bluuebunny/crossref_metadata_2025 huggingface dataset:
An analysis of Taguchi's on‐line quality monitoring procedure for attributes with diagnosis errors
Authors: Borges Wagner , Ho Linda Lee , Turnes Osiris
Published: August 2002

The on‐line quality monitoring procedure for attributes proposed by Taguchi, Elsayed and Hsiang for processes in which the fraction defective shifts from 0 at some point are examined under the assumption of diagnosis errors. The renewal reward (economic) approach of Nayebpour and Woodall is used to develop a mathematical expression for the long‐run expected cost per item produced and assessment of the optimum inspection interval is discussed. Copyright © 2001 John Wiley & Sons, Ltd.
Stereoselective metabolism and pharmacokinetics of tegafur
Authors: Damle Bharat D. , Narasimhan Narayana I. , Kaul Sanjeev
Published: August 2002

Objectives. UFT is composed of racemic tegafur (FT), a prodrug of 5‐fluorouracil (5‐FU), and uracil in a fixed molar combination (1:4). FT contains a chiral center and has two stereoisomers, R‐FT and S‐FT. The objectives of this study were to assess the stereoselectivity in the metabolism of FT to 5‐FU in vitro and to determine stereoselective differences in the disposition of FT in vivo.

Methodology. R‐FT, S‐FT, and racemic FT were incubated with pooled human liver microsomes and S‐9 fraction for a period of up to 30 min for in vitro studies. For pharmacokinetics, plasma samples were obtained from fasted cancer patients over a period of 24 h after oral administration of 200 mg UFT. Samples from in vitro studies and patient plasma samples were analyzed for FT using a validated achiral and a chiral assay, and for 5‐FU using a validated GC/MS assay.

Results. R‐FT was metabolized at a rate 5.6‐times faster than S‐FT by human liver microsomes. Similarly, stereoselective metabolism of R‐FT was also seen in the S‐9 incubations. In cancer patients, the peak plasma concentrations (Cmax) and the time to reach Cmax (Tmax) were similar for the two isomers after the administration of UFT suggesting no apparent differences in their absorption kinetics. However, the area under the curve from zero to infinity [AUC(INF)] and the terminal elimination half‐life (T‐HALF) values for R‐FT were about 4.6‐ and 4.4‐fold lower compared to S‐FT, respectively, suggesting the preferential elimination of R‐FT. The T‐HALF of racemic FT (8.3 h) was comparable to the T‐HALF of S‐FT (10.3 h) which indicated that the kinetics of the racemate are governed by S‐FT. The active cytotoxic moiety, 5‐FU, exhibited formation rate limited kinetics from R‐FT because the T‐HALF of 5‐FU (3.4 h) was similar to that of R‐FT (2.4 h).

Conclusions. The R‐isomer of FT is preferentially metabolized to 5‐FU compared to the S‐isomer in vitro. The distinct kinetic profiles of the stereoisomers of FT following the administration of UFT is apparently due to the stereoselective disposition of the R‐isomer relative to the S‐isomer. These data suggest that the R‐isomer of FT is worthy of further preclinical and clinical evaluation for safety, efficacy, and pharmacokinetics. Copyright © 2001 John Wiley & Sons, Ltd.
The pharmacokinetics of ethosuximide enantiomers in the rat
Authors: Mifsud J. , Collier P.S. , Millership J.S.
Published: August 2002

A chiral gas chromatographic assay previously developed for quantitative analysis of ethosuximide and its major metabolites in rat urine has been adapted for the analysis of the drug in plasma. Ethosuximide, both as a racemic mixture and as the individual enantiomers, was administered to conscious rats by the intravenous (i.v.) and intraperitoneal (i.p.) routes. Pharmacokinetic parameters were estimated using standard non‐compartmental methods. Comparison of the pharmacokinetic parameters of (S)‐ethosuximide and (R)‐ethosuximide showed that total body clearance of (R)‐ethosuximide was significantly larger than that of (S)‐ethosuximide and that elimination half‐life was significantly shorter following administration of both 40 mg i.v. and i.p. doses, indicating that there is stereoselective elimination of ethosuximide. However, no significant differences were found between apparent volumes of distribution. In addition, no significant differences were found for either enantiomer between the estimates of the pharmacokinetic parameters obtained following administration as the individual enantiomer and as a constituent of the racemic mixture. This indicates that, at the doses studied, the preferential faster elimination of (R)‐ethosuximide is not dependent upon the presence of the (S)‐enantiomer. Also, for each enantiomer, the lack of any significant difference between estimates of clearance when administered as part of a racemic mixture and when administered separately indicates that neither enantiomer affects the clearance of the other. Copyright © 2001 John Wiley & Sons, Ltd.
Why biologists should support the exploration of Mars
Authors: Maurel Marie‐Christine , Zaccai Giuseppe
Published: August 2002

Physicists, chemists and geologists in the USA and Europe propose that the search for extraterrestrial life is an important justification for the exploration of Mars. Biologists, however, much more excited by the advent of the postgenome sequencing era, in general display little enthusiasm for planetary exploration. We argue that the search for traces of life on Mars represents a major thought‐provoking challenge for the life sciences that should be taken up by the biological community. BioEssays 23:977–978, 2001. © 2001 John Wiley & Sons, Inc.
Quantitative analysis of the regulation scheme of invertase expression in Saccharomyces cerevisiae
Authors: Herwig Christoph , Doerries Christos , Marison Ian , von Stockar Urs
Published: August 2002

In Saccharomyces cerevisiae, the expression of invertase, which is the hydrolyzing enzyme of sucrose, is controlled by the presence of monosaccharides, such as glucose and fructose, and referred to as carbon catabolite repression. To date, efforts have been made to identify the mechanism by which cells sense extracellular monosaccharide concentrations and trigger the genes involved in the repression pathway. The aim of the present work was to quantitatively investigate the cellular regulation of invertase expression in the wild‐type strain S. cerevisiae CEN.PK113‐7D during batch growth containing mixed sugar substrates under different initial conditions.

Because of the high frequency and accurate online analysis of multiple components, a tight control of invertase expression could be observed, and threshold concentrations of the monosaccharides for derepression could be determined to 0.5 gl−1 for glucose and 2 gl−1 for fructose. Also, the existence of a hitherto undescribed regulatory state, in which cells regulate invertase expression very precisely and operate over long periods at monosaccharide concentrations lower than the above thresholds, could be demonstrated. All experimental observations could be summarized in a formulation of the cellular regulation scheme of invertase expression. A simple kinetic model could show that the regulation scheme explains the observed behavior very well. Additionally, the model was able to explain consequences of the regulation on the global metabolism. © 2001 John Wiley & Sons, Inc. Biotechnol Bioeng 76: 247–258, 2001.
High‐performance liquid chromatographic method for determination of leucovorin in plasma: validation and application to a pharmacokinetic study in healthy volunteers
Authors: Duan Geng‐Li , Zheng Lu‐Xia , Chen Jun , Cheng Wu‐Ben , Li Duan
Published: August 2002

A sensitive and reliable high‐performance liquid chromatographic (HPLC) method, using a solid‐phase extraction (SPE), was developed and validated for determination of leucovorin (LV) in human plasma. Plasma sample was extracted by using a Sep‐Pak cartridge which could be renewable. The sample was analyzed by HPLC with UV detection at 286 nm. The method was shown to perform selectively and sensitively for LV. The main metabolite of LV, 5‐methyltetrahydrofolic acid, and endogenous substances in plasma did not show any interference in the analysis. The limit of detection was 10 ng/mL for LV in plasma and the linear range was 50–1500 ng/mL in plasma. The relative standard deviation (RSD) of intra‐day and inter‐day assays was 2.8–6.1% and 2.4–5.3%, respectively. The extraction recoveries of LV in plasma were over 90%. The method was proved to be applicable to the pharmacokinetic study of LV in healthy volunteers after a single oral administration (75 mg). The pharmacokinetic parameters and relative bioavailability were investigated for domestic LV tablet and capsule vs an imported tablet. Copyright © 2002 John Wiley & Sons, Ltd.
Simultaneous determination of flucytosine and fluorouracil in human plasma by high‐performance liquid chromatography
Authors: Sastre Toraño J. , Vermes A. , Guchelaar H.‐J.
Published: August 2002

A validated, sensitive and precise reversed‐phase high‐performance liquid chromatographic method for the simultaneous determination of 5‐flucytosine (5‐FC) and 5‐fluorouracil (5‐FU) in human plasma is described. Two compounds, 5‐methylcytosine (5‐MC) and 5‐chlorouracil (5‐CU), were used as internal standards for the determination of 5‐FC and 5‐FU, respectively. Plasma samples were deproteinized with trichloroacetic acid and chromatographed on an octylsilica column, maintained at 30°C during elution, using a 0.04 M phosphate buffer, pH 7.0, as eleunt. Spectrophotometric diode array detection was used at 266 nm. 5‐FC, 5‐FU, 5‐MC and 5‐CU were found to have retention times of 4.8, 5.8, 7.7 and 11.0 min respectively. Recoveries of 91–120% with reproducibility and repeatability coefficients of variation of 0.8–6% were obtained. Mean correlation coefficients of 0.99989 and 0.9995 were found for the linear calibration curves (n = 2) of 5‐FC (4.816–192.6 mg/l) and 5‐FU (0.05368–5.368 mg/l), respectively. The limits of quantitation were 0.3 mg/l for 5‐FC and 0.05 mg/l for 5‐FU. Copyright © 2001 John Wiley & Sons, Ltd.

Abbreviations used:

5‐CU

5‐chlorouracil

5‐FC

5‐flucytosine

FdUMP

5‐fluorodeoxyuridine monophosphate

5‐FU

5‐fluorouracil

FUTP

5‐fluorouridine triphosphate

HLQ

higher limit of quantitation

LLQ

lower limit of quantitation

5‐MC

5‐methylcytosine

TDM

therapeutic drug monitoring.
A solid phase extraction reversed‐phase HPLC method for the simultaneous determination of methoprene, permethrin and selected metabolites in rat plasma and urine
Authors: Abu‐Qare Aqel W. , Abou‐Donia Mohamed B.
Published: August 2002

A method was validated and applied for the analysis of the insect growth regulator methoprene [Isopropyl (2E,4E)‐11‐methoxy‐3,7,11‐trimethyldodeca‐2,4‐dienoate], its metabolite methoprene acid, the insecticide permethrin [3‐(2,2‐dichloro‐ethenyl)‐2,2‐dimethylcyclopropanecarboxylic acid(3‐phenoxyphenyl)methylester], and two of its metabolites, m‐phenoxybenzyl alcohol and m‐phenoxybenzoic acid, in rat plasma and urine using solid‐phase extraction and reversed‐phase high performance liquid chromatography. The analytes were separated using gradient of 55–100% acetonitrile in water (pH 4.0) at a flow rate ranging between 0.6 and 1.0 mL/min over a period of 20 min, and UV detection at 210 and 254 nm. The retention times ranged from 7.3 to 18.4 min. The limits of detection ranged between 50 and 100 ng/ml, while limits of quantitation were 100–150 ng/mL. Average percentage recovery of five spiked plasma samples was 83.6 ± 3.9, 80.1 ± 5.4, 82.1 ± 4.4, 83.7 ± 3.9 and 83.1 ± 4.7, and from urine 79.3 ± 4.3, 82.0 ± 5.4, 80.7 ± 4.2, 78.9 ± 5.7 and 83.9 ± 4.5 for methoprene, methoprene acid, permethrin, m‐phenoxybenzyl alcohol and m‐phenoxybenzoic acid, respectively. The method was linear and reproducible over the range of 100–1000 ng/mL. This method was applied to analyze the above chemicals and metabolites following their combined administration in rats. Copyright © 2001 John Wiley & Sons, Ltd.

Abbreviations used:

LOD

limit of detection

LOQ

limit of quantitation
Evaluation of practical sessions in clinical anatomy: A strategy for educational improvement
Authors: Tavares M.A.F. , Amandio J. Vieira , Cunha N. Trigueiros , Machado J. Dinis , Cardoso V. , Silva M.C.
Published: August 2002

We have evaluated the students' response to the practical teaching sessions in Clinical Anatomy in our Medical School using an action‐research method. The aim was to identify problems and to introduce changes that might improve both the program and the performance of the teaching staff. At the end of each section of the program, each student completed a “target type” questionnaire with eight different components. As each one quarter of the whole class had its own teacher, we used an analysis of variance to evaluate the target questions in the various sections of the program, and the performance of the four teachers. This research method gave us feedback on the students' responses while the program was in progress. The results emphasize the importance of action‐research in assessing and improving a developing program in a basic discipline of the medical curriculum. Clin. Anat. 15:51–55, 2002. © 2002 Wiley‐Liss, Inc.
Anomalous relationship of the spinal accessory nerve to the internal jugular vein
Authors: Gardiner K.J. , Irvine B.W. , Murray A.
Published: August 2002

A patient with an early cancer of the tongue and undergoing a staging neck dissection was noted to have an anomalous relationship of the internal jugular vein and spinal accessory nerve. At the upper end of the dissection (level II, Memorial Sloan‐Kettering classification), the internal jugular vein was observed to divide above and reconstitute below the spinal accessory nerve. Although apparently not previously described in the literature, this finding may be encountered by other surgeons who operate in this area, and it is important that these anatomical variations are borne in mind to prevent inadvertent injury. Clin. Anat. 15:62–63, 2002. © 2002 Wiley‐Liss, Inc.
The evaluation of retractions in sexual abuse cases
Authors: Tully Bryan
Published: August 2002

In some cases of alleged sexual abuse, the child or adult retracts allegations made. This poses problems for both civil and criminal legal proceedings. It is argued that the collection and examination of retraction statements often does not receive the same careful attention as is the case with the investigation of the original allegations. Logically, depending on whether the original complaints were true or false or a mixture, so the meaning of a retraction may vary. Where retractions are examined and evaluated with care they may be shown to add to the confidence of the final conclusion rather than simply throwing doubt on that. A systematic approach is described, followed by three cases where such application assisted and paradoxically added to the probative value of earlier statements. Copyright © 2002 John Wiley & Sons, Ltd.
Amplatzing a 6 Fr Judkins right guiding catheter for increased success in complex right coronary artery anatomy
Authors: Abhaichand Rajpal K. , Lefèvre Thierry , Louvard Yves , Morice Marie‐Claude
Published: August 2002

Stent supported angioplasty is being performed in an increasing number of patients and, with advances in device technology, more morphologically complex lesions are being treated. In such a setting, it is extremely important to deliver the device to the target lesion. We describe a new technique that allows successful stent delivery in complex right coronary anatomy using the Judkins right guiding catheter. Cathet Cardiovasc Intervent 2001;53:405–409. © 2001 Wiley‐Liss, Inc.
Acute and 6‐month clinical and angiographic outcome after implantation of the ACS Duet stent for single‐vessel coronary artery disease: Final results of the European and U.S. ACS Multi‐link Duet Registry
Authors: Foley David P. , Kererakes Dean , te Riele Jan A.M. , Nishimura Naomi , Veldhof Susan , Fink Stan , Yeung Alan , van Hoogenhuyze Diederik , Lansky Alexandra M. , van Es Gerrit‐Anne , Kutryk Michael J.B. , Serruys Patrick W.
Published: August 2002

The aim of the study was to determine the safety and efficacy of the second‐generation ACS Multi‐Link Duet coronary stent system for the treatment of single, symptomatic, de novo, native coronary artery lesions. Between February and June 1998, 427 patients (69.3% male, 51.5% class 3 or 4 angina, 20.1% diabetic, 43.6% hyperlipidemia) were included at 38 centers in this prospective observational study. All patients received ticlopidine 500 mg/day for 1 month and aspirin ≥100 mg/day. The Duet stent was available in 8, 18, and 28 mm length and 3.0, 3.5, and 4.0 mm diameter. After adequate predilatation, stents were successfully implanted, at up to 16 atm, in 99.3% of patients. Mean vessel diameter by core laboratory quantitative coronary angiography was 3.0 ± 0.53 mm and postprocedural minimum luminal diameter was 2.79 ± 0.43 mm (12% ± 9.3% diameter stenosis). At 30 days, 96.7% of patients were event‐free and at 6 months 88.1% remained free of major adverse cardiac events. The restenosis rate was 18.1%. The ACS Duet stent was safely implanted in >99% of target lesions by a diverse group of international investigators. With late outcomes at least comparable to the best published results, this stent platform provides safe and effective percutaneous treatment of obstructive coronary artery disease. Cathet Cardiovasc Intervent 2001;54:25–33. © 2001 Wiley‐Liss, Inc.
Is the “candy‐wrapper” effect of 32P radioactive β‐emitting stents due to remodeling or neointimal hyperplasia?: Insights from Intravascular Ultrasound
Authors: Hansen Alexander , Hehrlein Christoph , Hardt Stefan , Bekeredjian Raffi , Brachmann Johannes , Kubler Wolfgang , Bode Christoph , Kuecherer Helmut F.
Published: August 2002

A recognized limitation of radioactive stents is the development of restenosis at the stent edges, known as the “candy‐wrapper” effect. The mechanisms of this effect remain incompletely understood and controversial. The aim of this study is to assess the effect of endovascular irradiation on neointima formation and vascular remodeling. 32P Palmaz‐Schatz stents (1.5–4 μCi) were implanted in 11 patients with restenosis after previous percutaneous transluminal coronary angioplasty (PTCA). Intravascular ultrasound (IVUS) images of target sites and adjunct vessel segments were acquired both during intervention and after 6 months. The angiographic restenosis rate was 54%, and the MLD decreased from 2.21 ± 0.6 mm to 1.38 ± 0.4 mm at follow‐up (P < 0.01). IVUS analysis demonstrated that late lumen loss was the result of neointimal tissue proliferation, which was nonuniformly distributed and exaggerated at both the central articulation and the distal stent edges. Negative remodeling did not contribute to restenosis. In contrast, we found a linear relationship between increase of area stenosis and a positive remodeling index (r = 0.84, P < 0.0001). Restenosis after implantation of 32P Palmaz‐Schatz stents was mainly the result of neointimal tissue proliferation which tended to be nonuniformly distributed in the stent articulation and edges. Negative remodeling or stent recoil was not observed. Cathet Cardiovasc Intervent 2001;54:41–48. © 2001 Wiley‐Liss, Inc.
Clinical and angiographic outcomes following elective implantation of the carbostent in patients at high risk of restenosis and target vessel failure
Authors: Antoniucci David , Valenti Renato , Migliorini Angela , Moschi Guia , Trapani Maurizio , Bolognese Leonardo , Santoro Giovanni Maria , Cerisano Giampaolo
Published: August 2002

The Carbostent is a new balloon‐expandable, stainless steel, tubular stent with innovative multicellular design and unique turbostratic carbon coating. The aim of this study was to assess clinical and angiographic outcomes after Carbostent implantation in 112 patients poorly suitable for an effective treatment with stenting because of the high risk of thrombosis, late restenosis, and clinical target vessel failure. The inclusion criteria were age > 75 years, diabetes mellitus, a lesion length > 10 mm, a reference vessel diameter < 3.0 mm, an ostial location of the target lesion, and chronic total occlusion. Overall, a total of 175 stents ranging from 9 to 25 mm in length were placed in 147 lesions. There were no stenting attempt failures. The acute gain after stent implantation was 2.46 ± 0.51 mm, and the residual stenosis 0 ± 4%. No stent thrombosis occurred, nor myocardial infarction. The 6‐month event‐free survival rate was 74% ± 5%. The 6‐month angiographic follow‐up showed a late loss of 0.81 ± 0.88 mm and a binary (≥ 50%) restenosis rate of 25%. The results of this study suggest that the Carbostent may be highly effective in patients at high risk of restenosis and target vessel failure. Cathet Cardiovasc Intervent 2001;54:420–426. © 2001 Wiley‐Liss, Inc.
Monitoring of a batch organic synthesis by near‐infrared spectroscopy: modeling and interpretation of three‐way data
Authors: Geladi Paul , Forsström Jennie
Published: August 2002

Three‐way data of the type batch × time × NIR wavelength were obtained by NIR spectroscopic multivariate monitoring of an organic synthesis as a batch process. The model synthesis, an ester synthesis, was carried out as an experimental design. Unexpected technical problems caused a blocking effect that forced a modification of the design. After preprocessing of a reduced three‐way array, the spectral data in the three‐way array were subjected to parallel factor analysis (PARAFAC). The loadings from this analysis could be interpreted and explained as a function of the synthesis studied. For the spectral interpretation, spectra of pure chemicals were needed. The paper is an illustration of what can be done with three‐way modeling in order to increase the understanding of a reaction, and it attempts to show how the results can be interpreted and presented. The data sets are available from the authors. Copyright © 2002 John Wiley & Sons, Ltd.
Deleteagene: a fast neutron deletion mutagenesis‐based gene knockout system for plants
Authors: Li Xin , Lassner Michael , Zhang Yuelin
Published: August 2002

Deleteagene™ (Delete‐a‐gene) is a deletion‐based gene knockout system
for plants. To obtain deletion mutants for a specific gene, random deletion
libraries created by fast neutron mutagenesis are screened by polymerase chain
reaction (PCR) using primers flanking the target gene. By adjusting the PCR
extension time to preferentially amplify the deletion alleles, deletion mutants
can be identified in pools of DNA samples with each sample representing more
than a thousand mutant lines. In Arabidopsis, knockout plants for greater
than 80% of targeted genes have been obtained from a population of 51 840
lines. A large number of deletion mutants have been identified and multiple
deletion alleles are often recovered for targeted loci. In Arabidopsis,
the method is very useful for targeting small genes and can be used to find
deletion mutants mutating two or three tandem homologous genes. In addition,
the method is demonstrated to be effective in rice as a deletion mutant for
a rice gene was obtained with a similar approach. Because fast neutron mutagenesis
is applicable to all plant genetic systems, Deleteagene™ has the potential
to enable reverse genetics for a wide range of plant species. Copyright ©
2002 John Wiley & Sons, Ltd.
Structure, conformation, and mechanism in the membrane transport of alkali metal ions by ionophoric antibiotics
Authors: Riddell Frank G.
Published: August 2002

Recent progress in studies of the mechanism of transport of alkali metal ions by ionophoric antibiotics and the structures of alkali metal salts of the ionophores monensin and narasin is reviewed. The structures obtained from 2D NMR experiments in solution provide considerable insights into the mechanisms of transport. Chirality 14:121–125, 2002. © 2002 Wiley‐Liss, Inc.
Pharmacokinetics of the active antifungal enantiomer, SCH 42427 (RR), and evaluation of its chiral inversion in animals following its oral administration and the oral administration of its racemate genaconazole (RR/SS)
Authors: Kim Hong , Radwanski Elaine , Lovey Raymond , Lin Chin‐Chung , Nomeir Amin A.
Published: August 2002

Genaconazole (SCH 39304) is a potent triazole antifungal agent that is active both orally and topically. Genaconazole is a racemic mixture which contains 50% of the RR (SCH 42427) and 50% of the SS (SCH 42426) enantiomers. The RR isomer accounts for most of the antifungal activity of genaconazole. Serum concentrations of the RR and SS enantiomers were analyzed by a chiral HPLC method which involved extraction of serum with organic solvent followed by separation on a Cyclobond I column and quantification by UV absorbance at 205 nm. The bioavailability and pharmacokinetic profiles of the two enantiomers after oral administration of the racemate (genaconazole) were very similar in cynomolgus monkeys. In rats following dosing with genaconazole, the RR enantiomer had a lower Cmax and a longer t1/2 than the SS enantiomer, while the AUC(I) values of the two enantiomers were similar. Based on chiral HPLC analysis, there was no evidence for the inversion of the RR to the SR isomer, or of the SS to the SR isomer, indicating that there was no chiral inversion of the RR or SS enantiomers in either species. Genaconazole at 20 mg/kg and the RR (SCH 42427) enantiomer at 10 mg/kg had very similar serum concentration–time profiles and Cmax, AUC(I), and t1/2 values for the RR enantiomer in both rats and monkeys, indicating that the two treatments were equivalent with respect to the bioavailability of the RR enantiomer. Chirality 14:436–441, 2002. © 2002 Wiley‐Liss, Inc.
Simultaneous analysis of enantiomeric composition of amino acids and N‐acetyl‐amino acids by enantioselective chromatography
Authors: Yu Yi‐Ping , Wu Shih‐Hsiung
Published: August 2002

Among the three chiral columns, CHIROBIOTIC T™, CHIRLPAK WH, and CHIRALCEL OD‐R, tested for the separation of racemic amino acids and N‐acetyl‐amino acids, only CHIROBIOTIC T™ chiral column which is based on covalently bonded amphoteric glycopeptide, teicoplanin, as the stationary phase ligand could be successfully developed to enantiomerically separate racemic amino acids and N‐acetyl amino acids simultaneously. This method can be used to determine the enantiomeric composition of amino acids and N‐acetyl‐amino acids in the catalysis of D‐aminoacylase or L‐aminoacylase and the conversion rate of N‐acylamino acid racemases. Chirality 13:231–235, 2001. © 2001 Wiley‐Liss, Inc.
Prognostic significance of serum thymidine phosphorylase concentration in esophageal squamous cell carcinoma
Authors: Shimada Hideaki , Takeda Akihiko , Shiratori Tooru , Nabeya Yoshihiro , Okazumi Shin‐ichi , Matsubara Hisahiro , Funami Yutaka , Hayashi Hideki , Gunji Yoshio , Kobayashi Susumu , Suzuki Takao , Ochiai Takenori
Published: August 2002

BACKGROUND

Thymidine phosphorylase (dThdPase), which also is referred to as platelet‐derived endothelial cell growth factor, is a potent inducer of angiogenesis in malignant tumors. Increased dThdPase expression and activity have been found to be associated with poor prognosis in various solid tumor tissues. Because very little was known about the significance of serum dThdPase concentration (S‐dThdPase), the objective of this study was to analyze the clinicopathologic significance of S‐dThdPase in the patients with esophageal squamous cell carcinoma.

METHODS

The S‐dThdPase was measured by enzyme‐linked immunosorbent assay in 77 healthy controls and 153 patients with primary esophageal squamous cell carcinoma. A total of 80 patients underwent surgery alone; 46 patients received chemoradiotherapy alone; 17 patients received chemoradiotherapy followed by surgery; and 10 patients did not receive any treatment. Thymidine phosphorylase expression in esophageal carcinoma tissues was examined by immunohistochemistry. The clinicopathologic value and prognostic value of S‐dThdPase was determined in 80 patients treated by surgery alone.

RESULTS

The S‐dThdPase is significantly higher in patients with esophageal carcinoma than in healthy controls (30.8 ± 31.8 ng/mL vs. 13.8 ± 7.6 ng/mL; P < 0.001). Statistically significant differences in S‐dThdPases were observed depending on tumor size (P < 0.01) and tumor depth (P < 0.01). A S‐dThdPase of more than 29.0 ng/mL (which represented the mean plus 2 standard deviation of the concentration in healthy controls) was associated with dThdPase expression (P = 0.022), poor response (P = 0.022), and poor survival (P < 0.01). Because S‐dThdPase was associated with tumor depth, S‐dThdPase was not an independent prognostic factor (P = 0.095).

CONCLUSIONS

A high S‐dThdPase is associated with depth of tumor invasion and poor response to treatment. Cancer 2002;94:1947–54. © 2002 American Cancer Society.

DOI 10.1002/cncr.10418
In vitro effects of STI 571‐containing drug combinations on the growth of Philadelphia‐positive chronic myelogenous leukemia cells
Authors: Scappini Barbara , Onida Francesco , Kantarjian Hagop M. , Dong Li , Verstovsek Srdan , Keating Michael J. , Beran Miloslav
Published: August 2002

BACKGROUND

Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR‐ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR‐ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR‐ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML.

METHODS

The single agents and their combinations were studied for in vitro effect on proliferation of BCR‐ABL positive cell lines KBM5 and KBM7 by 3(4,5‐dimethylthiazol‐2yl)‐2,5 diphenyl‐tetrazolium bromide assay and on primary patient‐derived BCR‐ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer‐assisted analysis using the CalcuSyn software.

RESULTS

STI571 consistently suppressed BCR‐ABL positive cell proliferation with a dose‐effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML‐derived clonogenic cells in semisolid cultures.

CONCLUSIONS

In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome‐positive leukemias. Cancer 2002;94:2653–62. © 2002 American Cancer Society.

DOI 10.1002/cncr.10543
Familial breast carcinoma risks by morphology
Authors: Hemminki Kari , Granström Charlotta
Published: August 2002

BACKGROUND

Familial risks in patients with breast carcinoma have not been assessed by morphologic types of medically verified cancers. Reliable data on familial risks would help to establish prevention programs and guide clinical decisions.

METHODS

We used the nationwide Swedish Family‐Cancer Database to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for invasive and in situ breast carcinomas in women with mothers and sisters. This database has information on 10.2 million individuals and on more than 13,000 morphology‐specific breast carcinomas.

RESULTS

SIRs for all invasive breast carcinomas were 1.82 (95% CI 1.71–1.93) for breast carcinoma in the mother and 1.89 (1.70–2.01) for breast carcinoma in a sister. The respective risks were 1.81 and 1.85 for a mother and sisters with ductal breast carcinoma. The SIRs were equally for lobular, tubuloductal, comedo, and mucinous breast carcinomas. However, the SIRs for lobular carcinoma were lower than those for the ductal type, whereas the opposite trend was noted for the comedo and mucinous type; none of the differences were significant. The risks for all morphologic types were highest when both a mother and a sister were affected, SIR 3.19 (2.36–4.22). The risks for in situ breast carcinomas were 2.09 (1.78–2.44) for an affected mother, 2.24 (1.88–2.85) for an affected sister, and 5.23 (2.59–9.39) when both a mother and a sister were affected.

CONCLUSIONS

The data suggest that the familial risk of breast carcinoma is independent of the morphologic type. The higher risks in in situ cancer may be due to medical surveillance. The risks were identical from a mother or sister proband, suggesting that recessive effects are unlikely as a heritable cause of breast carcinoma. Cancer 2002;94:3063–70. © 2002 American Cancer Society.

DOI 10.1002/cncr.10555
Serum arginase activity in postsurgical monitoring of patients with colorectal carcinoma
Authors: Porembska Zofia , Skwarek Anna , Mielczarek Magdalena , Barańczyk‐Kuźma Anna
Published: August 2002

BACKGROUND

Colorectal carcinoma (CRC) is one of the most common malignancies. In the current work, the role of arginase as a diagnostic marker in patients with recurrent CRC and colorectal liver metastases (CRCLM) was studied.

METHODS

Arginase activity was monitored in serum from 40 patients with primary CRC and from 100 patients with CRCLM. Blood was taken before and after patients underwent tumor resection. Studies were conducted for 3 years.

RESULTS

Preoperative arginase activity in serum from patients with CRC and CRCLM was much greater compared with the arginase activity in serum from healthy control blood donors. One and two cut‐off levels of increased arginase activity were observed in patients with CRC and CRCLM, respectively. After patients underwent tumor resection, the arginase activity decreased to normal values in both patients with CRC and patients with CRCLM. Activity levels remained low in patients who did not develop recurrent CRC or CRCLM (first or second). In patients who developed subsequent recurrences or metastases that appeared after surgery, during 3 years of surveillance, a significant rise in serum arginase activity was observed. The clinical prognosis for patients was worst when the postoperative serum arginase activity was very high, because those patients more often developed second liver metastases or died.

CONCLUSIONS

The authors conclude that the determination of serum arginase activity may be a complementary test to confirm the occurrence of CRC and may be useful for the early diagnosis of patients who develop recurrent CRC and/or CRCLM. Cancer 2002;94:2930–4. © 2002 American Cancer Society.

DOI 10.1002/cncr.10563
Distribution of two splice variants of the glutamate transporter GLT‐1 in the developing rat retina
Authors: Reye Peter , Sullivan Robert , Pow David V.
Published: August 2002

The distributions of a carboxyl terminal splice variant of the glutamate transporter GLT‐1, referred to as GLT‐1B, and the carboxyl terminus of the originally described variant of GLT‐1, referred to hereafter as GLT‐1α, were examined using specific antisera. GLT‐1B was present in the retina at very early developmental stages. Labelling was demonstrable at embryonic day 14, and strong labelling was evident by embryonic day 18. Such labelling was initially restricted to populations of cone photoreceptors, the processes of which extended through the entire thickness of the retina and appeared to make contact with the retinal ganglion cells. During postnatal development the GLT‐1B‐positive photoreceptor processes retracted to form the outer plexiform layer, and around postnatal day 7, GLT‐1B‐immunoreactive bipolar cells appeared. The pattern of labelling of bipolar cell processes within the inner plexiform layer changed during postnatal development. Two strata of strongly immunoreactive terminals were initially evident in the inner plexiform layer, but by adulthood these two bands were no longer evident and labelling was restricted to the somata and processes (but not synaptic terminals) of the bipolar cells, as well as the somata, processes, and terminals of cone photoreceptors. By contrast, GLT‐1α appeared late in postnatal development and was restricted mainly to a population of amacrine cells, although transient labelling was also associated with punctate elements in the outer plexiform layer, which may represent photoreceptor terminals. J. Comp. Neurol. 447:323–330, 2002. © 2002 Wiley‐Liss, Inc.
Distribution of myelinated and unmyelinated nerve fibers and their possible role in blood flow control in crotaline snake infrared receptor organs
Authors: Hisajima Tatsuya , Kishida Reiji , Atobe Yoshitoshi , Nakano Masato , Goris Richard C. , Funakoshi Kengo
Published: August 2002

We used transmission electron microscopic montages to examine the composition of nerve bundles serving the infrared pit organs of two species of crotaline snakes, Agkistrodon blomhoffii and A. brevicaudus. In the three main bundles, the myelinated fibers totaled 2,200–3,700, and unmyelinated fibers 2,400. We also discovered for the first time two accessory bundles composed almost entirely of unmyelinated fibers running alongside the main bundles, containing an average total of 3,300 unmyelinated fibers vs. an average of 10 myelinated fibers. Thus, the average total of unmyelinated fibers was nearly twice that of myelinated fibers. To study the nature of the unmyelinated fibers, we did double staining immunohistochemistry with antibodies for substance P (SP) and vasoactive intestinal polypeptide (VIP) in combination with and without capsaicin pretreatment. SP and VIP immunoreactive varicose fibers ran straight toward the center of the pit membrane in parallel with arterioles and venules, and also formed a dense network around the periphery of the membrane. There were three types of fibers: fibers containing only SP, fibers containing only VIP, and fibers containing both peptides. SP‐only fibers were distributed singly throughout the pit membrane and in small bundles around the periphery. SP+VIP fibers were distributed sparsely in the pit membrane and around its periphery. VIP‐only fibers were distributed throughout the pit membrane and were of smaller diameter than SP and SP+VIP fibers. After treatment with capsaicin, most of the three types of varicose fibers disappeared from the central part of the pit membrane, but those around the periphery remained unaffected. The capsaicin‐sensitive fibers may be unmyelinated sensory types, and the unaffected ones may be autonomic nerve fibers. J. Comp. Neurol. 449:319–329, 2002. © 2002 Wiley‐Liss, Inc.
Neuroepithelial bodies: A morphologic substrate for the link between neuronal nitric oxide and sensitivity to airway hypoxia?
Authors: Brouns Inge , Van Genechten Jeroen , Scheuermann Dietrich W. , Timmermans Jean‐Pierre , Adriaensen Dirk
Published: August 2002

Currently, the significance of nitric oxide (NO) in the respiratory tract is a matter of great interest because NO is believed to play a major role in the physiological regulation of airway function but also in lung pathology. What is especially intriguing with respect to the present investigation, are reports that the pulmonary expression of neuronal NO synthase (nNOS) is altered as a result of airway hypoxia. We examined the possible relationship between intrapulmonary nitrergic structures and pulmonary neuroepithelial bodies (NEBs), chemoreceptor‐like epithelial cell groups that are known to have all necessary components for oxygen perception. Tyramide‐enhanced immunostaining for nNOS was combined with known markers for NEBs in an ontogenetic study of rat lungs. From postnatal day 2 onward, nNOS‐immunoreactive (‐IR) neuronal cell bodies, present mainly in the lamina propria at all levels of intrapulmonary airways, were seen to give rise to remarkable intraepithelial terminal arborizations that invariably colocalized with NEBs. nNOS immunoreactivity was absent from the vagal calbindin D28k(CB) ‐IR and the spinal calcitonin gene‐related peptide(CGRP) ‐IR extrinsic sensory nerve fiber populations that our group reported earlier to selectively contact NEBs. Quantitative analysis showed that all NEBs receiving nNOS‐IR terminals were also contacted by CGRP‐IR nerve fibers, whereas approximately 55% were additionally contacted by CB‐IR nerves. The reported nitrergic neurons did not express the cholinergic marker vesicular acetylcholine transporter and were always surrounded by a basket of CGRP‐IR nerve terminals. In conclusion, part of the pulmonary NEBs selectively receive extensive nitrergic nerve terminals that originate from intrinsic neurons. Together with literature data on lung physiology and pharmacology, some interesting suggestions for the functional significance of the association between pulmonary CGRP‐IR NEBs, nNOS‐IR neurons, and CGRP‐IR afferents described in the present study, are discussed. J. Comp. Neurol. 449:343–354, 2002. © 2002 Wiley‐Liss, Inc.
Influence of sex and estrus cycle on the sexual dimorphisms of the hypothalamic ventromedial nucleus: Stereological evaluation and golgi study
Authors: Dulce Madeira M. , Ferreira‐Silva Luís , Paula‐Barbosa Manuel M.
Published: August 2002

Neurons in the ventromedial nucleus of the hypothalamus (VMN) display structural and biochemical sex differences in response to estrogen. Despite this fact, reports on sex differences in the morphology of the VMN are restricted to its volume and synaptic patterning. The aim of this study was to characterize the neuroanatomical sexual dimorphisms in the VMN and to investigate whether endogenous changes in ovarian steroid secretion influence such dimorphisms. The VMN of adult male rats and intact, aged‐matched female rats killed on proestrus and diestrus day 1 was examined by using stereological methods applied to conventionally stained sections and Golgi‐impregnated material. The VMN contained 55,000 neurons in rats of both sexes, but its volume was, on average, 1.25 times larger in males than in females. The volume was greater in proestrus than in diestrus rats due to parallel changes in the neuronal somatic size. Unlike the dorsomedial division, neurons in the ventrolateral division had longer dendritic trees in proestrus than in diestrus females and males. The spine density was consistently higher in females than in males in both VMN divisions. In addition, in the ventrolateral part the magnitude of the sex differences varied across the estrus cycle, and reached the greatest value when females were in proestrus. The volume of the neuropil was significantly larger in males than in females, and was not affected by the estrus phase. Our results reveal that the magnitude of the neuroanatomical sex differences in the VMN vary across the estrus cycle due to the trophic influence of estrogen upon its neurons. They also show that the fundamental sex difference in the structure of the VMN is accounted for by the neuropil components. J. Comp. Neurol. 432:329–345, 2001. © 2001 Wiley‐Liss, Inc.
Daily variation in the distribution of glycogen phosphorylase in the suprachiasmatic nucleus of Syrian hamsters
Authors: Harley Carolyn W. , Farrell Rosemarie C. , Rusak Benjamin
Published: August 2002

Dynamic changes in astrocytic processes in the Syrian hamster suprachiasmatic nucleus (SCN) have been reported with maximal process extension in the light phase and maximal process retraction in the dark phase of a daily light:dark cycle. In the present study, we asked whether dynamic changes occur in the distribution of an astrocytic metabolic marker, glycogen phosphorylase (GP), using a histochemical assay to reveal the distribution of both active and total GP, in the hamster SCN. Changes in glial acidic fibrillary protein (GFAP) immunoreactivity also were assessed using a relative optical density measure (ROD). We observed changes in the localization and distribution of GP both in the SCN and in the paraventricular nucleus of the hypothalamus (PVN) as a function of time of day. In the light phase, there were concentrated, large, dot‐like deposits of GP throughout the SCN and PVN on an empty background.
In the dark phase, diffuse, small, granular particles were seen throughout both nuclei. Selectively, in the dark‐phase SCN, these granular particles formed a rim of intense GP reactivity on the lateral, ventral, posterior, and medial borders. Significantly higher levels of GP reactivity were seen in anterior sections of the medial optic chiasm in the light phase. GFAP‐immunoreactive astrocytic processes had higher ROD levels in the dark phase. In conclusion, the astrocytic metabolic marker, GP, exhibits a significant daily variation in localization in both the SCN and the PVN that correlates with dynamic changes in the distribution of astrocytic processes in the SCN. Increased GP activity also occurs in astrocytes among optic fibers subjacent to the SCN during light input. J. Comp. Neurol. 435:249–258, 2001. © 2001 Wiley‐Liss, Inc.
The inner ear macular sensory epithelia of the Daubenton's bat
Authors: Kirkegaard Mette , Jørgensen Jørgen Mørup
Published: August 2002

The inner ear macular sensory epithelia of the Daubenton's bat were examined quantitatively to estimate the area and total number of hair cells. Ultrastructural examination of the sensory epithelium reveals two main types of hair cells: the chalice‐innervated hair cell and the bouton‐innervated hair cell. The existence of an intermediate type, with a nerve ending covering the lateral side of the hair cell, indicates that the chalice‐innervated hair cells are derived from bouton‐innervated hair cells. Thus, at least a part of the bouton‐innervated hair cells forms a transitional stage. A number of immature as well as apoptotic hair cells were observed. It is suggested that a continuous production of new hair cells takes place in mature individuals, probably based on transdifferentiation of supporting cells. J. Comp. Neurol. 438:433–444, 2001. © 2001 Wiley‐Liss, Inc.
Presence of luteinizing hormone‐releasing hormone fragments in the rhesus monkey forebrain
Authors: Terasawa Ei , Busser Brian W. , Luchansky Laure L. , Sherwood Nancy M. , Jennes Lothar , Millar Robert P. , Glucksman Mark J. , Roberts James L.
Published: August 2002

Previously, we have shown that two types of luteinizing hormone‐releasing hormone (LHRH) ‐like neurons, “early” and “late” cells, were discernible in the forebrain of rhesus monkey fetuses by using antiserum GF‐6, which cross‐reacts with several forms of LHRH. The “late” cells that arose from the olfactory placode of monkey fetuses at embryonic days (E) 32–E36, are bona fide LHRH neurons. The “early” cells were found in the forebrain at E32–E34 and settled in the extrahypothalamic area. The molecular form of LHRH in “early” cells differs from “late” cells, because “early” cells were not immunopositive with any specific antisera against known forms of LHRH. In this study, we investigated the molecular form of LHRH in the “early” cells in the nasal regions and brains of 13 monkey fetuses at E35 to E78. In situ hybridization studies suggested that both “early” and “late” LHRH cells expressed mammalian LHRH mRNA. Furthermore, “early” cells predominantly contain LHRH1‐5‐like peptide and its cleavage enzyme, metalloendopeptidase E.C.3.4.24.15 (EP24.15), which cleaves LHRH at the Tyr5‐Gly6 position. This conclusion was based on immunocytochemical labeling with various antisera, including those against LHRH1‐5, LHRH4‐10, or EP24.15, and on preabsorption tests. Therefore, in primates, a group of neurons containing mammalian LHRH mRNA arises at an early embryonic stage before the migration of bona fide LHRH neurons, and is ultimately distributed in the extrahypothalamic region. These extrahypothalamic neurons contain LHRH fragments, rather than fully mature mammalian LHRH. The origin and function of these neurons remain to be determined. J. Comp. Neurol. 439:491‐504, 2001. © 2001 Wiley‐Liss, Inc.