bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential effects of neurotrophins on neuronal survival and axonal regeneration after spinal cord injury in adult rats
Authors: Novikova Liudmila N. , Novikov Lev N. , Kellerth Jan‐Olof
Published: October 2002

Spinal cord injury (SCI) induces retrograde cell death in descending pathways, which can be prevented by long‐term intrathecal infusion of neurotrophins (Novikova et al. [2000] Eur J Neurosci 12:776–780). The present study investigates whether the same treatment also leads to improved regeneration of the injured tracts. After cervical SCI in adult rats, a peripheral nerve graft was attached to the rostral wall of the lesion cavity. The animals were treated by local application into the cavity of Gelfoam soaked in (1) phosphate buffered saline (untreated controls) or (2) a mixture of the neurotrophins brain‐derived neurotrophic factor (BDNF) and neurotrophin‐3 (NT‐3) (local treatment), or by intrathecal infusion of BDNF + NT‐3 for (3) 2 weeks (short‐term treatment) or (4) 5–8 weeks (long‐term treatment). Despite a very strong survival effect, long‐term treatment failed to stimulate ingrowth of descending tracts into the nerve graft. In comparison with untreated controls, the latter treatment also caused 35% reduction in axonal sprouting of descending pathways rostral to the lesion site and 72% reduction in the number of spinal cord neurons extending axons into the nerve graft. Local and short‐term treatments neither prevented retrograde cell death nor enhanced regeneration of descending tracts, but induced robust regeneration of spinal cord neurons into the nerve graft. These results indicate that the signal pathways promoting neuronal survival and axonal regeneration, respectively, in descending tracts after SCI respond differently to neurotrophic stimuli and that efficient rescue of axotomized tract neurons is not a sufficient prerequisite for regeneration. J. Comp. Neurol. 452:255–263, 2002. © 2002 Wiley‐Liss, Inc.
Report from a workshop on multianalyte microsphere assays
Authors: Earley Marie C. , Vogt Robert F. , Shapiro Howard M. , Mandy Francis F. , Kellar Kathryn L. , Bellisario Ronald , Pass Kenneth A. , Marti Gerald E. , Stewart Carleton C. , Hannon W. Harry
Published: October 2002

Multiplexed assays using fluorescent microspheres is an exciting technique that has been gaining popularity among researchers, particularly those in the public health field. Part of its popularity is due to its flexibility, as both immunoassays and oligonucleotide hybridization assays can be developed on this platform. This report summarizes a workshop held by the Centers for Disease Control and Prevention that discussed issues surrounding these assays and the Luminex 100 xMAP instrument. Topics included instrumentation, assay design, sample matrix and volume, quality control, and development of commercial applications. Cytometry (Clin. Cytometry) 50:239–242, 2002. Published 2002 Wiley‐Liss, Inc.
A sample injection device for flow cytometers
Authors: Steen Harald B.
Published: October 2002

Background

The sample injection systems of flow cytometers employ either a pressure differential between the sample vial and the sheath fluid reservoir or volumetric injection of the sample from a syringe. The pressure differential method facilitates rapid and efficient flushing to eliminate carryover between samples, but does not allow accurate determination of the rate of sample flow and cell concentration. Volumetric injection, which comprises a valve for switching the sample flow, facilitates highly accurate measurement of the cell concentration, but requires a less efficient and more time‐consuming flushing procedure.

Methods

Applying a removable syringe, which connects to the inlet of the sample tubing via a tight sealing, we eliminate the valve and obtain efficient flushing while maintaining the advantage of volumetric sample injection.

Results

This device gives highly constant sample flow rates strictly proportional to syringe velocity over the range 0.2–50 μl/min with a settling time of about 2 sec.

Conclusion

This device has the same precision as the conventional sample injection system, whereas the speed and efficiency of flushing are improved greatly. Cytometry 49:70–72, 2002. © 2002 Wiley‐Liss, Inc.
Quantification of epithelial cells in coculture with fibroblasts by fluorescence image analysis
Authors: Krtolica Ana , Ortiz de Solorzano Carlos , Lockett Stephen , Campisi Judith
Published: October 2002

Background

To demonstrate that senescent fibroblasts stimulate the proliferation and neoplastic transformation of premalignant epithelial cells (Krtolica et al.: Proc Natl Acad Sci USA 98:12072–12077, 2001), we developed methods to quantify the proliferation of epithelial cells cocultured with fibroblasts.

Methods

We stained epithelial–fibroblast cocultures with the fluorescent DNA‐intercalating dye 4,6‐diamidino‐2‐phenylindole (DAPI), or expressed green fluorescent protein (GFP) in the epithelial cells, and then cultured them with fibroblasts. The cocultures were photographed under an inverted microscope with appropriate filters, and the fluorescent images were captured with a digital camera. We modified an image analysis program to selectively recognize the smaller, more intensely fluorescent epithelial cell nuclei in DAPI‐stained cultures and used the program to quantify areas with DAPI fluorescence generated by epithelial nuclei or GFP fluorescence generated by epithelial cells in each field.

Results

Analysis of the image areas with DAPI and GFP fluorescences produced nearly identical quantification of epithelial cells in coculture with fibroblasts. We confirmed these results by manual counting. In addition, GFP labeling permitted kinetic studies of the same coculture over multiple time points.

Conclusions

The image analysis–based quantification method we describe here is an easy and reliable way to monitor cells in coculture and should be useful for a variety of cell biological studies. Cytometry 49:73–82, 2002. © 2002 Wiley‐Liss, Inc.
Cystic lesions of the salivary glands: Cytologic features in fine‐needle aspiration biopsies
Authors: Layfield Lester J. , Gopez Evelyn V.
Published: October 2002

A variety of neoplastic and nonneoplastic lesions of the salivary glands have a predominantly cystic architecture. Fine‐needle aspirates of these lesions yield watery or mucoid material, frequently of low cellularity. Such aspirates may be obtained from mucus retention cysts, lymphoepithelial cysts, cystadenomas, Warthin's tumors, cystic pleomorphic adenomas, low‐grade mucoepidermoid carcinomas, cystadenocarcinomas, and examples of polycystic disease of the parotid gland. The cellular component within the fluid obtained from these lesions may be exceedingly scant or absent, making cytologic diagnosis difficult and, at times, impossible. We studied a series of 56 cystic lesions of the salivary glands, including 38 Warthin's tumors, 6 benign cysts, 2 lymphoepithelial cysts, 5 low‐grade mucoepidermoid carcinomas, 1 cystic pleomorphic adenoma, 2 cystadenomas, and 2 cystadenocarcinomas. Careful attention to the cellular elements present often allowed definitive cytologic diagnosis, with an overall accuracy rate of 84%. The presence of atypical squamous metaplasia in oncocytic lesions was a significant cause of false‐positive diagnoses of carcinoma (4 cases, 7%). Aspirates of low‐grade mucoepidermoid carcinoma may contain no epithelial cells and result in false‐negative diagnoses (1 case, 2%). Diagn. Cytopathol. 2002;27:197–204. © 2002 Wiley‐Liss, Inc.
Diagnostic value of image‐guided needle aspiration cytology in the assessment of vertebral and intervertebral lesions
Authors: Gupta Raj K. , Cheung Y.K. , Al Ansari Abdul G. , Naran Sarla , Lallu Sharda , Fauck Robert
Published: October 2002

The aim of this study was to evaluate the diagnostic value of the noninvasive method of image‐guided needle aspiration cytology (NAC) in the assessment of radiologically detected vertebral and intervertebral space‐occupying lesions. NAC was performed under computed tomographic (CT) guidance on 70 patients suspected of having a vertebral or intervertebral lesion. Cytologic examination was performed on site after staining smears with the Papanicoloau method. In addition, air‐dried smears, fixed smears, filter preparations from needle washings, and cell blocks were studied. The NAC diagnosis was supported by examining cell blocks, which showed the reliability of histologic architecture; further support was obtained with a tissue biopsy in some cases. Additionally, immunoperoxidase and/or histochemical studies were done. Ten cases were diagnosed as inflammatory/degenerative lesions, and in 2 cases a diagnosis of neurofibroma was made. Twelve cases consisted of normal cellular elements, 7 cases were unsatisfactory/inadequate for diagnosis, and 4 cases were suspicious for malignancy. In 32 cases, a variety of metastatic tumors were diagnosed, while in 3 cases, a diagnosis of chordoma was made. Based on our study, we feel that NAC, as a first line of investigation, is not only useful in the diagnosis of space‐occupying lesions of vertebral and intervertebral regions, but can also help in deciding on appropriate management. Also, histologic architecture from cell blocks can be correlated with cytology, and such material can be used for histochemical and immunomarker studies. Diagn. Cytopathol. 2002;27:191–196. © 2002 Wiley‐Liss, Inc.
Evaluation of breast cancer metastases in pleural effusions by molecular biology techniques
Authors: de Matos Granja Nara , Soares Raquel , Rocha Simão , Paredes Joana , Longatto Filho Adhemar , Avancini Alves Venâncio , Wiley Elizabeth , Schmitt Fernando C. , Bedrossian Carlos
Published: October 2002

The aim of this study was to evaluate the presence of allelic loss in chromosomal regions previously described as exhibiting loss of heterozigosity (LOH) during breast carcinogenesis, in pleural effusions of breast cancer patients. LOH was analyzed in three loci (1p32, 7q31, and 17q21).

We studied 41 samples of pleural effusions from breast cancer patients (24 positive for neoplastic cells, 14 suspected, and 3 negative cases) and breast tissues from the patients (primary tumors and nonneoplastic adjacent tissue). DNA was extracted from pleural effusions, primary tumor, and adjacent normal tissue. LOH was evaluated by polymerase chain reaction assay and was observed in 38% of pleural effusions positive for neoplastic cells, and in 36% of suspected cases where morphology only did not allow the diagnosis of malignancy.

We conclude that LOH analysis in pleural effusions of breast cancer patients is able to identify metastases in cases where morphologic analysis becomes difficult. Diagn. Cytopathol. 2002;27:210–213. © 2002 Wiley‐Liss, Inc.
Preclinical experiments on cognition enhancement in Alzheimer's disease: Drugs affecting nicotinic acetylcholine receptors
Authors: Woodruff‐Pak Diana S.
Published: October 2002

Nicotinic acetylcholine receptors (nAChRs) play a role in a variety of diseases of the central nervous system including Alzheimer's disease (AD). There is currently great interest in evaluating AD‐related nAChR changes, and pharmacological treatment of nAChR deficits is a promising therapy. In AD, α7 nAChRs remain relatively stable in contrast to α4β2 nAChRs that are lost in substantial numbers. However, α7 nAChRs may be functionally impaired in AD because β‐amyloid, a major neuropathology in AD, blocks α4β2 and α7 nAChRs. Agonists selective to α7 or α4β2 nAChRs are neuroprotective against β‐amyloid. A preclinical test of cognition‐enhancing drugs affecting nAChRs is eyeblink classical conditioning. This task is severely impaired in human probable AD patients and is impaired by antagonists to nAChRs. Three drugs with different mechanisms of action on nAChRs (partial α7 nAChR agonism [GTS‐21], acetylcholinesterase inhibition and allosteric modulation [galantamine], nootropic activation [nefiracetam]) were tested in young and older rabbits using eyeblink classical conditioning. All three drugs ameliorated learning and memory impairments in older rabbits and reversed an antagonist to nAChRs in young rabbits. Galantamine, with its allosteric modulatory action, was the only drug that facilitated learning in young rabbits. On the basis of efficacy of these drugs that affect nAChRs in preclinical studies and in Phase I (GTS‐21), Phase II (nefiracetam), or Phase III (galantamine) clinical trials, exploration of nAChRs as targets for therapeutic intervention via a number of different pathways seems warranted. Drug Dev. Res. 56:335–346, 2002. © 2002 Wiley‐Liss, Inc.
Forgetting functions of reactivated memories over the first year of life
Authors: Hildreth Karen , Rovee‐Collier Carolyn
Published: October 2002

A reactivation treatment alleviates forgetting by reexposing organisms to an isolated component of the original event. How long a reactivated memory persists, however, has not been studied systematically. Presently, we documented the retention of a reactivated memory with 6‐, 9‐, and 12‐month‐old human infants. All infants learned an operant task, forgot it, and then received a brief reactivation treatment 1 week later. They were tested after increasingly longer delays until the reactivated memory also was forgotten. To provide a picture of retention over the entire first year of life, we combined their data with corresponding data previously obtained from 3‐ and 6‐month‐olds in an equivalent task. Although the maximum duration of original retention increases linearly between 3 and 12 months of age, infants consistently forgot the reactivated memory at the same rate as the original one over this period. In essence, a reactivation treatment doubles the life of the memory. © 2002 Wiley Periodicals, Inc. Dev Psychobiol 41: 277–288, 2002. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/dev.10044
Influences of postconceptional age and postnatal experience on the development of auditory recognition memory in the newborn infant
Authors: deRegnier Raye‐Ann , Wewerka Sandi , Georgieff Michael K. , Mattia Frank , Nelson Charles A.
Published: October 2002

We evaluated the effects of postconceptional age and postnatal experience on the development of neonatal auditory recognition memory. Three groups were tested: a premature newborn group (tested at 35–38 weeks postconceptional age, ≤1 week old), a full‐term newborn group (tested at 39–42 weeks postconceptional age, ≤1 week old), and a full‐term experienced group (tested at 39–42 weeks postconceptional age, >1 week old; range 8–30 days). Event‐related potentials were collected while infants listened to the maternal voice alternating with a stranger's voice. Postconceptional age was correlated with the development of recognition memory for the maternal voice while there were qualitative effects of postnatal experience on latency measurements. Maturity of auditory cortical responses was not correlated with recognition memory abilities. We conclude that maturation of the recognition memory pathways is primarily a function of postconceptional age with qualitative effects of postnatal experience. Maturation of the auditory recognition memory pathway is not contingent upon maturation of the “P2” peak thought to arise from primary auditory cortex. © 2002 Wiley Periodicals, Inc. Dev Psychobiol 41: 216–225, 2002. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/dev.10070
An empirical investigation of antecedents of B2B Websites’ effectiveness
Authors: Chakraborty Goutam , Lala Vishal , Warren David
Published: October 2002

The purpose of this study was to identify the factors that influence customers’ perceptions of the effectiveness of business-to-business Websites and to test empirically the significance of these factors. Based on a review of academic and trade press literature, we identified eight factors that are thought to influence business-to-business Website effectiveness. Following standard scale development procedures, we developed valid and reliable scales for measuring each of these eight factors. A Web survey-based field study was conducted in which 540 business customers of a power tool company gave their opinions about one of eight construction industry Websites with which they were most familiar. We simultaneously tested the significance of these eight factors in explaining the effectiveness of Websites. Our results suggest that of the eight factors considered, informativeness, organization, transaction-related interactivity, and personalization are significant predictors of Website effectiveness. We found no direct relationship between the other factors (non-transaction-related interactivity, privacy/security, accessibility, and entertainment) and Website effectiveness.
BMP4 modulates fibroblast growth factor–mediated induction of proximal and distal lung differentiation in mouse embryonic tracheal epithelium in mesenchyme‐free culture
Authors: Hyatt Brian A. , Shangguan Xiaofei , Shannon John M.
Published: October 2002

Lung morphogenesis and differentiation require interaction between the epithelium and mesenchyme, which is mediated by diffusible molecules such as fibroblast growth factors (FGFs), bone morphogenetic protein 4 (BMP4), and Shh. We have used mesenchyme‐free culture to study the effects of these molecules on lung epithelial differentiation. We have tested the individual abilities of FGF1, FGF2, FGF7, FGF9, FGF10, and FGF18, as well as BMP4 and Shh to promote growth and specify distal lung differentiation in mouse tracheal epithelium. The different FGFs exhibited distinct abilities to induce epithelial growth and the expression of the distal lung epithelial marker, surfactant protein C (SP‐C), although all FGFs were able to induce expression of BMP4. Tracheal epithelium treated with FGF10 showed little growth and failed to express SP‐C as measured by whole‐mount in situ hybridization and quantitative real‐time polymerase chain reaction. FGF1 treatment resulted in the strongest induction of SP‐C. Treatment with BMP4 inhibited epithelial growth and differentiation and antagonized the stimulatory effects of FGF1. In contrast, inhibition of endogenous BMP4 signaling with Noggin protein did not inhibit growth or expression of SP‐C but did increase the expression of the proximal lung markers CCSP and HFH4. Expression of Shh was not affected by any of the conditions tested. These results suggest that BMP4 does not signal epithelial cells to adopt a distal fate but may regulate the expansion of proximal epithelial cells in the lung. © 2002 Wiley‐Liss, Inc.
Effects of high‐frequency electromagnetic fields on DNA strand breaks using comet assay method
Authors: Miyakoshi Junji , Yoshida Masami , Tarusawa Yosiaki , Nojima Toshio , Wake Kanako , Taki Masao
Published: October 2002

We investigated whether exposure to high‐frequency electromagnetic fields causes DNA damage in cells, using the alkaline comet assay. The exposure device made for this study used a TE01 circular waveguide operating at a frequency of 2.45 GHz. Cells of the human brain tumor‐derived MO54 cell line were exposed to an electromagnetic field (input power: 7.8 W, average SAR in the middle well of an annular culture plate: CW 50 W/kg) for 2 hours and the tail moments of the cells in the inner, middle, and outer wells of the plate were compared with those of sham‐exposed cells. There was no significant difference between the high‐frequency electromagnetic field‐exposed groups and the sham‐exposed groups. Three studies performed under the same conditions gave similar results. Next, cells were exposed to a stronger electromagnetic field (input power: 13 W, average SAR in the middle well: CW 100 W/kg) for 2 hours and compared with sham‐exposed cells. There was also no significant difference in the tail moments of cells in the inner, middle, and outer wells of the plate in the high‐frequency electromagnetic field‐exposed groups and the sham‐exposed groups. These findings suggest that a high‐frequency electromagnetic field does not cause direct DNA damage, and does not induce DNA strand breaks, even at a SAR of 100 W/kg. © 2002 Wiley Periodicals, Inc. Electr Eng Jpn, 141(4): 9–15, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.10075
Genotoxic risk and oxidative DNA damage in workers exposed to antimony trioxide
Authors: Cavallo Delia , Iavicoli Ivo , Setini Andrea , Marinaccio Alessandro , Perniconi Barbara , Carelli Giovanni , Iavicoli Sergio
Published: October 2002

The growing use of antimony (Sb) compounds in industry and the consequent increase in the number of exposed workers make it important to carry out a health risk assessment. The main goal of this study was to assess the genotoxicity of Sb2O3 in occupationally exposed workers. Genotoxicity was evaluated by the sister chromatid exchange (SCE) and micronucleus tests, and the enzyme (Fpg)‐modified comet assay. In addition, antimony exposure levels were established by environmental monitoring with personal air samplers. We studied 23 male workers assigned to different fire retardant treatment tasks in the car upholstery industry and a control group of 23 healthy nonexposed males. The exposed workers were divided into two groups on the basis of their tasks and the work cycle: Group A comprised finishing and intermediate inspection operators who directly handled a mixture containing Sb2O3; Group B were jet operators, not directly exposed to the compound. Environmental monitoring detected low Sb exposure levels but significant differences between the two groups, with Group A having the higher exposure level. Cytogenetic analyses showed no difference between exposed workers and controls for micronuclei and SCE. The enzyme‐modified comet assay showed a probable relation between moderate levels of oxidative DNA damage and exposure to antimony, with a significantly higher proportion of workers in Group A having oxidative DNA damage compared to controls. The results support the theory that oxidative DNA damage is involved in the genotoxicity of antimony and indicate the need for further research in this field. Environ. Mol. Mutagen. 40:184–189, 2002. © 2002 Wiley‐Liss, Inc.
Heavy‐ion‐induced mutations in the gpt delta transgenic mouse: Effect of p53 gene knockout
Authors: Yatagai Fumio , Kurobe Toshihiro , Nohmi Takehiko , Masumura Ken‐ichi , Tsukada Teruyo , Yamaguchi Hirotake , Kasai‐Eguchi Kiyomi , Fukunishi Nobuhisa
Published: October 2002

The influence of the loss of p53 gene on heavy‐ion‐induced mutations was examined by constructing a new line of transgenic mice, p53 knockout (p53−/−) gpt delta. In this mouse model, deletions in lambda DNA integrated into the mouse genome are preferentially selected as Spi‐ phages, which can then be subjected to molecular analysis. Mice were exposed to 10 Gy of whole‐body carbon‐ion irradiation. The carbon ions were accelerated to 135 MeV/u by the RIKEN Ring Cyclotron. The p53 defect markedly enhanced the Spi‐ mutant frequency (MF) in the kidneys of mice exposed to C‐ion irradiation: the Spi‐ MF increased 4.4‐ and 2.8‐fold over the background level after irradiation in p53−/− and p53+/+ mice, respectively. There was no significant difference in the background Spi‐ MF between p53−/− and p53+/+ mice. Sequence analysis of the Spi‐ mutants indicated that the enhancement of kidney Spi‐ MF in p53−/− mice was primarily due to an increase in complex or rearranged‐type deletions. In contrast to the kidney, the p53 defect had no effect on the Spi‐ MF in liver: Spi‐ MF increased 3.0‐ and 2.7‐fold after the irradiation in p53−/− and p53+/+ mice, respectively. Our results suggest that p53 suppresses deletion mutations induced by heavy‐ion irradiation in an organ‐specific manner. Environ. Mol. Mutagen. 40:216–225, 2002. © 2002 Wiley‐Liss, Inc.
DNA damage in cytologically normal urothelial cells of patients with a history of urothelial cell carcinoma
Authors: de Miranda Cabral Gontijo Álisson Marques , de Castro Marcondes João Paulo , Nunes Elias Flávia , Cotrim Sartor de Oliveira Maria Luiza , Alves de Lima Rodrigo Otávio , Favero Salvadori Daisy Maria , Viana de Camargo João Lauro
Published: October 2002

In order to determine if patients with a history of previous urothelial cell carcinoma (UCC) but with current normal urinary cytology have DNA damage in urothelial cells, the single‐cell gel electrophoresis (comet) assay was conducted with cells obtained by urinary bladder washings from 44 patients (28 with a history of previous UCC). Increased DNA damage was observed in cytologically “normal” urothelial cells of patients with a history of UCC when compared with referents with no similar history and after correcting the data for smoking status and age (P < 0.018). Increased DNA damage also correlated with the highest tumor grade, irrespective of time or course of the disease after clinical intervention (Kendall tau correlation, 0.37, P = 0.016). Moreover, aneuploidy, as assessed by DNA content ratio (DCR; 75th/25th percentile of total DNA fluorescence of 50 comets/patient) was unaltered by smoking status, but increased with UCC grade: 1.39 ± 0.12 (median ± 95% confidence interval; referents); 1.43 ± 0.11 (Grade I UCC; P = 0.264, against referents); 1.49 ± 0.16 (Grade II UCC; P = 0.057); 1.57 ± 0.16 (Grade III UCC; P = 0.003). Micronucleated urothelial cells (MNC) were also scored on Giemsa‐stained routine cytological smears and were found not to correlate with DNA damage or DCR. MNC frequencies were higher for patients with a history of UCC and/or smoking than referents with neither history, but there was no statistical difference between groups. Taken together, these results suggest that the normal‐appearing urothelium of patients resected for UCC still harbor genetically unstable cells. Environ. Mol. Mutagen. 40:190–199, 2002. © 2002 Wiley‐Liss, Inc.
Space–time correlation models and contaminant plumes
Authors: Myers D. E.
Published: October 2002

A contaminant plume might be described by a function defined in space–time. Spatial integrals or time derivatives of this function as well as time derivatives of spatial integrals will quantify characteristics such as the total volume of the plume, the total concentration of the contaminant in the plume, rates of change of the volume, and rates of change of concentration.

The plume function usually cannot be derived in analytic form but instead must be estimated or approximated. The dual form of the kriging estimator, which is equivalent to the use of radial basis functions, provides a tool for modeling this function in analytic form. The extension of the kriging estimator, in its usual form or in its dual form, to space–time poses no problems since the estimator and the equations are essentially dimension free. The difficulty is an adequate choice of space–time variograms or covariances.

The product–sum and integrated product–sum models provide an extensive array of valid models and also lead to a simple process for fitting the models by the use of marginal variograms. Examples are given and an application to air pollution data from the Milan District (Italy) illustrates the method. Copyright © 2002 John Wiley & Sons, Ltd.
The use of distribution mixtures for dose–response modeling in toxicological experiments
Authors: Razzaghi Mehdi
Published: October 2002

In toxicological experiments, animal bioassays are conducted to estimate the risk from exposure to toxic substances. A critical step in the process of risk assessment is the development of a dose–response model which provides a mathematical relationship between the exposure level and the probability of incidence of an adverse effect. Here, we consider the use of mixture models as dose–response functions in animal bioassay experiments. Mixtures of distributions provide a rich and flexible class of models that can be used in a variety of settings and have received a significant amount of attention in recent years. Moreover, because of the existence of susceptibility in toxicological experiments—that is, the fact that some animals appear to be more susceptible to a drug than others—distribution mixtures seem to be a natural choice for dose–response models. Here, we consider various types of toxicological experiments and demonstrate how mixture models can be utilized to describe the relationship between dose and incidence rate. Copyright © 2002 John Wiley & Sons, Ltd.
High‐order algorithms for vascular flow modelling
Authors: Peiró J. , Giordana S. , Griffith C. , Sherwin S. J.
Published: October 2002

This paper presents the development of spectral/hphigh‐order elements for vascular flows with particular attention to surface reconstruction and high‐order mesh generation. Using ideas from computer visualization we apply a technique of constructing smooth implicit functions to reconstruct incomplete sectional imaging data from magnetic resonance imaging. Using this as a starting point we outline techniques to discretize and computationally solve the Newtonian flow within these geometries using high‐order spectral/hpelement methods. Finally we demonstrate the application of these ideas to anatomically correct and model distal bypass grafts. Copyright © 2002 John Wiley & Sons, Ltd.
An optimal control approach to optical flow computation
Authors: Borzì A. , Ito K. , Kunisch K.
Published: October 2002

An optimal control approach for determining optical flow is presented. The new framework differs from preceding approaches in that it does not require differentiation of the data. A numerical algorithm that solves the optimality system consisting of hyperbolic and elliptic partial differential equations is presented. Copyright © 2002 John Wiley & Sons, Ltd.
A numerical model to track two‐fluid interfaces based on a stabilized finite element method and the level set technique
Authors: Codina R. , Soto O.
Published: October 2002

The objective of this work is to present a stabilized finite element formulation for transient incompressible flows and to apply it to the tracking of two‐fluid interfaces. The stabilization technique employed allows us to use equal velocity–pressure interpolations and to deal with convection–dominated flows. The tracking of the fluid interface is based on the level set technique. A novel smoothing technique of this surface based on ideas of signal processing is presented. Copyright © 2002 John Wiley & Sons, Ltd.
Space‐time residual distribution schemes for hyperbolic conservation laws on unstructured linear finite elements
Authors: Á. Csík  , Deconinck H.
Published: October 2002

Multidimensional upwind residual distribution schemes are extended to the context of continuous linear space–time finite elements for the time accurate solution of scalar and hyperbolic systems of conservation laws. The formulation leads to a consistent discretization of the space‐time domain, thus retaining the properties of the underlying basic schemes both in space and time. We propose a particular space–time mesh configuration containing two layers of elements and three levels of nodes in time. This construction leads to unconditionally stable implicit time stepping while retaining second‐order spatial and temporal accuracy in smooth flows and monotone solution across steep gradients. The presented schemes have a strong potential in the field of moving grids, since they allow a dynamic change of the space–time mesh geometry. Numerical results demonstrate the robustness, accuracy and monotonicity of the method. Copyright © 2002 John Wiley & Sons, Ltd.
A note on the valuation of compound options
Authors: Lajeri‐Chaherli Fatma
Published: October 2002

The value of a compound option, an option on an option, has been derived by Geske
(1976) using Fourier integrals. This article presents two alternative proofs to derive the value of a
compound option. One proof is based on the martingale approach, which provides a simple and powerful tool for
valuing contingent claims. The second proof uses the expectation of a truncated bivariate normal variable. These
proofs allow for an intuitive interpretation of the three elements constituting the value of a compound option.
© 2002 Wiley Periodicals, Inc. Jrl Fut Mark 22:1103–1115, 2002
Clinical implications of chromosomal abnormalities in gastric adenocarcinomas
Authors: Wu Chew‐Wun , Chen Gen‐Der , Fann Cathy S.‐J. , Lee Anna F.‐Y. , Chi Chin‐Wen , Liu Jacqueline M. , Weier Ulli , Chen Jeou‐Yuan
Published: October 2002

Gastric carcinoma (GC) is one of the most common malignancies worldwide and has a very poor prognosis. Genetic imbalances in 62 primary gastric adenocarcinomas of various histopathologic types and pathologic stages and six gastric cancer–derived cell lines were analyzed by comparative genomic hybridization, and the relationship of genomic abnormalities to clinical features in primary GC was evaluated at a genome‐wide level. Eighty‐four percent of the tumors and all six cell lines showed DNA copy number changes. The recurrent chromosomal abnormalities including gains at 15 regions and losses at 8 regions were identified. Statistical analyses revealed that gains at 17q24‐qter (53%), 20q13‐qter (48%), 1p32–p36 (42%), 22q12‐qter (27%), 17p13‐pter (24%), 16p13‐pter (21%), 6p21‐pter (19%), 20p12‐pter (19%), 7p21‐pter (18%), 3q28‐qter (8%), and 13q13–q14 (8%), and losses at 18q12‐qter (11%), 3p12 (8%), 3p25‐pter (8%), 5q14–q23 (8%), and 9p21‐p23 (5%), are associated with unique patient or tumor‐related features. GCs of differing histopathologic features were shown to be associated with distinct patterns of genetic alterations, supporting the notion that they evolve through distinct genetic pathways. Metastatic tumors were also associated with specific genetic changes. These regions may harbor candidate genes involved in the pathogenesis of this malignancy. © 2002 Wiley‐Liss, Inc.
The SRCR/SID region of DMBT1 defines a complex multi‐allele system representing the major basis for its variability in cancer
Authors: Mollenhauer Jan , Müller Hanna , Kollender Gaby , Lyer Stefan , Diedrichs Laura , Helmke Burkhard , Holmskov Uffe , Ligtenberg Toon , Herbertz Stephan , Krebs Inge , Madsen Jens , Bikker Floris , Schmitt Liane , Wiemann Stefan , Scheurlen Wolfram , Otto Herwart F. , von Deimling Andreas , Poustka Annemarie
Published: October 2002

Deleted in malignant brain tumors 1 (DMBT1) at 10q25.3–q26.1 has been proposed as a candidate tumor‐suppressor gene for brain and epithelial cancer. DMBT1 encodes a multifunctional mucin‐like protein presumably involved in epithelial differentiation and protection. The gene consists of highly homologous and repeating exon and intron sequences. This specifically applies to the region coding for the repetitive scavenger receptor cysteine‐rich (SRCR) domains and SRCR‐interspersed domains (SIDs) that constitutes the major part of the gene. This particular structure may previously have interfered with the delineation of DMBT1 alterations in cancer. Uncovering these, however, is of mechanistic importance. By a combined approach, we conducted a detailed mutational analysis, starting from a panel of 51 tumors, including 46 tumor cell lines and five primary tumors. Alterations in the repetitive region were present in 22/31 (71%) tumors that were investigated in detail. Six tumors showed presumably de novo mutations, among these three with point mutations in combination with a loss of heterozygosity. However, none of the alterations unambiguously would be predicted to lead to an inactivation of DMBT1. We define seven distinct DMBT1 alleles based on variable numbers of tandem repeats (VNTRs). At least 11 tumors exclusively harbored these VNTRs. The data suggest that the SRCR/SID region defines a complex multi‐allele system that has escaped previous analyses and that represents the major basis for the variability of DMBT1 in cancer. DMBT1 thus compares to mucins rather than to conventional tumor suppressors. © 2002 Wiley‐Liss, Inc.
Oligodendrocyte and astrocyte development in rodents: An in situ and immunohistological analysis during embryonic development
Authors: Liu Ying , Wu Yuanyuan , Lee Jeffrey C. , Xue Haipeng , Pevny Larysa H. , Kaprielian Zaven , Rao Mahendra S.
Published: October 2002

Lineally related multipotent neuroepithelial cells (NEP), neuronal restricted precursors (NRP), and glial restricted precursors (GRP) have been identified in the spinal cord. To determine the sequence of differentiation and identify lineage and stage‐specific markers, we have examined the spatiotemporal expression of established glial markers during rodent embryonic development and within fetal cell culture. In this report, we show that proliferating stem cells in the developing neural tube do not express any glial markers at E10.5. By E11, however, glial precursors have begun to differentiate and at least two regions of the ventral neural tube containing glial precursor cells can be distinguished, an Nkx2.2/Neurogenin 3 (Ngn3) domain and a platelet‐derived growth factor receptor alpha (PDGFRα)/Olig2/Sox10 domain. Radial glia, as identified by RC1 immunoreactivity, develop in concert with other glial precursors and can be distinguished by their morphology, spatial distribution, and antigen expression. Astrocytes as assessed by glial fibrillary acidic protein (GFAP) immunoreactivity are first detected at E16. A novel dorsal domain of CD44 immunoreactivity that can be distinguished from the more ventral glial precursor domains can be detected as early as E13.5. GLIA 40:25–43, 2002. Published 2002 Wiley‐Liss, Inc.
Extracellular and intracellular regulation of oligodendrocyte development: Roles of Sonic hedgehog and expression of E proteins
Authors: Sussman Caroline R. , Davies Jeannette E. , Miller Robert H.
Published: October 2002

Recent advances in understanding oligodendrocyte development have revealed the importance of both extra‐ and intracellular molecules in regulating the induction, survival, and proliferation of early oligodendrocyte progenitors. The signaling molecule Sonic hedgehog (Shh) is critical for normal development of oligodendrocytes, although the precise influences of Shh on cells of the oligodendrocyte lineage are unclear. The present study shows that Shh increased the number of oligodendrocyte precursors in both pure cultures of oligodendrocyte precursors and mixed cultures from embryonic rat spinal cord. In pure precursor cultures Shh increased cell survival. In mixed cultures, Shh increased both the survival and proliferation of oligodendrocyte precursors in a concentration dependent manner. One intracellular consequence of exposure to Shh is the activation of transcription factors in oligodendrocyte lineage cells, which are critical for oligodendrocyte development, helix‐loop‐helix (HLH) transcription factors, Olig1 and 2. In many cases, HLH proteins such as Olig1 and Olig2 heterodimerize with other HLH proteins, such as members of the E subfamily, which are critical regulators of cell proliferation and differentiation. Immature (A2B5+) and more mature (O4+) rat oligodendrocyte precursors in dissociated cell culture expressed Olig1 as well as E proteins, HEB and E2A. Similarly, cells bearing the morphology of oligodendrocyte precursors expressed both Olig1 and HEB or E2A. We propose that E2A and/or HEB, possibly in combination with Olig1 and 2, are critical components of oligodendrogenesis and may regulate cell survival, proliferation, and fate decisions in the oligodendrocyte lineage. GLIA 40:55–64, 2002. © 2002 Wiley‐Liss, Inc.
Transforming growth factor β1 prevents IL‐1β–induced microglial activation, whereas TNFα‐ and IL‐6–stimulated activation are not antagonized
Authors: Basu Anirban , Krady J. Kyle , Enterline Jonathan R. , Levison Steven W.
Published: October 2002

Microglia rapidly respond to CNS injury, yet the mechanisms leading to their activation and inactivation remain poorly defined. In particular, few studies have established how interactions between inflammatory mediators affect the innate immune response of microglia. To begin to establish how microglia integrate signals from multiple inflammatory mediators, we examined the effects of interleukin 1β (IL‐1β), interleukin 6 (IL‐6), tumor necrosis factor α (TNFα), interferon γ (IFN‐γ), and transforming growth factor β1 (TGFβ1) on both newborn and bulk‐isolated adult microglia. To assess the functional state of the cells, we assayed the expression of cyclooxygenase 2 (Cox‐2), interleukin 6, and tumor necrosis factor α, and two protein tyrosine kinases that have been implicated in microglial responses to activational stimuli, HCK and FAK. These studies demonstrated that IL‐1β, TNFα, IL‐6, but not IFN‐γ increase the expression of Cox‐2, whereas they all increase the expression of HCK and FAK. In these studies, TGFβ1 either had no effect, or it decreased basal levels of these proteins. TGFβ1 blocked activation by IL‐1β when given prior to, or simultaneously with, IL‐1β. TGFβ1 blocked the induction of the tyrosine kinases, Cox‐2, and the induction of IL‐6 and TNFα mRNAs. However, TGFβ1 was ineffective in antagonizing the induction of Cox‐2 by either IL‐6 or TNFα. We conclude that the TGFβ receptor signaling cascades intersect with IL‐1, but they may not interact with IL‐6 or TNFα signaling pathways that lead to activation. GLIA 40:109–120, 2002. © 2002 Wiley‐Liss, Inc.
Apolipoprotein E ε4 and testosterone interact in the risk of Alzheimer's disease in men
Authors: Hogervorst E. , Lehmann D. J. , Warden D. R. , McBroom J. , Smith A. D.
Published: October 2002

Objectives

To assess the association between testosterone levels and APOEε4 in cases with AD and controls.

Method

We included 61 men with definite or probable Alzheimer's disease (AD) and 55 elderly male controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA). Testosterone was measured using a competitive enzyme immunoassay (Bayer®).

Results

We found that both low serum testosterone and the interaction between testosterone and APOEε4 were associated with AD. Furthermore, testosterone levels were lower in APOEε4‐positive controls (mean: 11.3 nmol/L) than in controls without the allele (19.1 nmol/L).

Conclusions

Low testosterone is potentially a modifiable risk factor, which may prove relevant to APOEε4 carriers who are at risk of AD. Copyright © 2002 John Wiley & Sons, Ltd.
A longitudinal evaluation of behavioural and psychological symptoms of probable Alzheimer's disease
Authors: Eustace A. , Coen R. , Walsh C. , Cunningham C. J. , Walsh J. B. , Coakley D. , Lawlor B. A.
Published: October 2002

Background

Non‐cognitive symptoms are a frequent feature of Alzheimer's disease (AD). Much of the literature that has accumulated pertains to cross‐sectional prevalence of these symptoms. There has been relatively little attention paid to the longitudinal course of Behavioural and Psychological Symptoms of Dementia (BPSD).

Aims

The purpose of this study is to examine the longitudinal course of BPSD in a group of patients with mild AD.

Methods

A retrospective review of a database was performed to identify patients with NINCDS/ADRDA criteria for probable AD and who had been evaluated three times at yearly interval over a two‐year period. Fifty‐two subjects were identified with probable AD that had completed follow‐up for 24 months. The BEHAVE‐AD was used to evaluate BPSD and data was analysed using a Markov analysis.

Results

Activity disturbance is a common and relatively persistent symptom in the mild stages of AD. Anxiety, paranoid ideation, and aggression were moderately persistent. Affective symptoms were not persistent with less than half the patients having the symptoms a year later.

Conclusions

Activity disturbance is common and persistent in early AD. Paranoid and delusional ideation shows moderate persistence and depressive symptoms infrequently last longer than a year. These findings may have clinical relevance for the pharmacological and non‐pharmacological management of BPSD. Copyright © 2002 John Wiley & Sons, Ltd.
FMRI reveals brain regions mediating slow prosodic modulations in spoken sentences
Authors: Meyer Martin , Alter Kai , Friederici Angela D. , Lohmann Gabriele , von Cramon D. Yves
Published: October 2002

By means of fMRI measurements, the present study identifies brain regions in left and right peri‐sylvian areas that subserve grammatical or prosodic processing. Normal volunteers heard 1) normal sentences; 2) so‐called syntactic sentences comprising syntactic, but no lexical‐semantic information; and 3) manipulated speech signals comprising only prosodic information, i.e., speech melody. For all conditions, significant blood oxygenation signals were recorded from the supratemporal plane bilaterally. Left hemisphere areas that surround Heschl gyrus responded more strongly during the two sentence conditions than to speech melody. This finding suggests that the anterior and posterior portions of the superior temporal region (STR) support lexical‐semantic and syntactic aspects of sentence processing. In contrast, the right superior temporal region, in especially the planum temporale, responded more strongly to speech melody. Significant brain activation in the fronto‐opercular cortices was observed when participants heard pseudo sentences and was strongest during the speech melody condition. In contrast, the fronto‐opercular area is not prominently involved in listening to normal sentences. Thus, the functional activation in fronto‐opercular regions increases as the grammatical information available in the sentence decreases. Generally, brain responses to speech melody were stronger in right than left hemisphere sites, suggesting a particular role of right cortical areas in the processing of slow prosodic modulations. Hum. Brain Mapping 17:73–88, 2002. © 2002 Wiley‐Liss, Inc.
Willingness to pay for health risk reduction in the context of altruism
Authors: Araña Jorge E. , León Carmelo J.
Published: October 2002

This paper presents results on the valuation of health risks in the presence of altruism. The contingent valuation method is utilised in a split sample experiment for estimating the private and public values in reducing the risk of flu. Data modelling for the dichotomous choice method follows a Bayesian approach, which accounts for zero responses and is adequate for the comparison of small sample results. The results of the experiment suggest that altruism is a positive component in the value of reducing the probability of flu, which depends positively on the number of days involved, the health status and the personal income of the subject. The marginal value of risk is found to be a decreasing function of the reduction in the probability of becoming ill. Copyright © 2002 John Wiley & Sons, Ltd.
Reconstruction of circumferential pharyngoesophageal defects with laryngotracheal flap and pectoralis major myocutaneous flap
Authors: Chu Pen‐Yuan , Chang Shyue‐Yih
Published: October 2002

Background

Hypopharyngeal cancer often presents at an advanced stage. Radical surgery has played an important role in the treatment of these cases; however, it always results in a large, or even a circumferential, defect of the pharyngoesophageal segment (PES) that causes some difficulties during reconstruction.

Materials and Methods

Twelve patients with advanced hypopharyngeal cancer and cervical esophageal invasion received surgery resulting in a circumferential defect of PES, which was reconstructed with the contralateral unaffected laryngotracheal flap and a patch‐on pectoralis major myocutaneous flap (PMMCF).

Results

The operation time of this method was shorter compared with free flap reconstruction. Only two minor complications and no pharyngocutaneous fistulas were found postoperatively. Nine patients can resume a regular diet. During the follow‐up period (median, 38 months), there were no local recurrences and only one contralateral neck recurrence.

Conclusions

The preliminary result shows this technique is a simple and effective method with low morbidity and satisfactory oncologic and functional results. © 2002 Wiley Periodicals, Inc.