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PubMed2000

Analytical strategy for detecting doping agents in hair.

Lists of banned classes of doping agents are released by the International Olympic Committee, adopted by other sports authorities and updated regularly, including the substance classes stimulants, narcotics, diuretics, anabolic agents, peptide hormones, beta-blockers etc. There are different classes of restriction: anabolic and masking agents (anabolic steroids, diuretics etc.) are always banned for athletes regardless of their topical activity (training or competition) several substances are permitted with certain restrictions (caffeine below a cut-off value, or inhalation of some beta 2 agonists) beta-blockers are prohibited in competitions of certain sports disciplines the majority of the substances (stimulants, narcotics etc.) is prohibited during competitions, so that they do not have to be analysed in out-of-competition samples. A differentiation between training and competition period is impossible by means of hair analysis due to the uncertainty of (especially short-term) kinetic considerations related to hair growth. Therefore, the analytical identification of doping relevant substances in hair is not always a sufficient criterion for a doping offence and the identification of stimulants, beta-blockers etc. in hair would be entirely irrelevant. The most interesting target substances are certainly the anabolic agents, because their desired action (enhanced muscle strength) lasts longer than the excretion, leading to sophisticated procedures to circumvent positive analytical results in competition control. Besides the analysis of out-of-competition control samples, the long term detection of steroids in hair could provide complementary information. An analytical approach to the identification of exogenous steroids in hair requires consideration of the presence of many other steroids in the hair matrix interfering the analysis at trace levels, and of a limited chemical stability. The analysis of endogenous steroids in hair appears to be even more complicated, because the possibility of many biotransformation reactions from (into) other precursors (metabolites) has to be taken into account. Precursor substances of anabolic steroids (especially esters as application forms) are very promising analytical targets of hair analysis, because they can only be detected after an exogenous intake. The quantitative evaluation of active parent compounds like testosterone (which is actively involved in physiological processes of hair growth) in hair is still controversial. Clinical applications under reproducible conditions can be useful, but the biovariability of these parameters will probably prevent the definition of acceptable cut-off levels as a criterion of abuse.

Adrenergic beta-Antagonists↗
PubMed1992

Pharmacokinetic studies in paediatric patients. Clinical and ethical considerations.

Important advances in paediatric clinical pharmacology have been made over the past 2 decades. However, there remains a reluctance to pursue pharmacodynamic and pharmacokinetic studies in children and, consequently, many important therapeutic agents have not been adequately studied in this population. Age-related pharmacokinetic/pharmacodynamic studies are not only essential to provide optimal drug therapy for children, but are quite feasible. Usually, paediatric pharmacokinetic studies are conducted in children receiving treatment for a specific medical condition. The approach to soliciting participation of paediatric subjects requires special sensitivity to the fears and anxieties of the child and the parents. Factors influencing subject enrollment and suggestions to enhance enrollment into study protocols are discussed. Pharmacokinetic/pharmacodynamic studies require repeated measurements over time and often entail obtaining multiple blood and urine samples. Techniques for reducing sample volume and number of necessary samples while minimising the discomfort and fear associated with obtaining multiple samples include the development of highly sensitive analytical methods to measure drug concentrations in small volume samples. The number of samples obtained from individual subjects can be minimised by using pharmacokinetic analytical approaches such as the nonlinear mixed effect model (NONMEM) which allows estimation of pharmacokinetic characteristics of a population using limited data from each subject. In addition, less invasive methods to measure drug metabolism/elimination such as salivary sampling, transcutaneous collection and breath analysis have been applied to the study of certain drugs. Children are a particularly vulnerable population because of their limited cognitive abilities and dependence on adults. Thus, they must be afforded greater protection from exploitation as research subjects than that provided to adults.

Clinical Trials as Topic↗
PubMed1996

Evolution of beta-amylase: patterns of variation and conservation in subfamily sequences in relation to parsimony mechanisms.

Soybean and sweet potato beta-amylases are structured as alpha/beta barrels and the same kind of folding may account for all known beta-amylases. We provide a comprehensive analysis of both protein and DNA (coding region) sequences of beta-amylases. The aim of the study is to contribute to the knowledge of the evolutionary molecular relationships among all known beta-amylases. Our approach combines the identification of the putative eightfold structural core formed by beta-strands with a complete multi-alignment analysis of all known sequences. Comparing putative beta-amylase (alpha/beta)8 cores from plants and microorganisms, two differentiated versions of residues at the packing sites, and a unique set of eight identical residues at the C-terminal catalytical site are observed, indicating early evolutionary divergence and absence of localized three-dimensional evolution, respectively. A new analytical approach has been developed in order to work out conserved motifs for beta-amylases, mostly related with the enzyme activity. This approach appears useful as a new routine to find sets of motifs (each set being known as a fingerprint) in protein families. We demonstrate that the evolutionary mechanism for beta-amylases is a combination of parsimonious divergence at three distinguishable rates in relation to the functional signatures, the barrel scaffold, and alpha-helix-containing loops.

Amino Acid Sequence↗
PubMed2004

Microelectrode arrays: a new tool to measure embryonic heart activity.

The analysis of the sequential excitation of cardiac tissue is of high relevance, both for clinical pathophysiological purposes, eg, detection of sustained ventricular arrhythmias, as well as for experimental electrophysiology. Clinically, different technical approaches such as single electrode measurements and bipolar mapping electrode catheters have been used. In experimental setups several techniques to record cardiac activity have been proposed. Beside the well-established intracellular current-clamp recordings of action potentials, recent studies have performed extracellularly activation sequence mapping or simultaneous multichannel action potential electrode array measurements. Measurement of extracellularly recorded field potentials (FPs) hereby especially provides detailed information about the origin and spread of excitation in the heart. A similar analytical approach for cardiac FPs advanced the analysis of excitation spread and arrhythmic activity in multicellular preparations like developmental differentiation tissue of mouse embryonic stem cells, multicellular preparations of isolated native embryonic cardiomyocytes or the embryonic heart in toto. The use of substrate-integrated Microelectrode Arrays (MEAs, Multi Channel Systems, Reutlingen, Germany) with 60 electrodes of 10-30 microm diameters on a 100-200 microm grid, coated with porous titanium nitride to minimize the impedance allows recording of FPs at a high signal to noise ratio. The possibility to electrically stimulate the tissue further expands the range of applications and bioassays. It may thus facilitate the evaluation of drug research providing detailed information about the interplay of the complex cardiac network, and might improve the predictability of physiological and pathophysiological conditions or drug effects in embryonic heart tissue.

Action Potentials↗
PubMed1999

Does the use of mean or median Z-score of the thyroid volume indices provide a more precise description of the iodine deficiency disorder status of a population?

Endemic iodine deficiency is largely an environmental problem affecting whole populations. Currently, thyroid volume data from a population are analyzed with the sole objective of obtaining an estimate of goitre prevalence using +97th percentile or +2 standard deviations of an appropriate reference as cut-off. This paper proposes an alternative approach to the analysis and presentation of thyroid volume data using Z-scores (standard deviation scores) of the thyroid volume indices such as thyroid volume-for-age or thyroid volume-for-body surface area. The calculation of the summary statistics of the Z-scores, such as mean or median, provides an alternative to the prevalence-based approach for expressing severity of iodine deficiency disorders (IDD). An advantage of the mean or median Z-score is that it describes the thyroid volume profile (and therefore the IDD status) of the entire population directly, unlike goitre prevalence which gives information only about the extremes of distribution. The frequency curve or histogram of the Z-scores provides a complete picture of the whole distribution. Although qualitatively similar conclusions on IDD severity can be drawn from both analytical approaches, only the Z-score system is able to capture adequately the trends or changes in thyroid size over time, and to establish whether a previously iodine-deficient community's thyroid volume profile has returned to 'normal' (as indicated by a distribution that is not significantly different from that of the reference) following intervention. As a continuous variable, Z-scores are particularly useful for the analysis of data from populations where the sample size is relatively small, or where many individuals lie outside the extreme percentiles of the reference population. In view of its advantages in the context of activities based on single and multiple measurements, the Z-score system is to be preferred for the reporting and use of thyroid volume indices. A desirable consequence of this preference is that national goals will be oriented towards an improvement of the overall thyroid volume profile of the population, rather than just a reduction of the number of individuals at the extremes.

Goiter↗
PubMed2004

Copper detection in the Asiatic clam Corbicula fluminea: optimum valve closure response.

When exposed to a contaminant, bivalves close their shell as a protective strategy. The aim of the present study was to estimate the maximum expected dissolved copper sensitivity in the freshwater bivalve Corbicula fluminea using a new approach to determine their potential and limit to detect contaminants. To take into account the rate of spontaneous closures, we integrated stress problems associated with fixation by a valve in usual valvometers and the spontaneous rhythm associated with nycthemeral activity, to optimize the response in conditions where the probability of spontaneous closing was lowest. Moreover, we used an original system with impedance valvometry, using lightweight impedance electrodes, to study free-ranging animals in low stress conditions combined with an analytical approach describing dose-response curves by logistic regression, with valve closure reaction as a function of response time and concentration of contaminant. In C. fluminea, we estimated that copper concentrations > 4 microg/l (95% confidence interval (CI95%), 2.3-8.8 microg/l) must be detected within 5 h after Cu addition. Lower values could not be distinguished from background noise. The threshold values were 2.5 times lower than the values reported in the literature.

Animals↗
PubMed2004

Accurate assignment of ethanol origin in postmortem urine: liquid chromatographic-mass spectrometric determination of serotonin metabolites.

Toxicological examination of fatal aviation accident victims routinely includes analysis of ethanol levels. However, distinguishing between antemortem ingestion and postmortem microbial formation complicates all positive ethanol results. Development of a single analytical approach to determine concentrations of 5-hydroxytryptophol (5-HTOL) and 5-hydroxyindole-3-acetic acid (5-HIAA), two well-known metabolites of serotonin, has provided a convenient, rapid and reliable solution to this problem. Antemortem ethanol leads to an elevation in the 5-HTOL/5-HIAA ratio for 11-19 h after acute ingestion. The liquid-liquid extracts of postmortem urine samples were subjected to liquid chromatography-mass spectrometry (LC-MS) for the simultaneous quantitation of these two analytes, yielding detection limits of 0.1 ng/ml for each. Examination of the 5-HTOL/5-HIAA ratio was undertaken for 44 urine samples known to be antemortem ethanol-positive or antemortem ethanol-negative. Recent ethanol ingestion was conveniently and accurately separated using a 5-HTOL/5-HIAA ratio of 15 pmol/nmol, a value previously suggested using human volunteers. All 21 ethanol-negative postmortem samples were below this cutoff, while all 23 ethanol-positive postmortem samples were above this cutoff. Thus, we recommend the employment of this cutoff value, established using this straightforward LC-MS procedure, to confirm or deny recent antemortem ethanol ingestion in postmortem urine samples.

Chromatography, High Pressure Liquid↗
PubMed2003

Copper detection in the Asiatic clam Corbicula fluminea: optimum valve closure response.

When exposed to a contaminant, bivalves close their shell as a protective strategy. The aim of the present study was to estimate the maximum expected dissolved copper sensitivity in the freshwater bivalve Corbicula fluminea using a new approach to determine their potential and limit to detect contaminants. To take into account the rate of spontaneous closures, we integrated stress problems associated with fixation by a valve in usual valvometers and the spontaneous rhythm associated with nycthemeral activity, to optimize the response in conditions where the probability of spontaneous closing was lowest. Moreover, we used an original system with impedance valvometry, using lightweight impedance electrodes, to study free-ranging animals in low stress conditions combined with an analytical approach describing dose-response curves by logistic regression, with valve closure reaction as a function of response time and concentration of contaminant. In C. fluminea, we estimated that copper concentrations >4 microg/l (95% confidence interval (CI(95%)), 2.3-8.8 microg/l) must be detected within 5 h after Cu addition. Lower values could not be distinguished from background noise. The threshold values were 2.5 times higher than the values reported in the literature.

Animals↗
PubMed2004

Affinity distribution functions in multicomponent heterogeneous adsorption. Analytical inversion of isotherms to obtain affinity spectra.

An analytical approach for the interpretation of multicomponent heterogeneous adsorption or complexation isotherms in terms of multidimensional affinity spectra is presented. Fourier transform, applied to analyze the corresponding integral equation, leads to an inversion formula which allows the computation of the multicomponent affinity spectrum underlying a given competitive isotherm. Although a different mathematical methodology is used, this procedure can be seen as the extension to multicomponent systems of the classical Sips's work devoted to monocomponent systems. Furthermore, a methodology which yields analytical expressions for the main statistical properties (mean free energies of binding and covariance matrix) of multidimensional affinity spectra is reported. Thus, the level of binding correlation between the different components can be quantified. It has to be highlighted that the reported methodology does not require the knowledge of the affinity spectrum to calculate the means, variances, and covariance of the binding energies of the different components. Nonideal competitive consistent adsorption isotherm, widely used in metal/proton competitive complexation to environmental macromolecules, and Frumkin competitive isotherms are selected to illustrate the application of the reported results. Explicit analytical expressions for the affinity spectrum as well as for the matrix correlation are obtained for the NICCA case.

Journal Article↗
PubMed2005

High-throughput proteomics using matrix-assisted laser desorption/ ionization mass spectrometry.

It has become evident that the mystery of life will not be deciphered just by decoding its blueprint, the genetic code. In the life and biomedical sciences, research efforts are now shifting from pure gene analysis to the analysis of all biomolecules involved in the machinery of life. One area of these postgenomic research fields is proteomics. Although proteomics, which basically encompasses the analysis of proteins, is not a new concept, it is far from being a research field that can rely on routine and large-scale analyses. At the time the term proteomics was coined, a gold-rush mentality was created, promising vast and quick riches (i.e., solutions to the immensely complex questions of life and disease). Predictably, the reality has been quite different. The complexity of proteomes and the wide variations in the abundances and chemical properties of their constituents has rendered the use of systematic analytical approaches only partially successful, and biologically meaningful results have been slow to arrive. However, to learn more about how cells and, hence, life works, it is essential to understand the proteins and their complex interactions in their native environment. This is why proteomics will be an important part of the biomedical sciences for the foreseeable future. Therefore, any advances in providing the tools that make protein analysis a more routine and large-scale business, ideally using automated and rapid analytical procedures, are highly sought after. This review will provide some basics, thoughts and ideas on the exploitation of matrix-assisted laser desorption/ ionization in biological mass spectrometry - one of the most commonly used analytical tools in proteomics - for high-throughput analyses.

Computational Biology↗
PubMed1999

Economic analysis of finasteride: a model-based approach using data from the Proscar Long-Term Efficacy and Safety Study.

Benign prostatic hyperplasia (BPH) is one of the most common medical conditions in older men in the United States. BPH is often associated with a reduction in quality of life and may progress to acute urinary retention (AUR), the inability to pass any urine. Recently, a 4-year placebo-controlled clinical trial known as the Proscar Long-Term Efficacy and Safety Study (PLESS) demonstrated that finasteride use reduces the risk of developing AUR by 57% and the need for BPH-related surgery by 55%. The economic implications of these findings were investigated using a model-based decision-analytic approach to compare finasteride with both watchful waiting and alpha-blocker therapy. The modeling used the longest-term published controlled data concerning alpha-blockers, which were for the alpha-blocker terazosin. The base case considered a 64-year-old man (the mean age of a PLESS patient) with prostatic enlargement on digital rectal examination and moderate-to-severe symptoms of BPH. The model suggested savings in surgical and AUR costs with finasteride versus watchful waiting, with an estimated 25% of total finasteride costs recouped in savings on surgical events avoided in the first year. Over 2 years, the expected cost per patient starting finasteride therapy was $2304, whereas the expected cost per patient starting terazosin was $2334. Analyses also explored the variation in economic results by baseline levels of prostate-specific antigen (PSA), a proxy for prostate volume. For patients with PSA levels > or =1.4 ng/mL, expected 2-year costs with finasteride and terazosin were $2342 and $2479, respectively. For patients with PSA levels > or =3.3 ng/mL, expected 2-year costs with finasteride were $373 less than with terazosin ($2347 vs $2720). Results were robust over a range of model assumptions and cost estimates. The analyses illustrate that all medical interventions, including watchful waiting, have associated costs. Finasteride shows cost offsets compared with watchful waiting and cost savings compared with terazosin over 2 years. Finasteride appears to be more economical in men with higher PSA levels.

Adrenergic alpha-Antagonists↗
PubMed1999

Regions of interest in the venous sinuses as input functions for quantitative PET.

UNLABELLED: As clinical PET becomes increasingly available, quantitative methods that are feasible in busy clinical settings are becoming necessary. We investigated the use of intracranial blood pools as sources of an input function for quantitative PET. METHODS: We studied 25 patients after the intravenous injection of [18F]6-fluoro-L-m-tyrosine and compared sampled blood time-activity curves with those obtained in small regions of interest (ROIs) defined in the blood pools visible in the PET images. Because of the comparatively large dimensions of the blood pool at the confluence of the superior sagittal, straight and transverse sinuses, a venous ROI input function was chosen for further analysis. We applied simple corrections to the ROI-derived time-activity curves, deriving expressions for partial volume, spillover and partition of tracer between plasma and red blood cells. The results of graphic and compartmental analysis using both sampled [Cs(t)] and ROI [Cr(t)] venous input functions for each patient were compared. We also used an analytic approach to examine possible differences between venous and arterial input functions in the cerebral circulation. RESULTS: Cr(t) peaked significantly earlier and higher than Cs(t) in this patient population, although the total integral under the curves did not differ significantly. We report some apparent differences in the results of modeling using the two input functions; however, neither the graphically determined influx constant, Ki, nor the model parameter that reflects presynaptic dopaminergic metabolism, k3, differed significantly between the two methods. The analytic results suggest that the venous ROI input function may be closer to the arterial supply of radiotracer to the brain than arterialized venous blood, at least in some patient populations. CONCLUSION: We present a simple method of obtaining an input function for PET that is applicable to a wide range of tracers and quantitative methods and is feasible for diagnostic PET imaging.

Cerebrovascular Circulation↗
PubMed2001

A new approach to the concept of "relevance" in information retrieval (IR).

The concept of "relevance" is the fundamental concept of information science in general and information retrieval, in particular. Although "relevance" is extensively used in evaluation of information retrieval, there are considerable problems associated with reaching an agreement on its definition, meaning, evaluation, and application in information retrieval. There are a number of different views on "relevance" and its use for evaluation. Based on a review of the literature the main problems associated with the concept of "relevance" in information retrieval are identified. The authors argue that the proposal for the solution of the problems can be based on the conceptual IR framework built using a systems analytic approach to IR. Using this framework different kinds of "relevance" relationships in the IR process are identified, and a methodology for evaluation of "relevance" based on methods of semantics capturing and comparison is proposed.

Evaluation Studies as Topic↗
PubMedDate not supplied

Applying sample survey methods to clinical trials data.

This paper outlines the utility of statistical methods for sample surveys in analysing clinical trials data. Sample survey statisticians face a variety of complex data analysis issues deriving from the use of multi-stage probability sampling from finite populations. One such issue is that of clustering of observations at the various stages of sampling. Survey data analysis approaches developed to accommodate clustering in the sample design have more general application to clinical studies in which repeated measures structures are encountered. Situations where these methods are of interest include multi-visit studies where responses are observed at two or more time points for each patient, multi-period cross-over studies, and epidemiological studies for repeated occurrences of adverse events or illnesses. We describe statistical procedures for fitting multiple regression models to sample survey data that are more effective for repeated measures studies with complicated data structures than the more traditional approaches of multivariate repeated measures analysis. In this setting, one can specify a primary sampling unit within which repeated measures have intraclass correlation. This intraclass correlation is taken into account by sample survey regression methods through robust estimates of the standard errors of the regression coefficients. Regression estimates are obtained from model fitting estimation equations which ignore the correlation structure of the data (that is, computing procedures which assume that all observational units are independent or are from simple random samples). The analytic approach is straightforward to apply with logistic models for dichotomous data, proportional odds models for ordinal data, and linear models for continuously scaled data, and results are interpretable in terms of population average parameters. Through the features summarized here, the sample survey regression methods have many similarities to the broader family of methods based on generalized estimating equations (GEE). Sample survey methods for the analysis of time-to-event data have more recently been developed and implemented in the context of finite probability sampling. Given the importance of survival endpoints in late phase studies for drug development, these methods have clear utility in the area of clinical trials data analysis. A brief overview of methods for sample survey data analysis is first provided, followed by motivation for applying these methods to clinical trials data. Examples drawn from three clinical studies are provided to illustrate survey methods for logistic regression, proportional odds regression and proportional hazards regression. Potential problems with the proposed methods and ways of addressing them are discussed.

Clinical Trials as Topic↗
PubMed2003

New hybrid technique for accurate and reproducible quantitation of dynamic contrast-enhanced MRI data.

The accuracy and precision of two major approaches for analyzing dynamic MRI data from the first passage of a Gd-DTPA contrast bolus are examined, using a Monte Carlo simulation. Method 1 fits the contrast concentration curve of the first pass to a two-compartment kinetic model to determine the tissue pharmacokinetic parameters. Method 2 decomposes intravascular and interstitial components of the first-pass curve based on a leakage profile (LP) model. Based on the results of these Monte Carlo simulations, a new "hybrid" method is proposed that combines both analytical approaches to optimize accuracy and precision of estimates of K(trans), v(e), and v(p). The new method was evaluated by computer simulation and used on experimental results from a patient with primary brain tumors. The new method has the potential to provide more accurate quantification of tissue plasma volume and vessel permeability.

Blood Volume↗
PubMed2002

Analysis and the hierarchy of nature in eighteenth-century chemistry.

What was the impact of Lavoisier's new elementary chemical analysis on the conception and practice of chemistry in the vegetable kingdom at the end of the eighteenth century? I examine how this elementary analysis relates both to more traditional plant analysis and to philosophical and mathematical concepts of analysis of current in the Enlightenment. Thus I explore the relationship between algebra, Condillac's philosophy and Lavoisier's chemical system as well as comparing Lavoisier's analytical approach to those of his predecessors, such as Baumè and Bucquet. With reference to the aims of vegetable analysis, I show how the dominance of elementary analysis devalued a tradition that sought to isolate immediate principles (plant extracts), marginalizing the chemical practices of many doctors and pharmacists in the context of the new chemistry in France.

Chemistry, Analytic↗
PubMed2006

Semiautomated high-sensitivity profiling of human blood serum glycoproteins through lectin preconcentration and multidimensional chromatography/tandem mass spectrometry.

We describe an effective analytical approach to identify trace glycoproteins in a small volume of human serum. The system is based on automatable affinity enrichment through silica-based lectin microcolumns and a further separation of the retained glycoproteins on a reversed-phase liquid chromatography with superficially porous packing, operating at high temperature. The fractionated sample is further directed into a 96-well plate for trypsinization and LC-MS/MS analysis. Using a major-component depleted blood serum (16 microg total protein), we were able to identify 271 glycoproteins through this analytical system.

Chromatography, Affinity↗
PubMed2005

Characterization of phospholipid-protein interactions by capillary isoelectric focusing with whole-column imaging detection.

The integration of functional proteins in the phospholipid bilayer is one of the most crucial features of biological membrane architecture. Phospholipid-protein interactions play an important role in the functions of bounded proteins in the phospholipid membrane. When the phospholipid-protein interactions occur, the protein structure tends to alter, which can result in a change in the isoelectric points (pI) of protein. Capillary isoelectric focusing (cIEF) with whole-column imaging detection (WCID) is an attractive technique that has the features of simple operation, high resolution, and fast separation without focused band mobility for detection of amphoteric biomolecules. In this study, a cIEF-WCID method was developed to characterize the phospholipids-protein interactions by monitoring the protein cIEF profiles. Seven proteins with different pI and molecular mass , and a zwitterionic phosphatidylcholine (PC) with zwitterionic properties, were used to evaluate the feasibility of the cIEF-WCID approach in the study of phospholipid-protein interactions. The cIEF profiles changed in response to the changes in protein conformation, clearly exhibiting interactions between the PC vesicles and the targeted proteins. The formation of PC-protein complex was observed in the cIEF electropherograms. It was demonstrated that seven proteins displayed distinct interactions with the PC vesicles due to their different chemical and physical properties. The influences of the PC concentration, incubation time, and incubation temperature on the phospholipids-protein interactions were investigated. This study validated a novel analytical approach for the characterization of phospholipid-protein interactions.

Animals↗