacokinetics following once daily application of bioadhesive tablets (50 or 100 mg), vs the current treatment with a gel (3 times a day, 375 mg day(-1)). METHODS: A three way cross over study was carried out in 18 healthy subjects (nine males, nine females) with a 1 week washout period between each treatment. Plasma and salivary pharmacokinetics of miconazole were assessed over a 24-h period. RESULTS: In all subjects the tablets gave higher and more prolonged salivary miconazole concentrations than the gel. Thus salivary miconazole AUC(0,24 h) was 37.2 times greater for the 100 mg tablet (90% confidence interval [CI] 22.9, 60.5) and 18.9 times greater for the 50 mg tablet (CI 11.7, 30.6) compared with the gel. Similarly, Cmax was 17.2 times greater (CI 11.8, 25.2) and 7.8 times greater (CI 5.3, 11.4) for the 100 mg tablet and 50 mg tablet, respectively. Comparison of the 100 mg and 50 mg tablets gave ratios of 2.2 and 2.0 for Cmax and AUC(0,24 h), respectively (CI 1.5, 3.2 and 1.2, 3.2). The mean time that salivary miconazole concentrations were above 0.4 micro g ml(-1) (the concentration reached 3 h after application of the oral gel according to published data) or above 1.0 microg ml(-1) (the MIC of some Candida species) was greater for both bioadhesive tablets than for the oral gel (10-14 h vs 1.5 h and 7 h vs 0.6 h). Only 19 plasma samples from eight subjects had concentrations of miconazole above 0.4 micro g ml(-1). Ten of these were taken from five subjects after administration of the gel and nine from three subjects after administration of the tablets. CONCLUSIONS: These data strongly support the further development of miconazole bioadhesive tablets as a sustained release formulation leading to improved antifungal exposure in the buccal cavity. A single daily application should improve compliance, whereas the low systemic absorption of miconazole will alleviate concerns regarding drug interactions and adverse effects.

Scientific evaluations of interventions to improve the adequate use of pharmaceuticals in Third World countries.

The inadequate use of pharmaceuticals continues to be a severe problem in most parts of the world. Developing nations waste very large amounts of scarce health resources on medicines of doubtful therapeutic value, and many persons do not comply with physicians advice or engage in risky self-medication practices contributing to additional misuse of resources and iatrogenia. This paper examines the few scientifically designed interventions at the community and patient s levels to improve the appropriate use of pharmaceuticals in developing nations. The authors analyze the contribution made by these studies and identify several limitations including the absence of independent evaluations of outcomes, lack of sufficient information to judge the quality and adequacy of the instruments used, problems relating to replicability of interventions at regional or country level, or outside the cultural context within which they took place, lack of information on costs of interventions, a crucial variable in poor countries, and the absence of standardized outcome measures that makes comparative analysis very difficult.

Delivery systems for antisense oligonucleotides.

In vitro, the efficacy of the antisense approach is strongly increased by systems delivering oligodeoxyribonucleotides (ODNs) to cells. Up to now, most of the developed vectors favor ODN entrance by a mechanism based on endocytosis. Such is the case for particulate systems, including liposomes (cationic or non-cationic), cationic polyelectrolytes, and delivery systems targeted to specific receptors. Under these conditions, endosomal compartments may represent a dead end for ODNs. Current research attempts to develop conditions for escaping from these compartments. A new class of vectors acts by passive permeabilization of the plasma membrane. It includes peptides, streptolysin O, and cationic derivatives of polyene antibiotics. In vivo, the interest of a delivery system, up to now, has appeared limited. Development of vectors insensitive to the presence of serum seems to be a prerequisite for future improvements.

A cationic derivative of amphotericin B as a novel delivery system for antisense oligonucleotides.

A novel approach based on a plasma membrane permeability-disturbing agent was proposed as an antisense oligonucleotide delivery system. AMA, a derivative of the polyene antibiotic amphotericin B, formed a stable complex when mixed with phosphodiester oligodeoxynucleotides and enhanced the intracellular uptake of a 5' fluoresceinated anti-mdr1 20-mer into NIH-MDR-G185 cells. The nonlabeled phosphorothioate form of the oligodeoxynucleotide, complexed to AMA, inhibited P-glycoprotein expression with better efficiency and less nonspecific effects than when vectorized by Lipofectin. AMA may thus be a good agent for antisense strategy.