ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.

INTRODUCTION: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies. METHODS: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group. RESULTS: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed. CONCLUSION: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

Office of Location and Environment Manual, August 2009

This manual captures the experience of practitioners in the Iowa Department of Transportation’s (Iowa DOT’s) Office of Location and Environment (OLE). It also documents the need for coordinated project development efforts during the highway project planning, or location study phase and engineering design. The location study phase establishes: * The definition of, and need for, the highway improvement project * The range of alternatives and many key attributes of the project’s design * The recommended alternative, its impacts, and the agreed-to conditions for project approval The location study process involves developing engineering alternatives, collecting engineering and environmental data, and completing design refinements to accomplish functional designs. The items above also embody the basic content required for projects compliant with the National Environmental Policy Act (NEPA) of 19691, which directs federal agencies to use a systematic, interdisciplinary approach during the planning process whenever proposed actions (or “projects”) have the potential for environmental impacts. In doing so, NEPA requires coordination with stakeholders, review, comment, and public disclosure. Are location studies and environmental studies more about the process or the documents? If properly conducted, they concern both—unbiased and reasonable processes with quality and timely documents. In essence, every project is a story that needs to be told. Engineering and environmental regulations and guidance, as documented in this manual, will help project staff and managers become better storytellers.

Activity measurements of 18F and 90Y with commercial radionuclide calibrators for nuclear medicine in Switzerland.

The activity of radiopharmaceuticals in nuclear medicine is measured before patient injection with radionuclide calibrators. In Switzerland, the general requirements for quality controls are defined in a federal ordinance and a directive of the Federal Office of Metrology (METAS) which require each instrument to be verified. A set of three gamma sources (Co-57, Cs-137 and Co-60) is used to verify the response of radionuclide calibrators in the gamma energy range of their use. A beta source, a mixture of (90)Sr and (90)Y in secular equilibrium, is used as well. Manufacturers are responsible for the calibration factors. The main goal of the study was to monitor the validity of the calibration factors by using two sources: a (90)Sr/(90)Y source and a (18)F source. The three types of commercial radionuclide calibrators tested do not have a calibration factor for the mixture but only for (90)Y. Activity measurements of a (90)Sr/(90)Y source with the (90)Y calibration factor are performed in order to correct for the extra-contribution of (90)Sr. The value of the correction factor was found to be 1.113 whereas Monte Carlo simulations of the radionuclide calibrators estimate the correction factor to be 1.117. Measurements with (18)F sources in a specific geometry are also performed. Since this radionuclide is widely used in Swiss hospitals equipped with PET and PET-CT, the metrology of the (18)F is very important. The (18)F response normalized to the (137)Cs response shows that the difference with a reference value does not exceed 3% for the three types of radionuclide calibrators.

Effect of collection and preprocessing methods on neutrophil elastase plasma concentrations.

OBJECTIVES: Elevated plasma levels of the elastase alpha 1-proteinase inhibitor complex (E-alpha 1 PI) have been proposed as a marker of bacterial infection and neutrophil activation. Liberation of elastase from neutrophils after collection of blood may cause falsely elevated results. Collection methods have not been validated for critically ill neonates and children. We evaluated the influence of preanalytical methods on E-alpha 1 PI results including the recommended collection into EDTA tubes. DESIGN AND METHODS: First, we compared varying acceleration speeds and centrifugation times. Centrifugation at 1550 g for 3 min resulted in reliable preparation of leukocyte free plasma. Second, we evaluated all collection tubes under consideration for absorption of E-alpha 1 PI. Finally, 12 sets of samples from healthy adults and 42 sets obtained from critically ill neonates and children were distributed into the various sampling tubes. Samples were centrifuged within 15 min of collection and analyzed with a new turbidimetric assay adapted to routine laboratory analyzers. RESULTS: One of the two tubes containing a plasma-cell separation gel absorbed 22.1% of the E-alpha 1 PI content. In the remaining tubes without absorption of E-alpha 1 PI no differences were observed for samples from healthy adult patients. However, in samples from critically ill neonates or children, significantly higher results were obtained for plain Li-heparin tubes (mean = 183 micrograms/L), EDTA tubes (mean = 93 micrograms/L), and citrate tubes (mean = 88.5 micrograms/L) than for the Li-hep tube with cell-plasma separation gel and no absorption of E-alpha 1 PI (mean = 62.4 micrograms/L, p < 0.01). CONCLUSION: Contrary to healthy adults, E-alpha 1 PI results in plasma samples from critically ill neonates and children depend on the type of collection tube.

Rational design of indoleamine 2,3-dioxygenase inhibitors.

Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

A program for the computation of power and determination of sample size in hierarchical experimental designs.

We have devised a program that allows computation of the power of F-test, and hence determination of appropriate sample and subsample sizes, in the context of the one-way hierarchical analysis of variance with fixed effects. The power at a fixed alternative is an increasing function of the sample size and of the subsample size. The program makes it easy to obtain the power of F-test for a range of values of sample and subsample sizes, and therefore the appropriate sizes based on a desired power. The program can be used for the 'ordinary' case of the one-way analysis of variance, as well as for hierarchical analysis of variance with two stages of sampling. Examples are given of the practical use of the program.

Plant species richness and environmental heterogeneity in a mountain landscape: effects of variability and spatial configuration

The loss of biodiversity has become a matter of urgent concern and a better understanding of local drivers is crucial for conservation. Although environmental heterogeneity is recognized as an important determinant of biodiversity, this has rarely been tested using field data at management scale. We propose and provide evidence for the simple hypothesis that local species diversity is related to spatial environmental heterogeneity. Species partition the environment into habitats. Biodiversity is therefore expected to be influenced by two aspects of spatial heterogeneity: 1) the variability of environmental conditions, which will affect the number of types of habitat, and 2) the spatial configuration of habitats, which will affect the rates of ecological processes, such as dispersal or competition. Earlier, simulation experiments predicted that both aspects of heterogeneity will influence plant species richness at a particular site. For the first time, these predictions were tested for plant communities using field data, which we collected in a wooded pasture in the Swiss Jura mountains using a four-level hierarchical sampling design. Richness generally increased with increasing environmental variability and "roughness" (i.e. decreasing spatial aggregation). Effects occurred at all scales, but the nature of the effect changed with scale, suggesting a change in the underlying mechanisms, which will need to be taken into account if scaling up to larger landscapes. Although we found significant effects of environmental heterogeneity, other factors such as history could also be important determinants. If a relationship between environmental heterogeneity and species richness can be shown to be general, recently available high-resolution environmental data can be used to complement the assessment of patterns of local richness and improve the prediction of the effects of land use change based on mean site conditions or land use history.

Mobility of inorganic and organic phosphorus forms under different levels of phosphate and poultry litter fertilization in soils

The eutrophication of aquifers is strongly linked to the mobility of P in soils. Although P mobility was considered irrelevant in a more distant past, more recent studies have shown that P, both in organic (Po) and inorganic forms (Pi), can be lost by leaching and eluviation through the soil profile, particularly in less weathered and/or sandier soils with low P adsorption capacity. The purpose of this study was to determine losses of P forms by leaching and eluviation from soil columns. Each column consisted of five PVC rings (diameter 5 cm, height 10 cm), filled with two soil types: a clayey Red-Yellow Latosol and a sandy loam Red-Yellow Latosol, which were exposed to water percolation. The soils were previously treated with four P rates (as KH2PO4 ) to reach 0, 12.5, 25.0 and 50 % of the maximum P adsorption capacity (MPAC). The P source was homogenized with the whole soil volume and incubated for 60 days. After this period the soils were placed in the columns; the soil of the top ring was mixed with five poultry litter rates of 0, 20, 40, 80, and 160 t ha-1 (dry weight basis). Treatments consisted of a 4 x 5 x 2 factorial scheme corresponding to four MPAC levels, five poultry litter rates, two soils, with three replications, arranged in a completely randomized block design. Deionized water was percolated through the columns 10 times in 35 days to simulate about 1,200 mm rainfall. In the leachate of each column the inorganic P (reactive P, Pi) and organic P forms (unreactive P, Po) were determined. At the end of the experiment, the columns were disassembled and P was extracted with the extractants Mehlich-1 (HCl 0.05 mol L-1 and H2SO4 0.0125 mol L-1) and Olsen (NaHCO3 0.5 mol L-1; pH 8.5) from the soil of each ring. The Pi and Po fractions were measured by the Olsen extractant. It was found that under higher poultry litter rates the losses of unreactive P (Po) were 6.4 times higher than of reactive P (Pi). Both the previous P fertilization and increasing poultry litter rates caused a vertical movement of P down the soil columns, as verified by P concentrations extracted by Mehlich-1 and NaHCO3 (Olsen). The environmental critical level (ECL), i.e., the P soil concentration above which P leaching increases exponentially, was 100 and 150 mg dm-3 by Mehlich-1 and 40 and 60 mg dm-3 by Olsen, for the sandy loam and clay soils, respectively. In highly weathered soils, where residual P is accumulated by successive crops, P leaching through the profile can be significant, particularly when poultry litter is applied as fertilizer.

Rice grown in nutrient solution with doses of manganese and silicon

Although silicon is not recognized as a nutrient, it may benefit rice plants and may alleviate the Mn toxicity in some plant species. The dry matter yield (root, leaf, sheaths and leaf blade) and plant architecture (angle of leaf insertion and leaf arc) were evaluated in rice plants grown in nutrient solutions with three Mn doses, with and without Si addition. The treatments were arranged in a 2 x 3 factorial [with and without (2 mmol L-1) Si; three Mn doses (0.5; 2.5 and 10 µmol L-1)], in a randomized block design with 4 replications. The experimental unit was a 4 L plastic vase with 4 rice (Metica-1 cultivar) plants. Thirty nine days after keeping the seedlings in the nutrient solution the plant dry matter yield was determined; the angle of leaf insertion in the sheath and the leaf arc were measured; and the Si and Mn concentrations in roots, sheaths and leaves were determined. The analysis of variance (F test at 5 and 1 % levels) and the regression analysis (for testing plant response to Mn with the Si treatments) were performed. The Si added to the nutrient solution increased the dry matter yield of roots, sheaths and leaf blades and also decreased the angle of leaf blade insertion into the sheath and the foliar arc in the rice plant. Additionally, it ameliorated the rice plant architecture which allowed an increase in the dry matter yield. Similarly, the addition of Mn to the solution improved the architecture of the rice plants with gain in dry matter yield. As Si was added to the nutrient solution, the concentration of Mn in leaves decreased and in roots increased thus alleviating the toxic effects of Mn on the plants.

Genetic association tests: a method for the joint analysis of family and case-control data.

With the trend in molecular epidemiology towards both genome-wide association studies and complex modelling, the need for large sample sizes to detect small effects and to allow for the estimation of many parameters within a model continues to increase. Unfortunately, most methods of association analysis have been restricted to either a family-based or a case-control design, resulting in the lack of synthesis of data from multiple studies. Transmission disequilibrium-type methods for detecting linkage disequilibrium from family data were developed as an effective way of preventing the detection of association due to population stratification. Because these methods condition on parental genotype, however, they have precluded the joint analysis of family and case-control data, although methods for case-control data may not protect against population stratification and do not allow for familial correlations. We present here an extension of a family-based association analysis method for continuous traits that will simultaneously test for, and if necessary control for, population stratification. We further extend this method to analyse binary traits (and therefore family and case-control data together) and accurately to estimate genetic effects in the population, even when using an ascertained family sample. Finally, we present the power of this binary extension for both family-only and joint family and case-control data, and demonstrate the accuracy of the association parameter and variance components in an ascertained family sample.

A Computerized Method for the Hydrologic Design of Culverts, February 1974

Nationwide, about five cents of each highway construction dollar is spent on culverts. In Iowa, average annual construction costs on the interstate, primary, and federal-aid secondary systems are about $120,000,000. Assuming the national figure applies to Iowa, about $6,000,000 are spent on culvert construction annually. For each one percent reduction in overall culvert costs, annual construction costs would be reduced by $60,000. One area of potential cost reduction lies in the sizing of the culvert. Determining the flow area and hydraulic capacity is accomplished in the initial design of the culvert. The normal design sequence is accomplished in two parts. The hydrologic portion consists of the determination of a design discharge in cubic feet per second using one of several available methods. This discharge is then used directly in the hydraulic portion of the design to determine the proper type, size, and shape of culvert to be used, based on various site and design restrictions. More refined hydrologic analyses, including rainfall-runoff analysis, flood hydrograph development, and streamflow routing techniques, are not pursued in the existing design procedure used by most county and state highway engineers.

Water-soluble nutrients in aerial plant parts of peanut and white oat as affected by lime and gypsum application

Lime and gypsum influence nutrient availability and uptake, as well as the content of organic acids in the aerial plant parts. These changes, quantified by plant analysis of soluble nutrients, may potentiate the effect of soil amendment, ensuring the sustainability of the no-tillage system. In this sense the effect of lime and gypsum surface application on the content of water-soluble nutrients in peanut and oat residues was evaluated. The experiment was conducted on an Oxisol in Botucatu (SP) in the growing seasons 2004/2005 and 2005/2006. It was arranged in a randomized block design in split plots with four replications, where lime rates represented the plots and presence or absence of gypsum application the subplots. Peanut was grown in summer and white oat in the winter in the entire experimental area. Gypsum applied to peanut increased soluble Ca only in the first season, due to the short period between product application and determination of soluble nutrient contents in the plant extract. Liming of peanut and oat increased soluble Ca, Mg, K contents, did not alter Cu content and reduced Zn, Mn and Fe contents in both years of cultivation. Gypsum on the other hand reduced the electrical conductivity of peanut (2004/2005 and 2005/2006) and white oat (2004/2005).

Application of Visualization and Simulation Program to Improve Work Zone Safety and Mobility, January 2010

A previous study sponsored by the Smart Work Zone Deployment Initiative, “Feasibility of Visualization and Simulation Applications to Improve Work Zone Safety and Mobility,” demonstrated the feasibility of combining readily available, inexpensive software programs, such as SketchUp and Google Earth, with standard two-dimensional civil engineering design programs, such as MicroStation, to create animations of construction work zones. The animations reflect changes in work zone configurations as the project progresses, representing an opportunity to visually present complex information to drivers, construction workers, agency personnel, and the general public. The purpose of this study is to continue the work from the previous study to determine the added value and resource demands created by including more complex data, specifically traffic volume, movement, and vehicle type. This report describes the changes that were made to the simulation, including incorporating additional data and converting the simulation from a desktop application to a web application.

The role of WNT and mTOR in human memory T cell formation

Cancer is one of the world's leading causes of death with a rising trend in incidence. These epidemiologic observations underline the need for novel treatment strategies. In this regard, a promising approach takes advantage of the adaptive effector mechanisms of the immune system, using T lymphocytes to specifically target and destroy tumour cells. However, whereas current approaches mainly depend on short-lived, terminally differentiated effector T cells, increasing evidence suggests that long lasting and maximum efficient immune responses are mediated by low differentiated memory T cells. These memory T cells should display characteristics of stem cells, such as longevity, self-renewal capacity and the ability to continuously give rise to further differentiated effectors. These stem celllike memory T (TSCM) cells are thought to be of key therapeutic value as they might not only attack differentiated tumour cells, but also eradicate the root cause of cancer, the cancer stem cells themselves. Thus, efforts are made to characterize TSCM cells and to identify the signalling pathways which mediate their induction. Recently, a human TSCM cell subset was described and the activation of the Wnt-ß-catenin signalling pathway by the drug TWS119 during naive CD8+ T (TN) cell priming was suggested to mediate their induction. However, a precise deciphering of the signalling pathways leading to TSCM cell induction and an in-depth characterization of in vitro induced and in vivo occurring TSCM cells remain to be performed. Here, evidence is presented that the induction of human and mouse CD8+ and CD4+ TSCM cells may be triggered by inhibition of mechanistic/mammalian target of rapamycin (mTOR) complex 1 with simultaneously active mTOR complex 2. This molecular mechanism arrests a fraction of activated TN cells in a stem cell-like differentiation state independently of the Wnt-ß-catenin signalling pathway. Of note, TWS119 was found to also inhibit mTORCl, thereby mediating the induction of TSCM cells. Suggesting an immunostimulatory effect, the acquired data broaden the therapeutic range of mTORCl inhibitors like rapamycin, which are, at present, exclusively used due to their immunosuppressive function. Furthermore, by performing broad metabolic analyses, a well-orchestrated interplay between intracellular signalling pathways and the T cells' metabolic programmes could be identified as important regulator of the T cells' differentiation fate. Moreover, in vitro induced CD4+ TSCM cells possess superior functional capacities and share fate-determining key factors with their naturally occurring counterparts, assessed by a first-time full transcriptome analysis of in vivo occurring CD4+ TN cell, TSCM cells and central memory (TCM) cells and in vitro induced CD4+ TSCM cells. Of interest, a group of 56 genes, with a unique expression profile in TSCM cells could be identified. Thus, a pharmacological mechanism allowing to confer sternness to activated TN cells has been found which might be highly relevant for the design of novel T cell-based cancer immunotherapies.

Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination.

Methylphenidate and 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') are widely misused psychoactive drugs. Methylphenidate increases brain dopamine and norepinephrine levels by blocking the presynaptic reuptake transporters. MDMA releases serotonin, dopamine and norepinephrine through the same transporters. Pharmacodynamic interactions of methylphenidate and MDMA are likely. This study compared the pharmacodynamic and pharmacokinetic effects of methylphenidate and MDMA administered alone or in combination in healthy subjects using a double-blind, placebo-controlled, crossover design. Methylphenidate did not enhance the psychotropic effects of MDMA, although it produced psychostimulant effects on its own. The haemodynamic and adverse effects of co-administration of methylphenidate and MDMA were significantly higher compared with MDMA or methylphenidate alone. Methylphenidate did not change the pharmacokinetics of MDMA and vice versa. Methylphenidate and MDMA shared some subjective amphetamine-type effects; however, 125 mg of MDMA increased positive mood more than 60 mg of methylphenidate, and methylphenidate enhanced activity and concentration more than MDMA. Methylphenidate and MDMA differentially altered facial emotion recognition. Methylphenidate enhanced the recognition of sad and fearful faces, whereas MDMA reduced the recognition of negative emotions. Additionally, the present study found acute pharmacodynamic tolerance to MDMA but not methylphenidate. In conclusion, the combined use of methylphenidate and MDMA does not produce more psychoactive effects compared with either drug alone, but potentially enhances cardiovascular and adverse effects. The findings may be of clinical importance for assessing the risks of combined psychostimulant misuse. Trial registration identification number: NCT01465685 (http://clinicaltrials.gov/ct2/show/NCT01465685).