bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanistic modelling in large case‐control studies of lung cancer risk from smoking
Authors: Heidenreich W. F. , Wellmann J. , Jacob P. , Wichmann H. E.
Published: October 2002

The two‐step clonal expansion (TSCE) model is applied to large case‐control studies, frequency matched for age, which allow estimation of the RR of lung tumour risk caused by smoking. For estimating background hazard rates, mortality data from the study areas are used to supplement the case‐control data. Two approaches are used to analyse the data, based on the unconditional and the conditional likelihoods. They are demonstrated to give nearly identical results. Some model diagnostics are performed and demonstrate a good model fit. Our results indicate that smoking acts on the promotion and transformation parameters, but not on the initiation parameter of the TSCE model. The fitted relative risk of current smokers peaks between ages 50 and 60 years. The relative risk of male ex‐smokers decreases strongly with time since end of exposure, but does not reach the risk of non‐smokers, and does not decrease as much as for female ex‐smokers. Copyright © 2002 John Wiley & Sons, Ltd.
The ebb and flow of the NHS waiting list: how do recruitment and admission affect event‐based measures of the length of ‘time‐to‐admission’?
Authors: Armstrong Paul W.
Published: October 2002

The likelihood of admission is reported in England as the percentage of elective episodes occurring within a certain time, for example, within three months of the date of enrolment on the waiting list. This event‐based measure is calculated from cross‐sectional data: the denominator is the number of elective episodes occurring in a specified calendar period, and the numerator is the number found to have enrolled on the waiting list less than three months previously. Now the number of elective episodes occurring within three months reflects the likelihood of admission and the numbers eligible to be admitted. If there is any increase in the likelihood of admission or in the number of people exposed to that likelihood then there will be an increase in the number of elective episodes found to have enrolled on the waiting list less than three months previously. Thus the numerator used by the Government Statistical Service accurately reflects conditions during the calendar period and within the enrolment cohorts of interest. The Government Statistical Service also needs a denominator so the episodes observed 0–2, 3–5, 6–8, 9–11 etc. months after enrolment are added as an indication of the number of people that could have been admitted within three months. This denominator implies that the number of people eligible for admission from the 3–5 month waiting time category is the same as the number surviving admission from the 0–2 month waiting time category but, during the period of interest, these two groups of people belong to cohorts that were recruited to the waiting list quite independently. As a result, this denominator will be too big if the number surviving to the end of one waiting time category is bigger than the number eligible for admission from the next and it will be too small if the number surviving to the end of one waiting time category is smaller than the number eligible for admission from the next. The event‐based measure assumes that the waiting list is stationary and closed and only gives unbiased estimates under these conditions. This paper describes three alternative measures which recognize that the number of people recruited or admitted may vary from one quarter to the next. It uses Department of Health data to assess the size of the error if the event‐based measure is used in these circumstances. Copyright © 2002 John Wiley & Sons, Ltd.
On changing a long‐term clinical trial midstream
Authors: Wittes Janet
Published: October 2002

Clinical triallists are often reluctant to alter the protocol or the design of an ongoing study in part because of concern that changes may affect the integrity of the study. This paper encourages considering changes in long‐term clinical trials when the medical environment changes or when the accruing data from the trial lead to questioning the assumptions underlying the original design. One must make such changes in a way that will not cast doubt on the integrity of the trial. An important aspect of the design is choice of sample size. Methodology for sample size recalculation has matured over the decade. Several techniques are now available for the usual types of endpoints – continuous, discrete and time‐to‐failure – as well as for longitudinal analysis. Published papers describe the choices of variance at the time of recalculation, approaches to estimation and testing at the end of the study, and the time of recalculation. In a study with a sponsor, a Data Safety Monitoring Board (DSMB) and an Executive Committee, one or more of these three groups is responsible for recommending increases in sample size when the accruing data indicate that the assumed variance underestimated the true variance. Sometimes a statistician independent of all three bodies performs the relevant calculations and sends the recommendation to the sponsor. This paper argues that the DSMB should not generally be the responsible body because knowledge of treatment effect can place it in an uncomfortable position. Copyright © 2002 John Wiley & Sons, Ltd.
Regulatory perspectives on data monitoring
Authors: O'Neill Robert T.
Published: October 2002

Data monitoring is a critical component of the conduct of clinical trials that provide the evidence of efficacy and safety of investigational drugs. These trials may be conducted either by a pharmaceutical sponsor or by the government, especially those large trials that assess the impact of therapies on serious morbidity and/or mortality. While not extensive, I will review a regulatory history of FDA's evolving concerns and positions on data monitoring. I will review the key aspects of data monitoring and interim analysis of clinical trials contained in the recently published International Conference on Harmonization's statistical guidance as well as some other issues being considered for a draft guidance on data monitoring. Finally, some suggestions for improving and enhancing tools and statistical methods for monitoring clinical trials for safety assessment will be offered. This latter area deserves more consideration by statisticians than it has received to date. Published in 2002 by John Wiley & Sons, Ltd.
The role of covariates in estimating treatment effects and risk in long‐term clinical trials
Authors: Ford Ian , Norrie John
Published: October 2002

This paper reviews previously published work showing that the impact of including covariates in models used to estimate the magnitude of treatment effects in long‐term clinical trials is different from what would be predicted from results for the normal linear model. Typically, models with and without covariates cannot simultaneously be valid. A case is made for the use of data from clinical trials to model the future risk and potential benefits of treatment in individual subjects. The methods and results are illustrated using data from the West of Scotland Coronary Prevention Study. Copyright © 2002 John Wiley & Sons, Ltd.
Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practiceand problems
Authors: Pocock Stuart J. , Assmann Susan E. , Enos Laura E. , Kasten Linda E.
Published: October 2002

Clinical trial investigators often record a great deal of baseline data on each patient at randomization. When reporting the trial's findings such baseline data can be used for (i) subgroup analyses which explore whether there is evidence that the treatment difference depends on certain patient characteristics, (ii) covariate‐adjusted analyses which aim to refine the analysis of the overall treatment difference by taking account of the fact that some baseline characteristics are related to outcome and may be unbalanced between treatment groups, and (iii) baseline comparisons which compare the baseline characteristics of patients in each treatment group for any possible (unlucky) differences. This paper examines how these issues are currently tackled in the medical journals, based on a recent survey of 50 trial reports in four major journals. The statistical ramifications are explored, major problems are highlighted and recommendations for future practice are proposed. Key issues include: the overuse and overinterpretation of subgroup analyses; the underuse of appropriate statistical tests for interaction; inconsistencies in the use of covariate‐adjustment; the lack of clear guidelines on covariate selection; the overuse of baseline comparisons in some studies; the misuses of significance tests for baseline comparability, and the need for trials to have a predefined statistical analysis plan for all these uses of baseline data. Copyright © 2002 John Wiley & Sons, Ltd.
A rational‐expectations revision of Makadok's resource/capability synthesis
Authors: Makadok Richard
Published: October 2002

Makadok has recently developed a mathematical model aimed at synthesizing the resource‐based and dynamic‐capabilities views of the rent creation process. One unstated implicit assumption in that model is that each bidding firm in the resource market is ignorant not only of the content of rival firms' private information, but also of the quality (i.e., the noisiness or reliability) of that information. Consequently, that model does not qualify as a rational‐expectations Bayesian Nash equilibrium—a fact that both generates questionable results (e.g., the possibility of negative expected profits) and impedes any effort to extend the model. The rational‐expectations critique in economics points out that this sort of nonrational assumption becomes increasingly implausible as economic actors learn more about each other's patterns over time through repeated interactions (in this case, as bidders repeatedly compete against each other to buy different resources over time). So, over the long run, the only truly stable, viable, and robust assumption would be rational‐expectations behavior. The primary purpose of this paper is to put Makadok's model on the firmer methodological footing of rational‐expectations Bayesian Nash equilibrium, so that it will no longer generate questionable results, and so that future researchers can more easily extend it. The secondary purpose of this paper is to demonstrate that this shift to rational‐expectations assumptions has little substantive impact on the testable hypotheses generated by Makadok's original model. Copyright © 2002 John Wiley & Sons, Ltd.
The strategic impact of external networks: subsidiary performance and competence development in the multinational corporation
Authors: Andersson Ulf , Forsgren Mats , Holm Ulf
Published: October 2002

This paper explores the importance of relational embeddedness in external networks as a strategic resource for performance and competence development in multinational corporations (MNCs). Two different types of relational embeddedness at the subsidiary level—business embeddedness and technical embeddedness—are proposed to have an influence on the subsidiary's market performance as well as its importance for competence development in the MNC. Using data on 97 Swedish MNC subsidiaries, five hypotheses are tested in a LISREL model analysis. The results suggest that technical embeddedness has a positive impact on both the subsidiary expected performance and its role in the development of products and production processes in the MNC. Indirectly, through external technical embeddedness, external business embeddedness also influences the sister units' product and process development and subsidiary market performance. Copyright © 2002 John Wiley & Sons, Ltd.
Management control systems and their effects on strategy formation at middle‐management levels: evidence from a U.K. organization
Authors: Marginson David E. W.
Published: October 2002

The relationship between management control systems (MCS) and the strategy process is a largely unexplored area of strategic management. This paper reports the findings of an in‐depth, longitudinal case study of a major British‐based organization operating within the increasingly globalized telecommunications industry. Informed by Simons' (1991, 1994, 1995) theoretical model of the strategy process–MCS relationship, the study examines the nature and extent of this relationship at middle‐ and lower‐management levels. Of particular interest were the effects that the design and use of three groups of MCS have on the development of new ideas and initiatives. Findings suggest that beliefs systems influence managers' initiation or ‘triggering’ decisions, the use of administrative controls affects the location of strategic initiatives and may lead to the polarization of roles, and simultaneous emphasis on a range of key performance indicators can create a bias towards one set of measures and against another. Copyright © 2002 John Wiley & Sons, Ltd.
Formation of R&D consortia: industry and company effects
Authors: Sakakibara Mariko
Published: October 2002

This study investigates economic and strategic inducements of R&D cooperation. We focus on industry and company factors that affect a firm's rate of participation in R&D consortia. These factors are analyzed in a dynamic context using a sample of 312 Japanese firms in 74 industries between 1969 and 1992. We find a firm in an industry with weak competition and appropriability conditions has a higher rate of consortia participation. A firm's R&D capabilities, network formation through past consortia, encounter with other firms in product markets, age, and past participation in large‐scale consortia also positively affect its tendency of consortia formation. Copyright © 2002 John Wiley & Sons, Ltd.
Centers of excellence in multinational corporations
Authors: Frost Tony S. , Birkinshaw Julian M. , Ensign Prescott C.
Published: October 2002

This paper seeks to understand the conditions under which ‘centers of excellence’ emerge in foreign subsidiaries of multinational firms. We define a center of excellence as an organizational unit that embodies a set of capabilities that has been explicitly recognized by the firm as an important source of value creation, with the intention that these capabilities be leveraged by and/or disseminated to other parts of the firm. Drawing on overlapping research in international business and strategic management, we argue that the formation of centers of excellence is shaped by conditions in the subsidiary's local environment as well as by various aspects of the subsidiary's relationship with other parts of the multinational firm. Based on a survey of 99 foreign units in Canada, our results highlight the fundamental role played by parent firm investment as well as the role of internal and external organizations in the development of subsidiary capabilities. Performance implications of the center of excellence phenomenon are also explored. Copyright © 2002 John Wiley & Sons, Ltd.
Confronting undesirable traditions: A case study
Authors: Clement Linda M.
Published: October 2002

The necessity of extensive planning for major campus events has become essential to ensure a safe environment for all participants. This chapter explores the way one campus is challenging negative major event behaviors from pre‐event preparations to post‐event celebrations.
Adenosine A2A antagonism reverses levodopa‐induced motor alterations in hemiparkinsonian rats
Authors: Bové J. , Marin C. , Bonastre M. , Tolosa E.
Published: October 2002

To evaluate the possible involvement of adenosine A2A receptor‐mediated mechanisms in levodopa‐induced motor fluctuations, we investigated the effects of CSC (8‐(3‐chlorostryryl) caffeine), a selective adenosine A2A receptor antagonist, on levodopa‐induced motor alterations in rats with unilateral 6‐OHDA lesion. Acute and chronic administration of CSC was studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 CSC (5 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and CSC (5 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of CSC on day 23 reversed levodopa‐induced shortening in motor response duration (P < 0.01). Chronic CSC administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the adenosine A2A receptor antagonist CSC reverses but does not prevent levodopa‐induced motor alterations in parkinsonian rats. These results suggest a role for adenosine A2A receptor‐mediated mechanisms in the pathophysiology of levodopa‐induced motor response complications. These findings suggest that the antagonism of adenosine A2A receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome. Synapse 46:251–257, 2002. © 2002 Wiley‐Liss, Inc.
Repeated cocaine administration differentially affects NMDA receptor subunit (NR1, NR2A‐C) mRNAs in rat brain
Authors: Yamaguchi Mika , Suzuki Toshihito , Abe Shuzo , Hori Takafumi , Kurita Hirofumi , Asada Takashi , Okado Nobuo , Arai Heii
Published: October 2002

We investigated the effects of intermittent intraperitoneal (i.p.) injections of cocaine (20 mg/kg) on subunit mRNAs of N‐methyl‐D‐aspartate (NMDA) receptors (NR1/NR2A‐2C) in the rat brain by in situ hybridization using phosphor screen analysis. The level of NR1 subunit mRNA significantly increased in hippocampal complexes 1 h after a single i.p. injection of cocaine. After repeated cocaine injection, the mean scores of stereotyped behavior were increased with the number of injections. The level of NR1 subunit mRNA was obviously decreased in the striatum and cortices 24 h (early withdrawal) after a final injection following 14 days of subchronic administration. During the early withdrawal period, the amount of the NR1 subunit decreased in the nucleus accumbens, globus pallidus, and subiculum. In the dentate gyrus, the NR1 mRNA level significantly increased during early withdrawal in rats subchronically treated with cocaine. Levels of NR2B subunit mRNA were reduced in the cortices and striatum. During late withdrawal from cocaine, the level of NR2C subunit mRNA in the cerebellum was also reduced. These findings suggest that the disruption of NR1, NR2B, and NR2C subunits in the discrete brain regions occurs under the cocaine‐related behavioral abnormalities and would be closely implicated in the initiation and expression of behavioral sensitization induced by repeated cocaine administration. Further studies on the changes in non‐NMDA receptors are required to elucidate the biological significance of glutamate receptors for the mechanisms underlying the development of behavioral sensitization. Synapse 46:157–169, 2002. © 2002 Wiley‐Liss, Inc.
Amphetamine‐sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges
Authors: Seeman Philip , Tallerico Teresa , Ko Françoise , Tenn Catherine , Kapur Shitij
Published: October 2002

While a range of dopamine D2‐related behaviors are exaggerated in amphetamine‐sensitized animals, studies of the dopamine D2 receptor have reported either no change or a decrease in dopamine D2 receptor density—especially when measured using radioraclopride. We hypothesized that a decrease in D2 receptors may actually be “apparent” and that these receptors may still be present, but are noncompetitively “occupied” by endogenous dopamine. Animals sensitized to amphetamine (and their saline controls) were examined 4 weeks after their last injection. We first measured the [3H]raclopride binding in vivo, and observed that sensitized animals showed a 29% lower level of raclopride binding in vivo, suggesting an apparently lower level of dopamine D2 receptors. To assess the reason for this we examined the density of receptors (using Scatchard analysis in vitro) measured by [3H]raclopride in the presence and absence of guanilylimidodiphosphate. This guanine nucleotide converts the dopamine‐bound high‐affinity state of D2 receptors into low‐affinity states, thereby making measurable the absolute density of the sites. As previously reported, the amphetamine‐sensitized animals showed a 31% lower number of D2 receptors in conventional binding (Bmax 15.6 vs. 22.7 pmol/g). However, with the addition of guanilylimidodiphosphate there was an equalization of both groups (Bmax 25.9 vs. 25.6 pmol/g), revealing an additional 10.3 pmol/g in the sensitized animals, but only 2.9 pmol/g in saline controls. There were no changes in the dissociation constant of [3H]raclopride for the receptors. The nearly four‐fold increase of dopamine D2 receptors in the high‐affinity state occupied by dopamine may explain why amphetamine‐sensitized animals show almost an order of magnitude greater response to dopamine‐releasing challenges or dopamine agonists, even though the absolute receptor number is unchanged and the “apparent” receptor number is decreased. Synapse 46:235–239, 2002. © 2002 Wiley‐Liss, Inc.
A three‐dimensional model for system design evolution
Authors: Tomer Amir , Schach Stephen R.
Published: October 2002

We represent the life cycle of the design of a system in a three‐dimensional space with engineering, reengineering, and reuse axes. The three‐dimensional model is evolution‐oriented. It incorporates not only the evolution that occurs after the product has been produced and delivered, but also three types of system design evolution that take place before the product is produced. Associated with each axis are a mathematical operator and its inverse. These operators, together with their inverses, can describe the various systems engineering activities. The model can be used to describe the life cycle of a product line, the evolution of an individual product within that product line, and even the evolution of an individual artifact. The model can be used in conjunction with any life‐cycle model and any set of artifacts. © 2002 Wiley Periodicals, Inc. Syst Eng 5, 264–273, 2002
Professional development for university scientists around issues of equity and diversity: Investigating dissent within community
Authors: Bianchini Julie A. , Hilton‐Brown Bryan A. , Breton Therese D.
Published: October 2002

We investigated the role of dissent in a community of university scientists, engineers, mathematicians, and social scientists engaged in a 2‐year professional development project around issues of equity and diversity. Members of this teacher learning community explored issues related to gender and ethnicity in science education, and attempted to develop course materials and instructional strategies inclusive of students from underrepresented groups. We focused our attention on those professional development sessions (6 of the 19) devoted to a contentious yet integral topic in science education: the gendered and multicultural nature of science. We examined conversations initiated by a member's concerns to learn how dissent led (or failed to lead) to new insights into feminist science studies scholarship or to greater understanding of ways to address equity issues in undergraduate science education. We also explored how teacher learners' resulting views of feminist science studies scholarship informed (or failed to inform) changes in their own educational practices. From our qualitative analyses, we highlight the challenges in balancing respect for members' individual voices with collective progress toward project goals, and in structuring conversations initiated by dissent to provide adequate space for deliberation and movement toward deeper understanding of equity and excellence. © 2002 Wiley Periodicals, Inc. J Res Sci Teach 39: 738–771, 2002
Integration of DNA sample collection into a multi‐site birth defects case‐control study
Authors: Rasmussen Sonja A. , Lammer Edward J. , Shaw Gary M. , Finnell Richard H. , McGehee Robert E. , Gallagher Margaret , Romitti Paul A. , Murray Jeffrey C.
Published: October 2002

Background

Advances in quantitative analysis and molecular genotyping have provided unprecedented opportunities to add biological sampling and genetic information to epidemiologic studies. The purpose of this article is to describe the incorporation of DNA sample collection into the National Birth Defects Prevention Study (NBDPS), an ongoing case‐control study in an eight‐state consortium with a primary goal to identify risk factors for birth defects.

Methods

Babies with birth defects are identified through birth defects surveillance systems in the eight participating centers. Cases are infants with one or more of over 30 major birth defects. Controls are infants without defects from the same geographic area. Epidemiologic information is collected through an hour‐long interview with mothers of both cases and controls. We added the collection of buccal cytobrush DNA samples for case‐infants, control‐infants, and their parents to this study.

Results

We describe here the methods by which the samples have been collected and processed, establishment of a centralized resource for DNA banking, and quality control, database management, access, informed consent, and confidentiality issues.

Conclusions

Biological sampling and genetic analyses are important components to epidemiologic studies of birth defects aimed at identifying risk factors. The DNA specimens collected in this study can be used for detection of mutations, study of polymorphic variants that confer differential susceptibility to teratogens, and examination of interactions among genetic risk factors. Information on the methods used and issues faced by the NBDPS may be of value to others considering the addition of DNA sampling to epidemiologic studies. Teratology 3:177–184, 2002. Published 2002 Wiley‐Liss, Inc.
Assessing students' written projects
Authors: Gray Robert
Published: October 2002

This chapter discusses procedures that on‐line instructors use when “marking the screen” or using separate attachments for commentary. It explores the use of e‐mail as the analogue of face‐to‐face conferencing for providing feedback.
Group assessment in the on‐line learning environment
Authors: Nicolay John A.
Published: October 2002

Assessing the student group poses rewards and challenges for on‐line instructors. This chapter offers five principles for assessment, derived from field research among on‐line instructors, with some cautionary discussion on how to handle plagiarism.
Enhancing on‐line learning for individuals with disabilities
Authors: Brown James M.
Published: October 2002

Attention to key concepts, resources, and strategies such as testing and assessment can greatly enhance the ability of on‐line curricular offerings to accommodate learners with a wide range of disabilities.
Fractal analysis of Daphnia motion for acute toxicity bioassay
Authors: Shimizu Nobuaki , Ogino Chiaki , Kawanishi Takuya , Hayashi Yoshishige
Published: October 2002

To quantify individual behavioral responses to toxic chemicals, the swimming motion of individual Daphnia magna was continuously monitored using a motion analysis system. The fractal dimension was introduced to compare the straightness or complexity of the swimming trajectory before and after exposure to toxic chemicals. Analysis indicated that the swimming trajectory of individual Daphnia has a fractal structure. The basal fractal dimension in the control medium was 1.35±0.01 (n = 50 Daphnia). Exposure to CuSO4 (10 μg/L), organophosphorus (Dichlorvos; 10 μg/L), and carbamate (Propoxur; 500 μg/L) pesticide caused a significant increase in the fractal dimension with a latency of 60 min, reaching a maximal level of 2.26±0.34, 2.43±0.19, and 2.51±0.21, respectively, after a 120‐min exposure. The magnitude of the change in the fractal dimension was related to the toxic chemical concentration and the exposure time. Threshold concentrations determined at 60 min of exposure were 10 μg/L for CuSO4, 5 μg/L for Dichlorvos, and 500 μg/L for Propoxur. The toxicity index (EC50) values after 120 min of exposure were 6.31 μg/L, 7.64 μg/L, and 466 μg/L for CuSO4, Dichlorvos, and Propoxur, respectively. Thus, the fractal dimension seems useful for analyzing and comparing complex trails, such as swimming trajectories, which could be used as the endpoint for an acute bioassay. © 2002 Wiley Periodicals, Inc. Environ Toxicol 17: 441–448, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/tox.10077
Sublethal responses of wolf spiders (Lycosidae) to organophosphorous insecticides
Authors: Van Erp S. , Booth L. , Gooneratne R. , O'Halloran K.
Published: October 2002

The activities of cholinesterase (ChE) and glutathione S‐transferase (GST) enzymes were assessed in the wolf spider (Lycosa hilaris) as biomarkers of organophosphate contamination in agricultural ecosystems. Spiders were exposed to simulated field rates of two commercially available organophosphorous insecticides [Basudin (diazinon) and Lorsban (chlorpyrifos)] under laboratory conditions. In terms of survival, chlorpyrifos and diazinon were more toxic to male than to female wolf spiders, but gender‐specific differences in ChE activities were not evident. Cholinesterase activity in male spiders was inhibited to 14% and 61% of control activity by Basudin and Lorsban, respectively. Gluthathione S‐transferase activity was not affected by either pesticide. Mortality and biomarker responses in the wolf spider were further investigated following the application of Basudin to pasture. Wolf spiders were deployed into field mesocosms; after 24 h mortality was 40%, and surviving spiders displayed significant inhibition of ChE activity (87%) compared with controls. Cholinesterase activity in spiders exposed for subsequent 24‐ or 48‐h time periods was monitored until it returned to control levels 8 days post‐application. Inhibition of ChE activity after a single application of Basudin indicate the potential use of this enzyme in wolf spiders as a biomarker for evaluating organophosphate contamination. © 2002 Wiley Periodicals, Inc. Environ Toxicol 17: 449–456, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/tox.10078
Sites of toxicity of specific photooxidation products of anthracene to higher plants: Inhibition of photosynthetic activity and electron transport in Lemna gibba L. G‐3 (Duckweed)
Authors: Mallakin Ali , Babu T. Sudhakar , Dixon D. George , Greenberg Bruce M.
Published: October 2002

Sites of toxicity of polycyclic aromatic hydrocarbons (PAHs) were examined to determine if inhibition of photosynthetic activity could be correlated to whole‐organism toxicity. The inhibition of photosynthesis was observed by detecting the induction kinetics of endogenous chlorophyll a (Chl a) fluorescence. Anthracene (ANT) photooxidation products were applied to the aquatic higher plant Lemna gibba L. G‐3 at concentrations ranging from 0.01 to 10 ppm. The impact on Chl a fluorescence was found to correlate with whole‐organism toxicity for the 13 PAH compounds tested in this in vivo study. The mechanism of toxic action starts with inhibition of photosystem I (PSI) or the cytochrome‐b6/f complex, followed by photooxidative damage to photosystem II (PSII). To study the effects of oxygenated ANTs on photosynthesis in vivo, the IC50s for FV/FM (PSII activity) and FQ/FM (activity downstream from PSII) were determined. The IC50s for a decrease of FQ/FM for all 13 chemicals were on average twofold lower than those for FV/FM. FV/FM was found to be a measure of acute toxicity, whereas FQ/FM was found to be a measure of chronic toxicity. Thus, Chl a fluorescence by use of the whole organism was able to detect the impacts of photomodified ANT products and indicate a site of action for the chemicals. © 2002 Wiley Periodicals, Inc. Environ Toxicol 17: 462–471, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/tox.10080
Improving realism of a surgery simulator: linear anisotropic elasticity, complex interactions and force extrapolation
Authors: Picinbono Guillaume , Lombardo Jean‐Christophe , Delingette Hervé , Ayache Nicholas
Published: October 2002

In this article, we describe the latest developments of the minimally invasive hepatic surgery simulator prototype developed at INRIA. The goal of this simulator is to provide a realistic training test bed to perform laparoscopic procedures. Therefore, its main functionality is to simulate the action of virtual laparoscopic surgical instruments for deforming and cutting tridimensional anatomical models. Throughout this paper, we present the general features of this simulator including the implementation of several biomechanical models and the integration of two force‐feedback devices in the simulation platform. More precisely, we describe three new important developments that improve the overall realism of our simulator. First, we have developed biomechanical models, based on linear elasticity and finite element theory, that include the notion of anisotropic deformation. Indeed, we have generalized the linear elastic behaviour of anatomical models to ‘transversally isotropic’ materials, i.e. materials having a different behaviour in a given direction. We have also added to the volumetric model an external elastic membrane representing the ‘liver capsule’, a rather stiff skin surrounding the liver, which creates a kind of ‘surface anisotropy’. Second, we have developed new contact models between surgical instruments and soft tissue models. For instance, after detecting a contact with an instrument, we define specific boundary constraints on deformable models to represent various forms of interactions with a surgical tool, such as sliding, gripping, cutting or burning. In addition, we compute the reaction forces that should be felt by the user manipulating the force‐feedback devices. The last improvement is related to the problem of haptic rendering. Currently, we are able to achieve a simulation frequency of 25 Hz (visual real time) with anatomical models of complex geometry and behaviour. But to achieve a good haptic feedback requires a frequency update of applied forces typically above 300 Hz (haptic real time). Thus, we propose a force extrapolation algorithm in order to reach haptic real time. Copyright © 2002 John Wiley & Sons, Ltd.
A survey on quality‐of‐service support for mobile ad hoc networks
Authors: Perkins Dmitri D. , Hughes Herman D.
Published: October 2002

The general field of mobile ad hoc networking is still in its infancy. Particularly, the challenge of providing Quality‐of‐Service (QoS) support for ad hoc networks is an open problem and remains relatively uncharted territory. Providing a complete QoS solution for the ad hoc networking environment requires the interaction and cooperation of several components. These components include: (1) a QoS routing protocol, (2) a resource reservation scheme and (3) a QoS capable medium access control (MAC) layer. In this paper, we present a survey of the current research that has addressed each of these components in the context of ad hoc networks. This work is intended to provide a broad and comprehensive view of the various components and protocols required to provide QoS support in computer networks, focusing primarily on ad hoc networks. First, we introduce the unique characteristics of mobile ad hoc networks, which distinguishing this new network architecture from traditional infrastructured wired and wireless networks (i.e. cellular‐based networks). We also discuss the impact of these characteristics on QoS provisioning. Next, we describe the first QoS model proposed for mobile ad hoc networks and its relationship to QoS models proposed for the Internet. We then present a review of the proposed algorithms for each QoS component (e.g. QoS routing, resource reservation and the MAC layer). Copyright © 2002 John Wiley & Sons, Ltd.
Long‐chain fatty acid uptake and oxidation in the perfused liver of Walker‐256 tumour‐bearing rats
Authors: Vicentino Christiame , Constantin Jorgete , Bracht Adelar , Yamamoto Nair Seiko
Published: October 2002

Abstract: Aims/Background: The effect of the Walker‐256 tumour on uptake and oxidation of long‐chain fatty acids was investigated in perfused livers of rats.

Methods: Isolated livers were perfused in a non‐recirculating system. Fatty acid uptake, ketogenesis, oxygen uptake and 14CO2‐production were measured as well as the activities of the acyl carnitine transferases I and II (CAT I and CAT II).

Results: Basal oxygen uptake of livers from tumour‐bearing rats was lower. Ketone bodies production derived from the long‐chain fatty acids in livers from starved tumour‐bearing rats was lower relative to the controls, but 14CO2 production was similar in both groups. The oxygen uptake increment and the mitochondrial NADH/NAD+ redox ratio were also decreased in tumour‐bearing rats. The extent of these differences was dependent on the chain length and structure of the fatty acid, the following decreasing sequence of differences between control and tumour‐bearing animals being valid: palmitate > oleate > stearate. The CAT I activity of the enzyme isolated from livers of tumour‐bearing rats was half that from normal rats when palmitoyl‐CoA and oleoyl‐CoA were the substrates.

Conclusions: Ketogenesis from exogenous fatty acids is decreased in the livers of Walker‐256 tumour‐bearing rats in consequence of the diminished activity of the mitochondrial CAT I. The lower rates of oxygen uptake indicate a decreased ATP synthesis, which is consistent with the in vivo lower phosphorylation potential.
The effect of glucose on the potency of two distinct glycogen phosphorylase inhibitors
Authors: ANDERSEN Birgitte , WESTERGAARD Niels
Published: October 2002

Two distinct glycogen phosphorylase inhibitors, 5-chloro-1H-indole-2-carboxylic acid [1-(4-fluorobenzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxoethyl]amide (CP-320,626) and 1,4-dideoxy-1,4-d-arabinitol (DAB), were characterized in vitro with respect to the influence of glucose on their potencies. CP-320,626 has previously been shown to bind to a newly characterized indole site, whereas DAB seems to act as a glucose analogue, but with slightly different properties from those of glucose. When analysed in pig liver glycogen phosphorylase a (GPa) activity assays, the two inhibitors showed very different properties. When GPa activity was measured in the physiological direction (glycogenolysis), DAB was the most potent inhibitor with an IC50 value of 740±9nM compared with the IC50 value for CP-320-626 of 2.39±0.37μM. There was no effect of glucose on the inhibitory properties of DAB, whereas a glucose analogue N-acetyl-β-d-glucopyranosylamine (1-GlcNAc) antagonized the effect of DAB. Likewise, there was no synergistic effect of CP-320,626 and glucose, whereas CP-320,626 and 1-GlcNAc inhibited GPa in synergy. Moreover, the synergistic effect of glucose and CP-320,626 was GPa-isoform-specific, since CP-320,626 and glucose inhibited rabbit muscle GPa in synergy when the GPa activity was measured towards glycogenolysis. When GPa activity was measured towards glycogen synthesis, CP-320,626 showed a synergistic effect with glucose, whereas the effect of DAB was slightly antagonized by glucose in this assay direction. Caffeine was included in the investigation as a control GP inhibitor, and both glucose and 1-GlcNAc potentiated the effect of caffeine independent of the assay direction. In primary cultured rat hepatocytes 1-GlcNAc and CP-320,626 inhibited basal and glucagon-induced glycogenolysis in synergy, whereas the ability of DAB to inhibit basal or glucagon-induced glycogenolysis was unaltered by 1-GlcNAc. Glucose had no effect on either CP-320,626 or DAB inhibition of glycogenolysis in cultured rat hepatocytes. In conclusion, the present study shows that the two GP inhibitors are kinetically very distinct and neither of the inhibitors demonstrates a physiologically relevant glucose dependence in vitro.
Characterization of Ca2+/calmodulin-dependent protein kinase I as a myosin II regulatory light chain kinase in vitro and in vivo
Authors: SUIZU Futoshi , FUKUTA Yasuaki , UEDA Kozue , IWASAKI Takahiro , TOKUMITSU Hiroshi , HOSOYA Hiroshi
Published: October 2002

Ca2+/calmodulin (CaM)-dependent protein kinase I (CaM-KI), which is a member of the multifunctional CaM-K family, is thought to be involved in various Ca2+-signalling pathways. In this report, we demonstrate that CaM-KI activated by an upstream kinase (CaM-K kinase), but not unactivated CaM-KI, phosphorylates myosin II regulatory light chain (MRLC) efficiently (Kcat, 1.7s-1) and stoichiometrically (0.8mol of phosphate/mol) in a Ca2+/CaM-dependent manner in vitro. One-dimensional phosphopeptide mapping and mutational analysis of MRLC revealed that the activated CaM-KI monophosphorylates only Ser-19 in MRLC. Transient expression of the Ca2+/CaM-independent form of CaM-KI (CaM-KI1-293) in HeLa cells induced Ser-19 phosphorylation of myosin, II accompanied by reorganization of actin filaments in the peripheral region of the cells. CaM-KI-induced reorganization of actin filaments was suppressed by co-expression of non-phosphorylatable MRLC mutants (S19A and T18AS19A). Furthermore, a kinase-negative form of CaM-KI (CaM-KI1-293,K49E) significantly reduced reorganization of actin filaments, indicating a dominant negative effect. This is the first demonstration that the activation of the CaM-KI cascade induces myosin II phosphorylation, resulting in regulation of actin filament organization in mammalian cells.
Expression of creatine kinase isoenzyme genes during postnatal development of rat brain cerebellum: evidence for transcriptional regulation
Authors: SHEN Wei , WILLIS Dianna , ZHANG Yanping , SCHLATTNER Uwe , WALLIMANN Theo , MOLLOY George R.
Published: October 2002

Transcription and accumulation of brain-type creatine kinase (CKB) mRNA and its protein was examined during postnatal development of rat brain cerebellum, the brain region containing highest CKB mRNA in the adult. CKB protein was extremely low at day 1, increased about 10-fold until week 4 and remained constant until week 10. This time course was paralleled by cerebellar CKB mRNA, which was also extremely low at day 1 and increased 5-fold during the first 3 weeks and then remained constant. High levels of CKB protein were also detected in cultured primary cerebellar granular neurons. Nuclear run-on assays directly showed that CKB mRNA accumulation during postnatal cerebellar development was due to increased transcription. When compared with cerebrum and whole brain, cerebellar CKB mRNA accumulation during postnatal development was temporally delayed. Analysis of myocyte enhancer factor (MEF)-2 and Sp1, factors known to initiate or sustain CKB transcription in tissues other than brain, revealed that MEF-2 in cerebellum was low at week 1 but increased 3.5-fold by week 7, while Sp1 remained unchanged. The increase in CKB protein during cerebellar postnatal development was coincident with that of the ubiquitous mitochondrial CK protein and mRNA, indicating that a functional phosphocreatine energy shuttle probably exists for efficient ATP regeneration in the cerebellum. This should be beneficial for the many energy-demanding requirements during cerebellar development, as indicated by the observed temporal co-expression of CKB with myelin basic protein, which is involved in axon myelination by oligodendrocytes.
Role of endocytosis in the internalization of spermidine-C2-BODIPY, a highly fluorescent probe of polyamine transport
Authors: SOULET Denis , COVASSIN Laurence , KAOUASS Mohammadi , CHAREST-GAUDREAULT René , AUDETTE Marie , POULIN Richard
Published: October 2002

The mechanism of transmembrane polyamine internalization in mammalian cells remains unknown. A novel fluorescent spermidine conjugate [Spd-C2-BODIPY; N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl)-N′-{S-[spermidine-(N4-ethyl)]thioacetyl}ethylenediamine] was synthesized from N4-(mercaptoethyl)spermidine by a simple, one-step coupling procedure. In Chinese-hamster ovary (CHO) cells, Spd-C2-BODIPY accumulation was inhibited by exogenous putrescine, spermidine and spermine, was subject to feedback transport inhibition and was up-regulated by prior polyamine depletion achieved with a biosynthetic inhibitor. Probe internalization was decreased by about 85% in a polyamine-transport-deficient CHO mutant cell line. Using confocal laser scanning fluorescence microscopy, internalized Spd-C2-BODIPY was concentrated in vesicle-like structures similar to the recycling endosomes observed with fluorescent transferrin, which partly co-localized with the polyamine probe. In yeast, Spd-C2-BODIPY uptake was stringently dependent on receptor-mediated endocytosis, as determined with a mutant defective in early- endosome formation. On the other hand, Spd-C2-BODIPY did not mimic the substrate behaviour of natural polyamines in yeast, as shown by the lack of correlation of its uptake characteristics with the phenotypes of mutants defective in either polyamine transport or biosynthesis. These data suggest that endocytosis might be an integral part of the mechanism of polyamine transport in mammalian cells, and that the mammalian and yeast transport systems use qualitatively different transport mechanisms. However, the current data do not rule out the possibility that sequestration of the probe into vesicular structures might be secondary to its prior uptake via a ‘classical’ plasma membrane carrier. Spd-C2-BODIPY, a highly sensitive probe of polyamine transport with biochemical parameters qualitatively similar to those of natural polyamines in mammalian cells, should be very useful for dissecting the pathway responsible for polyamine internalization.
Functional identity of Drosophila melanogaster Indy as a cation-independent, electroneutral transporter for tricarboxylic acid-cycle intermediates
Authors: INOUE Katsuhisa , FEI You-Jun , HUANG Wei , ZHUANG Lina , CHEN Zhong , GANAPATHY Vadivel
Published: October 2002

Indy is a gene in Drosophila melanogaster which, when made dysfunctional, leads to an extension of the average adult life span of the organism. The present study was undertaken to clone the Indy gene-product and to establish its functional identity. We isolated a full-length Indy cDNA from a D. melanogaster cDNA library. The cDNA codes for a protein of 572 amino acids [(Drosophila Indy (drIndy)]. In its amino acid sequence, drIndy exhibits comparable similarity to the two known Na+-coupled dicarboxylate transporters in mammals; namely, NaDC1 (35% identity) and NaDC3 (34% identity). We elucidated the functional characteristics of drIndy in two different heterologous expression systems by using mammalian cells and Xenopus laevis oocytes. These studies show that drIndy is a cation-independent electroneutral transporter for a variety of tricarboxylic acid-cycle intermediates, with preference for citrate compared with succinate. These characteristics of drIndy differ markedly from those of NaDC1 and NaDC3, indicating that neither of these latter transporters is the mammalian functional counterpart of drIndy. Since drIndy is a transporter for tricarboxylic acid-cycle intermediates, dysfunction of the Indy gene may lead to decreased production of metabolic energy in cells, analogous to caloric restriction. This might provide the molecular basis for the observation that disruption of the Indy gene function in Drosophila leads to extension of the average adult life span of the organism.