High-performance liquid chromatography analysis of mezlocillin, piperacillin, their degradation products, and of ioxitalamic acid in plasma and urine of healthy volunteers

In plasma and urine of 10 healthy volunteers after intravenous administration of 4 g mezlocillin and piperacillin, respectively, the parent compounds as well as degradation products were assayed by high-performance liquid chromatography. Ioxitalamic acid, a renal contrast medium, was administered simultaneously, in order to measure the glomerular filtration rate, and to control the collection of 24-h urine. As metabolite of mezlocillin the corresponding penicilloic acid only was found, whereas in the case of piperacillin a further degradation product was observed. Half of the doses given was recovered in the urine as unchanged drugs, and in addition 5-10% as metabolites. No differences were found in the pharmacokinetic behaviour of both antibiotics

Transport through Zero-Dimensional States in a Quantum Dot

We have studied the electron transport through zero-dimensional (0D) states. 0D states are formed when one-dimensional edge channels are confined in a quantum dot. The quantum dot is defined in a two-dimensional electron gas with a split gate technique. To allow electronic transport, connection to the dot is arranged via two quantum point contacts, which have adjustable selective transmission properties for edge channels. The 0D states show up as pronounced oscillations in the conductance (up to 40% of e2/h), when the flux enclosed by the confined edge channel is varied, either by changing the magnetic field or the gate voltage. A prerequisite for the appearance of 0D states is that the transport through the entire device is adiabatic (i.e. with conservation of quantum numbers), which will be shown to occur at high magnetic field. The experimental results are in good agreement with theory and show that in the ballistic quantum Hall regime the current is carried entirely by edge channels.

Clinical relevance of P-glycoprotein expression in haematological malignancies

Although, generally speaking, haematological malignancies are chemotherapy-responsive tumours and high remission induction rates are obtained, disease-related death is the rule rather than the exception. The appearance of cell populations, resistant to multidrug-based chemotherapy, constitutes the major problem to achieve cures in these patients. Advances in cell biology have partly contributed to the elucidation of different multidrug resistance (MDR) mechanisms, which enable cells to survive the cytotoxic effects of multiple chemotherapeutic agents. Of these resistance mechanisms, the one that is referred to as classical MDR is the most extensively studied, both in the laboratory as well as in patients, and here we will focus on its clinical relevance in haematological malignancies. The classical MDR phenotype is caused by enhanced cellular drug efflux due to increased activity of a membrane-bound glycoprotein (P-glycoprotein) drug pump, that can pump out anthracyclines, anthracenediones, vinca alkaloids and epipodophyllotoxins, thereby actively lowering the intracellular drug concentrations to sublethal levels. As soon as molecular probes for the detection of MDR cells became available, clinical studies were initiated to answer three main questions. Do human tumour cells express P-glycoprotein? If so, is the expression indicative of a bad prognosis, c.q. resistant disease? And last but not least, can we interfere with the P-glycoprotein drug pump in the patient? Clinical data indicate that classical MDR may be involved in the development of drug resistance, especially in some haematological malignancies, such as acute myelocytic leukaemia (AML), non-Hodgkin's lymphomas (NHL), and multiple myelomas (MM). In almost all types of haematological malignancies, either untreated or treated, elevated P-glycoprotein levels have been reported, ranging from low to high. However, the acquisition of clinical MDR associated with P-glycoprotein expression occurs only in those diseases (for example, AML and MM) that are heavily treated with MDR-related drugs, probably by selection of pre-existing P-glycoprotein-expressing malignant cells. Since P-glycoprotein is found to be expressed on the membrane of normal haemopoietic progenitor cells as well, it seems likely that P-glycoprotein-positive haematological tumours develop by malignant transformation of P-glycoprotein-expressing normal haemopoietic counterparts. Especially for AML, convincing data have been reported in the literature to show that P-glycoprotein expression at diagnosis is a bad prognostic factor that predicts refractoriness. Using in vitro model systems for classical MDR, a large number of agents have been identified that can circumvent P-glycoprotein-mediated drug resistance, the so-called resistance modifying agents (RMA). Subsequently, clinical phase I and II studies have been initiated which combine the use of MDR-related drugs in conjunction with RMAs. The overall conclusions from such studies in AML, NHL, and MM are that modulation of drug resistance by RMAs seems promising and that further evaluation in prospective, randomized phase III trials is warranted

Reaching Hard-to-Survey Populations: Mode Choice and Mode Preference

This study assesses the effect of response-mode choices on response rates, and responsemode preferences of hard-to-survey populations: young adults, full-time workers, big city inhabitants, and non-Western immigrants. Using address-based sampling, a stratified sample of 3,496 households was selected. The first group of sample members was contacted face to face and could choose between a CAPI and web response mode. The second group, contacted by telephone, could choose between CATI and web. The third group, contacted by telephone, was randomly allocated to a response mode. Our address-based sampling technique was successful in reaching most of the hard-to-survey groups. Insufficient numbers of non- Western immigrants were reached; therefore this group was excluded from our analyses. In our mixed-effect models, no significant effects on the willingness to participate were found for mode choice. We found that full-time workers and young adults were significantly more likely to choose web over CAPI when contacted face to face

Defining and distributing longitudinal historical data in a general way through an intermediate structure

'Der Beitrag diskutiert am Beispiel von demographischen Mikrodaten methodologische Probleme von Längsschnittdaten. Die Herausforderungen bestehen darin, 1. Lebensverläufe in kartesische Datenformate zu transformieren, die mit den Erfordernissen gängiger statistischer Analysesysteme kompatibel sind, und 2. Datensätze für interlokale und interkulturelle Studien vergleichbar zu machen. Um dieses Ziel zu erreichen wird eine intermediäre Datenstruktur (IDS) vorgeschlagen, die auf alle Datenbanken übertragen kann. Die Autoren erläutern den Vorteil des IDS-Ansatzes und die Maßnahmen, die zur Umsetzung des Konzeptes führen werden.' (Autorenreferat)'In recent years, studies of historical populations have shifted from tracing large-scale processes to analyzing longitudinal micro data in the form of 'life histories'. This approach expands the scope of social history by integrating data on a range of life course events. The complexity of life-course analysis, however, has limited most researchers to working with one specific database. The authors discuss methodological problems raised by longitudinal historical data and the challenge of converting life histories into rectangular datasets compatible with statistical analysis systems. The logical next step is comparing life courses across local and national databases, and they propose a strategy for sharing historical longitudinal data based on an intermediate data structure (IDS) that can be adopted by all databases. They describe the benefits of the IDS approach and activities that will advance the goals of simplifying and promoting research with longitudinal historical data.' (author's abstract

A multigrid multilevel Monte Carlo method using high-order finite-volume scheme for lognormal diffusion problems

The aim of this paper is to show that a high-order discretization can be used to improve the convergence of a multilevel Monte Carlo method for elliptic partial differential equations with lognormal random coefficients in combination with the multigrid solution method. To demonstrate this, we consider a fourth-order accurate finite-volume discretization. With the help of the Matérn family of covariance functions, we simulate the coefficient field with different degrees of smoothness. The idea behind using a fourth-order scheme is to capture the additional regularity in the solution introduced due to higher smoothness of the random field. Second-order schemes previously utilized for these types of problems are not able to fully exploit this additional regularity. We also propose a practical way of combining a full multigrid solver with the multilevel Monte Carlo estimator constructed on the same mesh hierarchy. Through this integration, one full multigrid solve at any level provides a valid sample for all the preceding Monte Carlo levels. The numerical results show that the fourth-order multilevel estimator consistently outperforms the second-order variant. In addition, we observe an asymptotic gain for the standard Monte Carlo estimator

A multigrid multilevel Monte Carlo method for transport in the Darcy–Stokes system

A multilevel Monte Carlo (MLMC) method for Uncertainty Quantification (UQ) of advection-dominated contaminant transport in a coupled Darcy–Stokes flow system is described. In particular, we focus on high-dimensional epistemic uncertainty due to an unknown permeability field in the Darcy domain that is modelled as a lognormal random field. This paper explores different numerical strategies for the subproblems and suggests an optimal combination for the MLMC estimator. We propose a specific monolithic multigrid algorithm to efficiently solve the steady-state Darcy–Stokes flow with a highly heterogeneous diffusion coefficient. Furthermore, we describe an Alternating Direction Implicit (ADI) based time-stepping for the flux-limited quadratic upwinding discretization for the transport problem. Numerical experiments illustrating the multigrid convergence and cost of the MLMC estimator with respect to the smoothness of permeability field are presented

Reference Production as Search:The Impact of Domain Size on the Production of Distinguishing Descriptions

When producing a description of a target referent in a visual context, speakers need to choose a set of properties that distinguish it from its distractors. Computational models of language production/generation usually model this as a search process and predict that the time taken will increase both with the number of distractors in a scene and with the number of properties required to distinguish the target. These predictions are reminiscent of classic ndings in visual search; however, unlike models of reference production, visual search models also predict that search can become very e cient under certain conditions, something that reference production models do not consider. This paper investigates the predictions of these models empirically. In two experiments, we show that the time taken to plan a referring expression { as re ected by speech onset latencies { is in uenced by distractor set size and by the number of properties required, but this crucially depends on the discriminability of the properties under consideration. We discuss the implications for current models of reference production and recent work on the role of salience in visual search.peer-reviewe