bluuebunny/crossref_metadata_2025 huggingface dataset:
Education for Transformative Leadership in Southern Africa
Authors: Preece Julia
Published: July 2003

This article argues that education for transformative leadership in a southern African context needs to nurture an understanding of the relationship between spirituality and charisma. This argument is based on a review of some literature pertaining to transformative learning, transformative leadership, and African value systems. The article explores the relationship between transformative leadership and transformative learning and education theories, and relates them to a specific southern African context. It proposes three arguments. First, transformative education may facilitate the transformative leadership development process. Second, transformative education and transformative leadership, although offering features that are sympathetic to African indigenous values, must also take account of particular African contexts. The article does not claim to be reporting from empirical research on this issue but, to support its position, draws on recent literature from an ongoing southern Africa leadership development project and some early empirical data from a small, related study in one southern African country. Third, the article suggests that a key difference between transformative learning and transformative leadership perspectives is the transformative leadership focus on charismatic qualities that inspire motivation to change. However, a defining conceptual thread of spirituality runs through the transformative learning and leadership literature that resonates with southern African core value systems. It is this thread that provides the overall conceptual link between the different strands of thought.
The Social Construction of Transformation
Authors: Scott Sue M.
Published: July 2003

Ten Industrial Areas Foundation national community organizers were interviewed about their experiences of organizing in broad-based organizations. All were trainers and all shared stories of how participation in action facilitated transformation personally and socially. Three stories were chosen as exemplars for how transformation occurs in relationship-based organizing. They illustrate three themes: freedom from victimization, freedom from slavery, and use of controlled anger. Imagination, relationships, disequilibrium, internalization, and changes in consciousness are processes that seemed to bridge the rational with the emotional as the social is constructed in participative action.
Film Properties for Good Performance on Vertical Form-Fill-Seal Packaging Machines
Authors: Clark Terry A. , Wagner John R.
Published: July 2003

Technological improvements of flexible form, fill and seal packaging machines are yielding exceptional line speeds, productivity rates and bag features. This paper discusses the evolution of vertical packaging machine development and how it has impacted plastic film properties (e.g. COF, sealing temperature range, hot tack) required for optimal performance.
Morphology, Mechanical Properties and Stress-relaxation of Biaxially Oriented Polyethylene Films Irradiated with β-radiation
Authors: Bobovitch Arthur , Gutman Emmanuel M. , Henning Sven , Michler Goerg H. , Nir Yiftach
Published: July 2003

The present study describes an influence of β-radiation on morphology, mechanical properties and stress-relaxation of biaxially oriented polyethylene films. The mechanical properties and stress-relaxation of irradiated crosslinked films were studied as a function of the irradiation dose applied. The relaxation time spectra of crosslinked films were observed to display additional relaxation times. Irradiation dose of 4 megarads (MR) was found to be optimal from the viewpoint of mechanical properties. The crystallization of crosslinked and noncrosslinked polyethylene was compared. It was shown that irradiation affects the final crystallinity of polyethylene. Lower crystallinity was observed due to lower mobility of crosslinked molecules.
shibiremutations reveal distinct dynamin-independent and-dependent endocytic pathways in primary cultures ofDrosophilahemocytes
Authors: Guha A. , Sriram V. , Krishnan K. S. , Mayor S.
Published: July 2003

We have developed a primary cell culture system derived from embryonic and larval stages of Drosophila. This allows for high-resolution imaging and genetic analyses of endocytic processes. Here, we have investigated endocytic pathways of three types of molecules: an endogenous receptor that binds anionic ligands (ALs), glycosylphosphatidylinositol (GPI)-anchored protein (GPI-AP), and markers of the fluid phase in primary hemocytes. We find that the endogenous AL-binding receptor (ALBR) is internalized into Rab5-positive endosomes, whereas the major portion of the fluid phase is taken up into Rab5-negative endosomes; GPI-APs are endocytosed into both classes of endosomes. ALBR and fluid-phase-containing early endosomes subsequently fuse to yield a population of Rab7-positive late endosomes. In primary culture, the endocytic phenotype of ALBR internalization in cells carrying mutations in Drosophila Dynamin (dDyn) at the shibire locus(shits) parallels the temperature-sensitive behavior of shits animals. At the restrictive temperature in shits cells, receptor-bound ALs remain completely surface accessible, localized to clathrin and α-adaptin-positive structures. On lowering the temperature, ALs are rapidly sequestered, suggesting a reversible block at a late step in dDyn-dependent endocytosis. By contrast, GPI-AP and fluid-phase endocytosis are quantitatively unaffected at the restrictive temperature in shits hemocytes, demonstrating a constitutive dDyn and Rab5-independent endocytic pathway in Drosophila.
Left-right asymmetry: Nodal points
Authors: Mercola Mark
Published: July 2003

The striking left-right asymmetry of visceral organs is known to depend on left- and right-side-specific cascades of gene expression during early embryogenesis. Now, developmental biologists are characterizing the earliest steps in asymmetry determination that dictate the sidedness of asymmetric gene expression. The proteins and structures involved control fascinating physiological processes, such as extracellular fluid flow and membrane voltage potential and yet little is known about how their activities are coordinated to control laterality. By analogy with intercellular signalling in certain epithelial and endothelial cells, however, it is reasonable to speculate that at least three of these players, monocilia, gap junction communication and the Ca2+ channel polycystin-2, participate in a signalling pathway that propagates left-right cues through multicellular fields.
The ins and outs of fibronectin matrix assembly
Authors: Wierzbicka-Patynowski Iwona , Schwarzbauer Jean E.
Published: July 2003

Cell phenotype is specified by environmental cues embedded in the architecture and composition of the extracellular matrix (ECM). Much has been learned about matrix organization and assembly through analyses of the ECM protein fibronectin (FN). FN matrix assembly is a cell-mediated process in which soluble dimeric FN is converted into a fibrillar network. Binding of cell surface integrin receptors to FN converts it to an active form, which promotes fibril formation through interactions with other cell-associated FN dimers. As FN fibrils form on the outside of the cell, cytoplasmic domains of integrin receptors organize cytoplasmic proteins into functional complexes inside. Intracellular connections to the actin cytoskeletal network and stimulation of certain key intracellular signaling pathways are essential for FN–integrin interactions and propagation of FN fibril formation. Thus,assembly of native functional ECM depends on exquisite coordination between extracellular events and intracellular pathways.
Comprehensive approach to increased pedestrian safety in pedestrian—car accidents
Authors: Koch W , Howard M
Published: July 2003

At the Ford Forschungszentrum Aachen a finite element pedestrian humanoid model for use in pedestrian accident simulations was constructed in LS-DYNA3D. Validation of the humanoid model shows the ability to predict fractures and to examine the influence on injuries and injury reduction. The pedestrian accident simulation models can predict general injury mechanisms (shear, bending and fracture) by virtue of the construction philosophy and are thus capable of being used as vehicle engineering development tools. To improve further the understanding of the kinematics of pedestrian accidents and to optimize the computer simulation program it is necessary to collect a set of highly detailed real-world data. At present such data are either unavailable or not sufficiently accurate for this purpose. To meet these targets the In-Depth Medical Pedestrian Accident Investigation and Reconstruction Study has been established.
Design studies for a new suspension mechanism
Authors: Heuze L , Ray P , Gogu G , Serra L , André F
Published: July 2003

Development of innovative suspension mechanisms and optimization of their elastokinematic performances are usually studied by applying static constraints on the numerical model of the mechanism. During the development of the new Michelin optimized contact patch multilink suspension concept, a two-dimensional semi-analytical model is studied in order to validate it. After writing the loop closure equations and obtaining systems of multivariate polynomials, the method consists in using the determinant of Sylvester's matrix to solve them. The paper presents the design studies to determine the influence of the geometric parameters of the mechanism on the variation of the camber and the half-track under lateral loads.
Modelling the hysteretic characteristics of a magnetorheological fluid damper
Authors: Wang En Rong , Ma Xiao Qing , Rakhela S , Su C Y
Published: July 2003

A generalized model is proposed to characterize the biviscous hysteretic force characteristics of a magnetorheological (MR) fluid damper using symmetric and asymmetric sigmoid functions on the basis of a fundamental force generation mechanism, observed qualitative trends and measured data under a wide range of control and excitation conditions. Extensive laboratory measurements were performed to characterize the hysteretic force properties of an MR damper under a wide range of magnitudes of control current and excitation conditions (frequency and stroke). The global model is realized upon formulation and integration of component functions describing the preyield hysteresis, saturated hysteresis loop, linear rise and current-induced rise. The validity of the proposed model is demonstrated by comparing the simulation results with measured data in terms of hysteretic forcedisplacement and force-velocity characteristics under a wide range of test conditions. The results revealed reasonably good agreement between the measured data and model results, irrespective of the test conditions considered. The results of the study suggest that the proposed model could be effectively applied for characterizing the damper hysteresis and for development of an optimal controller for implementation in vehicular suspension applications.
A Study of caravan unsteady aerodynamics
Authors: Darling J , Staden P M
Published: July 2003

The high speed stability and handling characteristics of car-trailer combinations are affected by both road and aerodynamic forces. While the tyre-to-road interaction is well understood the action of gusts, passing large vehicles and even small steering inputs will disturb the symmetry of flow and generate aerodynamic forces and moments which are suffcient to affect the handling of the system. Although accidents caused by high speed instability are relatively uncommon a better understanding of these aerodynamic effects will improve safety. In this paper a series of wind tunnel investigations using scale models are presented. Steady state investigations were used to measure the aerodynamic properties of the car-caravan pair while a novel technique was developed to measure the aerodynamic damping derivatives in yaw and side force for a caravan model. These damping derivatives were shown to be destabilizing in most cases of sideslip and stabilizing in yaw although it was demonstrated that high damping derivatives were attained at certain frequencies of excitation.
Examination of different models following types of yaw moment control strategy for improving handling safety of a car-caravan combination
Authors: Mokhiamar O , Abe M
Published: July 2003

This paper examines the effect of two model responses on the performance of model following types of direct yaw control (DYC). The model responses are the side-slip angle and yaw rate vehicle response of two-degree-of-freedom vehicle motion (bicycle model). The controls aim primarily at stabilizing the handling behaviour of a car-caravan combination as well as making its handling characteristics close to those of a single vehicle. Sensing of the lateral force exerted on a hitch point is essential for the control systems proposed. The estimated side-slip angle using the model observer was compared with the real side-slip angle measured by optical side-slip sensors. The effect of the model response is proved by computer simulations of a closed-loop driver-vehicle system subjected to evasive lane change with braking. It is found that the influence of the model response has a significant effect on the control performance.
Simulation of the shift force for a manual transmission
Authors: Kim J , Park S , Seok C , Song H , Sung D , Lim C , Kim J , Kim H
Published: July 2003

A shift force simulator for manual transmission is developed to estimate the shift force that is transmitted to the driver's hand. In order to develop the simulator, dynamic models of the external linkage, internal linkage, synchronizer and drivetrain are obtained. The synchronizing motion is modelled as seven steps depending on the relative displacement of the sleeve to the ring spring, outer ring chamfer and gear chamfer. The chamfer-to-chamfer contact mechanism is modelled as a linear spring. In addition, a driver model is proposed to simulate the driver's shift lever operation. Based on the dynamic model of each element, a shift force simulator is developed. The simulator calculates the sleeve displacement, cone torque, index torque, sleeve force, shift force and the speed of the input and output shaft. It is found that the shift force by the simulator shows a good correlation with the test results, and it is expected that the shift force simulator developed in this study can be used as a useful design tool to evaluate the shift feeling in the initial design stage.
Combustion characteristics and heat release analysis of a direct injection compression ignition engine fuelled with diesel—dimethyl carbonate blends
Authors: Huang Z H , Jiang D M , Zeng K , Liu B , Yang Z L
Published: July 2003

The combustion characteristics and heat release of a direct injection (DI) compression ignition engine fuelled with diesel-dimethyl carbonate blends were investigated on a compression ignition engine. The study showed that the premixed combustion is prolonged and the duration of the diffusive combustion is shortened with increase in the dimethyl carbonate (DMC) addition. For a specific brake mean effective pressure (b.m.e.p.), the maximum cylinder gas pressure, the maximum rate of pressure rise and the maximum rate of heat release increase with increase in the DMC addition at medium and high loads, while they exhibit less variation with the DMC addition at small load. Meanwhile, the maximum gas temperature decreases with increase in the DMC addition. The ignition delay increases while the rapid combustion duration and the total combustion duration show less variation with the DMC addition. The brake specific fuel consumption (b.s.f.c.) increases while the diesel equivalent b.s.f.c. decreases and the thermal efficiency increases with increase in the DMC addition. The CO and smoke decrease with increase in the DMC addition, and NOx does not increase with increase in DMC.
Effects of tumble and swirl flows on turbulence scale near top dead centre in a four-valve spark ignition engine
Authors: Lee K H , Lee C S
Published: July 2003

The in-cylinder flowfield and the turbulence scale at the ignition timing play an important role in enhancing the propagation speed of the initial flame and the engine combustion. The aim of this work is to investigate the effect of tumble and swirl flows on the turbulence scale near the top dead centre in a four-valve spark ignition (SI) engine by an experimental method. In this study, various flowfields such as tumble and swirl flows were generated by intake flow control valves. For investigation of the flowfields, the single-frame particle tracking velocimeter (PTV) and the twocolour particle image velocimeter (PIV) techniques were developed to clarify the in-cylinder flow pattern during the intake stroke and the turbulence intensity near the spark plug during the compression stroke respectively. In addition, the flame propagation was visualized by an ICCD camera, and its images were analysed to compare the flowfields. From these experimental results, the effects of tumble and swirl flows on the turbulence scale and the flame propagation speed were clarified.
Investigation of the detection of knock and misfire of a spark ignition engine with the ionic current method
Authors: Wang Ying , Zhou Longbau
Published: July 2003

This paper reports an investigation of detection of knock and misfire in the spark ignition engine by means of the ionic current method. In the knock experiments, two detecting methods are used. One is the ionic current method. High frequency signals will be added to the ionic current signals where knocking is happening, which can be detected by picking up these signals. The other is the engine block vibration method. Knock can also be detected by monitoring signals of the vibration sensor in a proper position. The signals of the two kinds of methods are recorded at the same time with a dual-channel oscilloscope. With wave comparison and fast Fourier transform analysis, the advantages of the ionic current method can be shown and its feasibility and reliability can be proved further. In misfire experiments, misfire can occur by adjusting spark plug gap, adding carbon deposits and cutting out high voltages. A remarkable difference exists between misfire and non-misfire ionic current signals in shape and amplitude. By detecting these changes, misfire detection can be realized. The experiments prove that using the ionic current method to detect knock and misfire is simple, visual and cheap.
On the different uses of linguistic abstractness: from LIB to LEB and beyond
Authors: Fiedler Klaus , Bluemke Matthias , Friese Malte , Hofmann Wilhelm
Published: July 2003

Linguistic abstractness has been shown to mediate persuasive and attributional effects of communication. The linguistic intergroup bias (LIB) refers to the tendency to describe positive ingroup and negative outgroup behaviors more abstractly than negative ingroup and positive outgroup behavior. Recently, the LIB was shown to reflect to a large extent a linguistic expectancy bias (LEB). Abstract language need not have an ingroup‐serving function, but may be used to communicate expected information in a concise and condensed manner. The present research shows that the reverse may also be true. When the interaction goal is not merely to convey information that is shared anyway because it is typical of the communication target but to transmit unshared information (known to the communicator but new to the recipient), then it may be necessary to express (explain, teach, interpret) unexpected ideas or deviant attitudes in abstract, interpretive terms. The joint operation of both principles was demonstrated within the same experimental task. In communications about East Germans, more abstract predicates were used in typically East German domains (LEB). However, more abstract terms were also used when messages deviated from the recipient's prior attitude. A conceptual framework is proposed to integrate these findings. Copyright © 2003 John Wiley & Sons, Ltd.
Acquisition of dispositional attributions: effects of sample size and covariation
Authors: Van Overwalle Frank
Published: July 2003

Two experiments examined whether dispositional attributions are sensitive to the sample size of the evidence indicating a given level of covariation between person and behavior. Participants were given high or low levels of covariation (i.e. consensus and distinctiveness), and the acquisition of dispositional attributions was monitored by requesting dispositional trait ratings at fixed intervals. The results showed that dispositional attributions were sensitive to sample size, and increased given more evidence on high person‐behavior covariation while they decreased given more evidence on low person‐behavior covariation. Additional analyses suggested that in making dispositional inferences (e.g. about the actor), there was a slight preference for agreement information (e.g. low distinctiveness) over difference information (e.g. low consensus). The effects of sample size are inconsistent with current statistical or probabilistic models of covariation, but are in line with connectionist networks using an error‐correcting learning algorithm. Copyright © 2003 John Wiley & Sons, Ltd.
Perspective taking and prejudice reduction: the mediational role of empathy arousal and situational attributions
Authors: Vescio Theresa K. , Sechrist Gretchen B. , Paolucci Matthew P.
Published: July 2003

This research was designed to examine whether perspective taking promotes improved intergroup attitudes regardless of the extent that stereotypic perceptions of outgroups are endorsed, as well as examining the mechanisms (attributional or empathy related) by which perspective taking motivates improved intergroup attitudes. Participants were presented with an interview segment where an African American interviewee discussed the difficulties experienced as a result of his membership in a negatively stereotyped group. Materials were presented in a 2 (perspective taking: other focused or objective focused) × 2 (target stereotypicality: confirming or disconfirming) between participants design. Findings revealed that the manipulation of target stereotypicality influenced subsequent stereotype endorsement; those exposed to a stereotype confirming target later endorsed more stereotypic perceptions of African Americans than did those exposed to a stereotype disconfirming target. However, perspective taking promoted improved intergroup attitudes irrespective of stereotypicality; those encouraged to adopt the perspective of the target later reported more favourable intergroup attitudes than did those who remained detached and objective listeners. Whereas empathy partially mediated the relation between perspective taking and intergroup attitudes, situational attributions were a stronger and more reliable mediator. Copyright © 2003 John Wiley & Sons, Ltd.
Beyond attitudinal ambivalence: effects of belief homogeneity on attitude‐intention‐behaviour relations
Authors: Armitage Christopher J.
Published: July 2003

Attitudinal ambivalence extends the traditional unidimensional conceptualization of attitude by acknowledging that people can simultaneously evaluate attitude objects as positive and negative. The present paper argues that this bidimensional view of attitudes may be extended further to take account of multidimensional influences on attitudes using measures of belief homogeneity. Study 1 (n = 155) showed that attitudes based on homogeneous belief‐sets were significantly more predictive of subsequent behaviour (β = 0.47, p<0.01) than were attitudes based on heterogeneous belief‐sets (β = 0.08, ns). Study 2 (n = 136) manipulated belief homogeneity and found that when beliefs were made heterogeneous, attitudes based on heterogeneous belief‐sets were significantly less predictive of behavioural intentions (β = 0.46, p < 0.01) than attitudes based on homogeneous belief‐sets (β = 0.84, p < 0.01). Implications for research on attitudinal ambivalence and attribute importance are discussed. Copyright © 2003 John Wiley & Sons, Ltd.
In search of leading indicators of economic activity in Germany
Authors: Bandholz Harm , Funke Michael
Published: July 2003

In this paper we present two new composite leading indicators of economic activity in Germany estimated using a dynamic factor model with and without regime switching. The obtained optimal inferences of business cycle turning points indicate that the two‐state regime switching procedure leads to a successful representation of the sample data and provides an appropriate tool for forecasting business conditions. Copyright © 2003 John Wiley & Sons, Ltd.
A neural network versus Black–Scholes: a comparison of pricing and hedging performances
Authors: Amilon Henrik
Published: July 2003

An Erratum has been published for this article in Journal of Forecasting 22(6‐7) 2003, 551

The Black–Scholes formula is a well‐known model for pricing and hedging derivative securities. It relies, however, on several highly questionable assumptions. This paper examines whether a neural network (MLP) can be used to find a call option pricing formula better corresponding to market prices and the properties of the underlying asset than the Black–Scholes formula. The neural network method is applied to the out‐of‐sample pricing and delta‐hedging of daily Swedish stock index call options from 1997 to 1999. The relevance of a hedge‐analysis is stressed further in this paper. As benchmarks, the Black–Scholes model with historical and implied volatility estimates are used. Comparisons reveal that the neural network models outperform the benchmarks both in pricing and hedging performances. A moving block bootstrap is used to test the statistical significance of the results. Although the neural networks are superior, the results are sometimes insignificant at the 5% level. Copyright © 2003 John Wiley & Sons, Ltd.
Validation studies of drug exposures in pregnant women
Authors: Czeizel A. E. , Petik D. , Vargha P.
Published: July 2003

The aim of these studies was to check the quality of data collection concerning drug use during pregnancy in the Hungarian Case–Control Surveillance of Congenital Abnormalities from four different aspects. (a) The parents of non‐respondent cases were visited at home to collect data, but the Ethics Committee did not allow collection of comparable data from non‐respondent control women. Thus only 200 selected non‐respondent controls were visited at home and questioned about drug use as part of a validation study. There was no difference in the distribution and occurrence of frequently used drugs between the respondent and non‐respondent control groups. (b) Data collection was compared between the usual method of the Case–Control Surveillance and personal interview in cases with congenital limb deficiencies. In general, the two methods produced similar results with respect to drug use, but the personal interview revealed a higher use of unintended contraceptive pills while the use of antenatal care logbooks in the Case–Control Surveillance showed a higher use of drugs to prevent threatened abortion and preterm delivery. (c) A check of source and completeness of drug exposure showed that about one‐quarter of the drugs used during pregnancy were not recorded in the Case–Control Surveillance, and the proportion of lack of recall was about 23%. A small group of women (2.4%) did not use prescribed drugs due to the suspected teratogenic risk. (d) The teratogenic labelling of drugs deters pregnant patients from the use of prescribed drugs, or at least shortens the duration of drug intake. Thus the evaluation of drug use on the basis of medically recorded prescribed drugs and/or usual recommendations produces a bias thus it is necessary to complete it with information from the patients. Copyright © 2003 John Wiley & Sons, Ltd.
Indinavir did not further increase mean triglyceride levels in HIV‐infected patients treated with nucleoside reverse transcriptase inhibitors: An analysis of three randomized clinical trials
Authors: Rojas Carlos , Coplan Paul M. , Rhodes Thomas , Robertson Michael N. , DiNubile Mark J. , Guess Harry A.
Published: July 2003

Objectives

Metabolic abnormalities including hyperlipidemia have developed in patients infected with the human immunodeficiency virus (HIV) after treatment with protease inhibitor drugs. It is unclear whether the deleterious effects on plasma triglyceride concentrations observed in patients receiving highly active antiretroviral therapy are a class effect of protease inhibitors. Hypertriglyceridemia may constitute a risk factor for cardiovascular disease. The purpose of this retrospective analysis of HIV‐infected patients enrolled in three randomized, double‐blind trials of indinavir therapy was to determine whether indinavir use was associated with a larger increase in triglyceride levels than treatment without a protease inhibitor.

Methods

Using a mixed‐effects model, we compared average changes in nonfasting plasma triglyceride levels among randomized treatment groups for each protocol separately.

Results

The median increase in triglyceride levels during the 1st year of antiretroviral monotherapy was less with indinavir than with either zidovudine or stavudine. The combination of indinavir and nucleoside‐analogue reverse‐transcriptase inhibitors (NRTI) resulted in smaller increments in triglyceride levels than NRTI monotherapy. Indinavir also augmented the reduction in triglyceride levels observed with combination therapy using zidovudine and lamivudine in persons with far advanced HIV‐infection. However, up to 7% of patients receiving a NRTI and indinavir experienced elevations of nonfasting triglyceride levels in excess of 750 mg/dl.

Conclusions

On average, the combination of indinavir and NRTI therapy was not associated with a greater elevation of non‐fasting triglyceride levels in HIV‐infected men with at least moderately advanced immunosuppression than treatment with NRTI drugs alone. Copyright © 2003 John Wiley & Sons, Ltd.
The Cuban experience in focusing pharmaceuticals policy to health population needs: initial results of the National Pharmacoepidemiology Network (1996–2001)
Authors: Diogène Eduard , Peña Julián Pérez , Figueras Albert , Furones Juan Antonio , Debesa Frank , Laporte Joan‐Ramon
Published: July 2003

In 1996, a National Pharmacoepidemiology Network was set up in Cuba in order to disseminate problem‐oriented information and develop continuing education activities on drug therapy, to perform research on drug utilisation and to promote interventions to improve drug use. It is coordinated by the Centre for the Development of Pharmacoepidemiology, which is also in charge of regulatory and administrative duties and collaborates with the National Pharmaceutical Industry. By 2001, a number of educational and information initiatives had been undertaken, particularly in primary health care, which resulted in improvement of indicators of drug use. Cuba keeps good health standards in spite of a short health budget. Copyright © 2003 John Wiley & Sons, Ltd.
Doctors' prescription behaviour regarding dosage recommendations for preparations of kava extracts
Authors: Dietlein G. , Schröder‐Bernhardi D.
Published: July 2003

Background

There are many publications on the use of kava extracts as a treatment alternative to tricyclic antidepressants and benzodiazepines, but little has been done to investigate the potential adverse effects that may be associated with prolonged or high‐dose usage.

Objectives

To investigate the extent to which physicians comply with the recommended daily dose (RDD) of an antidepressant such as kava and the consequences of this behaviour with regard to the safety and efficacy of frequently prescribed kava extracts (Trade names: Antares™, Laitan™ and Kavasporal forte™).

Method

The analysis was carried out using the patient database MediPlus®, which provides anonymous access to a representative and valid panel of physicians and patients in Germany.

Results

Prescriptions for Antares showed that the RDD of 1 tablet per day was exceeded in 58.2% of the cases, while those for Laitan showed that the RDD of 1 capsule per day was significantly exceeded in 75.6% of the cases; a one‐off prescription was issued in 66% of the cases. As a result, the required effect diminished very quickly. Prescriptions for Kavasporal forte showed that the daily dosage of 2 capsules per day complied with the recommendations in only 49.1% of the cases; in 38.8% of the cases, the dosage dropped below the respective recommendation. As a consequence, the lower‐dosed Kavasporal forte was prescribed for longer periods than the higher‐dosed Antares and Laitan.

Conclusions

In the case of a low‐dosage recommendation, we saw a trend to over‐dose in prescribing behaviour, which increases the risk of undesirable adverse reactions. On the other hand, we saw a trend to under‐dose in the case of a higher dosage recommendation. This fact may explain the unexpected inefficacy of the therapy. These trends affected the duration of therapy, whereby a dosage lower than the RDD was prescribed for a longer period than a dosage higher than the RDD. Copyright © 2003 John Wiley & Sons, Ltd.
ROC curve analysis for biomarkers based on pooled assessments
Authors: Faraggi David , Reiser Benjamin , Schisterman Enrique F.
Published: July 2003

Interleukin‐6 is a biomarker of inflammation which has been suggested as having potential discriminatory ability for myocardial infarction. Because of its high assaying cost it is very expensive to evaluate this marker. In order to reduce this cost we propose pooling the specimens. In this paper we examine the efficiency of ROC curve analysis, specifically the estimation of the area under the ROC curve, when dealing with pooled data. We study the effect of pooling when there are only a fixed number of individuals available for testing and pooling is carried out to save on the number of assays. Alternatively we examine how many pooled assays of size g are necessary to provide essentially the same information as N individual assays. We measure loss of information by means of the change in root mean square error of the estimate of the area under the ROC curve and study the extent of this loss via a simulation study. Copyright © 2003 John Wiley & Sons, Ltd.
Properties of internal pilots with the univariate approach to repeated measures
Authors: Coffey Christopher S. , Muller Keith E.
Published: July 2003

Uncertainty surrounding the error covariance matrix often presents the biggest barrier to achieving accurate power analysis in the ‘univariate’ approach to repeated measures analysis of variance (UNIREP). A poor choice gives either an overpowered study which wastes resources, or an underpowered study with little chance of success. Internal pilot designs were introduced to resolve such uncertainty about error variance for t‐tests. In earlier papers, we extended the use of internal pilots to any univariate linear model with fixed predictors and independent Gaussian errors. Here we further extend our exact and approximate results to UNIREP analysis. For a fixed treatment effect, the inaccuracy in a power calculation depends only on the ratio of the true variance to the value used for planning. The greater complexity of repeated measures requires generalizing misspecification of error variance to the misspecification of the eigenvalues of the error covariance. We recommend approximating the misspecification in terms of the first and second moments of the eigenvalues, for both fixed sample and internal pilot designs. We also describe an unadjusted approach for internal pilots with repeated measures. Simulations illustrate the fact that both positive and negative properties in the univariate setting extend to repeated measures analysis. In particular, internal pilots allow maintaining power or reducing expected sample size when the covariance matrix used for planning differs from the true value. However, an unadjusted approach can inflate test size, at least with small to moderate sample sizes. Hence new, adjusted methods must be developed for small samples. At this time, we caution against using an internal pilot design with repeated measures without first conducting simulations to document the amount of test size inflation possible for the conditions of interest. Copyright © 2003 John Wiley & Sons, Ltd.
Misclassification in a matched case‐control study with variable matching ratio: application to a study of c‐erbB‐2 overexpression and breast cancer
Authors: Duffy Stephen W. , Rohan Thomas E. , Kandel Rita , Prevost Teresa C. , Rice Kenneth , Myles Jonathan P.
Published: July 2003

We provide a simple analytic correction for risk factor misclassification in a matched case‐control study with variable numbers of controls per case. The method is an extension of existing methodology, and involves estimating the corrected proportions of controls and cases in risk factor categories within each matched set. These estimates are then used to calculate the Mantel–Haenszel odds ratio estimate corrected for misclassification. A simulation‐based interval estimate is developed. An example is given from a study of risk factors for progression of benign breast disease to breast cancer, in which the risk factor is a biological marker measured with poor sensitivity. Copyright © 2003 John Wiley & Sons, Ltd.
Last observation carry‐forward and last observation analysis
Authors: Shao Jun , Zhong Bob
Published: July 2003

Drop‐out often occurs in clinical trials with multiple visits and drop‐out is often informative in the sense that the population of patients who dropped out is different from the population of patients who completed the study. To handle data with informative drop‐out, an intention‐to‐treat analysis, which evaluates treatment effects over the population of all randomized patients with at least one post‐treatment evaluation, is often required by the regulatory agencies. As a popular and simple intention‐to‐treat analysis, the last observation carry‐forward (LOCF) analysis of variance (ANOVA) performs a statistical test for treatment effects by treating the last observation prior to drop‐out as the observation from the last visit. Although discussions, examples and limited empirical results about the LOCF analysis can be found, its theoretical property is unclear. We find that the LOCF one‐way ANOVA test is actually asymptotically valid (that is, its asymptotic size is equal to the nominal size) in the special but important case where only two treatments are compared and the two treatment groups have the same number of patients, regardless of whether drop‐out is informative or not. In other cases, however, the asymptotic size of the LOCF test is different from the nominal size and is often too small when drop‐out is informative, which results in a loss in power of detecting treatment effects, a disadvantage to drug companies. We propose an asymptotically valid test for comparing the global means over subpopulations, where each subpopulation contains patients dropping out after a particular visit. Some simulation results are presented to study the finite sample performance of the LOCF test and our proposed test. Copyright © 2003 John Wiley & Sons, Ltd.
Modelling and analysing exchangeable binary data with random cluster sizes
Authors: Xu Jian‐Lun , Prorok Philip C.
Published: July 2003

Correlated binary data occur very frequently in cluster sample surveys, dependent repeated cancer screening, teratological experiments, ophthalmologic and otolaryngologic studies, and other clinical trials. The standard methods to analyse these data include the use of beta‐binomial models and generalized estimating equations with third and fourth moments specified by ‘working matrices’. However, in many applications it is reasonable to assume that the data from the same cluster are exchangeable. When all sampled clusters have equal sizes, Bowman and George introduced maximum likelihood estimates (MLEs) of the population parameters such as the marginal means, moments, and correlations of order two and higher. They also extended their approach to sampled clusters with unequal sizes. It seems that their extension has a gap. This paper points out the source of this gap and shows that estimates introduced by Bowman and George are not the MLEs of the parameters which are used to identify the joint distribution of correlated binary data. We show that the MLEs of the population parameters have no closed form in general and should be calculated by numerical methods. We apply our results and a generalized estimating equation procedure to a data set from a double‐blind randomized clinical trial comparing two antibiotics, cefaclor and amoxicillin, used for the treatment of acute otitis media. To see the performance of the MLEs with small or moderate sample sizes, several simulation studies are also conducted. Published in 2003 by John Wiley & Sons, Ltd.
Gene silencing in mammalian cells by PCR‐based short hairpin RNA
Authors: Gou Deming , Jin Nili , Liu Lin
Published: July 2003

RNA interference (RNAi) provides a powerful tool to silence genes in a sequence‐specific manner in a variety of systems. However, not all sequences are effective in the RNAi‐mediated gene silencing. In this study, we developed a polymerase chain reaction (PCR)‐based RNAi strategy for a quick screening of small interfering RNA (siRNA) efficiency. This method utilized a two‐step PCR to generate a chimeric DNA template containing the U6 promoter or cytomegalovirus promoter and short hairpin DNA. We demonstrated that the transfection of the PCR products into mammalian cells resulted in specific depressions of exogenous (luciferase, green fluorescent protein and β‐galactosidase) and endogenous (annexin II) gene expressions. This PCR strategy provides a rapid, easy and cheap approach for testing candidates siRNA sequences and is an attractive alternative to subcloning.
The membrane bound N‐terminal domain of human adenosine diphosphate ribosylation factor‐1 (ARF1)
Authors: Davies Sarah M.A , Harroun Thad A , Hauß Thomas , Kelly Sharon M , Bradshaw Jeremy P
Published: July 2003

The small G protein adenosine diphosphate ribosylation factor‐1 (ARF1) is activated by cell membrane binding of a self‐folding N‐terminal domain. We present a model of the human ARF1 N‐terminal peptide in planar lipid bilayers, determined from neutron lamellar diffraction and circular dichroism data with molecular modelling. This amphipathic domain lies at a shallow membrane depth, ideal for regulation of the ARF1 bio‐timer by rapid, reversible membrane binding. The helical region does not elongate upon membrane binding, leaving the connecting flexible linker region's length unchanged.
The cytochrome c3–[Fe]‐hydrogenase electron‐transfer complex: structural model by NMR restrained docking
Authors: ElAntak Latifa , Morelli Xavier , Bornet Olivier , Hatchikian Claude , Czjzek Mirjam , Dolla Alain , Guerlesquin Françoise
Published: July 2003

Cytochrome c3 (M
r 13 000) is a low redox potential cytochrome specific of the anaerobic metabolism in sulfate‐reducing bacteria. This tetrahemic cytochrome is an intermediate between the [Fe]‐hydrogenase and the cytochrome Hmc in Desulfovibrio vulgaris Hildenborough strain. The present work describes the structural model of the cytochrome c3–[Fe]‐hydrogenase complex obtained by nuclear magnetic resonance restrained docking. This model connects the distal cluster of the [Fe]‐hydrogenase to heme 4 of the cytochrome, the same heme found in the interaction with cytochrome Hmc. This result gives evidence that cytochrome c3 is an electron shuttle between the periplasmic hydrogenase and the Hmc membrane‐bound complex.
Inhibition of FGF receptor signalling in Xenopus oocytes: differential effect of Grb7, Grb10 and Grb14
Authors: Cailliau Katia , Le Marcis Véronique , Béréziat Véronique , Perdereau Dominique , Cariou Bertrand , Vilain Jean Pierre , Burnol Anne-Françoise , Browaeys-Poly Edith
Published: July 2003

The role of Grb7 adapters, Grb7, Grb10, and Grb14, was investigated in Xenopus oocytes expressing fibroblast growth factor receptors (FGFR). FGF‐induced maturation of FGFR‐expressing oocytes was blocked by previous injection of Grb7 or Grb14, but not Grb10. This effect correlated with Grb7/14 binding to the receptor, and inhibition of the Ras‐dependent pathway. Interestingly, the phosphorylated insulin receptor interacting region (PIR) and Src 2 homology domains (SH2) of Grb7 and Grb14 were differently implicated in the inhibition of FGFR signalling. This study provided further evidence for specificity of the biological action of the Grb7 adapters on receptor tyrosine kinase signalling.
Cardiac hypertrophy in vivo is associated with increased expression of the ribosomal gene transcription factor UBF
Authors: Brandenburger Yves , Arthur Jane F , Woodcock Elizabeth A , Du Xiao-Jun , Gao Xiao-ming , Autelitano Dominic J , Rothblum Lawrence I , Hannan Ross D
Published: July 2003

The ribosomal DNA transcription‐specific factor, UBF, is a key target for the regulation of ribosomal RNA synthesis and hypertrophic growth of isolated neonatal cardiomyocytes. In this study, we have examined whether UBF expression is also an important determinant of cardiac growth rates in vivo. We show that rDNA transcription, rRNA synthesis and UBF expression in left ventricular myocytes isolated from mice 1–6 weeks following transverse aortic constriction were significantly increased (2.5–3.5‐fold) compared to the levels in myocytes from the left ventricle of sham‐operated mice.
Prevention of passively transferred experimental autoimmune myasthenia gravis by an in vitro selected RNA aptamer
Authors: Hwang Byounghoon , Han Kyungsook , Lee Seong-Wook
Published: July 2003

Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are mainly caused by autoantibodies directed against acetylcholine receptors (AChR) located in the postsynaptic muscle membrane. Previously, we isolated an RNA aptamer with 2′‐fluoropyrimidines using in vitro selection techniques that acted as an effective decoy against both a rat monoclonal antibody called mAb198, which recognizes the main immunogenic region on the AChR, and a significant fraction of patient autoantibodies with MG. To investigate the therapeutic potential of the RNA, we tested the ability of the RNA aptamer to protect the receptors in vivo from mAb198. Clinical symptoms of EAMG in rats engendered by passive transfer of mAb198 were efficiently inhibited by a truncated RNA aptamer that was modified with polyethylene glycol, but not by control scrambled RNA. Moreover, the loss of AChR in the animals induced by the antibody was also significantly blocked with the modified RNA aptamer. These results suggested that RNA aptamers could be applied for antigen‐specific treatment for autoimmune diseases including MG.
New partners of acyl carrier protein detected in Escherichia coli by tandem affinity purification
Authors: Gully D , Moinier D , Loiseau L , Bouveret E
Published: July 2003

We report the first use of tandem affinity purification (TAP) in a prokaryote to purify native protein complexes, and demonstrate its reliability and power. We purified the acyl carrier protein (ACP) of Escherichia coli, a protein involved in a myriad of metabolic pathways. Besides the identification of several known partners of ACP, we rediscovered ACP/MukB and ACP/IscS interactions already detected but previously disregarded as due to contamination. Here, we demonstrate the specificity of these interactions and characterize them. This suggests that ACP is involved in additional previously unsuspected pathways. Furthermore, this study shows how the TAP method can be simply used in prokaryotes such as E. coli to identify new partners in protein–protein interactions under physiological conditions and thereby uncover novel protein functions.