bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Porosity on the Burn Rate of a Gas‐Generating Composition
Authors: Lessard Pierre , Beaupré France
Published: June 2003

In the course of the development of an oxidizer‐based extruded composite propellant for use as gas generant, a simple model to describe and evaluate the actual porosity using simple methods was developed. It is briefly described and used to assess the influence of porosity on the burn rate of propellants produced. For the formulation studied the presence of microporosities does not seem to significantly influence the burn rate. On the other hand, volume fraction of porosities in extruded composition grains can exert a large influence and can increase considerably under thermal treatment with a resulting augmentation in burn rate.
Multivariate Calibration of Semi‐Synthetic Data Sets: Gun Powder Analysis
Authors: Ouellet Nathalie , Lussier Louis‐Simon , Beaupré France
Published: June 2003

Quantitative analysis of multi‐component mixtures such as propellant powders is not trivial since it usually requires separation of the mixture constituents. Multivariate calibration combined to the use of semi‐synthetic data sets can eliminate the need for standard solutions preparation, and therefore allow the rapid determination of mixtures provided no intermolecular interactions occur in the systems. Multivariate compositional analyses of FTIR spectra of low‐vulnerability (LOVA), high‐energy low‐vulnerability (HELOVA) and energetic thermoplastic elastomer (ETPE) propellant powder systems were performed using the partial least‐squares (PLS) regression algorithm. All constituents except ethyl centralite (EC) were quantified. Concentrations were predicted within 1% error for the major component (1,3,5‐trinitro‐1,3,5‐triazacyclohexane or RDX), and within 5% error for the minor components (between 12 and 2% nominally by weight). LOVA, HELOVA, and ETPE gun powder samples concentrations were estimated and compared to expected compositions.
Synthesis of a functionalized high affinity mannose receptor ligand and its application in the construction of peptide‐, polyamide‐ and PNA‐conjugates
Authors: Kinzel Olaf , Fattori Daniela , Ingallinella Paolo , Bianchi Elisabetta , Pessi Antonello
Published: June 2003

The synthesis of a high affinity mannose receptor ligand, appropriately functionalized for chemoselective ligation with an antigen or DNA‐binding moieties is described. By a combination of solid‐ and solution‐phase chemistry a versatile synthesis of the target structure was accomplished. Examples of subsequent ligation reactions are described. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.
The chemistry of the opioid receptor binding sites
Authors: Medzihradszky Kálmán
Published: June 2003

Since the discovery of the opioid receptors and their endogenous ligands an immense research work has been devoted to the exploration of their specificity, the mechanism of ligand binding and ligand–receptor interactions. One of the main goals has been the location and characterization of the binding sites. The present review compiles the results achieved in this field in the last quarter of a century, and puts some questions concerning the success of these efforts. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.
Analogues of a potent oxytocin antagonist with truncated c‐terminus or shorter amino acid side chain of the basic amino acid at position 8
Authors: Flouret George , Chaloin Olivier , Slaninová Jirina
Published: June 2003

Twelve analogues were synthesized, their structure derived from modifications of [(S)Pmp1, D‐Trp2, Pen6, Arg8]oxytocin, PA, in which (S)Pmp = β,β‐(3‐thiapentamethylene‐β‐mercaptopropionic acid). PA is a potent antagonist of the uterotonic effect of oxytocin in the rat (uterotonic test in vitro, pA2 = 8.86) and in the baboon. Truncated analogues of PA from the C‐terminus were systematically prepared ending in either the free acid or the amide, i.e. PA1–9 acid, PA1–8 acid, PA1–7 acid, PA1–6 acid, PA1–8 amide, PA1–7 amide and PA1–6 amide. PA1–8 amide was roughly as potent as PA in the rat uterotonic assay in vitro, and the shorter amides were only somewhat weaker antagonists. All four acid analogues were weaker antagonists than PA but still maintained rather high antagonistic potency. These findings suggest that, if these truncated acids form as metabolites in vivo, they may contribute to the overall biological effect of PA and their contribution should be taken into account. Furthermore, using these analogues, the radioimmunoassay measurements of PA may be standardized, as they may cross react with PA antibodies and interfere with the determination. In addition, five analogues were made by substituting Arg8 of PA with Lys8, Orn8, Dab8, Dap8 and Cit8. All of these analogues maintained high potency as OTAs in the uterotonic assay, although their activity was only about 1.5–3 times lower than PA. The most potent analogue in the uterotonic assay, [Dap8]PA, pA2 = 8.53, had weak pressor activity (pA2 = 6.90) and no antidiuretic effect. The pressor activity was lower for all tested acids, and for PA1–6 acid it was even below the detection limit. Additionally, PA1–9 acid, PA1–7 acid and PA1–6 acid showed no antidiuretic activity. Hence, the PA1–6 acid is a potent OTA with pA2 = 8.27 and no measurable effect in the pressor or antidiuretic tests and thus it is a pure oxytocin antagonist. This fact makes it an attractive candidate for further studies on inhibition of OT biological effects and on preterm labour. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.
Modelling covariance structure in ascending dose studies of isolated tissues and organs
Authors: Brammer Richard John
Published: June 2003

This paper describes the analysis of two pharmacology assays: the guinea pig papillary muscle assay (an example of an isolated tissue assay) and an assay looking at pressure changes in isolated rat lungs. Both assays use an ascending dose design to minimize carryover effects. This is often necessary in these studies, due to the limited life span of the tissues. Various mixed models, with different covariance structures, are fitted to find the most appropriate model. These are then compared to two other possible methods of analysis: paired t‐tests and two‐way analysis of variance. For both assays, the mixed model was found to be the best approach. These examples illustrate the importance of modelling covariance structure correctly in any ascending dose study, whether in isolated organs/tissues, in animals or phase I volunteers. Copyright © 2003 John Wiley & Sons, Ltd.
Gamma failure‐time mixture models: yet another way to establish efficacy
Authors: Koti Kallappa M.
Published: June 2003

Using a Yamaguchi‐type generalized gamma failure‐time mixture model, we analyse the data from a study of autologous and allogeneic bone marrow transplantation in the treatment of high‐risk refractory acute lymphoblastic leukaemia, focusing on the time to recurrence of disease. We develop maximum likelihood techniques for the joint estimation of the surviving fractions and the survivor functions. This includes an approximation to the derivative of the survivor function with respect to the shape parameter. We obtain the maximum likelihood estimates of the model parameters. We also compute the variance‐covariance matrix of the parameter estimators.

The extended family of generalized gamma failure‐time mixture models is flexible enough to include many commonly used failure‐time distributions as special cases. Yet these models are not used in practice because of computational difficulties. We claim that we have overcome this problem. The proposed approximation to the derivative of the survivor function with respect to the shape parameter can be used in any statistical package. We also address the issue of lack of identifiability. We point out that there can be a substantial advantage to using the gamma failure‐time mixture models over nonparametric methods. Copyright © 2003 John Wiley & Sons, Ltd.
Examples of option values in drug development
Authors: Burman Carl‐Fredrik , Senn Stephen
Published: June 2003

The option to stop a project is fundamental in drug development. The majority of drugs do not reach the market. Furthermore, many marketed drugs do not repay their development costs. It is therefore crucial to optimize the value of the option to stop.

We formulate two examples of statistical models. One is based on success/failure in a series of trials; the other assumes that the commercial value evolves as a stochastic process as more information becomes available. These models are used to study a number of issues: the number and timing of decision points; value of information; speed of development; and order of trials.

The results quantify the value of options. They show that early information that can change key decisions is most valuable. That is, we should nip bad projects in the bud. Modelling is also useful to analyse more complex decisions, for example, weighting the value of decision points against the cost of information or the speed of development. Copyright © 2003 John Wiley & Sons, Ltd.
Inhibition of the progression of type 2 diabetes in the C57BL/6J mouse model by an anti‐diabetes herbal formula
Authors: Winters Wendell D. , Huo Yu Shu , Yao Da‐Lin
Published: June 2003

The effects of a speciﬁcally prepared anti‐diabetic herbal formula (ADHF) on the course of established diet‐induced type 2 diabetes in animal subjects has been studied. In a C57BL/6J mouse model for diet induced type 2 diabetes, intervention for 12 weeks using ADHF as a diet supplement resulted in a signiﬁcant inhibition of diabetes related changes in major organs usually targeted by type 2 diabetes and a signiﬁcant reduction in circulating levels of glucose and insulin. Young male mice were randomly assigned to receive ad libitum exposure to either a standard rodent chow diet or to a high fat, high simple sugar, low ﬁbre diet (diabetes induction diet), respectively for 8 weeks. All mice fed the induction diet developed abnormally high blood glucose levels at 8 weeks. Animals with conﬁrmed diet induced diabetic blood glucose levels were again randomly assigned into one of three groups (10 subjects per group), one group was thereafter fed only the diabetes induction diet and the other two groups were thereafter fed the diabetes induction diet into which ADHF had been mixed at 4% or at 8% ﬁnal concentrations. Normal mice were also randomized into two groups that were fed either a regular diet alone or 8% ADHF mixed in the regular diet. Blood glucose levels markedly increased over the 20 weeks of study in the diabetic mice fed the diabetes induction diet only. In contrast, diabetic mice fed induction diet into which 4% or 8% ADHF had been incorporated showed signiﬁcantly decreased blood glucose and insulin levels over the time of the study. Additional parameters signiﬁcantly reduced in diabetic mice fed ADHF included insulin resistance and histopathological changes in the pancreas and liver. This is the ﬁrst report to our knowledge to show in vivo evidence for signiﬁcantly decreased circulating glucose and insulin levels and a signiﬁcant reduction of progressive damage to major target organs by the addition of an herbal diet supplement to a diabetes induction diet proven to be capable of causing and maintaining type 2 diabetes. Copyright © 2003 John Wiley & Sons, Ltd.
Antifungal compounds from Zanthoxylum chiloperone var. angustifolium
Authors: Thouvenel Céline , Gantier Jean‐Charles , Duret Philippe , Fourneau Christophe , Hocquemiller Reynald , Ferreira Maria‐Elena , de Arias Antonieta Rojas , Fournet Alain
Published: June 2003

An alkaloidal extract of the stem barks of Zanthoxylum chiloperone var. angustifolium exhibited antifungal activity against Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes var. interdigitale using a TLC bioautographic method. Bioassay‐guided fractionation of this extract resulted in the isolation of two active compounds identiﬁed as canthin‐6‐one and 5‐methoxycanthin‐6‐one. Canthin‐6‐one exhibited a broad spectrum of activities against Aspergillus fumigatus, A. niger, A. terreus, Candida albicans, C. tropicalis, C. glabrata, Cryptococcus neoformans, Geotrichum candidum, Saccharomyces cerevisiae, Trichosporon beigelii, Trichosporon cutaneum and Trichophyton mentagrophytes var. interdigitale with MICs values between 5.3 and 46 µmol/L. 5‐methoxy‐canthin‐6‐one was active against only Trichophyton mentagrophytes var. interdigitale with a MIC value of 12.3 µmol/L. Copyright © 2003 John Wiley & Sons, Ltd.
Antiprotozoal activity of the constituents of Rubus coriifolius
Authors: Alanís Alma Delia , Calzada Fernando , Cedillo‐Rivera Roberto , Meckes Mariana
Published: June 2003

Extraction of the aerial parts of Rubus coriifolius, a medicinal plant used by the Maya communities in Southern Mexico to treat bloody diarrhoea, resulted in the isolation of seven known compounds (−)‐epicatechin, (+)‐catechin, hyperin, nigaichigoside F1, β‐sitosterol 3‐O‐β‐d‐glucopyranoside, gallic acid and ellagic acid. All compounds were tested for their antiprotozoal activity against Entamoeba histolytica and Giardia lambia. Epicatechin was the main responsible for the antiprotozoal activity of the extract against both protozoa, its activity was comparable to emetine, but no exceeded that of metronidazole. Copyright © 2003 John Wiley & Sons, Ltd.
Evaluation of efficacy and safety of a herbal medicine used for the treatment of malaria
Authors: Ankrah Nii‐Ayi , Nyarko Alexander K. , Addo Phyllis G. A. , Ofosuhene Mark , Dzokoto Comfort , Marley Ethel , Addae Michael M. , Ekuban Frederick A.
Published: June 2003

Resistance of Plasmodium falciparum to chloroquine has been reported in several countries. Other anti‐malarial drugs in use are expensive and not readily accessible to most people in malaria endemic countries. This has led to renewed interest in the development of herbal medicines that have the potential to treat malaria with little or no side effects. This study obtained a preliminary information on the safety and effectiveness of a plant decoction (AM‐1), used in treating malaria.

The AM‐1 is formulated from Jatropha curcas, Gossypium hirsutum, Physalis angulata and Delonix regia. Patients with suspected malaria attending a herbal clinic were enrolled in the study on voluntary basis. They were hospitalized for treatment, clinical observation, biochemical and haematological monitoring, and parasite clearance while on AM‐1. In addition male and female Sprague Dawley rats were used to evaluate the acute and subchronic toxicity effects of AM‐1.

The AM‐1 eliminated malaria parasites (Plasmodium falciparum and Plasmodium malarie) from the peripheral blood of patients with malaria. In addition the AM‐1 did not show any undesired effects in the patients as well as in laboratory rats. The AM‐1, however, showed differential effect on the activities of selected cytochrome P450 isozymes (7‐pentoxyresorufin‐O‐depentylation, 7‐ethoxyresorufin‐O‐deethylation and p‐nitrophenol hydroxylase) in relation to sex of the laboratory rats.

These results indicate that AM‐1 could be used to treat malaria. However, it could precipitate interactions with other drugs via their biotransformation and elimination. The obtained data warrant further studies in a large number of malaria subjects with monitoring for possible drug interactions. Copyright © 2003 John Wiley & Sons, Ltd.
Anti‐herpesvirus activity of an extract of Ribes nigrum L.
Authors: Suzutani Tatsuo , Ogasawara Masahiro , Yoshida Itsuro , Azuma Masanobu , Knox Yoko M.
Published: June 2003

An extract of Ribes nigrum L., known as blackcurrant in Europe and Kurokarin® in Japan, has been used as an ingredient in a variety of foods and folk medicine. In this study, the anti‐herpesvirus activity of this extract was examined in vitro. The extract inhibited herpes simplex virus type 1 attachment on the cell membrane completely at a 100‐fold dilution, as well as the plaque formation of herpes simplex virus types 1 and 2, and varicella‐zoster virus by 50% at a 400‐fold dilution or lower concentrations. This latter activity, which inhibits virus replication in cells, was due to the inhibition of protein synthesis in infected cells from the early stage of infection. Kurokarin is a possible candidate as a herbal medicine for herpesvirus infectious diseases. Copyright © 2003 John Wiley & Sons, Ltd.
Protective effects of saffron (Crocus sativus Linn.) on genotoxins‐induced oxidative stress in Swiss albino mice
Authors: Premkumar K. , Abraham Suresh K. , Santhiya S. T. , Ramesh A.
Published: June 2003

The modifying effects of the aqueous extract of saffron (dried stigmas of Crocus sativus Linn.) on cisplatin (CIS), cyclophosphamide (CPH), mitomycin‐C (MMC) and urethane (URE) induced alterations in lipid peroxidation and antioxidant status were investigated in Swiss albino mice. Three doses of saffron (20, 40 and 80 mg/kg body weight) were orally administered to mice for 5 consecutive days prior to administration of genotoxins. A signiﬁcant reduction in the extent of lipid peroxidation with a concomitant increase in the liver enzymatic (SOD, CAT, GST, GPx) and non‐enzymatic antioxidants (reduced glutathione) were observed in saffron pretreated animals compared with the genotoxins alone treated animals. However, the modulatory effects were not always dose dependent. Our data suggest that saffron may exert its chemopreventive effects by modulation of lipid peroxidation, antioxidants and detoxiﬁcation systems. Copyright © 2003 John Wiley & Sons, Ltd.
Antiamoebic activity of benzyl glucosinolate from Lepidium virginicum
Authors: Calzada Fernando , Barbosa Elizabeth , Cedillo‐Rivera Roberto
Published: June 2003

In a continuation of our search for potential antiprotozoal agents from plants, we found that a crude extract from the roots of Lepidium virginicum exhibited antiprotozoal activity against Entamoeba histolytica trophozoites (IC50 of 100.1 µg/mL). Bioassay‐guided fractionation resulted in the isolation of one known glucosinolate responsible for such activity. This compound was identiﬁed as benzyl glucosinolate. It showed in vitro activity against Entamoeba histolytica strain HM1‐IMSS (IC50 of 20.4 µg/mL). The results support the anecdotal reports for the traditional use of L. virginicum roots in the control of diarrhoea and dysentery in the highlands of Chiapas, Mexico. Copyright © 2003 John Wiley & Sons, Ltd.
Comparison of antimalarial activity of the alkaloidal fraction of Hydrangea macrophylla var. Otaksa leaves with the hot‐water extract in ICR mice infected with Plasmodium yoelii 17 XL
Authors: Ishih Akira , Miyase Toshio , Terada Mamoru
Published: June 2003

The antimalarial activity of the fractions isolated from the leaves of Hydrangea macrophylla Seringe var. Otaksa Makino was evaluated against Plasmodium yoelii 17 XL in mice. Four different fractions were prepared in the usual manner to obtain an alkaloid fraction. All mice treated with the fraction containing febrifugine and isofebrifugine mixture at 1 mg/kg twice a day for 5 consecutive days survived during the experiment, and the change of mean parasitemia level showed almost the same pattern as that from mice treated with the hot‐water extract of the same plant leaves. Activity of this fraction, however, was markedly reduced compared with the hot‐water extract. Furthermore, no antimalarial activity was shown in the hotwater extract from H. macrophylla var. Otaksa roots or Dichroa febrifuga Lour. leaves. Copyright © 2003 John Wiley & Sons, Ltd.
Main flavonoids in the root of Scutellaria baicalensis cultivated in Europe and their comparative antiradical properties
Authors: Bochořáková Hana , Paulová Hana , Slanina Jiří , Musil Pavel , Táborská Eva
Published: June 2003

The content of the main flavonoids in the root of Scutellaria baicalensis Georgi cultivated in Central Europe was evaluated using the new simple RP‐HPLC method with gradient of acetonitrile in mobile phase. The main components of the roots were baicalin (8.12% of dry root mass) and wogonin glucuronide (2.52%). The content of flavonoids was comparable with the content in plants cultivated in natural localities. Five main flavonoids were evaluated for their scavenging ability with DPPH radical‐generating system and due to limited solubility only two flavonoids were investigated for their ability to scavenge hydroxyl radical by the aromatic hydroxylation method. The total extract was also tested in both the experimental arrangements. In experiments with DPPH, only baicalin and baicalein displayed a significant scavenging effect, while the production of OH radicals generated by UV photolysis of H2O2 was considerable decreased in the presence of baicalin and wogonin glucuronide. After comparison with results obtained for the total extract, it was concluded, that the scavenging activity of the extract against DPPH is mainly derived from baicalin. On the other hand, baicalin, wogonin glucuronide and probably other flavonoids participate in scavenging OH radical. Copyright © 2003 John Wiley & Sons, Ltd.
Assessment of therapeutic effect of Inula heterolepsis Boiss in alcoholic rats
Authors: Saygi Şahan , Konuklugil Belma , Kutsal Osman , Uzbay İ. Tayfun , Deniz Gönen , Gören Zafer
Published: June 2003

An aqueous extract from the root of Inula heterolepsis Boiss was prepared and then tested for its ability to treat experimentally induced alcoholic hepatic injury in rats. Alcoholic rats were divided into two groups. The ﬁrst group of rats were given 200 mg/kg/day plant extract. Repeated doses of extract preparations were given at 12 h intervals for 10 days. Differences between the recovery of tissue injury, with and without Inula plant extract, were evaluated. The second group of rats were given vehicle. Liver, testis and kidney injuries due to the chronic alcohol consumption were proven biochemically and histopathologically. Rats were killed, serum SGOT, SGPT, alkaline phosphatase, and albumin levels were measured. SGOT, SGPT and alkaline phosphatase levels were signiﬁcantly higher in alcoholic rats due to the tissue damage compared with intact, vehicle and Inula treated groups of rats (p < 0.05). Liver, testis, kidneys, stomach, intestine, heart, lungs and bladder were examined histopathologically. According to our study, the root extract of Inula heterolepsis Boiss has a slight therapeutic effect on alcoholic liver, kidney and testis damage in rats. Comparing the therapeutic effects in these organs, the liver seemed to be affected meaningfully after treatment with the plant extract. Copyright © 2003 John Wiley & Sons, Ltd.
The effect of a strongly basic alkaloidal fraction of Rhazya stricta, a traditional medicinal plant, on cytochrome P450‐mediated metabolism of theophylline in mice
Authors: El‐Kadi A. O. , Tanira M. O. M. , Ali B. H. , Bashir A. K. , Souich P. Du
Published: June 2003

The strongly basic alkaloidal fraction of the traditional medicinal plant Rhazya stricta (RS) was given orally to mice, in a single dose of 10 mg/kg (group 1) or, twice daily for 3 days at the same dose (group 2). A third group (control) received normal saline. Liver homogenates from all animals were used to assess the microsomal activity of cytochrome P450 and its isoforms as well as its catalytic activity (using theophylline as a substrate). RS alkaloidal fraction had no signiﬁcant effect on the total amount of microsomal cytochrome P450, but it caused a signiﬁcant increase in the cytochrome P450 isoforms CYPs 1A1 and 1A2. It also signiﬁcantly increased the concentrations of some metabolites of theophylline. These results suggest that RS has the potential to interact with other drugs that are biotransformed by cytochrome P450, when given concomitantly with it. Copyright © 2003 John Wiley & Sons, Ltd.
Pharmacological effects of extracts from Valeriana adscendens Trel. II. Effects on GABA uptake and amino acids
Authors: De Feo Vincenzo , Faro Carlos
Published: June 2003

Methanolic and aqueous extracts from Valeriana adscendens (Valerianaceae), that previously demonstrated neuroleptic‐like properties, were studied for their effects on GABA uptake and amino acid neurotransmitter levels. The methanolic estract showed a significant effect in inhibiting GABA uptake and in decreasing the intracellular content of amino acid neurotransmitters in crude synaptosomes of rat. The data obtained could explain the neuroleptic activity of methanolic extract of the plant and confirm its traditional use. Copyright © 2003 John Wiley & Sons, Ltd.
Hepatoprotective effect of the extract and isocytisoside from Aquilegia vulgaris
Authors: Adamska T. , Młynarczyk W. , Jodynis‐Liebert J. , Bylka W. , Matławska I.
Published: June 2003

The hepatoprotective effect of the ethanol extract (AvEE) and the main ﬂavonoid compound 4′‐methoxy‐5,7‐dihydroxyﬂavone 6‐C‐β‐glucopyranoside (isocytisoside, ISOC) from the leaves and stems of Aquilegia vulgaris L. were studied using the CCl4‐induced hepatotoxicity test.

The acute toxicity test in mice showed that AvEE can be classiﬁed as nontoxic since a dose of 3000 mg/ kg did not cause mortality.

The barbiturate‐induced sleeping time prolonged by CCl4 administration to mice was signiﬁcantly reduced after AvEE treatment proving the protective effect of the extract on microsomal drug‐metabolizing enzymes.

AvEE and ISOC administered to rats 48 h, 24 h and 2 h before, and 6 h after CCl4 intoxication caused a signiﬁcant decrease in the CCl4‐induced elevation of hepatic enzymes activity in serum, i.e. sorbitol dehydrogenase (SDH), glutamate oxaloacetate and glutamate pyruvate transaminases (GOT, GPT).

Both substances induced CCl4‐diminished erythrocyte superoxide dismutase (SOD) and reduced the activities of glutathione peroxidase (GPx) and glutathione reductase (GR) preliminarily enhanced by CCl4.

The hepatoprotective properties of AvEE and ISOC were conﬁrmed by pathomorphological examination of the liver. Copyright © 2003 John Wiley & Sons, Ltd.
Designing an accelerated degradation experiment by optimizing the estimation of the percentile
Authors: Yu Hong‐Fwu
Published: June 2003

Degradation tests are widely used to assess the reliability of highly reliable products which are not likely to fail under traditional life tests or accelerated life tests. However, for some highly reliable products, the degradation may be very slow and hence it is impossible to have a precise assessment within a reasonable amount of testing time. In such cases, an alternative is to use higher stresses to extrapolate the product's reliability at the design stress. This is called an accelerated degradation test (ADT). In conducting an ADT, several decision variables, such s the inspection frequency, sample size and termination time, at each stress level are influential on the experimental efficiency. An inappropriate choice of these decision variables not only wastes experimental resources but also reduces the precision of the estimation of the product's reliability at the use condition. The main purpose of this paper is to deal with the problem of designing an ADT. By using the criterion of minimizing the mean‐squared error of the estimated 100$p$th percentile of the product's lifetime distribution at the use condition subject to the constraint that the total experimental cost does not exceed a predetermined budget, a nonlinear integer programming problem is built to derive the optimal combination of the sample size, inspection frequency and the termination time at each stress level. A numerical example is provided to illustrate the proposed method. Copyright © 2003 John Wiley & Sons, Ltd.
Determining the lifetime of CD‐RWs using efficient sampling on a production line
Authors: Chen Chie‐Bein
Published: June 2003

This work derives the intermittent batch size and sample size for product life testing on a production line. The sequential probability ratio test was adopted to determine the sample size, $n$, and the expected number of samples (ENS). An inverse chi‐square approximation was used to determine the relationship between the degree of freedom, $m-1$, and the estimated range of $\sigma^2$ $(ER\,\sigma^2)$ at various $(1-\alpha)$ levels of confidence. Consequently, ENS and $m$ were used to determine the intermittent batch size, $l$. Finally, rewritable compact disks (CD‐RWs) underwent testing to demonstrate the feasibility and effectiveness of the proposed efficient sampling approach. Copyright © 2003 John Wiley & Sons, Ltd.
An alternative desirability function for achieving ‘six sigma’ quality
Authors: Ribardo Charles , Allen Theodore T.
Published: June 2003

To achieve high process yields or ‘six sigma’ quality, engineers often need to evaluate and optimize processes that are characterized by multiple quality characteristics. Existing desirability functions weigh together multiple objectives but they have a number of limitations. Most importantly, available desirability functions do not explicitly account for the combined effect of the mean and the dispersion of the quality characteristic. Therefore, it is easy to incur excessive expenditures or unknowingly to fail to achieve targeted yields. In this paper, a desirability function is proposed that addresses these limitations. This function conservatively estimates the ‘effective yield’ under assumptions described in the ‘six sigma’ literature. We use an arc‐welding application to illustrate how the proposed desirability function can yield a substantially higher level of quality as well as a more accurate assessment of the process capability than available alternatives. We suggest that the proposed desirability function should be used to facilitate multicriterion optimization when dispersion data are available. Copyright © 2003 John Wiley & Sons, Ltd.
Reliability analysis of electronic devices with multiple competing failure modes involving performance aging degradation
Authors: Huang Wei , Askin Ronald G.
Published: June 2003

This paper presents an extension of reliability analysis of electronic devices with multiple competing failure modes involving performance aging degradation. The probability that a product fails on a specific mode is derived. Using this probability, the dominant failure mode on the product can be predicted. A practical example is presented to analyze an electronic device with two kinds of major failure modes–solder/Cu pad interface fracture (a catastrophic failure) and light intensity degradation (a degradation failure). Reliability modeling of an individual failure mode and device reliability analysis is presented and results are discussed. Copyright © 2003 John Wiley & Sons, Ltd.
Accidents, often the result of an ‘uncontrolled business process’—a study in the (Dutch) chemical industry
Authors: Sonnemans P. J. M. , Körvers P. M. W. , Brombacher A. C. , van Beek P. C. , Reinders J. E. A.
Published: June 2003

Often companies in the (petro‐) chemical industry claim that all possible countermeasures against potential accidents have been taken and therefore accidents are unforeseeable. In this paper we question this statement by analysing the pre‐warning signals (precursors) preceding a number of industrial accidents. 17 accidents that occurred in the (petro‐) chemical industry have been investigated by exploring FACTS, an accident database containing information about industrial accidents worldwide. This paper will demonstrate that the existence of precursor information could have been used to foresee and even prevent these accidents if a proper control action had been initiated. The accidents are analysed further, according to a control model, which was adapted from that of C. Argyris. It demonstrates the ineffectiveness of several elements of business process control loops and that the so‐called ‘double‐loop learning’ cycle is more important than the ‘single‐loop learning’ cycle if one considers safety improvement. Copyright © 2003 John Wiley & Sons, Ltd.
International Workshops on QSARs in the Environmental Sciences – The First 20 Years
Authors: Walker John D.
Published: June 2003

Since 1983, ten international workshops have been organized to discuss Quantitative Structure Activity Relationships (QSARs) in the environmental sciences. This letter identifies the dates, locations and organizers of these 10 workshops, quantifies the number of papers that have been published from the workshops and describes the topics that have been discussed at these workshops.
QSAR of Progestogens: Use of a Priori and Computed Molecular Descriptors and Molecular Graphics
Authors: Kiralj Rudolf , Takahata Yuji , Ferreira Márcia M. C.
Published: June 2003

Quantitative Structure‐Activity Relationship (QSAR) study of two sets of oral progestogens was carried out by using Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA) and Partial Least Squares (PLS). A priori, computed (at DFT 6‐31G** level) and molecular graphics and modeling descriptors were employed. Molecular graphics and modeling studies of crystal structures of complexes progesterone receptor (PR)‐progesterone, Fab′‐progesterone and PR‐metribolone have been performed. QSAR of progestogens is a three‐dimensional phenomenon (over 96% of information is explained by the first three Principal Components), which can be, although it exhibits significant non‐linearity, treated well with linear methods such as PLS. Progestogen activity depends primarily on double bond contents and resonance effects which define the skeletal conformation, and also on substituent characteristics (size, conformational and electronic properties). Sterical relationships between a substituent at C6(sp2) or C6(sp3)‐α and sulfur atom from Met 801 residue of PR are important for progesterone binding to the protein and can be quantified. Basically the same was observed for substituents at β‐C10 with respect to residue Met759.
Synthesis and QSAR Studies on the Antifungal Activity of 2,3,4‐Substituted Thiazolidines
Authors: Prabhakar Yenamandra S. , Jain P. , Khan Z. K. , Haq W. , Katti S. B.
Published: June 2003

2,3,4‐Substituted Thiazolidines were synthesized and explored for antifungal activity against Candida albicans, Cryptococcus neoformans, Tricophyton mentagrophyte and Aspergillus fumigatus. The 2D‐ and 3D‐QSAR studies indicate the usefulness of this skeleton as a potential scaffold to explore new antifungal agents. The activity of these compounds against Candida albicans appears to be non‐specific. For the remaining three fungal organisms, the 3D‐equations identified are based on three biophoric centers. In case of Cryptococcus neoformans and Tricophyton mentagrophyte, both 2D and 3D‐QSAR equations have highlighted the positive role of bulk properties of the compounds in deciding their antifungal activity. Among the models, the one against Aspergillus fumigatus is the most complex and identifies thiazolidines C4 and C2‐phenyl region as main players in deciding the activity in terms of steric and electronic properties, respectively. All these equations suggest the necessity of steric and hydrophobic groups at C4 substitution and C2‐phenyl moiety of thiazolidine for optimum and broad‐spectrum antifungal activity. Also, the models suggest that S1, N3, C2‐phenyl moiety, oxygen of t‐butyloxy carbonyl or benzoyl attached to N3 and carboxyl oxygen of C4 of thiazolidines are the part of most probable centers for biophoric sites.
Magic bimetallic cluster anions of M/Pb (M = Au, Ag and Cu) observed and analyzed by laser ablation and time‐of‐flight mass spectrometry
Authors: Xing Xiaopeng , Tian Zhixin , Liu Hongtao , Tang Zichao
Published: June 2003

By using laser ablation on mixtures of coinage metals M (Cu, Ag, Au) and lead, M/Pb binary cluster anions containing up to tens of atoms were produced and analyzed. Most of the magic clusters discovered can be described based on the electron shell models which were deduced from simple homogeneous metal cluster systems. The clustering activities of coinage metals and lead were also compared with the properties of their bulk binary alloys. Copyright © 2003 John Wiley & Sons, Ltd.
Quantitative determination of paroxetine and its 4‐hydroxy‐3‐methoxy metabolite in plasma by high‐performance liquid chromatography/electrospray ion trap mass spectrometry: application to pharmacokinetic studies
Authors: Segura Mireia , Ortuño Jordi , Farré Magí , Pacifici Roberta , Pichini Simona , Joglar Jesús , Segura Jordi , Torre Rafael de la
Published: June 2003

A high‐performance liquid chromatography (HPLC) method with tandem mass spectrometric detection is described for the determination of paroxetine, an antidepressant drug, and its metabolite (3S,4R)‐4‐(4‐fluorophenyl)‐3‐(4‐hydroxy‐3‐methoxyphenoxymethyl)piperidine (HM paroxetine) in human plasma. Plasma samples were hydrolysed with hydrochloric acid and then analytes were extracted with ethyl acetate at alkaline pH. Extracts were analysed by HPLC coupled to an atmospheric pressure ionisation‐electrospray (ESI) interface and an ion trap mass spectrometer. Chromatography was performed on a reversed‐phase column using acetonitrile/0.02% formic acid (66:34, v/v) as a mobile phase. The mass spectrometer was operated in the multiple reaction monitoring mode. The method was validated over concentration ranges of 0.75–100 μg/L and 5–100 μg/L for paroxetine and HM paroxetine, respectively. Mean recoveries of 77% for paroxetine and 76% for HM paroxetine were found, with precision always better than 15%. The limits of detection and quantification were 0.20 and 0.70 μg/L for paroxetine, and 0.70 and 2.20 μg/L for its metabolite. The method was applied to the analysis of plasma samples obtained from nine healthy male volunteers administered with a single oral dose of 20 mg paroxetine. After the 20‐mg dose, the mean peak plasma concentration was 8.60 μg/L for paroxetine and 92.40 μg/L for HM paroxetine showing a tenfold ratio between the metabolite and the parent drug along the entire time‐concentration curve. Copyright © 2003 John Wiley & Sons, Ltd.
An intramolecular benzyl rearrangement of 1‐(N‐benzyloxycarbonylamino)alkylphosphonate diesters under electrospray ionization conditions
Authors: Ma Yuan , Chen Yi , Sun Ming , Zhao Yufen
Published: June 2003

The mass spectrometric behavior of eleven 1‐(N‐benzyloxycarbonyl(Cbz)amino)alkylphosphonate diesters was studied under positive ion electrospray ionization (ESI) conditions. Their fragmentation pathways are depicted and supported by tandem mass spectrometry. Besides the common eliminations of ether, benzyl alcohol, phosphite and an ether plus benzyl alcohol from molecular ions, the title compounds show a tendency to undergo an interesting intramolecular benzyl rearrangement to yield benzylphosphonate ions. The fragmentation patterns do not depend on the substituent attached to the α‐carbon atom. Copyright © 2003 John Wiley & Sons, Ltd.
Topology of hepatitis C virus envelope glycoproteins
Authors: Op De Beeck Anne , Dubuisson Jean
Published: June 2003

Hepatitis C virus encodes two envelope glycoproteins, E1 and E2, that are released from a polyprotein precursor after cleavage by host signal peptidase(s). These proteins contain a large N‐terminal ectodomain and a C‐terminal transmembrane domain, and they assemble as a noncovalent heterodimer. The transmembrane domains of hepatitis C virus envelope glycoproteins have been shown to be multifunctional: (1) they are membrane anchors, (2) they bear ER retention signals, (3) they contain a signal sequence function, and (4) they are involved in E1‐E2 heterodimerisation. Due to these multiple functions, the topology adopted by these transmembrane domains has given rise to much controversy. They are less than 30 amino acid residues long and are composed of two stretches of hydrophobic residues separated by a short segment containing one or two fully conserved positively charged residues. The presence of a signal sequence function in the C‐terminal half of the transmembrane domains of E1 and E2 had suggested that these domains are composed of two membrane spanning segments. However, the two hydrophobic stretches are too short to make two membrane spanning α‐helices. These discrepancies can now be explained by a dynamic model, based on experimental data, describing the early steps of the biogenesis of hepatitis C virus envelope glycoproteins. In this model, the transmembrane domains of E1 and E2 form a hairpin structure before cleavage by a signal peptidase, and a reorientation of the second hydrophobic stretch occurs after cleavage to produce a single membrane spanning domain. Copyright © 2003 John Wiley & Sons, Ltd.
Treatment of chronic hepatitis B: current challenges and future directions
Authors: Chin Ruth , Locarnini Stephen
Published: June 2003

The clinical management of chronic hepatitis B infection has entered a new era with the introduction and widespread use of oral nucleoside analogues such as lamivudine and nucleotides such as adefovir dipivoxil. From this, new challenges have now emerged in terms of preventing antiviral drug resistance, promoting viral clearance and improving long‐term survival. For example, the natural history of nucleoside or nucleotide analogue‐associated hepatitis B virus resistant mutants has yet to be determined. Furthermore, the increasing prevalence of HBeAg negative disease with its reduced response to current therapies represents an ongoing challenge to attempts to improve standard of care. There is increasing recognition of the pivotal role that viral load and genotype, and their complex interactions with the host immune response, play in determining the outcome of these treatment interventions. The purpose of this paper is to highlight several key factors that should be considered in the context of future clinical research and management of chronic hepatitis B. Copyright © 2003 John Wiley & Sons, Ltd.
Analyzing dynamic behavior of multiagents' task allocation based on subjective cooperative relations
Authors: Katoh Takashi , Kinoshita Tetsuo , Shiratori Norio
Published: June 2003

In multiagent systems in general, the behavior of the individual agent generally affects the behavior of the whole system. Consequently, in order to improve the efficiency of the whole system, it is crucial to know how the operation of the individual agent affects the whole system and to design the agents on the basis of that knowledge. This paper considers a multiagent system in which the technique proposed by the authors is applied to task allocation, and presents a basic analysis of the effect of the individual agent on the behavior of the whole system. More precisely, we consider an environment in which the procedure for updating information concerning the reliance relation to other agents, or the procedure for transfer of information concerning the power of other agents, and so on, is modified, or agents in the system are dynamically generated or deleted, and we analyze the efficiency of task processing and the amount of message traffic among the agents. Experiments are performed by defining several kinds of operations of the agents, and generating or deleting the agents while the system is operating. Based on the results of these investigations, basic guidelines for multiagent systems are presented. © 2003 Wiley Periodicals, Inc. Syst Comp Jpn, 34(9): 93–104, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10108
A cipher strength evaluation system based on statistical methods
Authors: Tsunoo Yukiyasu , Ohta Ryoji , Miyauchi Hiroshi , Nakamura Katsuhiro
Published: June 2003

In this paper the authors describe a cipher strength evaluation system and an example of its operation. The authors have developed a system to evaluate the mutual relationships among the input and output data of a cipher using statistical methods. The authors' system includes features to display the statistical results in a three‐dimensional graph format. As a result, the behavior of a cipher algorithm can be understood intuitively and in detail, and several different cipher algorithms can be compared. In addition, the authors' system provides a unified environment for program development which allows for comparative evaluations of the results of improvements which accompany algorithm adjustments during the process of cipher design. © 2003 Wiley Periodicals, Inc. Syst Comp Jpn, 34(9): 83–92, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10163
Automated liver segmentation using multislice CT images
Authors: Masumoto Jun , Hori Masatoshi , Sato Yoshinobu , Murakami Takamichi , Johkoh Takeshi , Nakamura Hironobu , Tamura Shinichi
Published: June 2003

With practical applications of multislice CT, high‐speed imaging has drastically become possible in recent years as compared with the past and imaging the liver twice during the time a patient holds his breath once has become possible in liver CT imaging using contrast media. Thus, three‐dimensional images of two time phases differing in the circulatory state of a contrast medium are obtainable without positional discrepancies. The authors propose an automated liver area extracting (segmenting) method using three‐dimensional CT images of two time phases of a contrast medium for extracting the shape of the liver. This method first constructs a two‐dimensional characteristic (feature) space having the CT values of time phases on each axis from the three‐dimensional images of a two time phase portion imaged immediately after and 10‐plus seconds after the infusion of a contrast medium. The method extracts areas showing changes in the contrast medium corresponding to the liver in this space and generates images with the liver region emphasized using these. The method then determines the liver region by performing opening and closing procedures on the liver area‐emphasized images generated. Finally, it determines the liver region by a three‐dimensional component connecting procedure using geometric shape characteristics of the blood vessels, tumors, and so on. The efficacy of using images of two time phases simultaneously has been verified by applying the proposed method to nine cases. © 2003 Wiley Periodicals, Inc. Syst Comp Jpn, 34(9): 71–82, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10210
Quantitative evaluation of spatial distribution of line structure in the lung for computer‐aided diagnosis of pulmonary nodules
Authors: Shikata Hidenori , Kitaoka Hiroko , Sato Yoshinobu , Johkou Takeshi , Nakamura Hironobu , Tamura Shinichi
Published: June 2003

In the discrimination of benign and malignant pulmonary nodules, it is considered very important to evaluate the spatial distribution of the line structure around the nodule. For quantitative evaluation, a computer must be used. This paper proposes a method in which line structures, such as vessels, in the chest CT image are extracted, and their spatial distribution is quantitatively evaluated. First, the line structures in the three‐dimensional CT image are extracted, and the direction of the central line is estimated from the eigenvector of the Hessian matrix. The angle between the direction vector of a point on the central line and the vector directed from that point to the nodule center is defined as the “centripetal angle.” By a statistical analysis of the distribution of the centripetal angle, the spatial distribution of the line structure is estimated. In the proposed method, only the variation of the nodule center can affect the result. Consequently, stable operation is expected with a simple manipulation. The method is applied to 20 clinical cases, and satisfactory classification results are obtained. The effects of the image reconstruction algorithm and of parameter values such as the threshold of line structure extraction on the results of the proposed method are examined, and its robustness and range of application are determined. © 2003 Wiley Periodicals, Inc. Syst Comp Jpn, 34(9): 58–70, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10222