bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia
Authors: Gracely Richard H. , Petzke Frank , Wolf Julie M. , Clauw Daniel J.
Published: October 2002

Objective

To use functional magnetic resonance imaging (fMRI) to evaluate the pattern of cerebral activation during the application of painful pressure and determine whether this pattern is augmented in patients with fibromyalgia (FM) compared with controls.

Methods

Pressure was applied to the left thumbnail beds of 16 right‐handed patients with FM and 16 right‐handed matched controls. Each FM patient underwent fMRI while moderately painful pressure was being applied. The functional activation patterns in FM patients were compared with those in controls, who were tested under 2 conditions: the “stimulus pressure control” condition, during which they received an amount of pressure similar to that delivered to patients, and the “subjective pain control” condition, during which the intensity of stimulation was increased to deliver a subjective level of pain similar to that experienced by patients.

Results

Stimulation with adequate pressure to cause similar pain in both groups resulted in 19 regions of increased regional cerebral blood flow in healthy controls and 12 significant regions in patients. Increased fMRI signal occurred in 7 regions common to both groups, and decreased signal was observed in 1 common region. In contrast, stimulation of controls with the same amount of pressure that caused pain in patients resulted in only 2 regions of increased signal, neither of which coincided with a region of activation in patients. Statistical comparison of the patient and control groups receiving similar stimulus pressures revealed 13 regions of greater activation in the patient group. In contrast, similar stimulus pressures produced only 1 region of greater activation in the control group.

Conclusion

The fact that comparable subjectively painful conditions resulted in activation patterns that were similar in patients and controls, whereas similar pressures resulted in no common regions of activation and greater effects in patients, supports the hypothesis that FM is characterized by cortical or subcortical augmentation of pain processing.
Assessment of proximal finger joint inflammation in patients with rheumatoid arthritis, using a novel laser‐based imaging technique
Authors: Scheel Alexander K. , Krause Andreas , Rheinbaben Ingolf Mesecke‐von , Metzger Georg , Rost Helmut , Tresp Volker , Mayer Peter , Reuss‐Borst Monika , Müller Gerhard A.
Published: October 2002

Objective

To evaluate a newly developed laser‐based imaging technique for the study of soft tissue changes and acute inflammatory processes of the proximal interphalangeal (PIP) joints in patients with rheumatoid arthritis (RA).

Methods

A novel imaging device was developed which allows the transillumination of PIP joints using laser light in the near‐infrared wavelength range. In a first clinical followup study, a total of 72 PIP joints of 22 patients with RA and 64 PIP joints of 8 healthy controls were examined both clinically and with the new laser device. At baseline and at followup after a mean of 6 weeks, clinical signs of synovitis, the joint circumference, and the degree of pain were assessed for each PIP joint in order to determine the clinical degree of inflammation. Different features were extracted from the laser images and evaluated by a neural network.

Results

At baseline, 72 PIP joints in the RA patients showed clinical signs of inflammation. At followup, 45 PIP joints showed clinical improvement, 13 showed steady active inflammation, and 14 showed deterioration compared with the first visit. None of the 64 PIP joints in the healthy individuals showed any signs of synovitis. The inflammatory status of 60 of the 72 RA joints examined was classified correctly by laser examination and joint circumference determination, giving a sensitivity of 80%, a specificity of 89%, and an accuracy of 83% in detecting inflammatory changes in affected joints. Laser data and joint circumference determination of healthy joints at followup resulted in an accuracy of 85% in reproducing the image.

Conclusion

The new laser‐based imaging technique allows the transillumination of PIP joints and gives information about the inflammatory status of the joint after processing through a neural network. Our data indicate that laser imaging may provide additional information in the early diagnosis of an inflammatory joint process and may prove particularly useful in assessing acute joint inflammation at followup.
Two NOD Idd‐associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjögren's syndrome) on a healthy murine background
Authors: Cha Seunghee , Nagashima Hiroyuki , Brown Vinette B. , Peck Ammon B. , Humphreys‐Beher Michael G.
Published: October 2002

Objective

The NOD mouse is genetically predisposed to the development of at least 2 autoimmune diseases, autoimmune diabetes and autoimmune exocrinopathy (AEC). More than 19 chromosomal intervals (referred to as Idd regions) that contribute to diabetes susceptibility in the NOD mouse model have been identified, but only 2 chromosomal intervals (associated with Idd3 and Idd5) have been shown to control sialadenitis. In the present study, we bred the Idd3 and Idd5 chromosomal intervals from NOD mice into non‐autoimmune C57BL/6 mice to determine if these intervals recreate a Sjögren's syndrome (SS)‐like phenotype.

Methods

C57BL/6.NODc3 mice carrying Idd3 and C57BL/6.NODc1t mice carrying Idd5 were crossed and intercrossed to generate a C57BL/6.NODc3.NODc1t mouse line homozygous for the Idd3 and Idd5 chromosomal intervals on an otherwise disease‐resistant genetic background. C57BL/6.NODc3.NODc1t mice were evaluated for biochemical, pathophysiologic, and immunologic markers characteristic of the SS‐like phenotype present in the NOD mouse.

Results

C57BL/6.NODc3.NODc1t mice fully manifested the SS‐like phenotype of the NOD mouse, including decreased salivary and lacrimal gland secretory flow rates, increased salivary protein content due in part to less fluid, aberrant proteolytic enzyme activity, decline in amylase activity, appearance of autoantibodies to exocrine gland proteins, and glandular lymphocytic focal infiltrates. Loss of secretory function occurred more rapidly in C57BL/6.NODc3.NODc1t mice (by 12 weeks of age) than in NOD mice (by 16 weeks of age). No signs of insulitis or autoimmune (type 1) diabetes were observed in the C57BL/6.NODc3.NODc1t mice.

Conclusion

Genes located within the 2 chromosomal intervals Idd3 and Idd5 appear necessary and sufficient for manifestation of AEC. We propose that this murine model of SS‐like disease be designated C57BL/6.NOD‐Aec1Aec2. Identification of specific genes within the Aec1 and Aec2 genetic regions should help elucidate the mechanism(s) underlying SS‐like disease.
Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis
Authors: Knijff‐Dutmer E. A. J. , Koerts J. , Nieuwland R. , Kalsbeek‐Batenburg E. M. , Van De Laar M. A. F. J.
Published: October 2002

Objective

Platelets are involved in various thrombotic events, often by means of platelet‐derived microparticles (PMPs). It is likely that platelets are also involved in inflammation. Because inflammatory processes play a central role in rheumatoid arthritis (RA), we sought to determine whether PMPs are present in this disease.

Methods

This descriptive, cross‐sectional study included 19 RA patients and 10 healthy controls. Nine of the patients had active RA (erythrocyte sedimentation rate [ESR] ≥28 mm/hour and/or C‐reactive protein [CRP] level ≥28 mg/liter, ≥9 painful joints, and ≥6 swollen joints), and 10 had inactive disease (ESR ≤27 mm/hour, CRP ≤27 mg/liter, no tender joints, and no swollen joints). Platelet counts and PMP numbers were determined using cell counter and flow cytometry, respectively.

Results

Platelet counts in the 3 groups were similar. However, levels of PMPs in RA patients were significantly higher than those in healthy controls (median 616 versus 118 × 106/liter; P = 0.005). PMP levels were higher in patients with active RA than in those with inactive RA (median 2,104 versus 504 × 106/liter; P > 0.05). Moreover, PMP levels correlated with disease activity (r = 0.67, P = 0.05).

Conclusion

PMPs are associated with RA, and PMP levels are correlated with disease activity. Thus, platelets probably play a part in the inflammatory process of RA by means of PMPs. Given the importance of PMPs in cardiovascular diseases, this may be one reason for the enhanced cardiovascular morbidity and mortality in RA.
Psychological interventions for rheumatoid arthritis: A meta‐analysis of randomized controlled trials
Authors: Astin John A. , Beckner William , Soeken Karen , Hochberg Marc C. , Berman Brian
Published: October 2002

Objective

To carry out a systematic review of the literature examining the efficacy of psychological interventions (e.g., relaxation, biofeedback, cognitive–behavioral therapy) in the treatment of rheumatoid arthritis (RA).

Methods

Studies that met the following criteria were included: random assignment, wait‐list or usual care control condition; publication in peer‐reviewed journals; treatment that included some psychological component beyond simply providing education information; and separate data provided for patients with RA if subjects with conditions other than RA were included. Two investigators independently extracted data on study design, sample size and characteristics, type of intervention, type of control, direction and nature of the outcome(s).

Results

Twenty‐five trials met the inclusion criteria. Methodologic quality was assessed, and effect sizes were calculated for 6 outcomes. Significant pooled effect sizes were found postintervention for pain (0.22), functional disability (0.27), psychological status (0.15), coping (0.46), and self efficacy (0.35). At followup (averaging 8.5 months), significant pooled effect sizes were observed for tender joints (0.33), psychological status (0.30), and coping (0.52). No clear or consistent patterns emerged when effect sizes for different types of treatment and control conditions were compared, or when higher quality trials were compared to lower quality ones. Findings do, however, suggest that these psychological interventions may be more effective for patients who have had the illness for shorter duration.

Conclusions

Despite some methodologic flaws in the literature, psychological interventions may be important adjunctive therapies in the medical management of RA.
The effects of age and sex on chondroitin sulfates in normal synovial fluid
Authors: Nakayama Yoshihito , Narita Tetsuya , Mori Atsushi , Uesaka Shinji , Miyazaki Kyosuke , Ito Hiromoto
Published: October 2002

Objective

To examine how age and sex influence chondroitin sulfates (CS) in normal synovial fluid, we measured the concentrations of chondroitin 6‐sulfate (C6S), chondroitin 4‐sulfate (C4S), and hyaluronic acid (HA) in healthy subjects of different ages.

Methods

Synovial fluid samples were obtained from 82 healthy volunteers, ages 20–79 years.

Results

The concentrations of CS and HA and the C6S:C4S ratio varied with age. Their values were highest between 20 and 30 years of age, and thereafter they showed a tendency to decrease. Statistically, the C6S concentration and the C6S:C4S ratio at ages 60–70 years were significantly lower than those at 20–30 years of age. There was also a clear between‐sex difference, in which the CS concentrations and the C6S:C4S ratio in women were significantly lower than those in men (P= 0.0003 for C6S,P= 0.02 for C4S,P= 0.002 for C6S:C4S ratio). In sharp contrast, little between‐sex difference was found in the HA concentration. In multiple regression analysis, age correlated strongly with the C6S concentration and the C6S:C4S ratio (r = −0.521 and r = −0.617, respectively), weakly with the C4S concentration (r = −0.202), and moderately with the HA concentration (r = −0.483). Sex showed a weak correlation with the concentrations of C6S and C4S and the C6S:C4S ratio (r = 0.307, r = 0.225, and r = 0.237, respectively), and little correlation was seen between sex and the HA concentration.

Conclusion

The CS concentrations and the sulfation patterns in normal synovial fluid vary with age and sex, and these physiologic variations need to be taken into account when using synovial fluid CS as markers for arthritic conditions.
The safety of celecoxib in patients with aspirin‐sensitive asthma
Authors: Woessner Katharine M. , Simon Ronald A. , Stevenson Donald D.
Published: October 2002

Objective

To determine whether celecoxib, a selective cyclooxygenase 2 (COX‐2) inhibitor, cross‐reacts in patients with aspirin‐exacerbated respiratory disease (AERD) with asthma.

Methods

Sixty patients with asthma underwent double‐blinded, placebo‐controlled oral challenges with celecoxib (100 mg, 200 mg, and 2 placebos) over 48 hours in our General Clinical Research Center. The next day, sensitivity to acetylsalicylic acid (ASA) was proven in all patients with the use of single‐blinded ASA challenges.

Results

None of the 60 patients experienced any symptoms, changes in nasal examinations, or declines in forced expiratory volume in 1 second during the celecoxib challenges. All 60 patients experienced oculonasal and/or asthmatic reactions to ASA, with a mean provoking dose of 69 mg. The exact 1‐sided confidence interval for the probability of celecoxib inducing cross‐reactions in AERD patients was calculated to be between 0% and 5%.

Conclusion

Cross‐reactivity between ASA and celecoxib does not occur in patients with AERD. These results do not preclude the possibility of other types of immune reactions occurring with celecoxib after prior exposure. Our results add to the growing body of evidence that inhibition of COX‐1 is a critical initiating event in the precipitation of respiratory reactions in AERD patients following ingestion of nonsteroidal antiinflammatory drugs.
Epigallocatechin‐3‐gallate inhibits interleukin‐1β–induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes: Suppression of nuclear factor κB activation by degradation of the inhibitor of nuclear factor κB
Authors: Singh Rashmi , Ahmed Salahuddin , Islam Najmul , Goldberg Victor M. , Haqqi Tariq M.
Published: October 2002

Objective

The proinflammatory cytokine interleukin‐1β (IL‐1β) induces the production of high levels of nitric oxide (NO) in human chondrocytes. Green tea (Camellia sinensis) polyphenols are potent antiinflammatory agents and have been shown to inhibit NO production in tumor cell lines. In the present study, we examined the effect of epigallocatechin‐3‐gallate (EGCG), a green tea polyphenol, on IL‐1β–induced production of NO in primary human osteoarthritis (OA) chondrocytes.

Methods

Human chondrocytes were derived from OA cartilage and were treated with EGCG (100 μM) and IL‐1β (2 ng/ml) for different periods, and inducible nitric oxide synthase (iNOS) messenger RNA and protein expression was determined by real‐time quantitative reverse transcriptase–polymerase chain reaction and Western blotting, respectively. Production of NO was determined as nitrite in culture supernatant. Activation and translocation of nuclear factor κB (NF‐κB), levels of inhibitor of nuclear factor κB (IκB), and NF‐κB DNA binding activity were determined by Western blotting and a highly sensitive and specific enzyme‐linked immunosorbent assay. Activity of IκB kinase was determined using in vitro kinase assay.

Results

Human chondrocytes cotreated with EGCG produced significantly less NO compared with chondrocytes stimulated with IL‐1β alone (P < 0.005). The inhibition of NO production correlated with the suppression of induction and expression of NF‐κB–dependent gene iNOS. EGCG inhibited the activation and translocation of NF‐κB to the nucleus by suppressing the degradation of its inhibitory protein IκBα in the cytoplasm.

Conclusion

Our results indicate that EGCG inhibits the IL‐1β–induced production of NO in human chondrocytes by interfering with the activation of NF‐κB through a novel mechanism. Our data further suggest that EGCG may be a therapeutically effective inhibitor of IL‐1β–induced inflammatory effects that are dependent on NF‐κB activation in human OA chondrocytes.
When negative evidence increases confidence: change in belief after hearing two sides of a dispute
Authors: McKenzie Craig R. M. , Lee Susanna M. , Chen Karen K.
Published: October 2002

Four experiments examined change in confidence after hearing two sides of a dispute. The results showed that a case independently judged to weakly support one side often increased confidence that the opposing side was correct. Furthermore, the stronger the first case, the more likely a subsequent weak case had a reverse impact. Traditional belief‐updating models, which tend to focus on change in belief after individual pieces of evidence rather than entire cases, cannot account for these results, and a model that can account for them is introduced. In the new model, case strength is evaluated with respect to a relatively demanding (and malleable) reference point. A weak case can fall below this demanding reference point, resulting in a reverse impact on confidence. Cases must exceed relatively high strength thresholds in order to have their intended impact because they are expected to be biased summaries of evidence. When it is clear that a weak case is unbiased, it affects confidence in the intended direction. Copyright © 2002 John Wiley & Sons, Ltd.
Vibrational,1H‐NMR spectroscopic, and thermal characterization of gladiolus root exudates in relation toFusarium oxysporum f.sp.gladioliresistance
Authors: Taddei P. , Tugnoli V. , Bottura G. , Dallavalle E. , Zechini D'Aulerio A.
Published: October 2002

Fourier transform Raman (FT Raman) and IR (FTIR) and1H‐NMR spectroscopies coupled with differential scanning calorimetry (DSC) were applied to the characterization of root exudates from two cultivars of gladiolus (Spic Span and White Prosperity) with different degrees of resistance and susceptibility toFusarium oxysporum gladioli, the main pathogen of gladiolus. This work was aimed at correlating the composition of root exudates with the varietal resistance to the pathogen. Spectroscopic analysis showed that White Prosperity root exudate differs from Spic Span root exudate by a higher relative amount of the aromatic‐phenolic and sugarlike components and a lower relative amount of carbonylic and aliphatic compounds. DSC analysis confirmed the spectroscopic results and showed that White Prosperity root exudate is characterized by an aromatic component that is present in a higher amount than in the Spic Span root exudate. The results are discussed in relation to the spore germination tests showing that White Prosperity, which is characterized by a remarkable resistance towardF. oxysporum gladioli, exudes substances having a negative influence on microconidial germination of the pathogen; root exudates from Spic Span, one of the most susceptible cultivars toF. oxysporum gladioli, proved to have no effect. White Prosperity's ability to inhibit conidial germination ofF. oxysporum gladiolican be mainly related to the presence of a higher relative amount of aromatic‐phenolic compounds. © 2002 Wiley Periodicals, Inc. Biopolymers (Biospectroscopy) 67: 428–439, 2002
Solution structure of a D,L‐alternating oligonorleucine as a model of double‐stranded antiparallel β‐helix
Authors: Navarro E. , Fenude E. , Celda B.
Published: October 2002

Conformational characteristics of alternating D,L linear peptides are of particular interest because of their capacity to form transmembrane channels with different transport properties, as some natural antibiotics do. Single‐ and double‐stranded β‐helical structures are common for alternating D,L peptides. The stability of the β‐helix depends on several structural factors, such as the backbone peptide length, type and position of side chains, and nature of terminal groups. The NMR and molecular dynamics solution conformation of a synthetic alternating D,L‐oligopeptide with 15 norleucines (XVMe) has been used as a model to get insight in to the conformational features of double‐stranded β‐helix structures. The NH chemical shift values (δNH) and long‐range nuclear Overhauser effects (NOE) cross peaks, in particular interstrand connectivities, clearly point to an antiparallel double‐stranded β‐helix for the XVMe major conformation in solution. An extensive set of distances (from NOE cross peaks) and H‐bonds (from δNH) has been included in the molecular dynamics calculations. The experimental NMR data and theoretical calculations clearly indicate that the most probable conformation of XVMe in solution is a double‐strand antiparallel β5.6↑↓‐helix structure. © 2002 Wiley Periodicals, Inc. Biopolymers 64: 198–209, 2002
Structural transformation and aggregation of human α‐synuclein in trifluoroethanol: Non‐amyloid component sequence is essential and β‐sheet formation is prerequisite to aggregation
Authors: Li Hong‐Tao , Du Hai‐Ning , Tang Lin , Hu Jun , Hu Hong‐Yu
Published: October 2002

Amyloid‐like aggregation of α‐synuclein and deposit in Lewy bodies are thought to be the major cause of Parkinson′s disease. Here we describe the secondary structural transformation and aggregation of human α‐synuclein and its C‐terminus truncated fragments in trifluoroethanol. Proteins containing the NAC (non‐amyloid component) segment undergo a three‐state transition: from native random coil to β‐sheet and to α‐helical structure, while the NAC deficient fragment and γ‐synuclein undergo a typical two‐state coil‐to‐α transition. The β‐sheet form is highly hydrophobic that strongly binds to 1‐anilinonaphthalene‐8‐sulfonic acid (ANS) and is prone to self‐aggregation. The results suggest that the NAC sequence is essential to β‐sheet formation and the aggregation originates from the β‐sheet intermediate, which may be implicated in the pathogenesis of Parkinson′s disease. © 2002 Wiley Periodicals, Inc. Biopolymers 64: 221–226, 2002
Characterization of acid catalytic domains for cellulose hydrolysis and glucose degradation
Authors: Mosier Nathan S. , Ladisch Christine M. , Ladisch Michael R.
Published: October 2002

Cellulolytic enzymes consist of a catalytic domain, a linking peptide, and a binding domain. The paper describes research on carboxylic acids that have potential as catalytic domains for constructing organic macromolecules for use in cellulose hydrolysis that mimic the action of enzymes. The tested domains consist of the series of mono‐, di‐, and tricarboxylic acids with a range of pKa's. This paper systematically characterizes the acids with respect to hydrolysis of cellobiose, cellulose in biomass, and degradation of glucose and compares these kinetics data to dilute sulfuric acid. Results show that acid catalyzed hydrolysis is proportional to H+ concentration. The tested carboxylic acids did not catalyze the degradation of glucose while sulfuric acid catalyzed the degradation of glucose above that of water alone. Consequently, overall yields of glucose obtained from cellobiose and cellulose are higher for the best carboxylic acid tested, maleic acid, when compared to sulfuric acid at equivalent solution pH. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 79: 610–618, 2002.
Engineering of molecular and cellular biocatalysts: Selected contributions by James E. Bailey
Authors: Dordick Jonathan S. , Khosla Chaitan
Published: October 2002

James (Jay) E. Bailey was a pioneer in biotechnology and biochemical engineering. During his 30 years in academia he made seminal contributions to many fields of chemical engineering science, including catalysis and reaction engineering, bioprocess engineering, mathematical modeling of cellular processes, recombinant DNA technology, enzyme engineering, and metabolic engineering. This article celebrates some of his contributions to the engineering of molecular and cellular biocatalysts, and identifies the influence he had on current and future research in biotechnology. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 79: 490–495, 2002.
Application of osteology to forensic medicine
Authors: Scheuer Louise
Published: October 2002

The four main features of biological identity are sex, age, stature, and ethnic background. The forensic osteologist aims to establish these attributes for an individual from their skeletal remains. Many techniques are available for the osteological determination of sex in the adult but it is one of the most difficult biological factors to ascribe to juvenile remains. Conversely, there are a multitude of markers to estimate age in the young skeleton but ageing becomes less accurate with increasing years. Stature is usually a relatively straightforward parameter to establish in the adult. In the juvenile, it is naturally correlated with age but is complicated by differences in rates of growth both between the sexes and between individuals. Determination of ethnic identity is the least reliable and is hampered by lack of data on many populations. This paper reviews the principal methods used to establish identity and comments on their reliability and accuracy in the forensic context. Clin. Anat. 15:297–312, 2002. © 2002 Wiley‐Liss, Inc.
University reference group identification among community college faculty
Authors: Lee Jenny J.
Published: October 2002

Understanding faculty reference groups is critical to understanding faculty values and behavior, as well as to introducing and implementing change efforts. This chapter focuses on the extent to which the university serves as a reference group for community college faculty and distinguishes notable differences by faculty characteristics and teaching fields.
Screening for subclavian artery stenosis in patients who are candidates for coronary bypass surgery
Authors: Osborn Larry A. , Vernon Sarah M. , Reynolds Bryan , Timm T. Craig , Allen Kathleen
Published: October 2002

We prospectively evaluated 59 patients who were deemed candidates for coronary bypass surgery after coronary artery angiography for subclavian artery narrowing, which could compromise the ipsilateral internal thoracic artery graft. Bilateral arm blood pressure (BP) measurements, ausculatation for supraclavicular or cervical bruits, and questioning about cerebrovascular ischemic symptoms were compared to brachiocephalic‐subclavian arteriography. One neurologic complication occurred during arteriography. An upper extremity BP difference of ≥ 15 mm Hg identified all patients with ≥ 50% subclavian artery narrowing. We recommend brachiocephalic‐subclavian arteriography only in patients with abnormal noninvasive screening for subclavian stenosis, not routinely. Cathet Cardiovasc Intervent 2002;56:162–165. © 2002 Wiley‐Liss, Inc.
Paradoxical embolization of a fractured guidewire: Successful retrieval from left atrium using a snare device
Authors: Casserly Ivan P. , Goldstein Jeffrey A. , Rogers Jason H. , Lasala John M.
Published: October 2002

In adults, paradoxical embolization of catheters or guidewire fragments related to central venous catheterization is a rare phenomenon. Reports of successful percutaneous retrieval of foreign bodies from the left atrium is also rare. We describe the successful percutaneous retrieval of a fractured guidewire that had undergone paradoxical embolization to the left atrium in an adult patient. Cathet Cardiovasc Intervent 2002;57:34–38. © 2002 Wiley‐Liss, Inc.
Precision of prediction in second‐order calibration, with focus on bilinear regression methods
Authors: Linder Marie , Sundberg Rolf
Published: October 2002

We consider calibration of hyphenated instruments with particular focus on determination of the unknown concentrations of new specimens. A hyphenated instrument generates for each specimen a two‐way array of data. These are assumed to depend on the concentrations through a bilinear regression model, where each constituent is characterized by a pair of profiles to be determined in the calibration. We discuss the problem of predicting the unknown concentrations in a new specimen, after calibration. We formulate three different predictor construction methods, a ‘naive’ method, a least squares method, and a refined version of the latter that takes account of the calibration uncertainty. We give formulae for the uncertainty of the predictors under white noise, when calibration can be seen as precise. We refine these formulae to allow for calibration uncertainty, in particular when calibration is carried out by the bilinear least squares (BLLS) method or the singular value decomposition (SVD) method proposed by Linder and Sundberg (Chemometrics Intell. Lab. Syst. 1998;42: 159–178). By error propagation formulae and previous results on the precision of$\widehat{A}$and$\widehat{B}$we can obtain approximate standard errors for the predicted concentrations, according to each of the two estimation methods. The performance of the predictors and the precision formulae is illustrated on both real (fluorescence) and simulated data. Copyright © 2002 John Wiley & Sons, Ltd.
Orthogonal projections to latent structures (O‐PLS)
Authors: Trygg Johan , Wold Svante
Published: October 2002

A generic preprocessing method for multivariate data, called orthogonal projections to latent structures (O‐PLS), is described. O‐PLS removes variation from X (descriptor variables) that is not correlated to Y (property variables, e.g. yield, cost or toxicity). In mathematical terms this is equivalent to removing systematic variation in X that is orthogonal to Y. In an earlier paper, Wold et al. (Chemometrics Intell. Lab. Syst. 1998; 44: 175–185) described orthogonal signal correction (OSC). In this paper a method with the same objective but with different means is described. The proposed O‐PLS method analyzes the variation explained in each PLS component. The non‐correlated systematic variation in X is removed, making interpretation of the resulting PLS model easier and with the additional benefit that the non‐correlated variation itself can be analyzed further. As an example, near‐infrared (NIR) reflectance spectra of wood chips were analyzed. Applying O‐PLS resulted in reduced model complexity with preserved prediction ability, effective removal of non‐correlated variation in X and, not least, improved interpretational ability of both correlated and non‐correlated variation in the NIR spectra. Copyright © 2002 John Wiley & Sons, Ltd.
Bootstrap methods for assessing the performance of near‐infrared pattern classification techniques
Authors: Smith Brandye M. , Gemperline Paul J.
Published: October 2002

Two parametric bootstrap techniques were applied to near‐infrared (NIR) pattern classification models for two classes of microcrystalline cellulose, Avicel® PH101 and PH102, which differ only in particle size. The development of pattern classification models for similar substances is difficult, since their characteristic clusters overlap. Bootstrapping was used to enlarge small test sets for a better approximation of the overlapping area of these nearly identical substances, consequently resulting in better estimates of misclassification rates. A bootstrap that resampled the residuals, referred to as the outside model space bootstrap in this paper, and a novel bootstrap that resampled principal component scores, referred to as the inside model space bootstrap, were studied. A comparison revealed that classification rates for both bootstrap techniques were similar to the original test set classification rates. The bootstrap method developed in this study, which resampled the principal component scores, was more effective for estimating misclassification volumes than the residual‐resampling method. Copyright © 2002 John Wiley & Sons, Ltd.
Stereoselective protein binding of alprenolol in the renal diseased state
Authors: Imamura Hitoshi , Komori Takafumi , Ismail Ahmed , Suenaga Ayaka , Otagiri Masaki
Published: October 2002

The investigation was undertaken to study the stereoselective protein binding of alprenolol in renal disease patient sera, compared to that in the sera of healthy volunteers. The in vitro stereoselective protein binding of β‐blockers was determined in undiluted serum and in isolated α1‐acid glycoprotein (AGP) solutions by ultrafiltration. The stereoselctive serum protein binding of alprenolol, a β‐adrenergic blocking agent, in healthy volunteers was significantly altered in renal disease patients. We investigated the effects of AGP concentration and endogenous substances, including uremic toxins, on the stereoselective protein binding of alprenolol in renal disease patients. A good correlation between the unbound (R)/(S) ratio (FR/FS ratio), an apparent index of stereoselectivity in alprenolol serum binding and AGP concentration in serum, was found. However, stereoselective protein binding was not influenced by endogenous substances. This result can be explained by the difference in binding affinities of (R) and (S)‐isomers of alprenolol to AGP. We conclude that the stereoselective protein binding of alprenolol in healthy volunteers and renal disease patients varies as a result of changes in AGP concentration. Accordingly, these findings might be useful in alprenolol therapy in renal disease patients. Chirality 14:599–603, 2002. © 2002 Wiley‐Liss, Inc.
Absolute configuration and conformational analysis of a degradation product of inhalation anesthetic Sevoflurane: A vibrational circular dichroism study
Authors: Wang Feng , Polavarapu Prasad L. , Schurig V. , Schmidt R.
Published: October 2002

1,1,1,3,3‐pentafluoro‐2‐(fluoromethoxy)‐3‐methoxypropane, compound B, is a product obtained in the degradation of the anesthetic Sevoflurane. Enantiopure (+)‐B was investigated using vibrational circular dichroism (VCD). Experimental absorption and VCD spectra of (+)‐B in CDCl3 solution in the 2,000–900 cm−1 region are compared with the ab initio predictions of absorption and VCD spectra obtained from density functional theory using B3LYP/6‐31G* basis set for different conformers of (S)‐1,1,1,3,3‐pentafluoro‐2‐(fluoromethoxy)‐3‐methoxypropane. This comparison indicates that (+)‐B is of the (S)‐configuration in CDCl3 solution, in agreement with previous literature results. Our results also indicate that this compound adopts six predominant conformations in CDCl3 solution. Chirality 14:618–624, 2002. © 2002 Wiley‐Liss, Inc.
Multimodal intensification therapy for previously untreated advanced resectable squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx
Authors: Schuller David E. , Grecula John C. , Agrawal Amit , Rhoades Chris A. , Orr Debra A. , Young Donn C. , Malone James P. , Merz Meredith
Published: October 2002

BACKGROUND

An intensified treatment regimen for previously untreated Stage III and IV resectable oral cavity, oropharyngeal, or hypopharyngeal squamous cell carcinoma was analyzed to assess disease control, patient compliance, and toxicity.

METHODS

Forty three patients with previously untreated, advanced, resectable squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx were enrolled in a prospective Phase II institutional clinical trial at a tertiary care comprehensive cancer center. This regimen was a continuum of multimodal treatment in a contracted time interval. It included preoperative slightly accelerated hyperfractionated radiotherapy with concurrent cisplatin, followed immediately with surgery and intraoperative radiotherapy, and completed with early postoperative weekly paclitaxel (beginning on Day 6 after surgery), two additional cisplatin cycles, and concurrent once daily radiotherapy beginning on Day 28 after surgery.

RESULTS

The current trial was designed to reduce the toxicity of the systemic therapy while maintaining or improving locoregional/distant disease control and patient compliance. There were 43 patients enrolled, and the range of time at risk was 2.6 to 24.7 months (median, 14.6 months). Of the 43 registered patients, 43 were evaluable. The locoregional (100%) and systemic (93%) disease control rates were excellent, with low rates of patient noncompliance (21%) and reduced levels of toxicity.

CONCLUSIONS

An intensive treatment regimen that improves disease control and treatment compliance is clearly feasible for this patient population. Future plans include modifications to continue to reduce toxicity and expansion to a multi‐center Phase II trial to determine if the single institutional results can be duplicated. Cancer 2002;94:3169–78. © 2002 American Cancer Society.

DOI 10.1002/cncr.10571
Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia
Authors: Liang Der‐Cherng , Shih Lee‐Yung , Hung Iou‐Jih , Yang Chao‐Ping , Chen Shu‐Huey , Jaing Tang‐Her , Liu Hsi‐Che , Chang Wan‐Hui
Published: October 2002

BACKGROUND

Recently, an internal tandem duplication of the FLT3 gene (FLT3/ITD) was found in approximately 20% of adult acute myeloid leukemia (AML) cases and associated with a poor outcome. However, there are few studies on FLT3/ITD in childhood AML, and the clinical significance of FLT3/ITD is thus unclear.

METHODS

FLT3/ITD was analyzed in 80 children with de novo AML. The genomic DNA polymerase chain reaction (PCR) assay was performed to identify FLT3/ITD. Genescan analysis to determine the allelic distribution was then performed for those PCR products with aberrant bands. Direct sequencing of PCR products was also carried out in each sample with FLT3/ITD.

RESULTS

The incidence of FLT3/ITD was 11.3% (9 out of 80 patients) in AML, with 25% (3 out of 12 patients) in acute promyelocytic leukemia (APL) and 8.8% (6 out of 68 patients) in non‐M3 AML. The size of duplicated fragments varied from 21 base pairs (bp) to 75 bp, and the mutant to wild type ratio of FLT3 ranged from 0.28 to 16.60 in the nine patients with FLT3/ITD. The incidence of FLT3/ITD in childhood AML in patients > 10 years of age was 24%, compared to 5% of those patients ≤ 10 years of age (P = 0.011). The six non‐M3 AML patients with FLT3/ITD were all older than 10 years of age. In APL, FLT3/ITD was found in 2 of 2 patients with S‐form PML/RARα, compared with 1 in 10 patients with non‐S form PML/RARα(P = 0.045). There were no cytogenetic abnormalities or fusion transcripts derived from common specific translocations found in non‐M3 AML patients with FLT3/ITD. There was no significant difference in treatment outcome between APL patients with FLT3/ITD and those without FLT3/ITD. The authors failed to find a correlation between the treatment outcome and the presence of FLT3/ITD in non‐M3 AML patients. Instead, the authors found that all three patients with a mutant FLT3 to wild type ratio of greater than 2.0 died within eight months after diagnosis; two of them failed to achieve complete remission.

CONCLUSIONS

The current study shows that the mutant FLT3 to wild type ratio, but not the presence of FLT3/ITD itself, may serve as a potential marker to improve risk‐assessment in childhood AML. Cancer 2002;94:3292–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10598
Evaluation of the proliferation marker MIB‐1 in the prognosis of cutaneous malignant melanoma
Authors: Hazan Carole , Melzer Kate , Panageas Katherine S. , Li Eric , Kamino Hideko , Kopf Alfred , Cordon‐Cardo Carlos , Osman Iman , Polsky David
Published: October 2002

BACKGROUND

The proliferation marker MIB‐1, which recognizes the Ki‐67 antigen, provides independent prognostic information in several tumor types. Its utility in melanoma has been evaluated mostly in studies of thick primary tumors. Its usefulness in thinner lesions has not been assessed adequately.

METHODS

A well characterized cohort of 137 patients diagnosed with primary cutaneous melanoma at the New York University School of Medicine between 1972 and 1982 was studied based on the availability of representative tissues and adequate clinical follow‐up. Twenty‐one tumors were less than or equal to 1.0 mm thick, 94 were between 1.01 and 4.0 mm thick, and 22 were thicker than 4.0 mm. Tumor cell proliferation was assessed by immunohistochemistry using the monoclonal antibody MIB‐1. MIB‐1 expression was correlated with baseline clinicopathologic parameters, as well as recurrence (RR), disease‐free (DFS), and overall survival (OS) rates. Median follow‐up among survivors was 6.5 years (range, 5.6–17.5).

RESULTS

High proliferative index, defined as 20% or more of tumor cells showing nuclear immunoreactivity, was observed in 65 of 137 (47.4%) cases. High proliferative index was significantly correlated with increased tumor thickness (P< 0.001) and higher stage (P= 0.03). Trends approaching statistical significance were observed with ulceration of the primary tumor (P= 0.09), male gender (P= 0.06), and shorter DFS (P= 0.12). No significant associations were seen between high proliferative index and RR or OS. In multivariate analyses, tumor thickness was the strongest predictor of clinical outcome.

CONCLUSIONS

In primary cutaneous melanoma, a high proliferative index is associated with clinicopathologic parameters predictive of worse clinical outcomes. However, it was not an independent predictor of clinical outcome. Cancer 2002;95:634–40. © 2002 American Cancer Society.

DOI 10.1002/cncr.10685
Contrast‐enhanced dynamic computed tomography for the evaluation of tumor angiogenesis in patients with lung carcinoma
Authors: Tateishi Ukihide , Kusumoto Masahiko , Nishihara Hiroshi , Nagashima Kazuo , Morikawa Toshiaki , Moriyama Noriyuki
Published: October 2002

BACKGROUND

The objective of this study was to investigate the role of contrast‐enhanced dynamic computed tomography (CT) in the evaluation of tumor angiogenesis in patients with lung carcinoma and to assess its importance in predicting tumor size and lymph node involvement.

METHODS

Dynamic CT scans were evaluated retrospectively in 130 patients with primary lung carcinoma who did not have distant metastasis and who underwent surgical resection with mediastinal lymph node dissection. Histopathologic findings of vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) were correlated with the maximum attenuation values of time‐attenuation curves (MAV) on dynamic CT scans.

RESULTS

The MAV in VEGF positive tumors was greater compared with the MAV in VEGF negative tumors (66.1 ± 4.6 vs. 30.9 ± 2.7, respectively; P < 0.0001). An association was found between the MAV in VEGF positive tumors and MVD (correlation coefficient = 0.650; P < 0.0001). No difference was found in tumor size with pathologic confirmation and the MAV, VEGF expression, or MVD. The MAV, VEGF expression, and MVD in lung tumors with lymph node involvement were greater compared with the same values in lung tumors without lymph node involvement.

CONCLUSIONS

The MAV of dynamic CT may be a predictor of tumor angiogenesis in patients with lung carcinoma and lymph node involvement. Cancer 2002;95:835–42. © 2002 American Cancer Society.

DOI 10.1002/cncr.10730
Association of overexpressed proline‐directed protein kinase FA with chemoresistance, invasion, and recurrence in patients with bladder carcinoma
Authors: Hsueh Sheng‐Fen , Lai Ming‐Tsung , Yang Chuan‐Ching , Chung Yuan‐Chiang , Hsu Chih‐Ping , Peng Chien‐Chung , Fu Hsiao‐Hui , Cheng Yung‐Ming , Chang King‐Jen , Yang Shiaw‐Der
Published: October 2002

BACKGROUND

It has been shown previously that proline‐directed protein kinase FA (PDPK FA) is overexpressed in various human malignancies compared with its expression in normal controls, and the suppression of overexpressed PDPK FA is capable of inhibiting the growth of various types of human carcinoma cells, suggesting a role for this PDPK in human malignancies. In this report, the authors combine immunohistologic, molecular, cellular, and clinicopathologic studies to demonstrate further an essential critical role for overexpressed PDPK FA in bladder carcinoma invasion, chemoresistance, and poor prognosis.

METHODS

The expression and localization of PDPK FA were analyzed by the immunohistochemical staining of specimens obtained from patients with primary transitional cell carcinoma (TCC) of the bladder. The stable antisense clones of human bladder carcinoma cells with specific suppression of overexpressed PDPK FA were established for invasion and chemosensitivity studies.

RESULTS

The immunohistochemical study revealed that PDPK FA was overexpressed preferentially in the invasive bladder carcinoma tissues. It was found that the stable antisense clones with specific suppression of overexpressed PDPK FA to ≈40% of the parental control level were capable of inhibiting the invasive activity and simultaneously enhancing the chemosensitivity of bladder carcinoma cells to various therapeutic drugs, such as vinblastine, vincristine, paclitaxel, and bleomycin. Clinicopathologic studies also revealed a correlation between overexpressed PDPK FA and disease recurrence/survival in patients with primary TCC (P < 0.05).

CONCLUSIONS

Taken together, the results demonstrate an essential critical role of overexpressed PDPK FA in invasion, chemoresistance, and poor prognosis. Suppression of overexpressed PDPK FA may provide a new potential target for therapeutic intervention aimed at preventing chemoresistance, disease progression, and recurrence in patients with bladder carcinoma. Cancer 2002;95:775–83. © 2002 American Cancer Society.

DOI 10.1002/cncr.10731
Proliferative activity is the most significant predictor of recurrence in noninvasive papillary urothelial neoplasms of low malignant potential and grade 1 papillary carcinomas of the bladder
Authors: Pich Achille , Chiusa Luigi , Formiconi Andrea , Galliano Diego , Bortolin Paola , Comino Alberto , Navone Roberto
Published: October 2002

BACKGROUND

Recurrence of transitional cell carcinoma of the bladder cannot be predicted accurately by traditional criteria alone. This study examined the value of cell proliferative activity, morphometry, and expression ofp53,c‐erbB‐2, andbcl‐2oncogenes in predicting recurrence of superficial papillary urothelial neoplasms of low malignant potential (LMP) and Grade 1 (G1) papillary carcinomas of the bladder.

METHODS

Sixty‐two patients (mean age, 62 years) with newly diagnosed superficial pTa bladder tumors (19 LMP, and 43 G1) were analyzed retrospectively. All patients underwent transurethral resection (TUR). Median follow‐up was 69 months. Serial sections from formalin‐fixed, paraffin‐embedded material at initial TUR were stained with monoclonal antibodies (MoAbs) DO7, CB11, andbcl‐2‐124. Cell proliferation was assessed by MIB‐1 MoAb, the quantity of argyrophilic nucleolar organizer region‐associated proteins (AgNORs), and mitotic count.

RESULTS

Of the 62 patients, 42 (67.7%) had one or more recurrences. Recurrence rates were higher in MIB‐1 (P< 0.0001) andp53immunopositive cases (P= 0.02), when the mitotic count was greater than 5 (P= 0.004), and in G1 carcinomas (P= 0.04). In univariate analysis, the disease‐free period was shorter for MIB‐1 (P< 0.0001) andp53immunopositive (P= 0.0001) cases, for cases with high AgNOR quantity (P= 0.04), mitotic count greater than 5 (P= 0.01), and in G1 carcinomas (P= 0.002). In multivariate analysis, only MIB‐1 immunoreactivity retained independent prognostic significance.

CONCLUSIONS

Despite the small cohort, the results confirm the prognostic value of cell proliferation andp53expression in patients with bladder neoplasms. The results also indicate that MIB‐1 immunopositivity is the most significant predictor of recurrence and disease‐free survival in superficial LMP and G1 papillary bladder carcinomas. Cancer 2002;95:784–90. © 2002 American Cancer Society.

DOI 10.1002/cncr.10733