bluuebunny/crossref_metadata_2025 huggingface dataset:
An evaluation of phase I clinical trial designs in the continuous dose–response setting
Authors: Storer Barry E.
Published: January 2005

Both traditional phase I designs and the increasingly popular continual reassessment method (CRM) designs select an estimate of maximum tolerable dose (MTD) from among a set of prespecified dose levels. Although CRM designs use an implied dose–response model to select the next dose level, in general it is neither assumed nor necessary that this model be tied to the actual dose of a drug. In contrast, in our two‐stage design the fitting of a dose–response model after data have been collected is a necessary feature of the design, and the MTD is not constrained to be one of the prespecified dose levels. We conducted a simulation study to evaluate the performance of the two‐stage design, two likelihood‐based CRM designs, and two traditional designs in estimating the MTD in situations where one assumes that an explicit dose–response model exists. Under a wide variety of dose–response settings, we examined the bias and precision of estimates, and the fraction of estimates that were extremely high or low. We also studied the effect of adding a model fitting step at the end of a traditional design or a CRM design. The best performance was achieved using the two‐stage and CRM designs. Although the CRM designs generally had smaller bias, the two‐stage design yielded equal or somewhat smaller precision in some cases. The addition of a model‐fitting step slightly improved the precision of the CRM estimates and decreased the percentage of extreme estimates. Allowing interpolation between doses for updating during CRM did not improve overall performance. Copyright © 2001 John Wiley & Sons, Ltd.
Analysis of recurrent failure times data: should the baseline hazard be stratified
Authors: Mahé Cédric , Chevret Sylvie
Published: January 2005

Over the past two decades, a variety of fruitful statistical methods for the analysis of recurrent events has been proposed for the estimation of covariates effect using the Cox proportional hazard model. Besides frailty modelling, two simple trends of modelling have been developed: the first one uses stratification on the rank of the event, whereas the second one, more closely related to Poisson processes theory, does not use stratification. Although they both take into account the correlation of the unit failure times, each of these approaches emphasizes a different aspect of the underlying point process and there is still an ongoing debate concerning the most appropriate method. The aim of this paper is to stress current interests and trends concerning these two approaches. For each model, main statistical methods for estimating the covariates effects are presented. Methods are illustrated and compared in two randomized clinical trials which involve recurrences of severe adverse events following chemotherapy in 938 patients with chronic lymphocytic leukaemia, and recurrences of infectious rhinitis episodes in 327 patients. The discussion, based on the previous examples and on the properties of underlying statistical inference, deals with the appropriateness of the model choice, which is closely related to the data structure. Copyright © 2001 John Wiley & Sons, Ltd.
A general goodness‐of‐fit approach for inference procedures concerning the kappa statistic
Authors: Altaye Mekibib , Donner Allan , Eliasziw Michael
Published: January 2005

The kappa statistic is frequently used as a measure of agreement among two or more raters. Although considerable research on statistical inferences for this statistic has been published for the case of two raters and a binary outcome, relatively little work has appeared on inference problems for the case of multiple raters and/or polytomous nominal outcome categories. In this paper we propose a new procedure for constructing inferences for the kappa statistic that may be applied to this general case. The procedure is based on a chi‐square goodness‐of‐fit test as applied to the Dirichlet multinomial model, and is a natural extension of previously proposed procedures that apply to more restricted cases. A simulation study shows that the new procedure provides confidence interval coverage levels and type I error rates close to nominal over a wide range of parameter combinations. We also present a sample size formula which may be used to determine the required number of subjects and raters for a given number of outcome categories. Copyright © 2001 John Wiley & Sons, Ltd.
Modelling variation of lower leg length growth in early life
Authors: Fong D. Y. T. , Wong S. W. S. , Karlberg J.
Published: January 2005

We consider the estimation of sources of variation for panel data with repeated measurements. With no repeated measurements and known measurement error, models for variation decomposition have been proposed when there are one or more types of measurements. Estimation was performed using the EM algorithm accompanied by model augmentation that demands more computational efforts. In this article we extend previous variation models and modify the estimation methods in order to estimate various variation components after eliminating the unknown effects of measurement error. Specifically, methods that dispense with model augmentation and estimation of time‐dependent covariates are considered. A set of lower leg length data from Chinese infants is analysed by using the proposed model. Interestingly, our results are consistent with the well‐accepted three‐phase (infancy–childhood–puberty) growth transition proposition for human growth. Moreover, gender effect is found to be time‐varying. Copyright © 2001 John Wiley & Sons, Ltd.
Evaluation of surrogate endpoints in randomized experiments with mixed discrete and continuous outcomes
Authors: Molenberghs Geert , Geys Helena , Buyse Marc
Published: January 2005

A statistical definition of surrogate endpoints as well as validation criteria was first presented by Prentice. Freedman et al. supplemented these criteria with the so‐called proportion explained. Buyse and Molenberghs pointed to inadequacies of these criteria and suggested a new definition of surrogacy based on (i) the relative effect linking the overall effect of treatment on both endpoints and (ii) an individual‐level measure of agreement between both endpoints. Using data from a randomized trial, they showed how a potential surrogate endpoint can be studied using a joint model for the surrogate and the true endpoint. Whereas Buyse and Molenberghs restricted themselves to the fairly simple cases of jointly normal and jointly binary outcomes, we treat the situation where the surrogate is binary and the true endpoint is continuous, or vice versa. In addition, we consider the case of ordinal endpoints. Further, Buyse et al. extended the approach of Buyse and Molenberghs to a meta‐analytic context. We will adopt a similar approach for responses of a mixed data type. Copyright © 2001 John Wiley & Sons, Ltd.
Synthetic estimators with moderating influence: the carry‐over in cross‐over trials revisited
Authors: Longford Nicholas T.
Published: January 2005

A general approach to combining alternative estimators of a parameter is described and applied to the analysis of 2×2 cross‐over trials in which the treatment effect is of principal interest and carry‐over is a nuisance feature. The approach requires prior information about the carry‐over. Although modest information is sufficient, more information is rewarded by greater efficiency. The combination, or synthetic, estimator exhibits a moderating influence: its mean squared error is a flat function of the carry‐over effect in the range of its feasible values, and for the largest feasible carry‐over effect it is superior to either of the originally considered estimators. An extension of the approach is outlined and two other applications in medical research discussed. Although the method can be regarded as Bayesian in spirit, we focus on its resampling (frequentist) properties. Copyright © 2001 John Wiley & Sons, Ltd.
Bayesian analysis of logistic regression with an unknown change point and covariate measurement error
Authors: Gössl Christoff , Küchenhoff Helmut
Published: January 2005

We discuss Bayesian estimation of a logistic regression model with an unknown threshold limiting value (TLV). In these models it is assumed that there is no effect of a covariate on the response under a certain unknown TLV. The estimation of these models in a Bayesian context by Markov chain Monte Carlo (MCMC) methods is considered with focus on the TLV. We extend the model by accounting for measurement error in the covariate. The Bayesian solution is compared with the likelihood solution proposed by Küchenhoff and Carroll using a data set concerning the relationship between dust concentration in the working place and the occurrence of chronic bronchitis. Copyright © 2001 John Wiley & Sons, Ltd.
Assessing physicians' accuracy in diagnosing paediatric patients with acute abdominal pain: measuring accuracy for multiple diseases
Authors: Obuchowski Nancy A. , Goske Marilyn J. , Applegate Kimberly E.
Published: January 2005

In evaluating the accuracy of diagnostic tests there are many situations where the true disease status can be one of multiple disorders. For example, when paediatric patients suffer acute abdominal pain, the underlying diagnosis could be appendicitis, intestinal obstruction, gastroenteritis, urinary tract infection, etc. In this paper we describe a format for collecting data for the case of multiple truth states. This new format allows one to make pairwise comparisons of the diagnostic accuracy between all of the different truth states. We propose a summary measure of accuracy which is a weighted average of the pairwise estimates of accuracy. Estimators are derived for the variance and covariance of the estimated summary accuracy. The small sample properties of the estimators are evaluated in a Monte Carlo simulation study. The new data collection format and summary measure were used in a paediatric acute abdominal pain study; data from this study are used to illustrate the methods. Copyright © 2001 John Wiley & Sons, Ltd.
A semi‐parametric regression analysis of CD4 cell counts
Authors: Sun Jianguo
Published: January 2005

This paper considers the regression analysis of CD4 cell counts, a commonly used indicator and prognostic factor of AIDS progression. For this purpose, a number of methods have been proposed and most of them are based on random effects models. We present an alternative that is based on a mean function regression model. The new method is more natural and particularly appropriate if population parameters such as treatment comparison are mainly of interest. To estimate regression parameters, we present an estimating equation‐based approach, which does not require estimation of the baseline mean function. This makes the implementation of the approach and the study of the properties of the estimated regression parameters much easier than those based on random effects models. The method is illustrated with a set of CD4 cell count data arising from an AIDS clinical trial and simulated data. Copyright © 2001 John Wiley & Sons, Ltd.
Allocation of subjects to test null relative risks smaller than one
Authors: Hoover Donald R. , Blackwelder William C.
Published: January 2005

Allocating a proportion k′=1/(1+√r0) of subjects to an intervention is a practical approach to approximately maximize power for testing whether an intervention reduces relative risk of disease below a null ratio r0<1. Furthermore, allocating k′s, a convenient fraction close to k′, to intervention performs nearly as well; for example, allocating k′s=3/5 for 0.5⩾r0>0.33,2/3 for 0.33⩾r0>0.17 and 3/4 for 0.17⩾r0⩾0.10. Both k′ and k′s are easily calculated and invariant to alterations in disease rate estimates under null and alternative hypotheses, when r0 remains constant. In examples that we studied, allocating k′ (or k′s) subjects to intervention achieved close to the minimum possible sample size, given test size and power (equivalently, maximum power, given test size and sample size), for likelihood score tests. Compared to equal allocation, k′ and k′s reduced sample sizes by amounts ranging from ∼5.5 per cent for r0=0.50 to ∼24 per cent for r0=0.10. These sample size savings may be particularly important for large studies of prophylactic interventions such as vaccines. While k′ was derived from variance minimization for an arcsine transformation, we do not recommend the arcsine test, since its true size exceeded the nominal value. In contrast, the true size for the uncorrected score test was less than the nominal size. A skewness correction made the size of the score test very close to the nominal level and slightly increased power. We recommend using the score test, or the skewness‐corrected score test, for planing studies designed to show a ratio of proportions is less than a prespecified null ratio r0<1. Copyright © 2001 John Wiley & Sons, Ltd.
Marginal and dynamic regression models for longitudinal data
Authors: Schmid Christopher H.
Published: January 2005

Regression models for longitudinal data often employ random effects and serial correlation to account for residual variation between and within subjects. Most of these models are marginal models, separating the mean and covariance parameters. This paper discusses the use of dynamic models in which a lagged response serves as a predictor and compares these to marginal models. Regression parameters have a different interpretation in dynamic models as they describe changes in response levels, rather than the levels themselves. Lagged predictors are also useful with longitudinal data, explicitly quantifying the effect of previous levels of risk factors. These models are explored through analysis of data from the Childhood Respiratory Study, modelling lung function (FEV1) levels as a function of age, height, sex and smoking status in children measured over a five‐year period. Copyright © 2001 John Wiley & Sons, Ltd.
Within‐subject exposure dependency in case‐crossover studies
Authors: Vines S. K. , Farrington C. P.
Published: January 2005

In the case‐crossover design, only cases are sampled and the hazard ratio is estimated from within‐subject comparisons of exposures at the event time and in M control periods prior to the event. We consider the effect of within‐subject dependence of exposures in successive time periods. We show that estimates obtained from the conditional logistic model are biased. This bias disappears if the distribution of exposures in the M+1 successive time intervals is exchangeable. In contrast, the Mantel–Haenszel estimator for the odds ratio is approximately unbiased provided that exposures are stationary. Suitable methods of analysis of case‐crossover designs using maximum likelihood may be derived from cohort rather than case‐control models. Copyright © 2001 John Wiley & Sons, Ltd.
Dynamic linear model and SARIMA: a comparison of their forecasting performance in epidemiology
Authors: Nobre Flávio Fonseca , Monteiro Ana Beatriz Soares , Telles Paulo Roberto , Williamson G. David
Published: January 2005

One goal of a public health surveillance system is to provide a reliable forecast of epidemiological time series. This paper describes a study that used data collected through a national public health surveillance system in the United States to evaluate and compare the performances of a seasonal autoregressive integrated moving average (SARIMA) and a dynamic linear model (DLM) for estimating case occurrence of two notifiable diseases. The comparison uses reported cases of malaria and hepatitis A from January 1980 to June 1995 for the United States. The residuals for both predictor models show that they were adequate tools for use in epidemiological surveillance. Qualitative aspects were considered for both models to improve the comparison of their usefulness in public health. Our comparison found that the two forecasting modelling techniques (SARIMA and DLM) are comparable when long historical data are available (at least 52 reporting periods). However, the DLM approach has some advantages, such as being more easily applied to different types of time series and not requiring a new cycle of identification and modelling when new data become available. Copyright © 2001 John Wiley & Sons, Ltd.
A statistical model for the evaluation of barrier contraceptive efficacy
Authors: Dominik Rosalie , Zhou Haibo , Cai Jianwen
Published: January 2005

This paper describes an approach for the analysis of barrier contraceptive efficacy trials that accounts for timing frequency of intercourse and compliance. We allow exposure variables to vary for each act of intercourse and we control for timing of each act through a specific parametric function of the day of the act relative to the last day of the follicular phase of the cycle. The model can be used to examine the level of protection provided by a barrier versus no contraceptive method even when no control group of non‐users is studied, as long as there are acts with no barrier use during the fertile window. We present results of a simulation study which examines performance of estimators and power under a variety of scenarios, including situations where an accurate benchmark for ovulation day is not available. As compared to the survival analysis approach commonly used in this setting, simulation results show that the new approach yields considerable gains in power to detect differences between the efficacy of contraceptive methods. An application to data from the FemCap® versus diaphragm trial show results consistent with previous findings suggesting superiority of the diaphragm but also provides new evidence of the per act protection provided by both methods. Copyright © 2001 John Wiley & Sons, Ltd.
A three‐stage clinical trial design for rare disorders
Authors: Honkanen Visa E. A. , Siegel Andrew F. , Szalai John Paul , Berger Vance , Feldman Brian M. , Siegel Jeffrey N.
Published: January 2005

Many clinical trials of uncommon diseases are underpowered because of the difficulty of recruiting adequate numbers of subjects. We propose a clinical trial design with improved statistical power compared to the traditional randomized trial for use in clinical trials of rare diseases. The three‐stage clinical trial design consists of an initial randomized placebo‐controlled stage, a randomized withdrawal stage for subjects who responded, and a third randomized stage for placebo non‐responders who subsequently respond to treatment. Test level and power were assessed by computer‐intensive exact calculations. The three‐stage clinical trial design was found to be consistently superior to the traditional randomized trial design in all cases examined, with sample sizes typically reduced by 20 per cent to 30 per cent while maintaining comparable power. When a treatment clearly superior to placebo was considered, our design reached a power of 75 per cent with a sample of 21 patients compared with the 52 needed to attain this power when only a randomized controlled trial was used. In situations where patient numbers are limited, a three‐stage clinical trial design may be a more powerful design than the traditional randomized trial for detecting clinical benefits. Copyright © 2001 John Wiley & Sons, Ltd.
Assessment of equivalence on multiple endpoints
Authors: Quan Hui , Bolognese Jim , Yuan Weiying
Published: January 2005

Some clinical trials aim to demonstrate therapeutic equivalence on multiple primary endpoints. For example, therapeutic equivalence studies of agents for the treatment of osteoarthritis use several primary endpoints including investigator's global assessment of disease activity, patient's global assessment of response to therapy, and pain. In this paper, thoughts on simultaneous equivalence assessment on three endpoints are presented. As pointed out by Berger and Hsu (1996), the conventional intersection‐union test can be conservative. Simulation and computation are conducted to provide an insight on the conservativeness. We also provide a method to lower the confidence level and at the same time maintain the type I error when endpoints have normal distributions and are independent. If, in a particular analysis, the goal is to demonstrate equivalence on as many endpoints as possible, a step‐up procedure can be used for selecting those endpoints for which equivalence may be demonstrated. This step‐up procedure at the same time controls experimentwise error rate. The techniques are illustrated by a data example. Copyright © 2001 John Wiley & Sons, Ltd.
The applications of capture‐recapture models to epidemiological data
Authors: Chao Anne , Tsay P. K. , Lin Sheng‐Hsiang , Shau Wen‐Yi , Chao Day‐Yu
Published: January 2005

Capture‐recapture methodology, originally developed for estimating demographic parameters of animal populations, has been applied to human populations. This tutorial reviews various closed capture‐recapture models which are applicable to ascertainment data for estimating the size of a target population based on several incomplete lists of individuals. Most epidemiological approaches merging different lists and eliminating duplicate cases are likely to be biased downwards. That is, the final merged list misses those who are in the population but were not ascertained in any of the lists. If there are no matching errors, then the duplicate information collected from a capture‐recapture experiment can be used to estimate the number of missed under proper assumptions. Three approaches and their associated estimation procedures are introduced: ecological models; log‐linear models, and the sample coverage approach. Each approach has its unique way of incorporating two types of source dependencies: local (list) dependence and dependence due to heterogeneity. An interactive program, CARE (for capture‐recapture) developed by the authors is demonstrated using four real data sets. One set of data deals with infection by the acute hepatitis A virus in an outbreak in Taiwan; the other three sets are ascertainment data on diabetes, spina bifida and infants' congenital anomaly discussed in the literature. These data sets provide examples to show the usefulness of the capture‐recapture method in correcting for under‐ascertainment. The limitations of the methodology and some cautionary remarks are also discussed. Copyright © 2001 John Wiley & Sons, Ltd.
The internationalization and performance of SMEs
Authors: Lu Jane W. , Beamish Paul W.
Published: January 2005

We discuss and explore the effects of internationalization, an entrepreneurial strategy employed by small and medium‐sized enterprises (SMEs), on firm performance. Using concepts derived from the international business and entrepreneurship literatures, we develop four hypotheses that relate the extent of foreign direct investment (FDI) and exporting activity, and the relative use of alliances, to the corporate performance of internationalizing SMEs. Using a sample of 164 Japanese SMEs to test these hypotheses, we find that the positive impact of internationalization on performance extends primarily from the extent of a firm's FDI activity. We also find evidence consistent with the perspective that firms face a liability of foreignness. When firms first begin FDI activity, profitability declines, but greater levels of FDI are associated with higher performance. Exporting moderates the relationship FDI has with performance, as pursuing a strategy of high exporting concurrent with high FDI is less profitable than one that involves lower levels of exports when FDI levels are high. Finally, we find that alliances with partners with local knowledge can be an effective strategy to overcome the deficiencies SMEs face in resources and capabilities, when they expand into international markets. Copyright © 2001 John Wiley & Sons, Ltd.
Resource‐based strategy and managerial power in networks of internationally dispersed technology units
Authors: Medcof John W.
Published: January 2005

A linking of the Resource Based View of the firm, Resource Dependency Theory and the Vroom‐Yetton model of leadership is used to show that when important technical (R&D) resources are located offshore for strategic and efficiency reasons, resource‐based power goes with them. The extra‐national technology units that embody those strategically important resources should be managed with inclusive methods that respect that power shift. Theoretical, empirical and managerial implications are drawn from this analysis. Copyright © 2001 John Wiley & Sons, Ltd.
Consensus formation during strategic change
Authors: Markóczy Lívia
Published: January 2005

This paper offers a refined conceptualization of consensus formation and demonstrates in three organizations how this conceptualization enables us to uncover new patterns of consensus building. It describes a longitudinal study which investigated consensus formation in three organizations undergoing major strategic change. The study explored whether consensus building occurred during the strategic change and, if so, how. Initial participants of consensus were also investigated as well as changes in the scope of participants in consensus. Consensus building did occur, but contrary to some views less through an increase in the strength of consensus and more through an increase in the scope of consensus. Additionally, initial consensus was not located among members of the top management team, but more within an interest group whose members benefited from the given direction of the change. Copyright © 2001 John Wiley & Sons, Ltd.
Compositional gaps and downward spirals in international joint venture management groups
Authors: Hambrick Donald C. , Li Jiatao , Xin Katherine , Tsui Anne S.
Published: January 2005

We argue that compositional gaps in international joint venture (IJV) management groups, along parent company lines, will accentuate distinct managerial coalitions. Such gaps can occur on dimensions of observable demography, less apparent demography, or psychological characteristics. While compositional gaps in IJV management groups can provide the basis for healthy substantive conflict, such gaps—particularly if they are large—also tend to induce relationship conflict and heighten substantive conflict beyond its beneficial range. This can set off a downward spiral of relationship conflict, substantive conflict, and behavioral disintegration in the group. These harmful group processes further interact reciprocally with any tensions that might exist between the IJV parents, engendering a second downward spiral. Our model has implications for the performance of international joint ventures, and it serves as a foundation for designing interventions to avoid the downward spirals we portray. Copyright © 2001 John Wiley & Sons, Ltd.
Marketing's contribution to the implementation of business strategy: an empirical analysis
Authors: Slater Stanley F. , Olson Eric M.
Published: January 2005

This paper describes a study that assesses the performance implications of matching marketing strategy to business strategy. In order to conduct this study we first reviewed the literature on marketing strategy to identify its key dimensions. We then conducted a survey of 1000 senior marketing executives about the strategic marketing practices adopted in their respective firms or business units, and developed scales to describe 11 strategic marketing activities. We next performed a K‐means cluster analysis using these scales to develop a taxonomy of marketing strategy types consisting of: Aggressive Marketers, Mass Marketers, Marketing Minimizers, and Value Marketers. We then observed that superior performance at the firm or SBU level was achieved when specific marketing strategy types were matched with appropriate Miles and Snow (1978) business strategy types. Copyright © 2001 John Wiley & Sons, Ltd.
Are aliens green? Assessing foreign establishments' environmental conduct in the United states
Authors: King Andrew A. , Shaver J. Myles
Published: January 2005

Previous research has found that foreign‐owned establishments often lack specific capabilities needed to respond to local business conditions and are held to a higher standard by local stakeholders. These establishments compensate, however, by possessing offsetting capabilities such as technological excellence. In this article, we investigate how these conflicting forces shape the environmental conduct of foreign‐owned facilities. Using data from the Environmental Protection Agency, we find that foreign‐owned establishments generate more waste yet manage more waste than U.S.‐owned establishments. We also find evidence that both domestic and foreign‐owned firms generate more waste if they operate multiple facilities across multiple jurisdictions in the United States. Copyright © 2001 John Wiley & Sons, Ltd.
Architectural support in industry: a reflection using C‐POSH
Authors: Bril R. J. , Krikhaar R. L. , Postma A.
Published: January 2005

Software architecture plays a vital role in the development (and hence maintenance) of large complex systems (containing millions of lines of code) with a long lifetime. It is therefore required that the software architecture is also maintained, i.e., sufficiently documented, clearly communicated, and explicitly controlled during its life‐cycle. In our experience, these requirements cannot be met without appropriate support.

Commercial‐off‐the‐shelf support for architectural maintenance is still scarcely available, if at all, implying the need to develop appropriate proprietary means. In this paper, we reflect upon software architecture maintenance taken within three organizations within Philips that develop professional systems. We extensively describe the experience gained with introducing and embedding of architectural support in these three organizations. We focus on architectural support in the area of software architecture recovery, visualization, analysis, and verification.

In our experience, the support must be carried by a number of pillars of software development, and all of these pillars have to go through a change process to ensure sustainable embedding. Managing these changes requires several key roles to be fulfilled in the organization: a champion, a company angel, a change agent, and a target. We call our reflection model C‐POSH, which is an acronym for Change management of the four identified pillars of software development: Process, Organization, Software development environment, and Humans. Our experiences will be presented in terms of the C‐POSH model. Copyright © 2005 John Wiley & Sons, Ltd.
Ethological resolution of behavioural topography and D1‐like versus D2‐like agonist responses in congenic D5 dopamine receptor mutants: Identification of D5:D2‐like interactions
Authors: O'Sullivan Gerard J. , Kinsella Anthony , Sibley David R. , Tighe Orna , Croke David T. , Waddington John L.
Published: January 2005

The phenotypic ethogram of congenic dopamine D5 receptor “knockout” mice was evaluated. Each individual topography of behaviour within the natural repertoire was assessed over the extended course of initial exploration of and subsequent habituation to the environment, and following challenge with a series of D1‐like agonists. Over initial exploration, D5‐null mice evidenced a modest reduction in locomotion and a modest increase in sifting. Subsequent habituation revealed additional phenotypic effects, primarily overall reduction in grooming and delayed habituation of rearing. Among D1‐like agonists, A 68930 stimulates both adenylyl cyclase and a putative D1‐like receptor coupled to stimulation of phospholipase C‐mediated phosphoinositide hydrolysis; conversely, SK&F 83959 stimulates phosphoinositide hydrolysis but not adenylyl cyclase while SK&F 83822 stimulates adenylyl cyclase but not phosphoinositide hydrolysis. Though programmed grooming syntax and episodic seizure activity induced by A 68930 and SK&F 83822 were unaltered, grooming induced by SK&F 83959 was reduced in D5 mutants. Stereotyped, ponderous locomotion induced by the D2‐like agonist RU 24213 was enhanced in D5 mutants. Phenotypic and pharmacological characterisation of congenic D5‐null mice at an ethological level identifies novel functional roles for the D5 receptor in mediating discrete topographies of behaviour relating to exploration, sequential motor coordination, and how these processes change over the course of interaction with and habituation to the environment. Additionally, they indicate the involvement of phosphoinositide hydrolysis and D5:D2‐like interactions in regulating these processes. Synapse 55:201–211, 2005. Published 2005 Wiley‐Liss, Inc.
Modulation of dopamine release by striatal 5‐HT2C receptors
Authors: Alex Katherine D. , Yavanian Gregory J. , McFarlane Hewlet G. , Pluto Charles P. , Pehek Elizabeth A.
Published: January 2005

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin‐2C (5‐HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5‐HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5‐HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5‐HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1‐100 μM) into the striatum increased DA efflux in a concentration‐dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553‐induced increase. In contrast, infusion of SB 206553 (0.1–500 μM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K+)‐stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5‐HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5‐HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5‐HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression. Synapse 55:242–251, 2005. Published 2005 Wiley‐Liss, Inc.
Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: A dual probe microdialysis study in awake rat
Authors: Ferraro Luca , Fuxe Kjell , Agnati Luigi , Tanganelli Sergio , Tomasini Maria Cristina , Antonelli Tiziana
Published: January 2005

In view of a postulated role of the vigilance‐promoting drug modafinil in depression, the interaction of modafinil and two classical antidepressant drugs, fluoxetine and imipramine, were studied in 5‐HT levels in the dorsal raphe‐cortical system using dual‐probe microdialysis. Fluoxetine (1–10 mg/kg) dose‐dependently increased dorsal raphe‐cortical 5‐HT levels. Modafinil at a very low dose (3 mg/kg), by itself ineffective, enhanced the fluoxetine (5 mg/kg)‐induced increases of 5‐HT levels in both brain areas. A synergistic interaction was observed in the prefrontal cortex with fluoxetine (1 mg/kg) in terms of 5‐HT release, but not in the dorsal raphe. Imipramine (1.3 mg/kg) increased 5‐HT levels in the dorsal raphe, but not in the prefrontal cortex, while the higher doses (10.9–21.8 mg/kg) caused substantial increases in both brain areas. Modafinil (3 mg/kg), injected before imipramine (1.3 mg/kg), which by itself was ineffective on cortical 5‐HT levels, increased cortical 5‐HT levels. On other hand, modafinil failed to affect the high‐dose imipramine (10.9 mg/kg)‐induced increase of 5‐HT levels in the prefrontal cortex and the imipramine (1.3; 10.9 mg/kg)‐induced increase of 5‐HT levels in the dorsal raphe nucleus. These results demonstrate that modafinil in low doses enhances the acute effects of fluoxetine and imipramine on 5‐HT levels in the dorsal raphe nucleus (fluoxetine only) and especially in the prefrontal cortex of the awake rat. These findings suggest a therapeutic potential of low doses of modafinil in the treatment of depression when combined with low doses of classical antidepressants, especially by increasing 5‐HT transmission in cortical regions. Synapse 55:230–241, 2005. © 2005 Wiley‐Liss, Inc.
Simplified quantification of cerebral A1 adenosine receptors using [18F]CPFPX and PET: Analyses based on venous blood sampling
Authors: Meyer Philipp T. , Elmenhorst David , Zilles Karl , Bauer Andreas
Published: January 2005

[18F]CPFPX was proposed as a novel ligand for in vivo quantification of cerebral A1 adenosine receptors (A1AR) using positron emission tomography (PET). The present study investigates the applicability of non‐invasive non‐compartment analyses to quantify the [18F]CPFPX total distribution volume (DV) without arterial blood sampling. Five healthy volunteers underwent dynamic PET (90 min) with arterial and venous blood sampling after [18F]CPFPX bolus injection. Area under curve (AUC) analysis and Logan's graphical analysis (GA) were performed employing venous blood samples as non‐invasive analyses. AUC analysis without data extrapolation (AUCr) and venous GA were also applied on voxel‐level to generate parametric images. A conventional two‐tissue compartment model (2TCM) using arterial blood samples served as reference method. Regional DV estimates provided by venous AUC and GA analyses and 2TCM demonstrated very high agreement (venous AUC vs. 2TCM: r2 = 0.968, linear regression slope = 0.943; venous GA vs. 2TCM: r2 = 0.972, slope = 0.906). Although on voxel‐level the venous AUCr and GA analyses were affected by a slight negative bias, they were still very highly correlated with the 2TCM (voxel‐wise venous AUCr vs. 2TCM: r2 = 0.969, slope = 0.858; voxel‐wise venous GA vs. 2TCM: r2 = 0.959, slope = 0.867). The proposed non‐invasive analysis methods (particularly venous GA) allow reliable quantification of human [18F]CPFPX PET studies. In populations with altered metabolic/kinetic properties, the applicability of venous sampling has to be separately verified. The applicability of [18F]CPFPX PET in basic and clinical neurosciences will be considerably enhanced by the avoidance of arterial blood sampling. Synapse 55:212–223, 2005. © 2005 Wiley‐Liss, Inc.
Behaviour of [11C]R(−)‐ and [11C]S(+)‐rolipram in vitro and in vivo, and their use as PET radiotracers for the quantificative assay of PDE4
Authors: Parker Christine A. , Matthews Julian C. , Gunn Roger N. , Martarello Laurent , Cunningham Vincent J. , Dommett David , Knibb Stephen T. , Bender Dirk , Jakobsen Steen , Brown John , Gee Antony D.
Published: January 2005

Cyclic AMP (cAMP) is a continually produced nucleotide which is inactivated by hydrolysis to 5′AMP via phosphodiesterase 4 (PDE4) enzymes. Rolipram is a selective PDE4 inhibitor which exists in two enantiomeric forms, R(−) and S(+). Both of these enantiomers have previously been labelled with carbon‐11 and used as positron emission tomography (PET) ligands for measuring PDE4 expression and function, and indirectly to explore the function of the cAMP second messenger, in vivo, using PET. The aim of these studies was to relate the in vitro affinities of the two rolipram enantiomers using standard pharmacological assays with the in vivo behaviour of the two enantiomers using PET. In vitro competition assays were performed using rat cortical membranes and [3H]R(−)‐ and [3H]S(+)‐rolipram with increasing concentrations of either unlabelled R(−)‐ or S(+)‐rolipram. In vivo, a series of PET studies were performed in the porcine brain using [11C]R(−)‐rolipram with co‐administration of increasing doses of either unlabelled R(−)‐ or S(+)‐rolipram. Additional in vivo PET studies were performed using [11C]S(+)‐rolipram with saturating doses of rolipram. In all studies, R(−)‐rolipram exhibited a higher affinity for the PDE4 enzyme than S(+)‐rolipram. The calculated affinity ratios were 7.97 from the in vitro studies; 12.5 from the in vivo studies using [11C]R(−)‐rolipram; and 14.7 from the in vivo studies using [11C]S(+)‐rolipram. To conclude, the in vitro affinities of R(−)‐ and S(+)‐rolipram predict their apparent in vivo behaviour in the porcine brain, as measured by PET. Synapse 55:270–279, 2005. © 2005 Wiley‐Liss, Inc.
Gabapentin fails to alter P/Q‐type Ca2+ channel‐mediated synaptic transmission in the hippocampus in vitro
Authors: Brown Jon T. , Randall Andrew
Published: January 2005

Gabapentin (Neurontin) has been successfully used in the treatment of both epilepsy and neuropathic pain. Despite its widespread clinical use, its mechanism of action is very poorly understood. Indeed, the only protein it is known to interact with is the α2δ subunit of the voltage‐gated Ca2+ channel complex. In a recent article, gabapentin was reported to inhibit synaptic transmission in the spinal cord through an inhibitory effect on presynaptic P/Q‐type Ca2+ channels in both glutamatergic primary afferents and glycinergic interneuones. To examine if such inhibition of P/Q‐channel‐mediated synaptic transmission by gabapentin generalised to other synaptic pathways, we tested the actions of gabapentin of P/Q‐type Ca2+ channel‐mediated synaptic responses in the CA1 subfield of the hippocampus. We found that gabapentin was completely inactive on such synaptic responses even at 10 times the maximally effective concentration used in the spinal cord. A small (∼10%) but consistent depression of control synaptic responses was elicited by 10 μM gabapentin. No greater response was observed at a 10 times higher concentration. From these data we conclude that gabapentin is not a generic inhibitor of presynaptic P/Q‐type channels and its actions at the spinal level must represent a feature of the P/Q‐type channel not present in the hippocampus. Given the known interactions of this compound, the best candidate for this is the presence, subtype, or state of the α2δ subunit. Synapse 55:262–269, 2005. © 2005 Wiley‐Liss, Inc.
Demonstration of hyperaccumulation of [18F]2‐fluoro‐2‐deoxy‐D‐glucose under oxygen deprivation in living brain slices using bioradiography
Authors: Sasaki Toru , Yamaguchi Mie , Kojima Shuji
Published: January 2005

To clarify the mechanism of hyperaccumulation of glucose in acute brain ischemia by PET, changes of glucose metabolism and mitochondrial electron transfer function were examined in living brain slices in vitro during control, hypoxic, and anoxic conditions by positron autoradiography using [18F]2‐fluoro‐2‐deoxy‐D‐glucose ([18F]FDG) and [15O]oxygen. [15O]Oxygen fixation reflecting mitochondrial electron transfer function was reduced and [18F]FDG uptake reflecting glucose metabolism was increased in proportion to the strength of oxygen deprivation during anoxia and hypoxia. Mitochondrial electron transfer function decreased with no regional differences, whereas the glucose metabolism was the most enhanced in the hippocampus and thalamus. The enhanced glucose metabolism was associated with an increased glutamate efflux after hypoxia and anoxia. Glucose metabolism was also increased by the addition of glutamate and was attenuated by the N‐methyl‐D‐aspartate (NMDA) receptor antagonist MK‐801 in the hippocampus and thalamus. The hyperaccumulation of glucose in acute brain ischemia was demonstrated in living brain slices using bioradiography with reduced mitochondrial electron transfer. The activation of NMDA receptors by glutamate during acute brain ischemia might be responsible for hyperutilization of glucose in the hippocampus and thalamus. Synapse 55:252–261, 2005. © 2005 Wiley‐Liss, Inc.
Multiple ionization in quantitative XRF
Authors: Ebel Horst , Svagera Robert , Ebel Maria F.
Published: January 2005

The influence of the neglect of multiple ionizations in quantitative XRF without standards is demonstrated by computer simulation and evaluation of characteristic x‐ray signals of binary bulk specimens of Al and Cu. An error of up to 4 wt% can be expected. Copyright © 2001 John Wiley & Sons, Ltd.
Elemental mapping using proton‐induced x‐rays
Authors: Przybyłowicz W. J. , Mesjasz‐Przybyłowicz J. , Pineda C. A. , Churms C. L. , Ryan C. G. , Prozesky V. M. , Frei R. , Slabbert J. P. , Padayachee J. , Reimold W. U.
Published: January 2005

The use of particle‐induced x‐ray emission (PIXE) in conjunction with a scanning nuclear microprobe (SNM) offers one of the few microanalytical techniques capable of studies of elemental concentrations at the ppm level, with a spatial resolution of the order of 1 µm. Beam scanning capabilities and advanced data treatment make it a technique of choice for quantitative two‐dimensional studies of elemental distribution. Although the ultimate aim is to obtain true quantitative elemental maps, free of concentration or thickness artifacts, some compromises are necessary owing to experimental and computational restrictions. Some approaches currently used are discussed with emphasis on true elemental imaging using the dynamic analysis method. Examples of applications in geology and biology are shown to illustrate its benefits and limitations. Copyright © 2001 John Wiley & Sons, Ltd.
Application of large‐area avalanche photodiodes to energy‐dispersive x‐ray fluorescence analysis
Authors: Fernandes L. M. P. , Lopes J. A. M. , dos Santos J. M. F. , Conde C. A. N.
Published: January 2005

The performance of several large‐area avalanche photodiodes (LAAPDs) for application to x‐ray spectrometry at room temperature was investigated. Optimum detector performance was obtained for gains of about 50–70. Good energy linearity of the LAAPDs' response to x‐rays was observed up to energies of about 25 keV. For this energy range the space charge effects are negligible for gains below 100–150. The energy resolutions obtained with LAAPDs can be better than those obtained with proportional counters. Our results indicate that the energy resolution of an LAAPD is better than that of a proportional counter only when the LAAPD maximum dark current is <300 nA. For this case, minimum detectable x‐ray energies of about 1 keV are possible. Spatial non‐uniformity is responsible for an absolute increase of 1–2% in energy resolution at 6 keV when illumination of the LAAPD is broadened from 1 mm diameter to full area. Counting rates up to 5 × 104 counts s−1 are possible without significant degradation of detector performance. Copyright © 2001 John Wiley & Sons, Ltd.
Upgrade of the x‐ray fluorescence beamline at HASYLAB/DESY
Authors: Falkenberg G. , Clauss O. , Swiderski A. , Tschentscher Th.
Published: January 2005

A new x‐ray optical system for the fluorescence beamline L at HASYLAB is currently under construction and its commissioning phase will start early in 2001. Basis elements of the optical system are a double single‐crystal — double multilayer monochromator, x‐ray mirrors and capillary optics. The high‐resolution Si crystal monochromator is designed for microscopic x‐ray absorption near‐edge structures (µ‐XANES) experiments in fluorescence mode for laterally resolved speciation of trace elements. Broadband excitation by the multilayer monochromator will be used in total reflection x‐ray fluorescence (TXRF) experiments and microscopic x‐ray fluorescence analysis (µ‐XRF). An energy range of 2.4–80 keV will be explored by the monochromator system, giving access to the K‐edges of elements with 16 < Z < 79. A set of plane and cylindrical x‐ray mirrors allows a high‐energy cut‐off at 12 and 30 keV, respectively and optional prefocusing. The microfocus is generated by monocapillaries and polycapillaries. The performance of different monocapillary optics in the synchrotron beam was measured in polychromatic and monochromatic modes. Copyright © 2001 John Wiley & Sons, Ltd.