bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of dental attrition and mortality in the Medieval village of Tirup, Denmark
Authors: Boldsen Jesper L.
Published: July 2004

New directions and new questions raised in the study of health in the past justify this reanalysis of the pattern of dental attrition in the Medieval Danish population of Tirup. Dental attrition was scored on all permanent molars from the Tirup skeletal sample. Scores were analyzed by means of logistic regression of the probability of having entered a given stage of wear for a given tooth in a way that is very similar to transition analysis. The primary determinant of dental attrition was age at death. In addition to age, the effects of sex, side, and dating were analyzed. In order to assess the homogeneity of the process of wearing teeth down, a third‐order polynomial in age‐at‐death was also fitted to the transition probabilities. It was found that age is the single most important determinant of dental attrition, and that sex or side did not differentiate the rate of attrition. In several transitions, there was evidence of heterogeneity, indicating both random and systematic interpersonal differences in the rate of attrition and an association between the rate of attrition and age‐at‐death. It was found that attrition proceeded more quickly after AD 1300 than prior to that date. It is suggested that this was due to a possible general deterioration of living conditions in Northern Europe and an increased reliance on grain for food during the first half of the 14th century. The temporal effect on attrition rate accounts for some but not all the observed heterogeneity wear. Am J Phys Anthropol 126:169–176, 2005. © 2004 Wiley‐Liss, Inc.
Humeral cross‐sectional morphology from 18th century Quebec prisoners of war: Limits to activity reconstruction
Authors: Weiss Elizabeth
Published: July 2004

This study uses measures of cross‐sectional robusticity and asymmetry (based on humeral areal and inertial cross‐sectional components) to test a prediction from bone remodeling theory that a physically active 18th century Quebec prisoner of war sample (N = 25) should have more robust and asymmetrical humeri than a nonphysically active 20th century New Mexico suburbanite sample (N = 27). Narrative accounts document that prisoners of war engaged in labor‐intensive activities, and these activities were confirmed by observations of osteoarthritis and other pathologies. The suburbanite sample, for the most part, did not engage in such activities. The prisoners had higher levels of pathology than the suburbanites (e.g., 80% vs. 22% osteoarthritis; F = 17.95, P < 0.01). For robusticity, the populations did not differ significantly in total area, cortical area, moment areas of inertia about the mediolateral plane, or polar moment area of inertia. The Quebec prison sample did have significantly higher values for moment areas of inertia about the anteroposterior plane. For asymmetry, the populations did not differ in any values (total area, cortical area, moment areas of inertia about the mediolateral plane, moment areas of inertia about the anteroposterior plane, or polar moment of inertia). Thus, examinations of cross‐sectional robusticity and asymmetry failed to conclusively confirm the hypothesis that intensive labor leads to changes in humeral morphology. Possible explanations for the lack of differences are discussed, such as poor diet impeding bone remodeling. Nevertheless, the one significant finding suggests that cross‐sectional shape is more useful in reconstructing activity patterns than amount of bone in a cross section. Results from this study join those from other recent investigations to suggest that additional controls are required before cross‐sectional differences may be confidently attributed to activity patterns. Am J Phys Anthropol, 2004. © 2004 Wiley‐Liss, Inc.
Interactions of tamoxifen, N‐desmethyltamoxifen and 4‐hydroxytamoxifen with P‐glycoprotein and CYP3A
Authors: Bekaii‐Saab Tanios S. , Perloff Michael D. , Weemhoff James L. , Greenblatt David J. , von Moltke Lisa L.
Published: July 2004

The effects of tamoxifen, N‐desmethyltamoxifen and 4‐hydroxytamoxifen on transport attributable to P‐glycoprotein were studied using Caco‐2 cell monolayers in a transwell system, with rhodamine‐123 as an index substrate for inhibition studies. The three compounds did not demonstrate differential flux between basal‐apical and apical‐basal directions in Caco‐2 monolayers. The mean IC50 values for inhibition of rhodamine‐123 transport were: 29 µM for tamoxifen; 26 µM for N‐desmethyltamoxifen; and 7.4 µM for 4‐hydroxytamoxifen. The three compounds were also evaluated as potential inhibitors of human CYP3A based on an in vitro model using triazolam hydroxylation by human liver microsomes as an index reaction. Mean (±SE) IC50 values versus formation of α‐hydroxy‐triazolam and 4‐hydroxy‐triazolam in human liver microsomes were, respectively: 23.5 (±3.9) and 18.4 (±5.3) µM for tamoxifen; 10.2 (±1.7) and 9.2 (±1.5) µM for N‐desmethyltamoxifen; and 2.6 (±0.5) and 2.7 (±0.3) µM for 4‐hydroxytamoxifen. Thus, tamoxifen, N‐desmethyltamoxifen and 4‐hydroxytamoxifen, do not appear to be substrates for transport by P‐glycoprotein. However, tamoxifen has the potential to inhibit transport mediated by P‐glycoprotein as well as CYP3A‐mediated metabolism. Inhibitory effects of the principal metabolites, N‐desmethyltamoxifen and 4‐hydroxytamoxifen, may exceed those of the parent drug. Tamoxifen, and possibly its metabolites, may have the potential to cause drug interactions by inhibiting both drug transport and metabolism. This possibility requires further evaluation in clinical studies. Copyright © 2004 John Wiley & Sons, Ltd.
Dynamics of water molecules buried in cavities of apolipoprotein E studied by molecular dynamics simulations and continuum electrostatic calculations
Authors: Prévost Martine
Published: July 2004

Molecular dynamics (MD) simulations of several nanoseconds each were used to monitor the dynamic behavior of the five crystal water molecules buried in the interior of the N‐terminal domain of apolipoprotein E. These crystal water molecules are fairly well conserved in several apolipoprotein E structures, suggesting that they are not an artifact of the crystal and that they may have a structural and/or functional role for the protein. All five buried crystal water molecules leave the protein interior in the course of the longest simulations and exchange with water molecules from the bulk. The free energies of binding evaluated from the electrostatic binding free energy computed using a continuum model and estimates of the binding entropy changes represent shallow minima. The corresponding calculated residence times of the buried water molecules range from tens of picoseconds to hundreds of nanoseconds, which denote rather short times as for buried water molecules. Several water exchanges monitored in the simulations show that water molecules along the exit/entrance pathway use a relay of H bonds primarily formed with charged residues which helps either the exit or the entrance from or into the buried site. The exit/entrance of water molecules from/into the sites is permitted essentially by local motions of, at most, two side chains, indicating that, in these cases, complex correlated atomic motions are not needed to open the buried site toward the surface of the protein. This provides a possible explanation for the short residence times. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
A novel convenient procedure for extractive work‐up of whole‐cell biotransformations using de‐emulsifying hydrolases
Authors: Jörg Gerhard , Leppchen Kathrin , Daussmann Thomas , Bertau Martin
Published: July 2004

Extractive work‐up of whole‐cell biotransformations generally suffers from the formation of stable gels and slimes upon addition of the organic solvent to the cell suspension and the cell‐free solution, respectively. This problem has been overcome by enzymatic lysis of emulsifying agents present in the medium through addition of hydrolases. Of these agents, proteases have exhibited the most powerful de‐emulsifying activity. Enzyme treatment of cell‐free culture media of Saccharomyces cerevisiae with pronase E drastically reduced phase separation time (tp) from 1 week to 30 min without significantly affecting product integrity. Yeast cell suspensions were de‐emulsified best with protease N‐01, where phase separation was complete after 1 h. As was exemplified with cell‐free culture media of Lactobacillus kefir, wherein addition of pronase E or protease N‐01 reduced tp from 1 week to 2 h each, this practical, ready‐to‐use method is appropriate for both fungal and bacterial biocatalysts. © 2004 Wiley Periodicals, Inc.
Multienzyme mevalonate pathway bioreactor
Authors: Sutherlin Autumn , Rodwell Victor W.
Published: July 2004

The five‐carbon metabolic intermediate isopentenyl diphosphate constitutes the basic building block for the biosynthesis of all isoprenoids in all forms of life. Two distinct pathways lead from amphibolic intermediates to isopentenyl diphosphate. The Gram‐positive cocci and certain other pathogenic bacteria employ exclusively the mevalonate pathway, a set of six enzyme‐catalyzed reactions that convert 3 mol of acetyl‐CoA to 1 mol each of carbon dioxide and isopentenyl diphosphate. The survival of the Gram‐positive cocci requires a fully functional set of mevalonate pathway enzymes. These enzymes therefore represent potential targets of inhibitors that might be employed as antibiotics directed against multidrug‐resistant strains of certain bacterial pathogens. A rapid throughput, bioreactor‐based assay to assess the effects of potential inhibitors on several enzymes simultaneously should prove useful for the survey of candidate inhibitors. To approach this goal, and as a proof of concept, we employed enzymes from the Gram‐positive pathogen Enterococcus faecalis. Purified recombinant enzymes that catalyze the first three reactions of the mevalonate pathway were immobilized in two kinds of continuous flow enzyme bioreactors: a classical hollow fiber bioreactor and an immobilized plug flow bioreactor that exploited a novel method of enzyme immobilization. Both bioreactor types employed recombinant acetoacetyl‐CoA thiolase, HMG‐CoA synthase, and HMG‐CoA reductase from E. faecalis to convert acetyl‐CoA to mevalonate, the central intermediate of the mevalonate pathway. Reactor performance was monitored continuously by spectrophotometric measurement of the concentration of NADPH in the reactor effluent. Additional potential applications of an Ni++ affinity support bioreactor include using recombinant enzymes from extremophiles for biosynthetic applications. Finally, linking a Ni++ affinity support bioreactor to an HPLC‐mass spectrometer would provide an experimental and pedagogical tool for study of metabolite flux and pool sizes of intermediates to model regulation in intact cells. © 2004 Wiley Periodicals, Inc.
Metabolic engineering and protein directed evolution increase the yield of L‐phenylalanine synthesized from glucose in Escherichia coli
Authors: Báez‐Viveros José Luis , Osuna Joel , Hernández‐Chávez Georgina , Soberón Xavier , Bolívar Francisco , Gosset Guillermo
Published: July 2004

L‐phenylalanine (L‐Phe) is an aromatic amino acid with diverse commercial applications. Technologies for industrial microbial synthesis of L‐Phe using glucose as a starting raw material currently achieve a relatively low conversion yield (YPhe/Glc). The purpose of this work was to study the effect of PTS (phosphotransferase transport system) inactivation and overexpression of different versions of feedback inhibition resistant chorismate mutase‐prephenate dehydratase (CM‐PDT) on the yield (YPhe/Glc) and productivity of L‐Phe synthesized from glucose. The E. coli JM101 strain and its mutant derivative PB12 (PTS−Glc+ phenotype) were used as hosts. PB12 has an inactive PTS, but is capable of transporting and phosphorylating glucose by using an alternative system constituted by galactose permease (GalP) and glucokinase activities (Glk). JM101 and PB12 were transformed with three plasmids, harboring genes that encode for a feedback inhibition resistant DAHP synthase (aroGfbr), transketolase (tktA) and either a truncated CM‐PDT (pheAfbr) or its derived evolved genes (pheAev1 or pheAev2). Resting‐cells experiments with these engineered strains showed that JM101 and PB12 strains expressing either pheAev1 or pheAev2 genes produced l‐Phe from glucose with YPhe/Glc of 0.21 and 0.33 g/g, corresponding to 38 and 60% of the maximum theoretical yield (0.55 g/g), respectively. In addition, in both engineered strains the reached qPhe high levels of 40 mg/g‐dcw*h. The metabolic engineering strategy followed in this work, including a strain with an inactive PTS, resulted in a positive impact over the YPhe/Glc, enhancing it nearly 57% compared with its PTS+ counterpart. This is the first report wherein PTS inactivation was a successful strategy to improve the YPhe/Glc. © 2004 Wiley Periodicals, Inc.
Serum‐free large‐scale transient transfection of CHO cells
Authors: Derouazi Madiha , Girard Philippe , Van Tilborgh Frédéric , Iglesias Keyvan , Muller Natalie , Bertschinger Martin , Wurm Florian M.
Published: July 2004

To date, methods for large‐scale transient gene expression (TGE) in cultivated mammalian cells have focused on two transfection vehicles: polyethylenimine (PEI) and calcium phosphate (CaPi). Both have been shown to result in high transfection efficiencies at scales beyond 10 L. Unfortunately, both approaches yield higher levels of recombinant protein (r‐protein) in the presence of serum than in its absence. Since serum is a major cost factor and an obstacle to protein purification, our goal was to develop a large‐scale TGE process for Chinese hamster ovary (CHO) cells in the absence of serum. CHO‐DG44 cells were cultivated and transfected in a chemically defined medium using linear 25 kDa PEI as a transfection vehicle. Parameters that were optimized included the DNA amount, the DNA‐to‐PEI ratio, the timing and solution conditions for complex formation, the transfection medium, and the cell density at the time of transfection. The highest levels of r‐protein expression were observed when cultures at a density of 2.0 × 106 cells/ml were transfected with 2.5 μg/ml DNA in RPMI 1640 medium containing 25 mM HEPES at pH 7.1. The transfection complex was formed at a DNA:PEI ratio of 1:2 (w/w) in 150 mM NaCl with a 10‐min incubation at room temperature prior to addition to the culture. The procedure was scaled up for a 20‐L bioreactor, yielding expression levels of 10 mg/l for an intracellular protein and 8 mg/l for a secreted antibody. © 2004 Wiley Periodicals, Inc.
Study of dye decolorization in an immobilized laccase enzyme‐reactor using online spectroscopy
Authors: Kandelbauer Andreas , Maute Oliver , Kessler Rudolf W. , Erlacher Angelika , Gübitz Georg M.
Published: July 2004

Decolorization of textile dyes by a laccase from Trametes modesta immobilized on γ‐aluminum oxide pellets was studied. An enzyme reactor was equipped with various UV/Vis spectroscopic sensors allowing the continuous online monitoring of the decolorization reactions. Decolorization of the dye solutions was followed via an immersion transmission probe. Adsorption processes were observed using diffuse reflectance measurements of the solid carrier material. Generally, immobilization of the laccase does not seem to sterically affect dye decolorization. A range of commercial textile dyes was screened for decolorization and it was found that the application of this enzymatic remediation system is not limited to a certain structural group of dyes. Anthrachinonic dyes (Lanaset Blue 2R, Terasil Pink 2GLA), some azo dyes, Indigo Carmine, and the triphenylmethane dye Crystal Violet were efficiently decolorized. However, the laccase displayed pronounced substrate specificities when a range of structurally related model azodyes was subjected to the biotransformation. Azodyes containing hydroxy groups in ortho or para position relative to the azo bond were preferentially oxidized. The reactor performance was studied more closely using Indigo Carmine. © 2004 Wiley Periodicals, Inc.
Development of a dedicated risk-adjustment scoring system for colorectal surgery (colorectal POSSUM)
Authors: Tekkis P P , Prytherch D R , Kocher H M , Senapati A , Poloniecki J D , Stamatakis J D , Windsor A C J
Published: July 2004

Background

The aim of the study was to develop a dedicated colorectal Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (CR-POSSUM) equation for predicting operative mortality, and to compare its performance with the Portsmouth (P)-POSSUM model.

Methods

Data were collected prospectively from 6883 patients undergoing colorectal surgery in 15 UK hospitals between 1993 and 2001. After excluding missing data and 93 patients who did not satisfy the inclusion criteria, 4632 patients (68·2 per cent) underwent elective surgery and 2107 had an emergency operation (31·0 per cent); 2437 operations (35·9 per cent) for malignant and 4267 (62·8 per cent) for non-malignant diseases were scored. Stepwise logistic regression analysis was used to develop an age-adjusted POSSUM model and a dedicated CR-POSSUM model. A 60 : 40 per cent split-sample validation technique was adopted for model development and testing. Observed and expected mortality rates were compared.

Results

The operative mortality rate for the series was 5·7 per cent (387 of 6790 patients) (elective operations 2·8 per cent; emergency surgery 12·0 per cent). The CR-POSSUM, age-adjusted POSSUM and P-POSSUM models had similar areas under the receiver–operator characteristic curves. Model calibration was similar for CR-POSSUM and age-adjusted POSSUM models, and superior to that for the P-POSSUM model. The CR-POSSUM model offered the best overall accuracy, with an observed: expected ratio of 1·000, 0·998 and 0·911 respectively (test population).

Conclusion

The CR-POSSUM model provided an accurate predictor of operative mortality. External validation is required in hospitals different from those in which the model was developed.
Pylorus-preserving pancreaticoduodenectomy for advanced duodenal disease in familial adenomatous polyposis
Authors: Gallagher M C , Shankar A , Groves C J , Russell R C G , Phillips R K S
Published: July 2004

Background

Although only 5 per cent of patients with familial adenomatous polyposis (FAP) die from duodenal cancer, a recent study indicated that the mortality rate is much higher in patients with Spigelman stage IV disease. This has prompted an increased rate of referral for excisional surgery and an analysis of the results.

Methods

Between January 1994 and June 2002, 16 patients with FAP (mean age 55 years; eight men) were referred to a single surgeon for pylorus-preserving pancreaticoduodenal resection for Spigelman stage IV duodenal adenomatosis.

Results

One patient died from multiple organ failure after relaparotomy for haemorrhage and a jejunal perforation; other major complications included anastomotic leak (one), primary haemorrhage (one), lymphatic leak (one), chylous ascites (one), pulmonary embolus (two) and prolonged delayed gastric emptying that required total parenteral nutrition (three). Overall there were 11 major complications in eight patients. Two patients developed insulin-dependent diabetes and one postprandial dumping. Postoperative histological examination revealed five unsuspected cancers, which led to four deaths within 3 years of surgery. One patient died 2 months after surgery from pulmonary thromboembolism and another at 5 months from an inoperable brain tumour. Nine of the 16 patients were alive and well at a mean of 38 months after surgery.

Conclusion

The choice between continued endoscopic surveillance and excisional surgery for Spigelman stage IV duodenal disease remains finely balanced.
Functional and physiological outcome following transanal repair of rectocele
Authors: Heriot A G , Skull A , Kumar D
Published: July 2004

Background

Rectoceles are traditionally repaired transvaginally and sexual dysfunction can be a significant complication. The aim of this study was to evaluate the functional and physiological outcome following transanal repair of rectoceles.

Methods

Forty-five patients of mean age 57·1 (range 34–78) years with a symptomatic anterior rectocele, selected by contrast retention greater than 15 per cent on isotope defaecography, underwent transanal repair of rectocele. Preoperative and postoperative symptoms were assessed by means of a questionnaire. A proportion of patients underwent anorectal physiology and isotope defaecography before and after surgery.

Results

Median(range) follow-up was 24 (2–50) months. One patient developed a wound infection after surgery. Thirty-five patients reported an excellent, good or fair result, with seven reporting a moderate and three a poor result. There was a reduction in incomplete evacuation (P < 0·001) confirmed by isotope defaecography (mean(s.d.) rectal emptying before surgery 57(14) per cent versus 76(9) per cent after surgery; P = 0·020), and a reduction in vaginal (P < 0·001) and perineal (P = 0·004) digitation. Symptomatic feeling of prolapse (vaginal bulging) was significantly improved (P < 0·001). There was no increase in incontinence (P = 0·688). Resting and squeeze anal canal pressures were unchanged after operation. Surgery did not result in sexual dysfunction.

Conclusion

Transanal repair of rectocele is a safe alternative to posterior colporrhaphy. It provides improvement in symptoms, reflected by anatomical improvement with minimal complications and no increase in dyspareunia.
Therapeutic strategy for signet ring cell carcinoma of the stomach
Authors: Kunisaki C , Shimada H , Nomura M , Matsuda G , Otsuka Y , Akiyama H
Published: July 2004

Background

Reports of clinicopathological characteristics and prognosis in patients with signet ring cell carcinoma (SRC) of the stomach are conflicting.

Methods

A retrospective review was undertaken of 1450 patients with gastric cancer who had undergone gastrectomy. Of 1113 patients who underwent a curative gastrectomy, 174 had SRC (early, 120; advanced, 54) and 939 had other types of gastric carcinoma. Clinicopathological features, prognostic factors and surgical outcome in patients with SRC and non-SRC were compared.

Results

In patients with early gastric cancer, age, histological type, and number and anatomical extent of lymph node metastases independently affected prognosis. Patients with SRC had a significantly better survival rate than those with non-SRC, although there was no difference in the extent or number of lymph node metastases. Mucosal tumours with a diameter of 40 mm or less and submucosal lesions with a diameter of 20 mm or less were not associated with lymph node metastasis. SRC in advanced disease was frequently poorly differentiated or scirrhous, but macroscopic appearance was not an independent prognostic factor.

Conclusion

Early SRC of the stomach is associated with a better prognosis than non-SRC. Conversely, in advanced gastric cancer histological type cannot be used to establish a definitive therapeutic strategy.
Identifying cause of quality defect in cheese using qualitative variables in a statistical experimental design
Authors: Wikström Malin , Sjöström Michael
Published: July 2004

Statistical experimental design was used to identify the stage or stages in a cheesemaking process that caused a quality defect. A full factorial design with five qualitative variables was constructed and a total of 32 experiments, each representing a unique combination of treatments, were then evaluated by a trained sensory panel. The average score for each sample was used as a response, and classical multiple linear regression (MLR) was used to find the relationship between the treatments (X) and the rate of quality defect (y). Evaluation of the design and the regression coefficients clearly showed that one of the factors, process step 3 (x3) at location B, was mainly responsible for high rates of the quality defect. In addition, process step 5 at location B, especially in combination with process step 2 or 4 at location A or step 3 at location B, increased the rate of quality defect in the cheese. The other factors had little or no effect. Copyright © 2004 John Wiley & Sons, Ltd.
Strategies for implementation and validation of on‐line models for multivariate monitoring and control of wood chip properties
Authors: Jonsson Pär , Sjöström Michael , Wallbäcks Lars , Antti Henrik
Published: July 2004

Here we present an approach for on‐line control and monitoring of pulpwood chip properties based on near infrared (NIR) spectroscopy and multivariate data analysis. In addition, this paper suggests how to deal with large multivariate data sets in order to extract information which can be used as a basis for changes in raw material or process conditions in the drive towards more optimal intermediate or end product properties within the pulp and paper industry. The pulpwood chips used as raw material in a pulp and paper making process were characterized at‐ and on‐line using NIR spectroscopic measurements. Collected NIR spectra were used in multivariate calibration models for prediction of the moisture content as well as the between‐ and within‐species variation in the studied raw material. Statistical experimental design was used to form a calibration data set including most of the variation occurring in a ‘real’ on‐line situation. NIR spectra for all designed samples were measured at‐line and the estimated calibration models were used for carrying out predictions on‐line. Predictions of the moisture content (% dry weight) as well as the percentage contents of pine and sawmill chips in the raw material were carried out using partial least squares projections to latent structures (PLS) methodology. NIR spectra were collected subsequently on‐line once every minute, and, to reduce the problem with noise in the time series predictions, the measured signals were filtered using a moving average of 100 predicted values. This provided smoother predictions more suitable for process monitoring and control. To validate the quality of the predictions, wood chips from the studied process were sampled and analysed in the laboratory before being subjected to predictions in the on‐line model. Comparison of the filtered on‐line predictions with the results obtained from the laboratory measurements indicated that moisture and pine chip contents could be well predicted by the on‐line model, while predictions of sawmill chip content showed less promising results. Copyright © 2004 John Wiley & Sons, Ltd.
Potentialities of multivariate approaches in genome‐based cancer research: identification of candidate genes for new diagnostics by PLS discriminant analysis
Authors: Musumarra G. , Barresi V. , Condorelli D. F. , Fortuna C. G. , Scirè S.
Published: July 2004

Partial least squares discriminant analysis (PLS‐DA) provides a sound statistical basis for the selection, from an original 9605‐data set, of a limited number of gene transcripts most effective in discriminating different tumour histotypes. The potentialities of the PLS‐DA approach are pointed out by its ability to identify genes which, according to current knowledge, are associated with cancer development. Moreover, PLS‐DA was able to identify MUC 13 and S100P proteins as candidates for the development of new colon cancer diagnostics. Various genes with unknown function and ESTs (expressed sequence tags), found to be important in discriminating genes for colon, leukaemia, renal and central nervous system tumour cells, are indicated as deserving high priority in future molecular studies. Copyright © 2004 John Wiley & Sons, Ltd.
Use of software to facilitate pharmaceutical formulation—experiences from a tablet formulation
Authors: Lindberg Nils‐Olof , Gabrielsson Jon
Published: July 2004

This paper exemplifies the benefits of using experimental design together with software to facilitate the formulation of a tablet for specific purposes, from screening to robustness testing. By applying a multivariate design for the screening experiments, many excipients were evaluated in comparatively few experiments. The formulation work was generally based on designed experiments. Most of the experiments were fractional or full factorial designs, generated and evaluated in Modde with the centre point replicated. The robustness of the formulation was evaluated with experimental designs on two different occasions. Tested flavours were found to have limited influence on the important responses, which was key information in order to proceed with that particular composition. The formulation was also robust towards normal batch‐to‐batch variation of the excipients and the active pharmaceutical ingredient. A process step was investigated and, by applying experimental design and keeping in mind previous findings, important information could be gained from the study. The different studies yielded good and very useful models. Established relationships between design factors and responses provided information that was vital for the project. In cases of poor models, essential information regarding robustness was obtained. Copyright © 2004 John Wiley & Sons, Ltd.
Onion design and its application to a pharmaceutical QSAR problem
Authors: Eriksson Lennart , Arnhold Thomas , Beck Bernd , Fox Thomas , Johansson Erik , Kriegl Jan M.
Published: July 2004

Statistical molecular design (SMD) is an efficient tool for selecting informative, representative and diverse sets of molecular structures to be used in conjunction with QSAR, combinatorial technologies and other areas of research depending on optimization of molecular properties. Onion design represents a recent addition to the plethora of designs encountered in the SMD toolbox. It is a flexible design approach relying on a combination of the best properties of other design families, notably the model support property of D‐optimal design and the uniform coverage ability of space‐filling design. The onion design splits the candidate set into a number of subsets (‘shells’ or ‘layers’), and a D‐optimal selection is made from each shell. This makes it possible to select representative sets of molecular structures throughout any property space with reasonable design sizes. The number of selected molecules is easily controlled by varying (i) the number of shells and (ii) the model on which the design is based. The applicability of onion design to a pharmaceutical QSAR problem is reported. The example data set contains 967 drug‐like molecules. The biological activity under investigation is the inhibition of the major human drug‐metabolizing enzyme cytochrome P450 3A4. Onion design is used to select an informative training set. QSAR modeling is accomplished by means of multivariate data analysis tools. Copyright © 2004 John Wiley & Sons, Ltd.
Quantification of pollution levels by multiway modelling
Authors: Flåten Geir Rune , Grung Bjørn , Kvalheim Olav M.
Published: July 2004

Environmental surveys are performed regularly in environmental monitoring of possible industrial pollution. The seabed pollution from industry in or near water, e.g. offshore oil production, can be biologically monitored as benthic species, and their diversity can be used as indicators of pollution. The community disturbance index (CDI) was recently proposed as a quantitative measure of pollution calculated from the benthic data. However, the CDI and other measurements are not optimal for quantifying the changes in level of environmental stress over several years. In this work it is suggested that the total environmental stress over several monitoring surveys can be determined by modelling the natural variation for a set of non‐polluted sites. The suggested approach uses a multiway method (Tucker3) to describe the natural variation, and the three‐way extension of CDI to quantify the pollution. Implicitly, the traditional soft independent modelling of class analogies (SIMCA) classification is extended to its three‐way counterpart. The proposed method is tested on the data from four subsequent surveys performed at the North Sea oil field Embla. Copyright © 2004 John Wiley & Sons, Ltd.
Peptide studies by means of principal properties of amino acids derived from MIF descriptors
Authors: Cruciani Gabriele , Baroni Massimo , Carosati Emanuele , Clementi Monica , Valigi Roberta , Clementi Sergio
Published: July 2004

The paper derives a new set of principal properties (PPs) for coded amino acids from GRID maps and experimental data. The three scales characterize side chains according to their polarity (PP1), size/hydrophobicity (PP2) and H‐bonding capability (PP3) and can be used profitably both for describing and designing peptide series. The new parameters are further used to develop modified auto‐ and cross‐covariance transforms which appear to be even more suitable for the stated goals, as they label each peptide according to its bonding capabilities. Copyright © 2004 John Wiley & Sons, Ltd.
Prediction and spectral profile estimation in multivariate calibration
Authors: Trygg Johan
Published: July 2004

Direct and indirect calibration have been compared with respect to both prediction and model interpretation. This included their ability to estimate the pure spectral profile of each known constituent in a mixture of different metal–ion complexes. In the examples, the predictions by indirect calibration, represented by the PLS and O‐PLS methods, were consistently better than those of direct calibration, exemplified by the CLS method. It was further demonstrated that indirect calibration is equally capable to direct calibration in estimating the pure spectral profiles, as long as the unknown systematic variation is properly handled. A linear transformation of the regression coefficient matrix, given by K = B(BTB)−1, is all that is needed. Note that this does not only apply to spectral data, but any situation where the Y‐variables can be assumed to additively contribute to the variation in the X matrix. Throughout the examples, the O‐PLS method was able to maintain good spectral profile estimates and predictions. This indicates that O‐PLS may be the approach for simultaneous good prediction and interpretation of complex multivariate systems. Copyright © 2004 John Wiley & Sons, Ltd.
The utility of multivariate design in PLS modeling
Authors: Wold Svante , Josefson Mats , Gottfries Johan , Linusson Anna
Published: July 2004

We discuss the use of multivariate design to ensure representativity and balance of the training set data for PLS multivariate modeling. Three application areas are used to illustrate the discussion, namely multivariate calibration in process analytical chemistry, quantitative structure activity relationships (QSAR) in medicinal and pharmaceutical chemistry, and data mining. In both QSAR and data mining, the multivariate design is also useful for the balanced sampling of data from a large, complex, and unbalanced data repository. Copyright © 2004 John Wiley & Sons, Ltd.
Bridge–PLS regression: two‐block bilinear regression without deflation
Authors: Gidskehaug Lars , Stødkilde‐Jørgensen Hans , Martens Magni , Martens Harald
Published: July 2004

Functional MRI (fMRI) represents experiments with experimental design in the time domain, and yields a very high number of response variables. In this paper an fMRI data set is analyzed for temporal response delays relative to the design, and for spatial response patterns. Two families of two‐block PLS are compared, namely PLS Regression (PLSR) and a method developed by F.L. Bookstein, here called Bookstein PLS (BPLS). In BPLS, all components are found simultaneously, making the deflation of X and/or y superfluous. When reformulated as a regression method y = f(X), the BPLS performs badly compared with PLSR in the case of only one dependent variable, y, because only one component can be calculated. Contrary to the asymmetrical PLSR, the symmetrical BPLS lacks a predictive direction from X to y, and is therefore difficult to assess, e.g. by cross‐validation. A new PLS method, here called bridge–PLS regression, is presented. It combines elements from both PLSR (predictive asymmetry) and BPLS (all components determined by one single eigen‐decomposition). Copyright © 2004 John Wiley & Sons, Ltd.
The Nenitzescu reaction: an initial screening of experimental conditions for improvment of the yield of a model reaction
Authors: Katkevica Daze , Trapencieris Peteris , Boman Arne , Kalvins Ivars , Lundstedt Torbjörn
Published: July 2004

This paper describes the synthesis of the biologically important indole scaffold by using the Nenitzescu reaction. The scope and limitation of the reaction is investigated by multivariate methods where concentration, ratio of substrate and reactant, solvent, temperature and time are varied in a systematic way. The present investigation is the first reported systematic study of the impact of the experimental settings in the Nenitzescu reaction and is part of a more thorough project in which this reaction will be explored in more detail. Copyright © 2004 John Wiley & Sons, Ltd.
Persistent area socioeconomic disparities in U.S. incidence of cervical cancer, mortality, stage, and survival, 1975–2000
Authors: Singh Gopal K. , Miller Barry A. , Hankey Benjamin F. , Edwards Brenda K.
Published: July 2004

BACKGROUND

Temporal cervical cancer incidence and mortality patterns and ethnic disparities in patient survival and stage at diagnosis in relation to socioeconomic deprivation measures have not been well studied in the United States. The current article analyzed temporal area socioeconomic inequalities in U.S. cervical cancer incidence, mortality, stage, and survival.

METHODS

County and census tract poverty and education variables from the 1990 census were linked to U.S. mortality and Surveillance, Epidemiology, and End Results cancer incidence data from 1975 to 2000. Age‐adjusted incidence and mortality rates and 5‐year cause‐specific survival rates were calculated for each socioeconomic group and differences in rates were tested for statistical significance at the 0.05 level.

RESULTS

Substantial area socioeconomic gradients in both incidence and mortality were observed, with inequalities in cervical cancer persisting against a backdrop of declining rates. Cervical cancer incidence and mortality rates increased with increasing poverty and decreasing education levels for the total population as well as for non‐Hispanic white, black, American Indian, Asian/Pacific Islander, and Hispanic women. Patients in lower socioeconomic census tracts had significantly higher rates of late‐stage cancer diagnosis and lower rates of cancer survival. Even after controlling for stage, significant differences in survival remained. The 5‐year survival rate among women diagnosed with distant‐stage cervical cancer was approximately 30% lower in low than in high socioeconomic census tracts.

CONCLUSIONS

Census‐based socioeconomic measures such as area poverty and education levels could serve as important surveillance tools for monitoring temporal trends in cancer‐related health inequalities and targeting interventions. Cancer 2004. Published 2004 by the American Cancer Society.
Quality of life and survival prediction in terminal cancer patients
Authors: Vigano Antonio , Donaldson Nora , Higginson Irene J. , Bruera Eduardo , Mahmud Salaheddin , Suarez‐Almazor Maria
Published: July 2004

BACKGROUND

It remains unclear whether health‐related quality of life (HRQoL) measurements from patients and staff can be combined with medical data to predict survival in patients with terminal cancer.

METHODS

The correlations between survival and potential health‐related quality‐of‐life (HRQoL) prognostic variables were explored in 2 independent cohorts of patients with terminal cancer (248 patients in Cohort 1 and 756 patients in Cohort 2) after adjusting for clinical and demographics variables using Cox regression models.

RESULTS

At the onset of the terminal phase (Cohort 1), the hazards of dying increased by 28% in the presence of dyspnea and by 68% in the presence of nausea/emesis; however, the most important predictors of worse survival were the presence of liver metastases (hazard ratio [HR], 2.5; 95% confidence interval [95% CI], 1.8–3.8), lung tumor (HR, 2.4; 95% CI, 1.7–3.4), and tumor burden (HR, 2.0; 95% CI, 1.4–2.7). In contrast, for patients who were seen in later stages of their terminal disease (Cohort 2), dyspnea (HR, 1.5; 95% CI, 1.1–1.9) and the coexistence of weakness with a diagnosis of digestive tumors (HR, 5.2; 95% CI, 1.2–21.8), breast tumors (HR, 3.1; 95% CI, 1.6–6.2), and genitourinary tumors (HR, 3.5; 95% CI, 1.6–7.8) were more predictive of survival than the type of tumor primary. Emotional functioning along with anxiety, spiritual distress, and lack of insight were not associated consistently with survival in both cohorts.

CONCLUSIONS

Health care professionals should focus on physical HRQoL indicators, such as nausea and emesis, dyspnea, and weakness, to gather prognostic clues in patients with terminal cancer. These symptoms may reflect consequences of cancer cachexia and the progress of patients toward this terminal syndrome. Psychosocial distress did not appear to be associated consistently with survival; however, future studies should clarify further the prognostic significance of “positive attitudes”, such as hope and optimism, in patients with advanced cancer. Cancer 2004. © 2004 American Cancer Society.
Moses Harris's The Natural System of Colours and its later representations
Authors: Spillmann Werner
Published: July 2004

In this article the only complete copy of the very rare Natural System of Colours by Moses Harris (ca. 1770) is reproduced. The color plates of the two hue circles are compared to those in the second edition of Harris's work (1811) as well as the so‐called facsimile edition by Faber Birren of 1963. Comparisons are also made against later reproductions and modifications of these circles, including those by Mérimée and Varley. The small number of authentic representations are identified. Four versions of the central triangles of the “prismatic” color circle are compared, including that by the painter J. M. W. Turner. © 2004 Wiley Periodicals, Inc. Col Res Appl, 29, 333–341, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20041
Estimation of fuzzy sets for computational colour categorization
Authors: Benavente Robert , Vanrell Maria , Baldrich Ramon
Published: July 2004

Colour is an important visual cue for computer vision applications. However, until recently, the automatic assignment of names to image regions has not been widely used due to the nonexistence of a general computational model for colour categorization. In this article we present a model for colour naming based on fuzzy‐set theory, in which each of the 11 basic colour terms defined by Berlin and Kay1is modeled as a fuzzy set with a characteristic function that assigns a membership value to the category to any colour sample. The model is based on combining two well‐known functions, a sigmoid and a Gaussian, to define a membership function for colour categories. It is denoted here as the sigmoid–Gaussian function and it fulfills a set of properties that make it adequate to this purpose. The characteristic functions for each colour category have been fitted to data obtained from a psychophysical experiment and the model has been tested on the Munsell colour array to show its validity. The results obtained indicate that our approach can be very useful as a first step to expand the use of colour‐naming information in computer vision applications. © 2004 Wiley Periodicals, Inc. Col Res Appl, 29, 342–353, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20042
Theoretical analysis of subtractive color mixture characteristics II—General colorants and single tristimulus dimension
Authors: Matsushiro Nobuhito , Ohta Noboru
Published: July 2004

To further understand the characteristics of the stimulus values in colors obtained via subtractive color mixture, new theorems are provided. The theorems aim to establish bounds on mixtures of colorants given stimulus measurements of the constituent single‐colorant samples and the illuminant. Previously we only proved theorems for the ideal color. In the present article, new theorems related to the removal of the restriction of the ideal color are provided and establish bounds for all cases of spectral transmittances. The results of this article contributes to a systematization of subtractive color mixture. © 2004 Wiley Periodicals, Inc. Col Res Appl, 29, 354–359, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20043
Colour matching using LEDs as primaries
Authors: Borbély Ákos , Schanda János
Published: July 2004

In our metameric experiment, the colour of a filtered incandescent lamp was matched with the additive mixture of three LEDs in a Lummer–Brodhun‐type visual photometer. Two sets of primaries were used, one had their dominant wavelengths at 467, 533, and 600 nm; the other set had dominant wavelengths at 478, 552, and 635 nm. These values correspond approximately to the characteristic wavelengths of the Prime and Non‐Prime Colour spectral regions defined by W. A. Thornton.1 Both the light of the incandescent lamp and that of the LED clusters were seen monocularly in a centrally divided bipartite field at a visual angle of 2°. The luminance of the matching fields was in the order of 20 cd/m2 to provide sufficient gamut for the LED mixture. Ten young observers with normal colour vision participated in the experiment. The emission spectra of the viewing fields were measured with an array‐type spectroradiometer, and two sets of colour‐matching functions were used to calculate the chromaticity of the matching stimuli: the CIE 1931 standard colorimetric observer and the Judd–Vos modification of the colour‐matching functions.

We found that the Judd–Vos modification of the CIE 1931 standard observer represents more accurately the real observers in the evaluation of our results. No systematic differences between the use of the two sets of LEDs were detected in contradiction to Thornton's findings. © 2004 Wiley Periodicals, Inc. Col Res Appl, 29, 360–364, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20044
Evaluation of the crispening effect using CRT‐displayed colour samples
Authors: Xin J. H. , Lam C. C. , Luo M. R.
Published: July 2004

In this study, the crispening effect was clearly observed when 38 neutral‐coloured sample pairs with only lightness differences were assessed under 5 neutral backgrounds of different lightness values. The sample pairs are CRT‐based colours, and they are selected along the CIELAB L* axis from 0 to 100. The magnitude of colour difference of each pair is 5.0 CIELAB units. The visual assessment results showed that there is a very large crispening effect. The colour differences of the same pair assessed under different backgrounds could differ by a factor of up to 8 for a sample pair with low lightness. The perceived colour difference was enlarged when the lightness of a sample pair was similar to that of the background. The extent of crispening effect and its quantification are discussed in this investigation. The performances of five colour‐difference equations were also tested, including the newly developed CIEDE2000. © 2004 Wiley Periodicals, Inc. Col Res Appl, 29, 374–380, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20045