bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct detection of particles formed by laser ablation of matrices during matrix‐assisted laser desorption/ionization
Authors: Alves Sandra , Kalberer Markus , Zenobi Renato
Published: September 2003

We report the detection of nanoparticles formed by irradiating matrix‐assisted laser desorption/ionization (MALDI) matrix samples. This is direct evidence for the ejection of large size aggregates in the MALDI process. Nanometer‐size particles were generated via a tunable solid‐state UV laser, irradiating a sample placed in a nitrogen atmosphere. Size distribution measurements were performed using a differential mobility analyzer and a condensation particle counter. Particles in the 10–1000 nm size range were detected. The dependence of the particle size distribution on the laser fluence, wavelength and matrix was investigated. The observed effects are discussed and related to the MALDI ablation dynamics and gas‐phase processes. Copyright © 2003 John Wiley & Sons, Ltd.
A microcapillary trap cartridge‐microcapillary high‐performance liquid chromatography electrospray ionization emitter device capable of peptide tandem mass spectrometry at the attomole level on an ion trap mass spectrometer with automated routine operation
Authors: Yi Eugene C. , Lee Hookeun , Aebersold Ruedi , Goodlett David R.
Published: September 2003

Reversed‐phase microcapillary chromatography (RP‐μLC) combined with electrospray ionization tandem mass spectrometry (ESI‐MS/MS) is one of two prevailing techniques in proteomic analysis, the other being matrix‐assisted laser desorption/ionization (MALDI). Despite the arguably better dynamic range obtainable with ESI, MALDI is increasingly popular due to ease of use, ruggedness and the ability to decouple separation from ionization. By contrast, in order to take advantage of the sensitivity and dynamic range afforded by the concentration‐dependent nature of ESI, it is directly coupled to separations that take place in small i.d. RP‐μLC columns. This gain in sensitivity often comes at a loss of ruggedness due to clogging of the small i.d. RP‐μLC columns, one result of which is limited sample throughput. Here we describe a combined μpre‐column‐μLC‐ESI device that is sensitive, rugged and modular in design allowing facile construction and troubleshooting. Due to low signal‐to‐noise as little as 1 attomole of a peptide can be selected by data‐dependent methods for collision‐induced dissociation. Importantly, the resulting tandem mass spectrum is of high enough quality to identify the peptide sequence by a database search against a complex database using SEQUEST. Finally, the device is demonstrated to be rugged as judged by >60 consecutive reversed‐phase μLC separations on complex peptide mixtures before chromatographic resolution is degraded. Copyright © 2003 John Wiley & Sons, Ltd.
Simultaneous quantitative analysis of three drugs by high‐performance liquid chromatography/electrospray ionization mass spectrometry and its application to cassette in vitro metabolic stability studies
Authors: Rajanikanth M. , Madhusudanan K. P. , Gupta R. C.
Published: September 2003

A sensitive and selective liquid chromatography/electrospray mass spectrometry (LC/ESI‐MS) method has been developed for the simultaneous quantitative determination of three new chemical entities (NCEs), of the class of aryloxy‐substituted aryl piperazines, in rat liver S9 fraction. S9 fraction samples (0.1 mL) were simply extracted with 2% isopropanol in diethyl ether and the extracts analyzed by HPLC with the detection of the analytes in the selective ion recording (SIR) mode. The determination of the analytes was accurate and reproducible, with a limit of quantification of 50 ng/mL for all the analytes in rat liver S9 fraction. The standard calibration curve for the analytes was linear over the concentration range 50–4000 ng/mL. Analysis accuracy and precision over the concentration range were lower than ±15%. This method offered significant increase in the analytical throughput, which is illustrated by the ‘N‐in‐One’ study of metabolic stability of the compounds in rat liver S9 fractions. The quantitative results from the ‘N‐in‐One’ procedure correlated well with those obtained from conventional discrete analyses. In addition, the samples were reanalyzed to allow for detection of the metabolites formed during the same incubation. The metabolites were first characterized by nominal mass measurement of the corresponding protonated molecules. Subsequent tandem mass spectrometry allowed confirmation of the detected metabolites. Copyright © 2003 John Wiley & Sons, Ltd.
Trace determination of organotin compounds in water, sediment and mussel samples by low‐pressure gas chromatography coupled to tandem mass spectrometry
Authors: Vidal J. L. Martínez , Vega A. Belmonte , Arrebola F. J. , González‐Rodríguez M. J. , Sánchez M. C. Morales , Frenich A. Garrido
Published: September 2003

A fast method for the determination of eight organotin compounds (OTs), monobutyltin (MBT), dibutyltin (DBT), tributyltin (TBT), tetrabutyltin (TeBT), monophenyltin (MPhT), diphenyltin (DPhT), triphenyltin (TPhT) and tetraphenyltin (TePhT), in water, sediments and mussels, was developed using low‐pressure gas chromatography/tandem mass spectrometry (LPGC/MS/MS). The method is based on sodium diethyldithiocarbamate (DDTC) complexation of the ionic organotins, followed by extraction of the target matrices and derivatization by a Grignard reagent, as described in a previously published method for water samples (S. Tsunoi et al., J. Chromatogr. A 2002; 962: 197). Solid‐phase extraction was selected as extraction method from water samples after comparison with liquid–liquid extraction, but extraction of the OTs from sediment and mussel samples was performed using toluene. Matrix‐matched calibration standards were used to minimize matrix effects. The analytical process was validated by the analysis of spiked blank samples. Performance characteristics such as linearity, detection limit (LOD), quantitation limit (LOQ), precision, and recovery were determined. Recoveries of OTs in spiked matrices ranged from 86–108% in water and from 78–110% in sediments and mussels, with precision values lower than 18%. Detection limits ranged from 0.1–9.6 ng L−1 in water, and 0.03–6.10 μg kg−1 in the other matrices. The present implementation of LPGC rather than conventional capillary GC permitted use of large‐volume injection and reduced analysis time by a factor of two. The proposed methodology was applied to the determination of OTs in real samples of water, marine sediments and mussels from the west coast of the Mediterranean Sea (Spain). Copyright © 2003 John Wiley & Sons, Ltd.
Investigation by solid‐phase microextraction and gas chromatography/mass spectrometry of trail pheromones in ants
Authors: Tullio Alessandra Di , Angelis Francesco De , Reale Samantha , Grasso Donato A. , Visicchio Roberto , Castracani Cristina , Mori Alessandra , Moli Francesco Le
Published: September 2003

The Dufour's gland content of workers of two ant species of the genus Messor has been analyzed by solid‐phase microextraction and gas chromatography with mass spectrometry (GC/MS). The structures of the compounds in the pheromonal mixtures have been determined. In both cases only one intact gland, inserted in a properly dimensioned capillary vial, is sufficient to produce a clean and fully interpretable GC/MS profile. It is worth noting that, for the first time in Messor ants, farnesol has been detected as a minor component of glandular secretion in Messor capitatus. Copyright © 2003 John Wiley & Sons, Ltd.
Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry of phosphorylated compounds using a novel phosphate capture molecule
Authors: Takeda Hironori , Kawasaki Akihiko , Takahashi Makoto , Yamada Atsushi , Koike Tohru
Published: September 2003

This paper introduces a simple, rapid, and sensitive procedure for the analysis of phosphorylated compounds (ROPO32−) by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOFMS). The method is based on a characteristic mass shift and a total‐charge change (from −2 to +1) of the phosphate residue due to complexation of ROPO32− with a dinuclear zinc(II) complex (1,3‐bis[bis(2‐pyridinylmethyl)amino]‐2‐propanolato dizinc(II) complex, Zn2L3+) in aqueous solution at physiological pH. Furthermore, the use of single zinc‐isotope derivatives (64Zn2L3+ and 68Zn2L3+) enables improvement of the sensitivity and accuracy of the analysis. Copyright © 2003 John Wiley & Sons, Ltd.
Quantitative analysis of betulinic acid in mouse, rat and dog plasma using electrospray liquid chromatography/mass spectrometry
Authors: Cheng Xun , Shin Young Geun , Levine Barry S. , Smith Adaline C. , Tomaszewski Joseph E. , van Breemen Richard B.
Published: September 2003

Betulinic acid is under development as a therapeutic agent for the treatment of metastatic malignant melanoma. In support of pharmacokinetic and toxicological evaluations, a robust assay based on liquid chromatography/mass spectrometry (LC/MS) was developed for the quantitative analysis of betulinic acid. Sample preparation consisted of deproteinization of the plasma by the addition of three volumes of acetonitrile and one volume of methanol followed by centrifugation. Aliquots of the supernatant were analyzed using an isocratic reversed‐phase high‐performance liquid chromatography (HPLC) system coupled to a negative ion electrospray mass spectrometer. Deprotonated molecules of betulinic acid and the isomeric internal standard oleanolic acid were detected using selected ion monitoring at m/z 455. The limit of detection of betulinic acid was 0.5 pg (1.1 fmol) injected on‐column (50 pg/mL, 10 μL injection volume), and the limit of quantitation was 2 pg (4.4 fmol, 200 pg/mL, 10 μL injection volume). Betulinic acid was stable in plasma samples at −20°C for at least 3 weeks. The intra‐day and inter‐day coefficients of variation of the assay were ≤6.4 and ≤9.0%, respectively. The utility of the assay was demonstrated by analyzing betulinic acid spiked into mouse, rat and dog plasma, by determining the extent of binding of betulinic acid to plasma proteins, and by measuring betulinic acid in mouse and rat plasma following intraperitoneal or intravenous administration in vivo. At 15 and 25 μg/mL in mouse, rat or dog plasma, betulinic acid was 99.99% bound to serum proteins, and, at 5 μg/mL, betulinic acid was ≥99.97% bound. Copyright © 2003 John Wiley & Sons, Ltd.
Validation of a screening method for corticosteroids in doping analysis by liquid chromatography/tandem mass spectrometry
Authors: Deventer K. , Delbeke F. T.
Published: September 2003

A selective and sensitive method for the screening of nine corticosteroids in human urine has been validated. Analyses were performed using an ion trap instrument equipped with an electrospray ionisation (ESI) interface. All corticosteroids were separated in less than 20 min after liquid/liquid extraction with diethyl ether. The limit of detection for all substances was 4 ng/mL or lower. The method was applied to detect betamethasone after the intramuscular injection of Diprophos®. Betamethasone could be detected for up to 12 days after administration. Validation of the chromatographic separation and mass spectrometric identification of mixtures of betamethasone and dexamethasone are also presented. Copyright © 2003 John Wiley & Sons, Ltd.
Differentiation of isomeric polyaromatic hydrocarbons by electrospray Ag(I) cationization mass spectrometry
Authors: Ming Ng Kwan , Ling Ma Ngai , Wai Tsang Chun
Published: September 2003

Abundant Ag(I)‐cationized complexes of 13 polyaromatic hydrocarbons (PAHs), [Ag+PAH]+ and [Ag+2(PAH)]+, were readily generated by electrospray ionization (ESI). In‐source collision‐induced dissociation (CID) of the [Ag+2(PAH)]+ complex yielded the monomer complex [Ag+PAH]+, which fragmented further to yield the radical molecular ion [PAH]+.. Based on significant differences in relative intensities of [Ag+2(PAH)]+, [Ag+PAH]+ and [PAH]+., isomeric PAHs can be differentiated. The [PAH]+./[Ag+PAH]+ ion intensity ratio was found to increase with decreasing ionization potentials (IPs) of PAHs. The ratio was significantly different for the isomeric PAHs studied over a wide range of PAH concentrations (1.6–100 nmol/mL), and showed good measurement reproducibility; the coefficient of variation of inter‐day measurements was in the range 3–12% for four representative PAHs (n = 5). Detection limits for phenanthrene, pyrene, chrysene and benzo[a]pyrene, in the form of the monomer complexes [107Ag+PAH]+ and measured in the selected‐ion monitoring (SIM) mode, were 0.31, 0.63, 0.16 and 1.25 pmol/5 μL injection, respectively (S/N ratio ∼2–3). Copyright © 2003 John Wiley & Sons, Ltd.
Secondary ion formation of low molecular weight organic dyes in time‐of‐flight static secondary ion mass spectrometry
Authors: Lenaerts Jens , Van Vaeck Luc , Gijbels Renaat
Published: September 2003

Time‐of‐flight static secondary ion mass spectrometry (TOF‐S‐SIMS) was used to characterize thin layers of oxy‐ and thiocarbocyanine dyes on Ag and Si. Apart from adduct ions a variety of structural fragment ions were detected for which a fragmentation pattern is proposed. Peak assignments were confirmed by comparing spectra of dyes with very similar structures. All secondary ions were assigned with a mass accuracy better than 50 ppm. The intensity of molecular ions as well as fragment ions has been studied as a function of the type of organic dye, the substrate, the layer thickness and the type of primary ion. A large yield difference of two orders of magnitude was observed between the precursor ions of cationic carbocyanine dyes and the protonated molecules of the anionic dyes. Fragment ions, on the other hand, yielded similar intensities for both types of dye. As the dye layers deposited on an Ag substrate yielded higher secondary ion intensities than those deposited on a Si substrate, the Ag metal clearly acts as a promoting agent for secondary ion formation. The effect was more pronounced for precursor signals than for fragment ions. The promoting effect decreased as the deposited layer thickness of the organic dye layer was increased. Copyright © 2003 John Wiley & Sons, Ltd.
Analysis of aromatic amines in cigarette smoke
Authors: Stabbert Regina , Schäfer Karl‐Heinz , Biefel Christine , Rustemeier Klaus
Published: September 2003

A method for the analysis of o‐toluidine, o‐anisidine, 2‐naphthylamine, and 4‐aminobiphenyl in cigarette mainstream smoke has been developed, which combines the sensitivity of their pentafluoropropionyl (PFP) derivatives in negative ion chemical ionization (NICI) mode with the selectivity of the gas chromatography/tandem mass spectrometry (GC/MS/MS) technique. The use of four deuterated analogues as internal standards along with the application of the standard addition method results in accurate and precise results; the interday precision for the aromatic amines was 3–10% and the accuracy ranged from 97–100%. This method was applied to two American‐blend University of Kentucky reference cigarettes, eight American‐blend market cigarettes, a bright (flue‐cured) tobacco cigarette, and an electrically heated cigarette smoking system (EHCSS). For the American‐blend cigarettes there was a linear correlation between aromatic amine yields and mainstream smoke ‘tar’ (‘tar’ = total particulate matter − (nicotine + water)), whereas the bright tobacco cigarette and the EHCSS demonstrated significantly lower aromatic amine yields on an equal ‘tar’ basis. The results support the hypothesis that the nitrogen content of the tobacco, and above all the cigarette combustion temperature, are determining factors for the yields of aromatic amines in smoke. Copyright © 2003 John Wiley & Sons, Ltd.
Electrospray ionization tandem mass spectrometric and electron impact mass spectrometric characterization of mycosporine‐like amino acids
Authors: Whitehead Kenia , Hedges John I.
Published: September 2003

Positive‐ion mass spectral fragmentations of seven mycosporine‐like amino acids (MAAs) are reported and discussed. The MAAs studied are small compounds composed of a cycloheximine ring substituted with amino acid or amino alcohol units. Techniques used include electron impact (EI) and electrospray ionization (ESI) with tandem mass spectrometry (MS/MS). ESI‐MS/MS showed unusual small radical losses, generally resulting from the loss of a methyl group with the exception of shinorine and porphyra for which the initial losses were 30 and 44 Da, respectively. As expected from structural similarities, porphyra, shinorine and palythinol displayed similar fragmentation patterns, while palythenic acid and palythene fragmented in a similar manner. Overall, the ESI‐MS/MS fragmentations at m/z <200 exhibited a distinctive pattern for all seven MAAs with characteristic ions at m/z 137, 168, 186, and 197 or 199. Several ions were observed for each of the MAAs analyzed, and together provide a useful and potentially diagnostic pattern for identification of MAAs and as an aid in structure elucidation of novel MAAs. For GC/EI‐MS analysis, trimethylsilyl (TMS) derivatives were made. The EI‐MS fragmentation patterns of TMS‐MAAs showed many features typical of TMS‐derivatized α‐amines. The precursor TMS‐MAA ion was not detected, but a [M–90]+. ion was the highest‐mass intense peak observed for palythine, palythinol and shinorine, while palythene gave a [M–116]+. ion. Besides determining the number of acidic hydrogens, EI‐MS of TMS‐derivatized MAAs will aid in structure elucidation of novel MAAs. Copyright © 2003 John Wiley & Sons, Ltd.
Studies on azaspiracid biotoxins. III. Instrumental validation for rapid quantification of AZA 1 in complex biological matrices
Authors: Blay Pearl K. S. , Brombacher Stephan , Volmer Dietrich A.
Published: September 2003

Azaspiracids are neurotoxins produced by marine algae that have been detected in harvested mussels since 1995. They pose a significant threat to human health through the consumption of contaminated shellfish, and negatively impact the economy of areas where shellfish are harvested and processed. Regulatory agencies are beginning to advocate instrumental assays over traditional mouse bioassay methods. The development and validation of an assay method for AZA 1, the predominant azaspiracid toxin, and the production of a calibration standard and reference material will therefore be vital for quality control in monitoring laboratories worldwide. This report demonstrates a rapid and reproducible liquid chromatography/mass spectrometry (LC/MS) method for separation of all twelve known azaspiracids. Using a triple‐quadrupole mass spectrometer, ultra‐high sensitivity was obtained at the low‐femtogram level injected on‐column. At the same time, a linear response of three orders of magnitude was observed. We compared the results with those measured on an ion‐trap mass spectrometer. The triple‐quadrupole instrument was more sensitive, reliable and reproducible than the ion‐trap instrument. The detection limit obtained on the ion‐trap mass spectrometer was ten times higher than that obtained on the triple quadrupole. During the study, a new azaspiracid analog (AZA 7c) was discovered. Copyright © 2003 John Wiley & Sons, Ltd.
Higher‐throughput screening for Caco‐2 permeability utilizing a multiple sprayer liquid chromatography/tandem mass spectrometry system
Authors: Fung Eliza N. , Chu Inhou , Li Cheng , Liu Tongtong , Soares Anthony , Morrison Richard , Nomeir Amin A.
Published: September 2003

In the current drug discovery environment, higher‐throughput analytical assays have become essential to keep pace with the screening demands for drug metabolism and pharmacokinetics (DMPK) attributes. This has been dictated by advances primarily in chemical procedures, notably combinatorial and parallel syntheses, which has resulted in many‐fold increases in the number of compounds requiring DMPK evaluation. Because of its speed and specificity, liquid chromatography/tandem mass spectrometry (LC/MS/MS) has become the dominant technology for sample analysis in the DMPK screening assays. For higher‐throughput assays, analytical speed as well as other factors such as method development, data processing, quality control, and report generation, must be optimized. The four‐way multiplexed electrospray interface (MUX®), which allows for the analysis of four LC eluents simultaneously, has been adopted to maximize the rate of sample introduction into the mass spectrometer. Generic fast‐gradient HPLC methods that are suitable for approximately 80% of the new chemical entities encountered have been developed. In‐house‐written software programs have been used to streamline information flow within the system, and for quality control by automatically identifying analytical anomalies. By integrating these components together with automated method development and data processing, a system capable of screening 100 compounds per week for Caco‐2 permeability has been established. Copyright © 2003 John Wiley & Sons, Ltd.
Electrospray mass spectrometric studies of noncovalent complexes of buspirone hydrochloride and other serotonin 5‐HT1A receptor ligands containing arylpiperazine moieties
Authors: Kowalski Piotr , Suder Piotr , Kowalska Teresa , Silberring Jerzy , Duszyńska Beata , Bojarski Andrzej J.
Published: September 2003

Noncovalent complexes consisting of two protonated amines and a chloride anion were observed under electrospray ionization mass spectrometry (ESI‐MS) conditions. The observed phenomenon was investigated for the hydrochlorides of buspirone, a well‐known anxiolytic drug, and 23 other arylpiperazine derivatives that had been developed as serotonin 5‐HT1A receptor ligands. Due to the major role of ionic interactions in a vacuum, it was proposed that the detected complexes were formed by NH+···Cl−···NH+ bridges. It was found that complexation depended on structural features of the analyzed compounds. For derivatives with a shorter linker (three methylene groups) containing a terminal cyclic amide fragment, complex ions were not observed. It was postulated that, in the latter case, steric hindrance due to a terminal group could disturb ionic bridge formation. Since both the observed complexation and ligand‐binding processes are driven by noncovalent forces, and a qualitative relationship between them was found (compounds with a 4‐carbon chain always display higher affinity for 5‐HT1A receptors than do their 3‐carbon analogues), such ESI‐MS studies may yield valuable information on ligand–receptor interactions. Copyright © 2003 John Wiley & Sons, Ltd.
Assessing individual bioequivalence with high‐order cross‐over designs: a unified procedure
Authors: Hsuan Francis C. , Reeve Russell
Published: September 2003

The U.S. FDA's newly issued guidance on bioequivalence recommends the use of individual bioequivalence (IBE) for highly variable drugs and possibly for modified release dosage forms. The recommended approach to the analysis is to follow the methodology of Hyslop, Hsuan and Holder (HHH), based on a linear mixed model. A limitation of the HHH method is that it works only for uniform designs, such as RTRT/TRTR. In this paper, we present an alternative approach based on a multivariate model. The multivariate model is shown to be a strict superset of the linear mixed model and can successfully model data where the mixed model fails. Our multivariate approach coincides with the HHH method where the HHH method applies, but generalizes to any high‐order cross‐over design, such as the Balaam design, RTR/TRT, and TRSS/RSTT/STRR. We present numerical examples to demonstrate the proposed method, and examine its properties with a simulation study. Copyright © 2003 John Wiley & Sons, Ltd.
Three methods for analysing correlated ROC curves: a comparison in real data sets from multi‐reader, multi‐case studies with a factorial design
Authors: Toledano Alicia Y.
Published: September 2003

This paper compares three published methods for analysing multiple correlated ROC curves: a method using generalized estimating equations with marginal non‐proportional ordinal regression models; a method using jackknifed pseudovalues of summary statistics; a method using a corrected F‐test from analysis of variance of summary statistics. Use of these methods is illustrated through six real data examples from studies with the common factorial design, that is, multiple readers interpreting images obtained with each test modality on each study subject. The issue of the difference between typical summary statistics and summary statistics from typical ROC curves is explored. The examples also address similarities and differences among the analytical methods. In particular, while point estimates of differences between test modalities are similar, the standard errors of these differences do not agree for all three methods. A simulation study supports the standard errors provided by the generalized estimating equations with marginal non‐proportional ordinal regression models. Copyright ©2003 John Wiley & Sons, Ltd.
Quality control and the identification of vaccine responders using ELISA‐derived antibody data
Authors: Le Chap T. , Grambsch Patricia M. , Giebink G. Scott
Published: September 2003

First vaccines are traditionally licensed after showing favourable results from phase III efficacy trials. Subsequent competing vaccines, however, have been licensed primarily on the basis of immunogenicity data rather than clinical efficacy. Focusing on pneumococcal vaccines where optical densities are measured and serum antibody concentrations are ‘estimated’ (from a statistical model) using an immunoglobulin (IgG) enzyme‐linked immunosorbent assay (ELISA), the focus of this paper will centre on two highly related issues: the determination of an upper limit for quality control used in the assay methodology (let us call it the maximum tolerated limit or MTL) and the identification of vaccine responders. The goal is to show that these two issues are inter‐related, so that investigators could reduce misclassification which would interfere with the eventual comparison of immunogenicity results. Copyright © 2003 John Wiley & Sons, Ltd.
‘Online’ monitoring and retrospective analysis of hospital outcomes based on a scan statistic
Authors: Ismail Noor Azina , Pettitt A. N. , Webster R. A.
Published: September 2003

Statistical tests based on the scan statistic are introduced for detecting possible increases in the occurrence of hospital events. The tests use a moving window and the theoretical aspects of the tests are investigated using Markov chain theory. The main objective of this study is to provide a statistical technique to assist hospital staff in deciding whether the variation they observe is greater than usually expected under random variation. In this paper we develop the test for Poisson data and apply the theory to monitor the occurrence of orthopaedic wound infection and Methicillin‐resistant Staphylo‐ coccus aureus colonization. We find that this method is sensitive in detecting the change in the process parameter which may not be detected by standard control chart methods. Both online and retrospective analyses are considered. Copyright © 2003 John Wiley & Sons, Ltd.
Lead‐time and overdiagnosis estimation in neuroblastoma screening
Authors: Spix Claudia , Michaelis Jörg , Berthold Frank , Erttmann Rudolf , Sander Johannes , Schilling Freimut H.
Published: September 2003

In Germany, neuroblastoma is the most frequent extracranial solid childhood tumour. Its properties made it seem an ideal candidate for screening. A German trial assessed the effect of screening at one year of age from 1995–2001 in a nationwide project. We present here the methods developed for the estimation of lead‐time and overdiagnosis in this project. Follow up on 1.5 million screened children and 2.1 million control children is currently available until June 2002. Ascertainment of control cohort cases and false negative cases is complete up to this date. A method for determining an empirical lead‐time distribution and overdiagnosis estimate from comparing the age specific incidences in the control group and the study group is presented. Lead‐time leads to an excess of cases in the screening group at the screening age and cases missing at higher age. If more cases are observed at the screening age than can be explained by lead‐time, the difference is attributed to overdiagnosis. The width of the screening age window and the empirical maximum lead‐time have to be chosen from graphs. About 1.0/100000 cases (20 per cent of the possible cases) experienced lead‐time while 6.8/100000 cases were overdiagnosed. The mean lead‐time was estimated to be about 15 months. The number of cases who might benefit is much smaller than was expected before the study while the overdiagnosed group is much larger. The method is robust against the choices that have to be made in the estimation process. Copyright © 2003 John Wiley & Sons, Ltd.
Measuring spatial effects in time to event data: a case study using months from angiography to coronary artery bypass graft (CABG)
Authors: Crook Angela M. , Knorr‐Held Leonhard , Hemingway Harry
Published: September 2003

The application of Bayesian hierarchical models to measure spatial effects in time to event data has not been widely reported. This case study aims to estimate the effect of area of residence on waiting times to coronary artery bypass graft (CABG) and to assess the role of important individual specific covariates (age, sex and disease severity). The data involved all patients with definite coronary artery disease who were referred to one cardiothoracic unit from five contiguous health authorities covering 488 electoral wards (areas). Time to event was the waiting time in months from angiography (diagnosis) to CABG (event). A number of discrete time survival models were fitted to the data. A discrete baseline hazard was estimated by fitting waiting time non‐parametrically into the models. Ward was fitted as a spatial effect using a Gaussian Markov random field prior. Individual specific covariates considered were age, sex and number of diseased vessels. The recently proposed DIC criteria was used for comparing models. Results showed a marked spatial effect on time to bypass surgery after including age, sex and disease severity in the model. Notably this spatial effect was not apparent when these covariates were not included in the model. The observed small area spatial variation in time to CABG warrants further investigation. Copyright © 2003 John Wiley & Sons, Ltd.
Design and sample size estimation in clinical trials with clustered survival times as the primary endpoint
Authors: Xie Tailiang , Waksman Joel
Published: September 2003

Many clinical trials involve the collection of data on the time to occurrence of the same type of multiple events within sample units, in which ordering of events is arbitrary and times are usually correlated. To design a clinical trial with this type of clustered survival times as the primary endpoint, estimating the number of subjects (sampling units) required for a given power to detect a specified treatment difference is an important issue. In this paper we derive a sample size formula for clustered survival data via Lee, Wei and Amato's marginal model. It can be easily used to plan a clinical trial in which clustered survival times are of primary interest. Simulation studies demonstrate that the formula works very well. We also discuss and compare cluster survival time design and single survival time design (for example, time to the first event) in different scenarios. Copyright © 2003 John Wiley & Sons, Ltd.
A comparison of recent methods for the analysis of small‐sample cross‐over studies
Authors: Chen Xun , Wei Lynn
Published: September 2003

The standard analysis of variance (ANOVA) method is usually applied to analyse continuous data from cross‐over studies. The method, however, has been known to be not robust for general variance–covariance structure. The simple empirical generalized least squares (EGLS) method, proposed in an attempt to improve the precision of the standard ANOVA method for general variance–covariance structure, is usually insufficient for small‐sample cross‐over trials. In this paper we compare the following commonly used or recent approaches: standard ANOVA; simple EGLS; modified ANOVA method derived from a modified approximate F‐distribution; and a modified EGLS method adjusted by the Kenward and Roger procedure in terms of robustness and power while applying to small‐sample cross‐over studies (say, the sample size is less than 40) over a variety of variance–covariance structures by simulation. We find that the unconditional modified ANOVA method has robust performance for all of the simulated small‐sample cross‐over studies over the various variance–covariance structures, and has comparable power with the standard ANOVA method whenever they are comparable in type I error rate. The EGLS method (simple or modified) is not reliable when the sample size of a cross‐over study is too small, say, less than 24 in the simulation, unless a simple covariance structure is correctly assumed. Given a relatively larger sample size, the modified EGLS method, assuming an unstructured covariance matrix, demonstrates robust performance over the various variance–covariance structures in the simulation and provides more powerful tests than those of the modified (or standard) ANOVA method. Copyright © 2003 John Wiley & Sons, Ltd.
General linear contrasts on latent variable means: structural equation hypothesis tests for multivariate clinical trials
Authors: Donaldson Gary W.
Published: September 2003

Structural equation models articulate the assumed measurement and causal relations among variables, imposing discipline on otherwise unstructured and redundant associations that arise in correlational studies. Biomedical research has eschewed such methods, relying on the generally superior causal inference afforded by randomized controlled trials. Increasingly, however, clinical trials incorporate numerous covariates that are measured but unmanipulated. Most clinical trials now also include multiple correlated endpoints, which can generate ambiguous outcome patterns refractory to simple statistical analysis and interpretation. Modern clinical trials are really multivariate longitudinal studies with at best a component of randomized control; as such, structural equation approaches can add rigour and clarity. The analysis of latent variance (LANOVA) conception combines structural equation and experimental analysis of variance legacies. It allows, for any design that can be decomposed into between‐group and within‐person models, tests on latent means (that is, the means of the unobserved factors) that are directly analogous to their analysis of variance counterparts. LANOVA variables are either outcomes (which may have a time structure), varying covariates (which may have a time structure), or background covariates (which are static). Allowable causal relations are set‐recursive: background covariates can affect all other variables; varying covariates can affect current outcomes and later outcomes and covariates; outcomes can affect only later outcomes. All standard ANOVA and ANCOVA hypotheses can then be tested by proper restrictions among the means and intercepts of these latent variables. Structural equation modelling programs can be used to estimate the models and test the hypotheses. I demonstrate the approach by expressing and testing hypotheses appropriate for two clinical studies that evaluate patient‐reported outcomes in populations with solid and haematological malignancies. Copyright © 2003 John Wiley & Sons, Ltd.
When founding entrepreneurs leave: the problem of succession in small firms in Nigeria, 1971–1980
Authors: Sam Monibo A.
Published: September 2003

Like its counterparts elsewhere, the small business sector of the Nigerian economy is extremely volatile. A corollary of this volatility is the dearth of long-established firms. One issue that can help to account for the scarcity of long-established firms and also contribute to our understanding of the sector's volatility is succession, the ease with which ownership changes from one hand to another. This paper explores the issue of succession in privately incorporated small firms in south-eastern Nigeria. The finding that nearly half of the closures are attributable to the succession problem has implications for research on the small business sector, and on the development expectations of the sector.
Explaining the unexpected: electoral reform and democratic governance in Burkina Faso
Authors: Santiso Carlos , Loada Augustin
Published: September 2003

The parliamentary elections of May 2002 in Burkina Faso saw the ruling party loose its exclusionary grip on power. For the first time since the restoration of democracy in 1991, the parliamentary opposition now represents a sizeable group. While it retains the majority, the ruling party has to share legislative power with the opposition. These elections marginally alter the structure of power in a deeply presidential system of government. Several institutional and electoral reforms have played a critical role in strengthening the mechanisms of ‘vertical accountability’ and representative democracy. By assessing recent electoral reforms in Burkina Faso, the article underlines the importance of the electoral system in multiparty elections and thus contributes to our understanding of the effects of changes in electoral rules on the distribution of political outcomes. In particular, it underscores the contribution that institutional engineering and electoral reform can make to further democratisation in a semi-authoritarian context. While many challenges to democratic governance and the rule of law remain, the new political landscape holds the promise of changes in the style of government and the emergence of more consensual modes of governance.
The 2002 legislative election in Cameroon: a retrospective on Cameroon's stalled democracy movement
Authors: Takougang Joseph
Published: September 2003

This paper examines the impressive victory by President Paul Biya and his ruling Cameroon People's Democratic Movement (CPDM) in the 2002 Cameroon legislative election, especially in the light of the near collapse of the regime and the party in 1992, when it almost lost its parliamentary majority. It argues that several factors contributed to this turn of events including the president's skilful use of his power of incumbency to forestall the democratic process, the ineffectiveness of the opposition parties, and the lack of sustained support for genuine democratic change in Cameroon by France and other Western industrialised nations.
Ethnic-sectoral cleavages and economic development: reflections on the second Kenya debate
Authors: Vandenberg Paul
Published: September 2003

The second Kenya debate has prompted a close examination of the role of an ethnic business community – Indians/Asians – in the country's industrial development. While this community does own up to three-quarters of the country's medium and large-scale manufacturing firms, a narrow focus on manufacturing understates the contribution which Africans have made to the economy. A progressive rural business class is more likely to re-invest in profitable farming activities and to branch out into agro-processing, transport and trading than to undertake risky investments in urban manufacturing. As a result, historical ethnic-sectoral cleavages will tend to be reinforced. The article provides new calculations on the extent of African involvement in manufacturing, and reviews an ancillary literature which uses institutional and socio-economic analysis to understand differences in Kenya's business communities.
Violence and history: a response to Thandika Mkandawire
Authors: Ellis Stephen
Published: September 2003

Last year, Thandika Mkandawire (2002) published an article in the Journal of Modern African Studies proposing ‘an explanation of the violence against the peasantry’ in Africa, referring to people in rural areas who have suffered so much in recent wars across the continent. The article starts by categorising suggestions made by some other authors as to why combatants have used ‘extremely brutal and spiteful forms of violence’ in such a disturbing number of cases. In the opening section of his paper, Mkandawire takes exception to suggestions I have made concerning the antecedents of the 1990s civil war in Liberia, describing my views as ‘essentialist’ and ‘poorly veiled racist’, and alleging that I believe ‘there is something fundamentally wrong with African culture’ (2002: 183).
Rejoinder to Stephen Ellis
Authors: Mkandawire Thandika
Published: September 2003

Stephen Ellis's response can be divided into two parts. One concerns my interpretation of the violence of rebel movements in Africa; the other relates to my misunderstanding of his position. With respect to the former, Ellis raises four objections. I will start with these.
African military coups d'état, 1956–2001: frequency, trends and distribution
Authors: McGowan Patrick J.
Published: September 2003

Described here is a new data set including all successful coups d'état (80), failed coup attempts (108) and reported coup plots (139) for all 48 independent sub-Saharan African (SSA) states for the 46-year period from January 1956 until December 2001. Elite political instability (PI) in this form remains widespread in SSA, in contrast to other regions of the global South. Military-led PI has been shown to adversely affect economic growth and human development in SSA, and is a major cause of the current African ‘crisis’. The frequency of these instability events is given for each state for all 46 years and for the two periods 1956–79 and 1980–2001. A Total Military Intervention Score (TMIS) for each state is calculated and examined over time to explore trends in coup behaviour. The distribution of these events among major African regions is presented. Appendix A lists all coups and failed coups by state and date. Major findings are that military interventions have continued to be pervasive in Africa, despite democratisation trends since 1990; that coups, failed coups and coup plots form a syndrome of military-led PI; that colonial heritage is unrelated to coup activity; that the chance of success when launching a coup attempt has averaged more than 40% since 1958; that once a successful coup has occurred, military factionalism often leads to more coup behaviour; that except for a declining rate of success once a coup is undertaken, there is no major difference between 1956–79 and 1980–2001; that no trends of increasing or decreasing coup behaviour are evident, except that up to around 1975 as decolonisation progressed, TMIS also increased; and that West Africa is the predominant centre of coup activity in SSA, although all African regions have experienced coups. States that have been free of significant PI since 1990 are examined and those with institutionalised democratic traditions appear less prone to coups.
Quality of American English front vowels before /r/
Authors: Clark Michael J. , Hillenbrand James M.
Published: September 2003

The vowels /i/ and /I/ are not contrastive before /r/ in American English, and the
phonetics literature is equivocal about which symbol to use for the nucleus in words such as beer.
Similarly /e/ and /ε/ are not contrastive before /r/, and the literature contains
varied references to one or the other in words such as bear. The purpose of this study was to investigate
these vowels by acoustic measurements, discriminant analyses, and listening tests. Eleven men and ten women residing
in southern Michigan recorded /r/-final monosyllables (beer, bear, hear,
hair), as well as words containing /i, I e, ε with other finals, such as beet,
bit, bait, bet. Acoustic measurements included the first three formants at steady state.
The high front vowel in /r/-final syllables (beer, hear) showed formant values intermediate
between /i/ and /I/, but closer to /i/, and the mid front vowel (in bear and
hair) was intermediate between /e/ and /ε/, but closer to /e/. Discriminant
analysis using the first three formants and listening tests using 60 ms vowel excerpts yielded results consistent
with the idea that the pre-/r/ vowels are acoustically intermediate between their tense and lax neighbors
but resemble /i/ and /e/ more closely than /I/ and /ε/.
Data structures in speech production
Authors: Tatham Mark , Morton Katherine
Published: September 2003

Computationally testable models in linguistics focus on declaring data structures and providing exemplar derivations. This paper outlines a comprehensive model of speech production which goes beyond derivations to show how actual instances of utterances can be formally characterised. Utterances contain a wealth of detail beyond the underlying utterance plan: some of this is a function of the mechanism itself (e.g. coarticulation) and some is the result of carefully supervised control. We develop the notion of managed or supervised speech production to enable the inclusion of EXPRESSIVE content in speech. Building on earlier work the Cognitive Phonetics Agent bridges the gap between the physical and cognitive processes in phonetics by controlling the way phonologically determined utterance plans are phonetically rendered in detail. The model is illustrated using different types of data structure which occur in speech, concentrating in particular on an XML characterisation of appropriate structures. We trace a simple utterance through from its phonological plan to a detailed intrinsic allophonic representation to show how stages in the model work.
A three-way VOT contrast in final position: data from Armenian
Authors: Hacopian Narineh
Published: September 2003

Standard Eastern Armenian has a three-way VOT contrast among its oral stop series. While it is rare for such a 3-way contrast to be preserved in final position, Standard Eastern Armenian is claimed to do just this (Khachaturian 1988; Ladefoged & Maddieson 1996; Vaux 1998). This phenomenon provides an ideal opportunity to explore how prosodic structure influences the realization of a complex and delicate system of contrast maintained by temporal and saliency distinctions. The cues to this contrast, including VOT, closure duration, and burst amplitude, are examined in a variety of segmental and prosodic environments. The experiment evaluates effects of intonation phrase final, intermediate phrase final, word final, and syllable final positions. We find that the 3-way VOT contrast is maintained in those prosodic domains in which the stop consonants are final. Speakers make significant VOT distinctions among the target consonants within the same boundary condition, and across prosodic conditions, larger prosodic domains exhibit longer VOT values.
Rhotic representation: problems and proposals
Authors: Whitley M. Stanley
Published: September 2003

Starting with an r that was already ambiguous, the IPA added new symbols and diacritics without arriving at a comprehensive treatment of rhotics. The results have been ad hoc solutions and potential confusion for languages such as Spanish, in which these need to be distinguished. A few modifications of the IPA diacritic system would suffice in order to capture the different types.
Polish
Authors: Jassem Wiktor
Published: September 2003

Polish is a West Slavonic language with about 41 million speakers in Poland and approximately 10 million in diasporas.
It can be described as a ‘consonantal’ language, in two respects: (a) it has a rich system of consonant
phonemes, as shown in the table, and (b) it allows heavy consonant clusters, especially word-initially.
Standard Chinese (Beijing)
Authors: Lee Wai-Sum , Zee Eric
Published: September 2003

The style of speech illustrated is that typical of the educated younger generation in Beijing. The recording is that of a 25-year-old female graduate student who has lived all her life in Beijing.