Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.

Determination of meropenem in plasma and filtrate-dialysate from patients under continuous veno-venous haemodiafiltration by SPE-LC.

Meropenem, a carbapenem antibiotic displaying a broad spectrum of antibacterial activity, is administered in Medical Intensive Care Unit to critically ill patients undergoing continuous veno-venous haemodiafiltration (CVVHDF). However, there are limited data available to substantial rational dosing decisions in this condition. In an attempt to refine our knowledge and propose a rationally designed dosage regimen, we have developed a HPLC method to determine meropenem after solid-phase extraction (SPE) of plasma and dialysate fluids obtained from patients under CVVHDF. The assay comprises the simultaneous measurement of meropenem's open-ring metabolite UK-1a, whose fate has never been studied in CVVHDF patients. The clean-up procedure involved a SPE on C18 cartridge. Matrix components were eliminated with phosphate buffer pH 7.4 followed by 15:85 MeOH-phosphate buffer pH 7.4. Meropenem and UK-1a were subsequently desorbed with MeOH. The eluates were evaporated under nitrogen at room temperature (RT) and reconstituted in phosphate buffer pH 7.4. Separation was performed at RT on a Nucleosil 100-5 microm C18 AB cartridge column (125 x 4 mm I.D.) equipped with a guard column (8 x 4 mm I.D.) with UV-DAD detection set at 208 nm. The mobile phase was 1 ml min(-1), using a step-wise gradient elution program: %MeOH/0.005 M tetrabutylammonium chloride pH 7.4; 10/90-50/50 in 27 min. Over the range of 5-100 microg ml(-1), the regression coefficient of the calibration curves (plasma and dialysate) were >0.998. The absolute extraction recoveries of meropenem and UK-1a in plasma and filtrate-dialysate were stable and ranged from 88-93 to 72-77% for meropenem, and from 95-104 to 75-82% for UK-1a. In plasma and filtrate-dialysate, respectively, the mean intra-assay precision was 4.1 and 2.6% for meropenem and 4.2 and 3.7% for UK-1a. The inter-assay variability was 2.8 and 3.6% for meropenem and 2.3 and 2.8% for UK-1a. The accuracy was satisfactory for both meropenem and UK-1a with deviation never exceeding 9.0% of the nominal concentrations. The stability of meropenem, studied in biological samples left at RT and at +4 degrees C, was satisfactory with < 5% degradation after 1.5 h in blood but reached 22% in filtrate-dialysate samples stored at RT for 8 h, precluding accurate measurements of meropenem excreted unchanged in the filtrate-dialysate left at RT during the CVVHDF procedure. The method reported here enables accurate measurements of meropenem in critically ill patients under CVVHDF, making dosage individualisation possible in such patients. The levels of the metabolite UK-1a encountered in this population of patients were higher than those observed in healthy volunteers but was similar to those observed in patients with renal impairment under hemodialysis.

Development of a Rational Characterization Method for Iowa Fly Ash, HR-286, 1988

This research project was conducted in an attempt to determine the cause of paste strength variability in Iowa fly ashes and to develop test methods to more adequately reflect fly ash physical and chemical characteristics. An extensive three year sampling and testing program was developed and initiated which incorporated fly ash from several Iowa power plants. Power plant design and operating data were collected. The variability was directly linked to power plant maintenance schedules and to sodium carbonate coal pretreatment. Fly ash physical and chemical properties can change drastically immediately before and after a maintenance outage. The concentrations of sulfate bearing minerals in the fly ash increases sharply during shutdown. Chemical, mineralogical, and physical testing indicated that the sodium, sulfate bearing minerals, lime and tricalcium aluminate contents of the fly ashes play important roles in the development of hydration reaction products in fly ash pastes. The weak pastes always contained ettringite as the major reaction product. The strong pastes contained straetlingite and monosulfoaluminate as the major reaction products along with minor amounts of ettringite. Recommendations for testing procedure changes and suggested interim test methods are presented.

Shear thinning and thixotropy of HMHEC and HEC water solutions

Steady state viscosity and thixotropy of hydrophobically modified hydroxyethyl cellulose HMHEC and nonassociative cellulose water solutions are studied. Although all the samples are shear thinning, only the HMHEC is thixotropic, since the migration of hydrophobes to micelles is controlled by diffusion. The Cross model fits steady state curves. The Mewis model, a phenomenological model that proposes that the rate of change of viscosity when the shear rate is suddenly changed is related to the difference between the steady state and current values of viscosity raised to an exponent, fits structure construction experiments when the exponent, n, is estimated to be around 2. The Newtonian assumption used by Mewis cannot be used here, however. This seems to be related to the fact that the thickening is due to bridged micelle formation, which is a slow process, and also to topological constraints and entanglements, which are rapid processes. The kinetic parameter was redefined to kn in order to make it independent of initial conditions. So, kn depends only on how the shear affects the structure. kn reaches a plateau at shear rates too low to produce structure destruction and decreases at higher shear rates.

Innovative Solutions for Slope Stability Reinforcement and Characterization: Vol. I, TR-489, 2005

Soil slope instability concerning highway infrastructure is an ongoing problem in Iowa, as slope failures endanger public safety and continue to result in costly repair work. Characterization of slope failures is complicated, because the factors affecting slope stability can be difficult to discern and measure, particularly soil shear strength parameters. While in the past extensive research has been conducted on slope stability investigations and analysis, this research consists of field investigations addressing both the characterization and reinforcement of such slope failures. The current research focuses on applying an infrequently-used testing technique comprised of the Borehole Shear Test (BST). This in-situ test rapidly provides effective (i.e., drained) shear strength parameter values of soil. Using the BST device, fifteen Iowa slopes (fourteen failures and one proposed slope) were investigated and documented. Particular attention was paid to highly weathered shale and glacial till soil deposits, which have both been associated with slope failures in the southern Iowa drift region. Conventional laboratory tests including direct shear tests, triaxial compression tests, and ring shear tests were also performed on undisturbed and reconstituted soil samples to supplement BST results. The shear strength measurements were incorporated into complete evaluations of slope stability using both limit equilibrium and probabilistic analyses. The research methods and findings of these investigations are summarized in Volume 1 of this report. Research details of the independent characterization and reinforcement investigations are provided in Volumes 2 and 3, respectively. Combined, the field investigations offer guidance on identifying the factors that affect slope stability at a particular location and also on designing slope reinforcement using pile elements for cases where remedial measures are necessary. The research findings are expected to benefit civil and geotechnical engineers of government transportation agencies, consultants, and contractors dealing with slope stability, slope remediation, and geotechnical testing in Iowa.

Innovative Solutions for Slope Stability Reinforcement and Characterization: Vol. II, TR-489, 2005

Soil slope instability concerning highway infrastructure is an ongoing problem in Iowa, as slope failures endanger public safety and continue to result in costly repair work. While in the past extensive research has been conducted on slope stability investigations and analysis, this current research study consists of field investigations addressing both the characterization and reinforcement of such slope failures. While Volume I summarizes the research methods and findings of this study, Volume II provides procedural details for incorporating an infrequently-used testing technique, borehole shear tests, into practice. Fifteen slopes along Iowa highways were investigated, including thirteen slides (failed slopes), one unfailed slope, and one proposed embankment slope (the Sugar Creek Project). The slopes are mainly comprised of either clay shale or glacial till, and are generally gentle and of small scale, with slope angle ranging from 11 deg to 23 deg and height ranging from 6 to 23 m. Extensive field investigations and laboratory tests were performed for each slope. Field investigations included survey of slope geometry, borehole drilling, soil sampling, in-situ Borehole Shear Testing (BST) and ground water table measurement. Laboratory investigations mainly comprised of ring shear tests, soil basic property tests (grain size analysis and Atterberg limits test), mineralogy analyses, soil classifications, and natural water contents and density measurements on the representative soil samples from each slope. Extensive direct shear tests and a few triaxial compression tests and unconfined compression tests were also performed on undisturbed soil samples for the Sugar Creek Project. Based on the results of field and lab investigations, slope stability analysis was performed on each of the slopes to determine the possible factors resulting in the slope failures or to evaluate the potential slope instabilities using limit equilibrium methods. Deterministic slope analyses were performed for all the slopes. Probabilistic slope analysis and sensitivity study were also performed for the slope of the Sugar Creek Project. Results indicate that while the in-situ test rapidly provides effective shear strength parameters of soils, some training may be required for effective and appropriate use of the BST. Also, it is primarily intended to test cohesive soils and can produce erroneous results in gravelly soils. Additionally, the quality of boreholes affects test results, and disturbance to borehole walls should be minimized before test performance. A final limitation of widespread borehole shear testing may be its limited availability, as only about four to six test devices are currently being used in Iowa. Based on the data gathered in the field testing, reinforcement investigations are continued in Volume III.

Innovative Solutions for Slope Stability Reinforcement and Characterization: Vol. III, TR-489, 2005

Soil slope instability concerning highway infrastructure is an ongoing problem in Iowa, as slope failures endanger public safety and continue to result in costly repair work. Volume I of this current study summarizes research methods and findings, while Volume II provides procedural details for incorporating into practice an infrequently-used testing technique–borehole shear tests. Volume III of this study of field investigation of fifteen slopes in Iowa demonstrates through further experimental testing how lateral forces develop along stabilizing piles to resist slope movements. Results establish the feasibility of an alternative stabilization approach utilizing small-diameter pile elements. Also, a step-by-step procedure that can be used by both state and county transportation agencies to design slope reinforcement using slender piles is documented. Initial evidence of the efficiency and cost-effectiveness of stabilizing nuisance slope failures with grouted micropiles is presented. Employment of the remediation alternative is deemed more appropriate for stabilizing shallow slope failures. Overall, work accomplished in this research study included completing a comprehensive literature review on the state of the knowledge of slope stability and slope stabilization, the preparation and performance of fourteen full-scale pile load tests, the analysis of load test results, and the documentation of a design methodology for implementing the technology into current practices of slope stabilization. Recommendations for further research include monitoring pilot studies of slope reinforcement with grouted micropiles, supplementary experimental studies, and advanced numerical studies.

Mobilizing and evaluating anticancer T cells: pitfalls and solutions.

Immunotherapy is a promising means to fight cancer, prompting a steady increase in clinical trials and correlative laboratory studies in this field. As antitumor T cells play central roles in immunity against malignant diseases, most immunotherapeutic protocols aim to induce and/or strengthen their function. Various treatment strategies have elicited encouraging clinical responses; however, major challenges have been uncovered that should be addressed in order to fully exploit the potential of immunotherapy. Here, we outline pitfalls for the mobilization of antitumor T cells and offer solutions to improve their therapeutic efficacy. We provide a critical perspective on the main methodologies used to characterize T-cell responses to cancer therapies, with a focus on discrepancies between T-cell attributes measured in vitro and protective responses in vivo. This review altogether provides recommendations to optimize the design of future clinical trials and highlights important considerations for the proficient analysis of clinical specimens available for research.

3D solutions in transmission electron (Cryo) -microscopy in biology

One of the main problems in transmission electron microscopy in thebiological field is the tri-dimensionality. This article explains the technicalprocedures and requirements to prepare biological specimens preserving themclosest to their native state to perform 3D reconstruction of the macromolecularcomplexes and cellular structures in their natural environment.

Prescription du monitoring pratique médicate: de l'empirisme eclairé aux stratégies rationnelles [Prescribing monitoring in clinical practice: from enlightened empiricism to rational strategies].

Monitoring of a medical condition is the periodic measurement of one or several physiological or biological variables to detect a signal regarding its clinical progression or its response to treatment. We distinguish different medical situations between diagnostic, clinical and therapeutic process to apply monitoring. Many clinical, variables can be used for monitoring, once their intrinsic properties (normal range, critical difference, kinetics, reactivity) and external validity (pathophysiological importance, predictive power for clinical outcomes) are established. A formal conceptualization of monitoring is being developed and should support the rational development of monitoring strategies and their validation through appropriate clinical trials.

Diabetes care: opinions, needs and proposed solutions of Swiss patients and healthcare professionals: a qualitative study.

AIMS: To explore, both among patients with diabetes and healthcare professionals, opinions on current diabetes care and the development of the "Regional Diabetes Program". METHODS: We employed qualitative methods (focus groups - FG) and used purposive sampling strategy to recruit patients with diabetes and healthcare professionals. We conducted one diabetic and one professional FG in each of the four health regions of the canton of Vaud/Switzerland. The eight FGs were audio-taped and transcribed verbatim. Thematic analysis was then undertaken. RESULTS: Results showed variability in the perception of the quality of diabetes care, pointed to insufficient information regarding diabetes, and lack of collaboration. Participants also evoked patients' difficulties for self-management, as well as professionals' and patients' financial concerns. Proposed solutions included reinforcing existing structures, developing self-management education, and focusing on comprehensive and coordinated care, communication and teamwork. Patients and professionals were in favour of a "Regional Diabetes Program" tailored to the actors' needs, and viewed it as a means to reinforce existing care delivery. CONCLUSIONS: Patients and professionals pointed out similar problems and solutions but explored them differently. Combined with coming quantitative data, these results should help to further develop, adapt and implement the "Regional Diabetes Program".