Oscillatory surface rheotaxis of swimming E. coli bacteria

Bacterial contamination of biological conducts, catheters or water resources is a major threat to public health and can be amplified by the ability of bacteria to swim upstream. The mechanisms of this rheotaxis, the reorientation with respect to flow gradients, often in complex and confined environments, are still poorly understood. Here, we follow individual E. coli bacteria swimming at surfaces under shear flow with two complementary experimental assays, based on 3D Lagrangian tracking and fluorescent flagellar labelling and we develop a theoretical model for their rheotactic motion. Three transitions are identified with increasing shear rate: Above a first critical shear rate, bacteria shift to swimming upstream. After a second threshold, we report the discovery of an oscillatory rheotaxis. Beyond a third transition, we further observe coexistence of rheotaxis along the positive and negative vorticity directions. A full theoretical analysis explains these regimes and predicts the corresponding critical shear rates. The predicted transitions as well as the oscillation dynamics are in good agreement with experimental observations. Our results shed new light on bacterial transport and reveal new strategies for contamination prevention.Comment: 12 pages, 5 figure

Towards an analytical description of active microswimmers in clean and in surfactant-covered drops

Geometric confinements are frequently encountered in the biological world and strongly affect the stability, topology, and transport properties of active suspensions in viscous flow. Based on a far-field analytical model, the low-Reynolds-number locomotion of a self-propelled microswimmer moving inside a clean viscous drop or a drop covered with a homogeneously distributed surfactant, is theoretically examined. The interfacial viscous stresses induced by the surfactant are described by the well-established Boussinesq-Scriven constitutive rheological model. Moreover, the active agent is represented by a force dipole and the resulting fluid-mediated hydrodynamic couplings between the swimmer and the confining drop are investigated. We find that the presence of the surfactant significantly alters the dynamics of the encapsulated swimmer by enhancing its reorientation. Exact solutions for the velocity images for the Stokeslet and dipolar flow singularities inside the drop are introduced and expressed in terms of infinite series of harmonic components. Our results offer useful insights into guiding principles for the control of confined active matter systems and support the objective of utilizing synthetic microswimmers to drive drops for targeted drug delivery applications.Comment: 19 pages, 7 figures. Regular article contributed to the Topical Issue of the European Physical Journal E entitled "Physics of Motile Active Matter" edited by Gerhard Gompper, Clemens Bechinger, Holger Stark, and Roland G. Winkle

Wave Speed Measurements in Non-Ideal Compressible Flows Using the Flexible Asymmetric Shock Tube (FAST)

Non-ideal compressible fluid dynamics (NICFD) are defined as compressible fluid flows occurring in the dense vapour, dense vapour-liquid equilibrium or supercritical thermodynamic region. This type of flow can occur in expanders of organic Rankine cycle power plants. In order to study NICFD, a Ludwieg tube-type facility has been designed and constructed at Delft University of Technology. A large variety of fluids can be employed in the facility, but for this study D6 siloxane is chosen as working fluid due to its high thermal stability and the possibility of encountering non-classical gasdynamic phenomena. This compound belongs to the siloxane class, which are also used as working fluids in ORC power systems. Gasdynamic experiments within the NICFD region are presented from which the wave speed and speed of sound can be inferred using the time-of-flight technique. These data can be used to improve and validate thermodynamic models

Inhibition of OATP1B1 by tyrosine kinase inhibitors: In vitro-in vivo correlations

Background:Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1.Methods:The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice.Results:All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics.Conclusion: These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI-chemotherapy interactions involving transporters

Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patients dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria.Methods:Three BSA bands were defined: BSA1.7 m2, 1.7 m2 BSA1.9 m 2, BSA1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m 2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug.Results:For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between 14% and 22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P=0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs.Conclusion:For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure

Organic film thickness influence on the bias stress instability in Sexithiophene Field Effect Transistors

In this paper, the dynamics of bias stress phenomenon in Sexithiophene (T6) Field Effect Transistors (FETs) has been investigated. T6 FETs have been fabricated by vacuum depositing films with thickness from 10 nm to 130 nm on Si/SiO2 substrates. After the T6 film structural analysis by X-Ray diffraction and the FET electrical investigation focused on carrier mobility evaluation, bias stress instability parameters have been estimated and discussed in the context of existing models. By increasing the film thickness, a clear correlation between the stress parameters and the structural properties of the organic layer has been highlighted. Conversely, the mobility values result almost thickness independent

Clinical pharmacokinetics and metabolism of irinotecan (CPT-11)

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent

The ambiguity of human ashes: exploring encounters with cremated remains in the Netherlands

This article explores cremation and disposal practices in the Netherlands, focusing on the attitudes and experiences of bereaved Dutch people in relation to cremated remains. In academic and professional narratives, human ashes are commonly described as “important,” as “sacred,” and as a vehicle to continue intense and physical relationships with the dead. Based on quantitative and qualitative data this article illustrates the ambiguity of such relationships. It highlights the diverse experiences, unexpected challenges, and moral obligations that can be evoked by the deceased’s ashes, where the latter are seen as embedded in material practices and entangled in social relationships

Irinotecan pathway genotype analysis to predict pharmacokinetics

PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups

Effects of St. John's wort on irinotecan metabolism

St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7 micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome