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PubMed2003

Ultrashort-pulse laser ellipsometric pump-probe experiments on gold targets.

Ultrashort-pulse laser pump-probe ellipsometry has been performed on gold targets at intensities 2 x 10(12)-5 x 10(13) W/cm(2). We measured time-resolved p- and s-polarized reflectivity (r(p) and r(s)) and the s-p phase difference (delta). When plotted as Y=[2|r(s)||r(p)|sin((delta)]/(|r(s)|(2)+|r(p)|(2)) versus X=|r(p)|(2)/|r(s)|(2), the experimental data follow approximately the same curve in X-Y space, even for different pump intensities. Although the input energy density is about 40 eV/atom and the plasma expansion is rapid (up to 10 km/sec), our data are consistent with a partially transparent blowoff having an atomic polarizability (-1.75+0.2i)x 10(-24) cm(3). We attribute this behavior to recombination in the expanding plasma. The Saha equation predicts recombination and formation of negative ions and a low density of free electrons in the low-density vapor, and solutions of the Maxwell equations approximately reproduce the data.

Journal Article↗

PubMed1998

Doppler perfusion index: an interobserver and intraobserver reproducibility study.

PURPOSE: To assess the potential of Doppler perfusion index (DPI) measurement as a routine diagnostic tool in the detection of occult colorectal liver metastases. MATERIALS AND METHODS: By using color doppler ultrasound, two independent sonologists performed DPI measurements blindly in 20 patients aged 30-82 years; interobserver reproducibility was assessed. A second group of 20 patients aged 37-88 years were examined to assess the level of intraobserver reproducibility of DPI measurements attained by one sonologist. For each patient in this group, the DPI was measured three times in succession, and the variability between measurements was analyzed. Calculations of the intraclass correlation coefficient and the coefficient of variation (CV) were used to determine the levels of reproducibility. The data were also analyzed by using the Student paired t test, with significance established at P less than .05. RESULTS: The interobserver CV and intraobserver CV were 20% and 16%, respectively. The two sonologists who examined the first group of patients agreed independently on the DPI status in 18 of 20 (90%) patients. CONCLUSION: In this study, both the intraobserver reproducibility and the interobserver reproducibility of DPI measurements were clinically acceptable.

Adult↗

PubMed2005

Comparison of non-human primate and human whole blood tissue gene expression profiles.

Gene expression profiling is an important tool in the development of medical countermeasures against chemical warfare agents (CWAs). Non-human primates (NHPs), specifically the rhesus macaque (Macaca mulatta), the cynomologus macaque (Macaca fascicularis), and the African green monkey (Chlorocebus aethiops), are vital models in the development of CWA prophylactics, therapeutics, and diagnostics. However, gene expression profiling of these NHPs is complicated by the fact their genomes are not completely sequenced, and that no commercially available oligonucleotide microarrays (genechips) exist. We, therefore, sought to determine whether gene expression profiling of NHPs could be performed using human genechips. Whole blood RNA was isolated from each species and used to generate genechip probes. Hybridization of the NHP samples to human genechips (Affymetrix Human U133 Plus 2.0) resulted in comparable numbers of transcripts detected compared with human samples. Statistical analysis revealed intraspecies reproducibility of genechip quality control metrics; interspecies comparison between NHPs and humans showed little significant difference in the quality and reproducibility of data generated using human genechips. Expression profiles of each species were compared using principal component analysis (PCA) and hierarchical clustering to determine the similarity of the expression profiles within and across the species. The cynomologus group showed the least intraspecies variability, and the human group showed the greatest intraspecies variability. Intraspecies comparison of the expression profiles identified probe sets that were reproducibly detected within each species. Each NHP species was found to be dissimilar to humans; the cynomologus group was the most dissimilar. Interspecies comparison of the expression profiles revealed probe sets that were reproducibly detected in all species examined. These results show that human genechips can be used for expression profiling of NHP samples and provide a foundation for the development of tools for comparing human and NHP gene expression profiles.

Animals↗

PubMed2003

Colorectal carcinoma: diagnostic, prognostic, and molecular features.

Surgical resection is the primary treatment modality for colorectal cancer, and the pathologic assessment of the resection specimen provides data that is essential for patient management, including the estimation of postoperative outcome and the rationale for adjuvant therapy. The essential elements of the pathological assessment of colorectal cancer resection specimens include the pathologic determination of TNM stage, tumor type, histologic grade, status of resection margins, and vascular invasion. The prognostic and/or predictive value of these elements, as well as guidelines for their derivation and interpretation, are reviewed in detail. Other tissue-based prognostic factors that are strongly suggested by existing data to have stage-independent prognostic value or to predict response to adjuvant therapy but that have not yet been validated for routine patient care are also reviewed. These include perineural invasion, tumor border configuration, host immune response to tumor, and molecular features such as microsatellite instability or loss of heterozygosity of chromosome 18. The need for high-quality, reproducible pathologic data in the care of the colorectal cancer patient, and the dependence of that data on standardization of all aspects of pathological assessment, is emphasized.

Biomarkers, Tumor↗

PubMed2003

Alcohols, ethers, carbohydrates, and related compounds. IV. Carbohydrates.

Ab initio calculations [B3LYP/6-311++G(2d,2p)] have been carried out on 84 conformations of 12 different sugars (hexoses), in both pyranose and furanose forms, with the idea of generating a data base for carbohydrate structural energies that may be used for developing the predictive value of molecular mechanics calculations for carbohydrates. The average value for the apparent gas phase anomeric effect for a series of 31 pairs of pyranose conformations was found to be 1.83 kcal/mol (vs. 2.67 kcal/mol with a smaller basis set used in earlier calculations). In developing MM4 to reproduce these data, it was necessary first to have good energies for simple alcohols and ethers, together with an adequate treatment of hydrogen bonding, and then to include the anomeric effect, and the ethylene glycol type system, as was previously recognized. It was also found that the so-called delta-2 effect, long recognized in carbohydrates, must be explicitly included, in order to obtain acceptable results. When a force field that included all of these items as developed from the small molecules based on the MM4 hydrocarbon force field was applied without any parameter adjustment to the set of hexopyranose and furanose conformations mentioned earlier, the E(beta) - E(alpha) was found to have an average value of 1.88 kcal/mol, versus 1.74 for the quantum calculations. The signed average and RMS deviations of the MM4 from the QM results were +0.15 and 0.87 kcal/mol.

Alcohols↗

PubMed2026

Robust replication of associations across patient-mediated and provider-sourced EHR data in the All of Us research program.

The All of Us Research Program is assembling a nationwide cohort with electronic health record (EHR) resources through two complementary pathways: healthcare provider organization (HPO)-sourced EHRs and patient-mediated EHR (PME) contributed through patient portal linkages. The comparative research utility of these two data sources has not been systematically evaluated. Here, we compared PME and HPO EHRs with respect to disease prevalence, phenotype-phenotype associations, and replication of established genotype-phenotype associations using data from 19,703 PME and 373,887 HPO participants. We benchmarked disease prevalence against national estimates, conducted phenome-wide association studies for 10 commonly studied diseases, and tested replication of more than 5000 established genotype-phenotype associations across multiple ancestral groups. Disease prevalence was consistently lower in PME than in HPO, although prevalence of most diseases in both cohorts exceeded national estimates. Both data sources reproduced known phenotype-phenotype associations and showed moderate-to-strong concordance in effect sizes across the phenome. The overall genotype-phenotype replication rate was 49.1% (5399/10,999) in HPO and 5.9% (381/6482) in PME across ancestral groups, with effect sizes strongly correlated among well-powered associations (R = 0.84, P < 0.001). To disentangle the impact of sample size from data quality, we performed 1:1 propensity score matching. After matching, the replication gap in genotype-phenotype associations narrowed from 8.3-fold to 1.3-fold, with equivalent replication rates among adequately powered associations and strongly concordant effect sizes; comorbidity patterns were also consistent across all 10 diseases tested. These findings demonstrate that both data sources are valuable for clinical and genomic research and can inform other cohorts integrating provider-derived and patient-mediated EHRs.

Computational biology and bioinformatics↗

PubMed1995

Applicability of Iceland spar as a stone model standard for lithotripsy devices.

The identification of a universal stone model standard would enable reproducible fragmentation data useful for the design, evaluation, and comparison of various lithotripsy devices. The clinical benefits of such a stone model include the elucidation of setting parameters that would optimize fragmentation strategies. Iceland spar is a pure form of calcite (CaCO3) that was subjected to experimental disintegration by electrohydraulic lithotripsy and extracorporeal shockwave lithotripsy. Iceland spar was fragmented with both lithotripsy methods in a reproducible fashion. The degree of fragmentation was directly related to alterations in either power or shock frequency. Iceland spar is radiopaque, inexpensive, easily obtained, homogenous in composition, and sizable. Iceland spar meets a variety of stone model criteria, warranting its continued investigation as a potential stone model standard.

Calcium Carbonate↗

PubMed1995

Development and reproducibility of a food frequency questionnaire to assess diets of older children and adolescents.

OBJECTIVE: To develop a self-administered food frequency questionnaire for older children and adolescents and to demonstrate reproducibility over a 1-year period. DESIGN: The youth/adolescent questionnaire (YAQ) was based on the validated Nurses' Health Study food frequency questionnaire and was developed to reflect the eating habits of this age group. SUBJECTS: The multiethnic sample consisted of 179 youths (ages 9 to 18 years) who completed the questionnaire twice, 1 year apart. STATISTICAL ANALYSIS: Pearson correlation coefficients were calculated on nutrient data adjusted in relation to energy intake and on unadjusted food data. RESULTS: Reproducibility for nutrients ranged from .26 for protein and iron to .58 for calcium, and for foods it ranged from .39 for meats to .57 for soda. Mean reproducibility was higher among girls than boys for energy and nutrients and for foods; no consistent pattern was observed for age. CONCLUSION: A self-administered food frequency questionnaire has a reasonable ability to assess the eating habits of older children and adolescents over time.

Adolescent↗

PubMed1996

Calpastatin autoantibodies: detection, epitope mapping, and development of a specific peptide ELISA.

Autoantibodies against calpastatin (CAST) were detected in a 53-year-old female patient with a history of arthritis and thrombosis. The specificity of the autoantibodies was determined by screening expression cDNA libraries, sequence analysis of positive clones, and subsequent Western blotting against recombinant antigen. Because the Western blot lacked satisfactory reproducibility, an ELISA for anti-CAST antibodies was established. The major epitope recognized by 24 Western blot-positive sera was located within the C-terminal 27 amino acids. The ELISA was therefore based on a synthetic peptide representing these amino acids. The assay was calibrated with serial dilutions of a positive reference serum. Intraassay precision is high with a CV of approximately 4% for low- and high-titer samples. Interassay precision (CV) was 5.6-8.2% for sera with low and intermediate titers [10-60 arbitrary units (AU), where 1:100 dilution of the positive reference serum = 100 AU, 1:1000 dilution = 10 AU, etc.], which increases with higher titers ( > 60 AU). Among 205 healthy blood donors, the mean + 3 SD (after logarithmic transformation) was 30 AU; higher values were seen in 2.9% of 138 hospitalized patients. The newly developed ELISA will be a useful tool for further clinical studies on the association of anti-CAST antibodies to disease, because it permits rapid and reproducible analysis of patient sera.

Adolescent↗

PubMed1997

Evaluation of the interferon-gamma ELISPOT-assay for quantification of peptide specific T lymphocytes from peripheral blood.

ELISPOT assays for detection of antigen specific HLA class I restricted T lymphocytes have recently been developed. Reliable quantitation of T cell frequencies is crucial for the monitoring of specific cancer vaccines. We have evaluated the accuracy of quantitative results obtained with the IFN-gamma ELISPOT assay and both sensitivity and specificity obtained with several pairs of antibodies was compared. The detection system was tested with IFN-gamma coupled latex beads and the quantitation of influenza specific T cells with several sets of dilution experiments. The reproducibility of the quantitative results was established. Only one pair of monoclonal antibodies had an acceptable specificity. In a serial dilution, almost 100% of IFN-gamma-coated beads could be detected. Furthermore, the number of influenza-peptide specific spots correlated closely with (a) the number of antigen specific T cells derived from an influenza-peptide specific T cell line diluted in PBMC, and (b) the number of CD8+ T cells diluted in autologous CD8-depleted PBMC. In three healthy individuals and three cohorts of healthy volunteers, the number of influenza-peptide specific spots was highly reproducible. The data presented here demonstrate that the frequency of peptide specific CD8+ T cells can be reliably determined from peripheral blood with the IFN-gamma ELISPOT assay.

Cell Line↗

PubMed2006

Toward an accurate determination of 195Pt chemical shifts by density functional computations: the importance of unspecific solvent effects and the dependence of Pt magnetic shielding constants on structural parameters.

Density functional theory using the zero-order regular approximate two-component relativistic Hamiltonian has been applied to calculate the 195Pt chemical shifts for the complexes [PtCl6]2-, [PtCl4]2-, and [Pt2(NH3)2Cl2((CH3)3CCONH)2(CH2COCH3)]Cl. It is demonstrated that, in contrast to recent findings by other authors, platinum chemical shift calculations require not only a basis set beyond polarized triple-zeta quality for the metal atom but also, in principle, the consideration of explicit solvent molecules in addition to a continuum model for the first two complexes. We find that the inclusion of direct solvent-solute interactions at the quantum mechanical level is important for obtaining reasonable results despite that fact that these solvent effects are rather nonspecific. The importance of solvent effects has also implications on how experimental data should be interpreted. Further, in contrast to several previous studies of heavy-metal NMR parameters, functionals beyond the local density approximation were required both in the geometry optimization and the NMR calculations to obtain reasonable agreement between the computed and experimental NMR data. This comes with the disadvantage, however, of increased Pt-ligand bond distances leading to less good agreement with experiment for structural data. A detailed analysis of the results for the two chloroplatinate complexes is presented. The same computational procedure has then been applied to the dinuclear Pt(III) complex. Chemical shifts have been calculated with respect to both [PtCl6]2- and [PtCl4]2- chosen as the NMR reference, yielding good agreement with experiment. The determination of preferred solvent locations around the complexes studied turned out to be important for reproducing experimental data.

Journal Article↗

PubMedDate not supplied

Collaborative Behavioral Teratology Study: implications, current applications and future directions.

The general conclusions from the Collaborative Behavioral Teratology Study (CBTS) and the implications for research and testing in the field of behavioral teratology are discussed. The results of the CBTS indicate that behavioral teratology data are reproducible, if appropriate attention to study design and testing procedures is maintained. The statistical detection sensitivity of most of the test procedures was excellent, requiring no more than a 5-20% change from control values to detect an effect. Litter, gender and early testing experience may contribute significant variation and should be controlled in any testing situation. The application of behavioral teratology testing and the regulatory role of data for hazard assessment and risk estimation to the human population are discussed. Future research needs were identified from the CBTS workshop discussions.

Animals↗

PubMed1992

A unified neural network [corrected] model of spatiotemporal processing in X and Y retinal ganglion cells. I. Analytical results.

This work presents unified analyses of spatial and temporal visual information processing in a feed-forward network of neurons that obey membrane, or shunting equations. The feed-forward shunting network possesses properties that make it well suited for processing of static, spatial information. However, it is shown here that those same properties of the shunting network that lead to good spatial processing imply poor temporal processing characteristics. This article presents an extension of the feed-forward shunting network model that solves this problem by means of preprocessing layers. The anatomical interpretation of the resulting model is structurally analogous to recently discovered data on a retinal circuit connecting cones to retinal ganglion cells through pairs of push-pull bipolar cells. Mathematical analysis of the lumped model leads to the hypothesis that X and Y retinal ganglion cells may consist of a single mechanism acting in different parameter ranges. This hypothesis is confirmed in the companion article, wherein the model--in conjunction with a nonlinear temporal adaptation mechanism--is used to reproduce experimental data of both X and Y cells by simple changes in morphological and physiological parameters.

Mathematics↗

PubMed2005

Assessing reproducibility of a protein dynamics study using in vivo labeling and liquid chromatography tandem mass spectrometry.

Measuring dynamics of proteins abundance in cells in response to stimuli such as growth factors or drugs requires analysis of more than one time point. Proteomic approaches have traditionally been used to measure only one state at a time because quantitation is difficult, especially when mass spectrometry is used as a readout. Isotopically labeled reagents have recently been introduced that allow comparison of two or three different states by mass spectrometry. Here, we evaluate the reproducibility of an experiment that measures three states simultaneously through stable isotope labeling of cells with amino acids in cell culture (SILAC) using light, medium, and heavy versions of amino acids. The major goal of this study was to assess the reproducibility of such experiments in combination with liquid chromatography tandem mass spectrometry (LC-MS/MS). Our results show that it is possible to obtain reproducible quantitative data to study protein dynamics based on our analysis of more than 220 peptide sets derived from 20 proteins from 3 different LC-MS/MS runs.

Arginine↗

PubMed2002

Intensity generalization: physiology and modelling of a neglected topic.

I briefly review empirical data about the generalization of acquired behaviour to novel stimuli, showing that variations in stimulus intensity affect behaviour differently from variations in characteristics such as, for instance, visual shape or sound frequency. I argue that such differences can be seen already in how the sense organs react to changes in intensity compared to changes in other stimulus characteristics. I then evaluate a number of models of generalization with respect to their ability to reproduce intensity generalization. I reach three main conclusions. First, realistic stimulus representations, based on knowledge of the sense organs, are necessary to account for intensity effects. Models employing stimulus representations too remote from the sense organs are unable to reproduce the data. Second, the intuitive notion that generalization is based on similarities between stimuli, possibly modelled as distances in an appropriate representation space, is difficult to reconcile with data about intensity generalization. Third, several simple models, in conjunction with realistic stimulus representations, can account for a wide array of generalization phenomena along both intensity and non-intensity stimulus dimensions. The paper also introduces concepts which may be generally useful to evaluate and compare different models of behaviour.

Animals↗

PubMed2002

Variations in the concentration of radon in parts of the Ogof Ffynnon Ddu system, Penwyllt, South Wales and estimates of doses to recreational cavers.

A new winter and summer investigation of radon concentrations in parts of the Ogof Ffynnon Ddu system at Penwyllt, South Wales, has been carried out using 100 environmental National Radiological Protection Board track etch detectors. Fifty detectors were installed in the system in December 1998 and again in August 1999 for a period of a month. The data obtained confirm that the system has moderately high radon concentrations with a system mean of 2318 Bq m(-3) in winter and 2844 Bq m(-3) in summer. Traverse means have a summer high of 3094 Bq m(-3) for OFDI to Cwm Dwr and a winter low of 1946 Bq m(-3). The extremely high concentrations approaching 20,000 Bq m(-3), reported previously from the system (Hyland, 1995), have not been reproduced. The data show that the airflow directions at the entrances are not what might have been predicted. Air appears to be largely continuously emerging from the lowest entrance but, at the higher entrances, conversely to the predictions, in winter air enters and in summer appears to be coming out or is variable. Internally, there are sites that in winter have very low radon concentrations that can only be explained by the ingress of fresh air. These are not matched in the summer experiment, again indicating that ingress of fresh air to some parts of the system is very variable. The data illustrate the complexity of airflow within a multi-entrance system but behind these variations several mean concentrations can be obtained from which an approximation of the dose likely to be received can be calculated. Using the maximum mean concentration obtained, 3094 Bq m(-3), and using the latest dose conversion, a 10 h underground trip in the Ogof Ffynnon Ddu system yields a calculated dose of 0.12 mSv. Given that the recommended limit for a member of the public is 1 mSv, this dose would be reached after about 80 h of caving in the system.

Air Pollutants, Radioactive↗

PubMed1996

Comparison of home and clinical blood pressure measurements: clinical applications.

While measurement of blood pressure in the doctor's office remains the method of reference of the WHO, self-measurement yields complementary information, namely: measures outside the surgery, good estimation of the level of blood pressure at home from several day's data, better reproducibility related to standardized conditions of measurement imposed by the constraints of immobility and manoeuvre of the machine. The modalities of variation of BP by automeasure are known: diminution in the BP by automeasure of about 2 to 4 mm Hg between the first and the third measure performed at 1-min intervals, no significant evolution over 3 days and BP more elevated in the evening than in the morning. In comparison with the WHO data, the BP is significantly lower. Recently reference values have been proposed, giving as the upper threshold of normotension = 127/ 83 mm Hg and hypertension = 147/ 86 mm Hg. As regards diagnosis SM allows the identification of "white coat hypertension", and thus avoids treating these patients. The indirect prognostic value via target organ effect is under evaluation, and may be at the same level as ambulatory blood pressure measurement (ABPM). Given the utilisation of validated automatic machines and a rigorous methodology SM is beginning to be used satisfactorily in clinical trials. Numerous studies are still necessary in order to clearly define the place of SM in comparison to WHO and AMBP in the management of hypertension.

Antihypertensive Agents↗

PubMed1995

Effects of chain unsaturation on the equation of state for lipid monolayers at the air-water interface.

An equation of state for lipid monolayers at the air-water interface is presented, which takes into account the effects of the conformation and the number and position of double bonds of the hydrocarbon chains. The total Hamiltonian of the monolayer is assumed to consist of three terms. Two of them are calculated exactly within the limitations of the formulation. These are the two-dimensional entropy of mixing of the lipid and water molecules at the surface and the conformational entropy of the chains using a model available from the literature. These two terms give rise to positive surface pressure. The third term, which includes all energies that are not amenable to calculation, was obtained as the difference between the sum of the two calculated terms and experimental data and is found to represent an approximately area-independent tension. The effects of chain unsaturation on the equation of state were modeled in the present theory in two ways; the chain bend caused by cis double bonds increases the minimal molecular area, and the double bond linkage on a chain decreases the degrees of freedom of the chain. Calculations revealed that the former is highly significant whereas the latter is negligible. The deduced equation of state reproduces experimental data with appropriate values for three parameters, which represent the collapse area, the overlap of adjacent chains, and the combined effects of the intra- and intermolecular interactions other than the surface mixing entropy and the chain conformational energy.

1,2-Dipalmitoylphosphatidylcholine↗