bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats
Authors: Meng Quanxin , Walker Dale M. , Scott Bobby R. , Seilkop Steve K. , Aden James K. , Walker Vernon E.
Published: February 2004

A multiplex PCR procedure for analysis of genomic DNA mutations in the mouse hypoxanthine‐guanine phosphoribosyltransferase (Hprt) gene was developed and then used with other established methods for the coincident identification of large‐ and small‐scale genetic alterations in theHprtgene of mutant T‐cell isolates propagated from sham‐ and 1,3‐butadiene (BD)‐exposed mice and rats. The spectra data for RT‐PCR/cDNA analysis and multiplex PCR of genomic DNA fromHprtmutants were combined, and statistical analyses of the mutant fractions for the classes of mutations identified in control versus exposed animals were conducted. Under the assumption that the mutant fractions are distributed as Poisson variates, BD exposure of mice significantly increased the frequencies of (1) nearly all types of base substitutions; (2) single‐base deletions and insertions; and (3) all subcategories of deletions. Significantly elevated fractions of G:C→C:G and A:T→T:A transversions in theHprtgene of BD‐exposed mice were consistent with the occurrence of these substitutions as the predominantrasgene mutations in multiple tumor types increased in incidence in carcinogenicity studies of BD in mice. BD exposure of rats produced significant increases in (1) base substitutions only at A:T base pairs; (2) single‐base insertions; (3) complex mutations; and (4) deletions (mainly 5′ partial and complete gene deletions). Future coincident analyses of large‐ and small‐scale mutations in rodents exposed to specific BD metabolites should help identify species differences in the sources of deletion mutations and other types of mutations induced by BD exposures in mice versus rats. Environ. Mol. Mutagen. 43:75–92, 2004. © 2004 Wiley‐Liss, Inc.
Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia
Authors: Canalle Renata , Burim Regislaine V. , Tone Luiz G. , Takahashi Catarina S.
Published: February 2004

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. Although exposure to environmental agents appears to predispose individuals to this disease, little attention has been paid to the role of genetic susceptibility to environmental exposures in the etiology of childhood ALL. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1, and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, alcoholic drinks, pesticides, and environmental pollutants. Polymorphisms in the genes coding for these enzymes have been associated with increased susceptibility to different cancers, including hematologic malignancies. To investigate whether these polymorphisms represent risk‐modifying factors for childhood ALL, a study was conducted involving 113 Brazilian patients of childhood ALL and 221 controls with similar ethnic backgrounds. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of ALL (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.1–6.8; P = 0.04). No difference was found in the prevalence of the GSTM1 and GSTT1 null genotypes between ALL patients and the controls, and no association was found between CYP1A1*2 and CYP2E1*3 variants and ALL. However, when the mutant CYP1A1 and CYP2E1 alleles were considered together with the GSTM1 and GSTP1 risk‐elevating genotypes, the risk of ALL was increased further (OR = 10.3; 95% CI = 1.0–111.8; P = 0.05), suggesting a combined effect. These results imply that genetic variants of xenobiotic metabolizing genes influence the risk of developing childhood ALL. Environ. Mol. Mutagen. 43:100–109, 2004. © 2004 Wiley‐Liss, Inc.
Spontaneous mutation in Big Blue® mice from fetus to old age: Tissue‐specific time courses of mutation frequency but similar mutation types
Authors: Hill Kathleen A. , Buettner Victoria L. , Halangoda Asanga , Kunishige Makoto , Moore Stephen R. , Longmate Jeffrey , Scaringe William A. , Sommer Steve S.
Published: February 2004

Transgenic mouse mutation detection systems permit rapid determination of the frequency and type of mutations allowing direct examination of mutational markers for aging, neurodegeneration, and cancer. The Big Blue® transgenic mouse mutation detection system was used to determine the frequency and nature of spontaneous mutations versus age in multiple tissue types. Nuclear DNA was extracted from whole fetus at 13.5 days postcoitus (dpc) and from six tissues postbirth (cerebellum, forebrain, thymus, liver, adipose tissue, and male germline) of Big Blue transgenic mice at four ages: 10 days and at 3, 10, and 25 months postbirth. Forty million total plaque‐forming units (pfu) were screened. The time course of mutation frequency with age had a significantly different shape in different tissues (P < 10−6). By 13.5 dpc, the whole fetus mutation frequency had already started increasing from the theoretical zero at conception to a value that was about one‐half the mid‐adulthood (3–10 months) average. From 10 days to 3 months, mutation frequency increased significantly in liver (P = 0.007) and showed an increasing trend in cerebellum, forebrain, and thymus. From 3 to 10 months, there was no significant change in mutation frequency in any tissue examined. From 10 to 25 months, the mutation frequency increased significantly in liver (P < 10−6) and adipose tissue (P = 0.002), but not in the other tissues examined (cerebellum, forebrain, and male germline). It is of interest that the mutation frequency in the male germline is consistently the lowest, remaining essentially unchanged in old age. The spectrum of mutation types was unaltered with age, tissue type and gender, although, as previously reported, tandem GG→TT mutations are tissue specific and show significant increases with age and certain hotspots (Buettner VL et al. [1999]: Environ Mol Mutagen 33:320–324; Hill KA et al. [2003]: Mutat Res 534:173–186). The spectrum of mutation types was generally the same for all tissue types, despite the tissue‐specific increases in mutation frequency with age. These data provide a useful reference for future studies of endogenous and exogenous mutagenesis. Environ. Mol. Mutagen. 43:110–120, 2004. © 2004 Wiley‐Liss, Inc.
Mutagenicity of carbon tetrachloride and chloroform in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli WP2uvrA/pKM101 and WP2/pKM101, using a gas exposure method
Authors: Araki Akihiro , Kamigaito Nobuyuki , Sasaki Toshiaki , Matsushima Taijiro
Published: February 2004

The volatile solvents carbon tetrachloride and chloroform are carcinogens that are often reported as nonmutagenic in bacterial mutagenicity assays. In this study, we evaluated the mutagenicity of these compounds in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli WP2uvrA/pKM101 and WP2/pKM101, with and without S9 mix, using a gas exposure method. Tests were also conducted with a glutathione‐supplemented S9 mix. Carbon tetrachloride was mutagenic in TA98 without S9 mix, and in WP2/pKM101 and WP2uvrA/pKM101 with and without S9 mix; carbon tetrachloride was not mutagenic in TA100, TA1535 or TA1537. Chloroform was mutagenic in WP2/pKM101, but only in the presence of glutathione‐supplemented S9 mix. Chloroform was not mutagenic in TA98, TA100, TA1535, TA1537, or WP2uvrA/pKM101 with or without S9 mix, and was not mutagenic in TA98, TA100, TA1535, TA1537, or WP2uvrA/pKM101 in the presence of glutathione‐supplemented S9 mix. The data indicate that carbon tetrachloride and chloroform are bacterial mutagens when adequate exposure conditions are employed and suggest that a genotoxic mode of action could contribute to the carcinogenicity of these compounds. Environ. Mol. Mutagen. 43:128–133, 2004. © 2004 Wiley‐Liss, Inc.
Clastogenicity of atrazine assessed with the Allium cepa test
Authors: Bolle Paola , Mastrangelo Sabina , Tucci Paolo , Evandri Maria G.
Published: February 2004

Atrazine is classified as a restricted use pesticide and it is currently included in an international revision program for re‐evaluating the human and ecological (non‐human populations) health risks associated with its release into the environment. The present study was undertaken to add new data on the genotoxic potential of atrazine using the Allium cepa chromosome aberration test. The test concentrations were based on the Maximum Contaminant Levels in water intended for human consumption set by European and US regulations. Atrazine produced a concentration‐related increase in the number of total somatic chromosome aberrations, although this increase was statistically significant (p<0.05) only at the highest test concentration (5 μg/L). Analysis of the categories of structural chromosome damage indicated that breaks were the predominant lesion induced; the percent of cells per bulb with breaks also increased in a concentration‐related manner, and the increase was statistically significant at the two highest test concentrations (1 and 5 μg/L) (p<0.05). The Allium cepa plant assay detected the clastogenicity of atrazine at concentrations that are likely to be encountered in water, a common site of atrazine contamination. Environ. Mol. Mutagen. 43:137–141, 2004. © 2004 Wiley‐Liss, Inc.
Analysis of health outcome time series data in epidemiological studies
Authors: Touloumi Giota , Atkinson Richard , Tertre Alain Le , Samoli Evangelia , Schwartz Joel , Schindler Christian , Vonk Judith M. , Rossi Giuseppe , Saez Marc , Rabszenko Daniel , Katsouyanni Klea
Published: February 2004

Several recent studies have reported significant health effects of air pollution even at low levels of air pollutants. These studies have been criticized for the statistical methods and for inconsistency in results between cities. An important development in air pollution epidemiology has come from multicenter studies. Within the APHEA‐2 project we have developed a statistical methodology to evaluate short‐term health effects of air pollution using data from 30 cities across Europe. For the analysis, a hierarchical modelling approach was adopted and implemented in two stages: (a) data from each city were analyzed separately to allow for local differences, using generalized additive Poisson regression models; (b) city‐specific effects estimates were regressed on city‐specific covariates to obtain an overall estimate and to explore heterogeneity across cities. In order to illustrate our methodology we present results for PM10 effects. It was found that a 10 μg/m3 increase in PM10 or NO2 concentrations is associated with a 0.67% (95% CI: 0.50 to 0.90) and 0.33% (0.20 to 0.40) increase in total mortality, respectively. After mutual adjustment, the PM10 effect was reduced by 40% and that of NO2 by 20%, but both pooled estimates remained significant. Long‐term mean NO2 concentrations act as an effect modifier for PM10 effects, even after adjustment for NO2 confounding effects. In the second stage we explored two different models for combining the adjusted for NO2, PM10 effects across cities: bivariate, which accounts for within‐city correlation of PM10 and NO2; and univariate, which ignores this correlation. Both models gave broadly the same results. Copyright © 2004 John Wiley & Sons, Ltd.
Optimization of ordered distance sampling
Authors: Nielson Ryan M. , Sugihara Robert T. , Boardman Thomas J. , Engeman Richard M.
Published: February 2004

Ordered distance sampling is a point‐to‐object sampling method that can be labor‐efficient for demanding field situations. An extensive simulation study was conducted to find the optimum number, g, of population members to be encountered from each random starting point in ordered distance sampling. Monte Carlo simulations covered 64 combinations of four spatial patterns, four densities and four sample sizes. Values of g from 1 to 10 were considered for each case. Relative root mean squared error (RRMSE) and relative bias were calculated for each level of g, with RRMSE used as the primary assessment criterion for finding the optimum level of g. A non‐parametric confidence interval was derived for the density estimate, and this was included in the simulations to gauge its performance.

Superior estimation properties were found for g > 3, but diminishing returns, relative to the potential for increased effort in the field, were found for g > 5. The simulations showed noticeable diminishing returns for more than 20 sampled points. The non‐parametric confidence interval performed well for populations with random, aggregate or double‐clumped spatial patterns, but rarely came close to target coverage for populations that were regularly distributed. The non‐parametric confidence interval presented here is recommended for general use. Copyright © 2004 John Wiley & Sons, Ltd.
Robust principal component analysis and outlier detection with ecological data
Authors: Jackson Donald A. , Chen Yong
Published: February 2004

Ecological studies frequently involve large numbers of variables and observations, and these are often subject to various errors. If some data are not representative of the study population, they tend to bias the interpretation and conclusion of an ecological study. Because of the multivariate nature of ecological data, it is very difficult to identify atypical observations using approaches such as univariate or bivariate plots. This difficulty calls for the application of robust statistical methods in identifying atypical observations. Our study provides a comparison of a standard method, based on the Mahalanobis distance, used in multivariate approaches to a robust method based on the minimum volume ellipsoid as a means of determining whether data sets contain outliers or not. We evaluate both methods using simulations varying conditions of the data, and show that the minimum volume ellipsoid approach is superior in detecting outliers where present. We show that, as the sample size parameter, h, used in the robust approach increases in value, there is a decrease in the accuracy and precision of the associated estimate of the number of outliers present, in particular as the number of outliers increases. Conversely, where no outliers are present, large values for the parameter provide the most accurate results. In addition to the simulation results, we demonstrate the use of the robust principal component analysis with a data set of lake‐water chemistry variables to illustrate the additional insight available. We suggest that ecologists consider that their data may contain atypical points. Following checks associated with normality, bivariate linearity and other traditional aspects, we advocate that ecologists examine their data sets using robust multivariate methods. Points identified as being atypical should be carefully evaluated based on background information to determine their suitability for inclusion in further multivariate analyses and whether additional factors explain their unusual characteristics. Copyright © 2004 John Wiley & Sons, Ltd.
Forecasting daily high ozone concentrations by classification trees
Authors: Bruno F. , Cocchi D. , Trivisano C.
Published: February 2004

This article proposes the use of classification trees (CART) as a suitable technique for forecasting the daily exceedance of ozone standards established by Italian law. A model is formulated for predicting, 1 and 2 days beforehand, the most probable class of the maximum daily urban ozone concentration in the city of Bologna. The standard employed is the so‐called ‘warning level’ (180 μg/m3). Meteorological forecasted variables are considered as predictors. Pollution data show a considerable discrepancy between the dimensions of the two classes of events. The first class includes those days when the observed maximum value exceeds the established standard, while the second class contains those when the observed maximum value does not exceed the said standard. Due to this peculiarity, model selection procedures using cross‐validation usually lead to overpruning. We can overcome this drawback by means of techniques which replicate observations, through the modification of their inclusion probabilities in the cross‐validation sets. Copyright © 2004 John Wiley & Sons, Ltd.
Parsimonious modelling, testing and forecasting of long‐range dependence in wind speed
Authors: Hussain S. , Elbergali A. , Al‐Masri A. , Shukur G.
Published: February 2004

Detecting and estimating long‐range dependence are important in the analysis of many environmental time series. This article proposes a periodogram roughness (PR) estimator and describes its uses for testing and estimating the dependence structure. Asymptotic critical values are generated for performing the test, and special attention is given to investigating the properties of the PR regarding size and power. The conventional short‐memory models, such as the autoregressive (AR), are shown to be less parsimonious. Forecasting errors of both fractional Gaussian noise (FGN) and fractional autoregressive moving average (FARMA) are investigated by conducting simulation studies. In addition to the PR, maximum likelihood (ML) and semi‐parametric (SP) estimators are used and evaluated. Our results have shown that more accurate forecasted points are obtained when using the fractional forecasting. The methods are illustrated using Swedish wind speed data. Copyright © 2004 John Wiley & Sons, Ltd.
The influence of molecular diffusion on the distributed moments of a scalar PDF
Authors: Sullivan Paul J.
Published: February 2004

Simple, physically based, approximations are used to obtain solutions to the exact, but intractable, equations that describe the evolution of the moments of the probability density function of a scalar (contaminant) released in a turbulent (environmental) flow. The effects of molecular diffusivity are assessed by comparing these solutions with the known results for the non‐physical case of zero molecular diffusivity. The results are also compared with experimental results from a steady source in wind tunnel, grid, turbulence. Copyright © 2004 John Wiley & Sons, Ltd.
Experimental study of the charring rate of tropical hardwoods
Authors: Njankouo Jacques Michel , Dotreppe Jean‐Claude , Franssen Jean‐Marc
Published: February 2004

This paper describes an experimental investigation of the charring rates of timber. An experimental procedure was designed for assessing the charring rate of 20 specimens exposed to fire in a single test, with one‐dimensional heat transfer conditions.

Each test specimen was manufactured by gluing seven laminates together. Four thermocouples were inserted at different depths in four different laminates located in the middle of the test specimen. The test was conducted using a gas‐fired furnace and specimens were exposed to the standard ISO 834 fire.

In order to evaluate the fire performance of tropical hardwoods, seven different species with densities ranging from 500 to 1000 kg/m3 were used. For the purpose of verifying the experimental procedure against existing data, two softwood species (spruce and fir) and one European hardwood species (oak) were also examined.

Experimental results indicate that the test method and procedure can be used for assessing the charring rate of timber both for softwood and for hardwood species. They also show that the density of wood significantly affects the charring rate and that the values recommended in Eurocode 5 for high densities are somewhat too conservative. Copyright © 2004 John Wiley & Sons, Ltd.
Flame retardant performance of various UL94 classified materials exposed to external ignition sources
Authors: Hong Sanghyun , Yang Jaeho , Ahn Sunghee , Mun Yongik , Lee Gyucheol
Published: February 2004

The flammability of eight halogen‐free styrene resins and one halogen‐containing styrene resin was characterized by UL 94 VB, LOI and cone calorimeter tests. Their burning behaviour was also measured when exposed to three external ignition sources (methenamine tablet, candle, paper ball). Five resins were used for 19″ monitor housings and the others for 25″ TV. The LOI values of UL 94 V‐2, V‐1 and V‐0 rated resins were higher than that of HB. The heat release rate decreased as the UL 94 ratings increased from HB to V‐0. When these resins were exposed to three external ignition sources, UL 94 V‐1 and V‐0 rated resins showed a self‐extinguishing property after removal of the fire and did not cause fire growth in either 19″ monitor or the 25″ TV housings in all cases. However, UL 94 V‐2 and HB rated resins were easily ignited and spread fire by dripping burning trickles. The burning rate of V‐2 resin was slower than that of HB. Copyright © 2004 John Wiley & Sons, Ltd.
Mechanical impact tests of some selected polymers in high pressure liquid oxygen environments
Authors: Hshieh Fu‐Yu , Hirsch David B. , Beeson Harold D.
Published: February 2004

The threshold impact energies of the liquid oxygen mechanical impact test were determined for eight polymers at 6.9 MPa (1000 psi) oxygen pressure. The results show that there was no correlation between the threshold impact energy and the autoignition temperature of the polymers in high pressure oxygen environments. A violent explosion was observed in some of the tests when nylon 6/6, nitrile rubber and polyurethane rubber were impacted in high pressure liquid oxygen. Copyright © 2004 John Wiley & Sons, Ltd.
Surface temperature measurements on burning materials using an infrared pyrometer: accounting for emissivity and reflection of external radiation
Authors: Urbas Joe , Parker William J. , Luebbers Gerald E.
Published: February 2004

This paper demonstrates the successful use of an infrared pyrometer, operating in the 8–10 µm wavelength band, to measure the surface temperature of combustible specimens in a heat release calorimeter. The temperature histories of ten different materials were measured in the ICAL (intermediate scale calorimeter). The set of materials comprised four wood products, gypsum board, polyisocyanurate foam, PVC floor tile, PMMA and two non‐combustible boards. A small‐diameter bare thermocouple was installed on each specimen in order to determine an accurate temperature for comparison.

The spectral emissivity and the spectral flux reflected from the surface were measured simultaneously and used to correct the apparent temperature measured by the pyrometer. The spectral emissivity and reflected spectral flux were both constant prior to ignition for all the combustible materials. During the burning phase all the combustible materials had a spectral emissivity very close to unity. The agreement between the temperatures measured with the pyrometer and thermocouple was not affected by the flame. The wood products, the polyisocyanurate foam and the calcium silicate board required no correction for reflected spectral flux over the whole temperature range. Copyright © 2004 John Wiley & Sons, Ltd.
A two‐dimensional vertical non‐hydrostatic σ model with an implicit method for free‐surface flows
Authors: Yuan Hengliang , Wu Chin H.
Published: February 2004

An implicit finite difference model in the σ co‐ordinate system is developed for non‐hydrostatic, two‐dimensional vertical plane free‐surface flows. To accurately simulate interaction of free‐surface flows with uneven bottoms, the unsteady Navier–Stokes equations and the free‐surface boundary condition are solved simultaneously in a regular transformed σ domain using a fully implicit method in two steps. First, the vertical velocity and pressure are expressed as functions of horizontal velocity. Second, substituting these relationship into the horizontal momentum equation provides a block tri‐diagonal matrix system with the unknown of horizontal velocity, which can be solved by a direct matrix solver without iteration. A new treatment of non‐hydrostatic pressure condition at the top‐layer cell is developed and found to be important for resolving the phase of wave propagation. Additional terms introduced by the σ co‐ordinate transformation are discretized appropriately in order to obtain accurate and stable numerical results. The developed model has been validated by several tests involving free‐surface flows with strong vertical accelerations and non‐linear waves interacting with uneven bottoms. Comparisons among numerical results, analytical solutions and experimental data show the capability of the model to simulate free‐surface flow problems. Copyright © 2004 John Wiley & Sons, Ltd.
Review of numerical special relativistic hydrodynamics
Authors: van Odyck D. E. A.
Published: February 2004

This paper gives an overview of numerical methods for special relativistic hydrodynamics (SRHD). First, a short summary of special relativity is given. Next, the SRHD equations are introduced. The exact solution for the SRHD Riemann problem is described. This solution is used in a Godunov scheme to compute solutions for two test problems. A third test problem is used to show non‐convergent behaviour of the numerical solution at the location of the contact discontinuity. Finally, a short description of numerical methods used so far in SRHD is given. Copyright © 2004 John Wiley & Sons, Ltd.
Unexpected embryonic stem (ES) cell mutations represent a concern in gene targeting: Lessons from “fierce” mice
Authors: Kumar Ravinesh A. , Chan Ka Ling , Wong Ambrose H.W. , Little Ken Q. , Rajcan‐Separovic Evica , Abrahams Brett S. , Simpson Elizabeth M.
Published: February 2004

The exceptional value of gene targeting technology to generate mouse models of human disease exists under the shadow of potential genetic errors. We previously observed an unexpected brain‐behavior phenotype that resulted from a gene‐targeting experiment designed to delete the Zfa gene. Given that the transcription of Zfa is restricted to the germ cell lineage of adult testis, it was both a surprise and a concern when the resulting mice had a phenotype present in both sexes that included abnormal brains and violent behavior. We hypothesized that an unrelated mutation may have been responsible for the unexpected phenotype. Here we show that the single gene mutation, Nr2e1frc (fierce), which was responsible for the brain‐behavior phenotype, existed in the embryonic stem (ES) cell even before the derivation of the Zfa knockout mice. Our work thus highlights a concern in gene targeting, namely, that ES cells can harbor unexpected mutations, which can lead to genotype‐phenotype misattribution. Based on our findings, we caution the gene‐targeting community to use low‐passage ES cells, to characterize mice derived from more than one independently targeted ES cell clone, and to backcross mice to allow for segregation of distant but linked mutations. genesis 38:51–57, 2004. © 2004 Wiley‐Liss, Inc.
Essential requirement for both hsf1 and hsf2 transcriptional activity in spermatogenesis and male fertility
Authors: Wang Guanghu , Ying Zhekang , Jin Xiongjie , Tu Naxin , Zhang Yan , Phillips Michele , Moskophidis Demetrius , Mivechi Nahid F.
Published: February 2004

Heat shock factors (Hsfs) are major transactivators of heat shock proteins but are also involved in regulation of other genes active in embryonic development. High expression levels of Hsfs in mouse testis during development suggest a role for these factors in spermatogenesis, a cyclic process of spermatogonia cell‐differentiation into mature spermatozoa. In contrast to hsf1−/− mice, which exhibit normal spermatogenesis, targeted disruption of hsf2 results in reduced testicular size but only a small impairment in male fertility. We show here that disruption of both hsf1 and hsf2 results in a more severe phenotype associated with male sterility due to severe defects in spermatogenesis. Earliest defects observed are the reduced number of germ cells in juvenile mice and germ cells that enter the meiotic prophase fail to progress beyond the pachytene stage. This was associated with a reduction or absence of transcription of genes critically involved in spermatogenesis. The findings suggest that additive or synergistic transcriptional activity of both hsf1 and hsf2 is required for normal mammalian spermatogenesis and male fertility. genesis 38:66–80, 2004. © 2004 Wiley‐Liss, Inc.
Solid‐Liquid Equilibrium of Tröger's Base Enantiomers in Ethanol: Experiments and Modelling
Authors: Worlitschek Jörg , Bosco Marcello , Huber Markus , Gramlich Volker , Mazzotti Marco
Published: February 2004

Thermodynamic properties of the enantiomers of the Tröger's base as crystals and in ethanol solutions have been studied by means of a suite of analytical techniques. We report the melting diagrams of the two enantiomers, providing evidence for the formation of a solid racemic compound. We present also ternary equilibrium data about the solubility of the two enantiomers in ethanol at 25°, 35°, and 50°. The melting‐diagram data are described well by the SchroederVan Laar and PrigogineVieland equations, when the melting temperatures and enthalpies of pure enantiomer and of the racemic compound are provided and with the assumption that the melting behavior is ideal. The ternary equilibrium data were well‐described when nonideality of mixtures of ethanol and the enantiomers is accounted for in terms of the non‐random two liquids (NRTL) model. Finally, we present the newly determined X‐ray crystal structure of an orthorhombic form of the pure Tröger's base (+)‐enantiomer.
Synthesis of Potentially Antiviral 2′,3′‐Dideoxy‐2′‐fluoro‐3′‐(hydroxyamino)nucleosides
Authors: Wang Songqing , Chang Junbiao , Pan Shifeng , Zhao Kang
Published: February 2004

A series of novel 3′‐(alkyl(hydroxy)amino)‐2′‐fluoronucleoside analogs were prepared via conjugate addition of N‐methylhydroxylamine to various 2‐fluorobutenolides. The adducts 13a and 16 were obtained as single isomers under absolute control of stereochemistry. The crucial N‐demethylation of 23–25 was readily achieved by means of DDQ oxidation, followed by nitrone/oxime exchange reaction. By this procedure, a variety of alkyl groups could be efficiently introduced at the 3′‐N‐atom of the nucleoside analogs, some of which might display potentially interesting anti‐HIV properties.
New Acylated Presenegenin Saponins from Two Species of Muraltia
Authors: Elbandy Mohamed , Miyamoto Tomofumi , Delaude Clément , Lacaille‐Dubois Marie‐Aleth
Published: February 2004

Six new acylated bisdesmosidic triterpene glycosides 1–6 were isolated from the roots of Muraltia heisteria (L.) DC., as three inseparable mixtures 1/2, 3/4, and 5/6 of the (E)‐ and (Z)‐3,4,5‐trimethoxycinnamoyl derivatives. The compound pair 1/2 along with four known saponins were also isolated from the roots of Muraltia satureioides DC. Their structures were elucidated mainly by spectroscopic experiments including 2D‐NMR techniques as 3‐O‐(β‐D‐glucopyranosyl)presenegenin 28‐{O‐β‐D‐apiofuranosyl‐(1→3)‐O‐[β‐D‐xylopyranosyl‐(1→4)]‐O‐α‐L‐rhamnopyranosyl‐(1→2)‐O‐[6‐O‐acetyl‐β‐D‐galactopyranosyl‐(1→3)]‐4‐O‐[(E)‐3,4,5‐trimethoxycinnamoyl]‐β‐D‐fucopyranosyl} ester (1) and its (Z)‐isomer 2, 3‐O‐(β‐D‐glucopyranosyl)presenegenin 28‐{O‐6‐O‐acetyl‐β‐D‐galactopyranosyl‐(1→3)‐O‐[3‐O‐acetyl‐α‐L‐rhamnopyranosyl‐(1→2)]‐4‐O‐[(E)‐3,4,5‐trimethoxycinnamoyl]‐β‐D‐fucopyranosyl} ester (3) and its (Z)‐isomer 4, and 3‐O‐(β‐D‐glucopyranosyl)presenegenin 28‐{O‐3‐O‐acetyl‐α‐L‐rhamnopyranosyl‐(1→2)‐O‐[β‐D‐xylopyranosyl‐(1→3)]‐4‐O‐[(E)‐3,4,5‐trimethoxycinnamoyl]‐β‐D‐fucopyranosyl} ester (5) and its (Z)‐isomer 6, respectively.
Synthesis of Highly Fluorinated Chloroformates and Their Use as Derivatizing Agents for Hydrophilic Compounds and Drinking‐Water‐Disinfection By‐Products
Authors: Vincenti Marco , Ghiglione Nicoletta , Valsania Maria Carmen , Davit Patrizia , Richardson Susan D.
Published: February 2004

A rapid, safe, and efficient procedure was developed to synthesize, on a small scale, fluorinated chloroformates often required to perform analytical derivatizations. This new family of agents allows straightforward derivatization of highly polar compounds (with multiple hydroxy, carboxy, and amino substituents) in the aqueous phase, compatible with GC and GC/MS analysis. A goal of this work was to develop a derivatization procedure that would enable the detection and identification of highly polar disinfection by‐products in drinking water.
Effect of the Media on the Quantum Yield of Singlet Oxygen (O2(1Δg)) Production by 9H‐Fluoren‐9‐one: Microheterogeneous Systems
Authors: Martínez Claudia G. , Braun André M. , Oliveros Esther
Published: February 2004

The quantum yield (ΦΔ) of singlet oxygen (O2(1Δg) production by 9H‐fluoren‐9‐one (FLU) is very sensitive to the nature of the solvent (0.02 in a highly polar and protic solvent, such as MeOH, to 1.0 in apolar solvents). This high sensitivity has been used for probing the interaction of FLU with micellar media and microemulsions based on anionic (sodium dodecyl sulfate, SDS; bis‐(2‐ethylhexyl)sodium sulfosuccinate, AOT), cationic (cetyltrimethylammonium chloride, CTAC) and nonionic (Triton X‐100, TX) surfactants. Values of ΦΔ of FLU vary in a wide range (0.05–1.0) in both microheterogeneous media and neat solvent, and provide information on the microenvironment of FLU, i.e., on its localization within organized media. In ionic and nonionic micellar media, as well as in four‐component microemulsions, FLU is, to various extents, exposed to solvation by the polar and protic components of the microheterogeneous systems (water and/or butan‐1‐ol) in the micellar interfacial region (ΦΔ=0.05–0.30). In contrast, in AOT reverse micelles (consisting of AOT as surfactant, cyclohexane as hydrophobic component, and water), FLU is located in the hydrophobic continuous pseudophase, and is totally separated from the micellar water pools (ΦΔ≈1.0).
NMR Conformational Analysis and Theoretical Calculations for 2‐Aryl‐ 1,3‐dihydroxy‐4,4,5,5‐tetramethylimidazolidines
Authors: Alcântara Antônio F. De C. , Vaz Maria G. F. , Stumpf Humberto O. , Piló‐Veloso Dorila , De Almeida Wagner B.
Published: February 2004

Conformational studies of 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐1‐yl)imidazolidine (1a) and 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐3‐yl)imidazolidine (1b), carried out by using 1D 1H‐ and 13C‐NMR and 2D HMQC, HMBC, and NOESY experiments and with the aid of theoretical calculations, indicate that the OH groups are trans to the pyridinyl substituent. Because the two 1H‐NMR signals of the Me groups are distinguishable and do not change between 290 and 380 K, it is proposed that 1a and 1b have each only one conformation in this temperature range. This behavior was not found with 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐2‐yl)imidazolidine (1c) because its Me 1H‐NMR signals cross over at 300 K. Hence, more than one conformation must be present, beyond those produced by simple inversions. Theoretical calculations including temperature and solvent effects were performed to provide further information on the conformational analysis and to help to assign the NMR data. The combination of NMR measurements and quantum‐chemical calculations is shown to be a very promising strategy for conformational analysis studies in solution.
Two Novel 14‐Nor‐13,14‐secopodocarpanes from the Bark of Taiwania cryptomeriodes
Authors: Chien Shih‐Chang , Kuo Yueh‐Hsiung
Published: February 2004

The two novel compounds cryptomelactones A (3) and B (4) were isolated from the bark of Taiwania cryptomeriodes, besides the two known podocarpane derivatives 1β,13,14‐trihydroxypodocarpa‐8,11,13‐trien‐7‐one (1) and 3β,13,14‐trihydroxypodocarpa‐8,11,13‐trien‐7‐one (2), and were characterized by spectroscopic means including 2D‐NMR techniques. Compounds 3 and 4 are novel‐14‐nor‐13,14‐seco‐podocarpanes. The absolute configurations of 3 and 4 were determined by the modified Mosher method. The biotransformation mechanism of 3 and 4 is proposed.
A pilot trial of quetiapine for the treatment of patients with delirium
Authors: Pae Chi‐Un , Lee Soo‐Jung , Lee Chang‐Uk , Lee Chul , Paik In‐Ho
Published: February 2004

Twenty‐two Korean inpatients with delirium were administered prospectively a flexible dose of quetiapine. The delirium rating scale‐revised‐severity 98 (DRS‐R‐98) and clinical global impression scale‐severity (CGI‐s) scores were assessed at the time of pre‐ and post‐treatment. The DRS‐R‐98 and CGI‐s scores were significantly reduced by 57.3% and 55.1%, respectively. Quetiapine was effective and safe for the treatment of patients with delirium, and could be a useful alternative agent to classical antipsychotics in the treatment of delirium. Copyright © 2004 John Wiley & Sons, Ltd.
Comorbid cannabis use and panic disorder: short term and long term follow‐up study
Authors: Dannon Pinhas N. , Lowengrub Katherine , Amiaz Revital , Grunhaus Leon , Kotler Moshe
Published: February 2004

Objectives

The aim of the study was to compare the treatment of panic disorder in patients with or without cannabis use according to response, relapse and side effects.

Materials and Methods

66 panic disorder (PD) patients were included in our study. All the subjects met the DSM‐IV diagnosis of panic disorder (n=45) or panic disorder with agoraphobia (n=21). Twenty four patients experienced their first panic attack within 48 h of cannabis use and then went on to develop PD. All the patients received pharmacologic treatment with paroxetine (gradually increased up to 40 mg/d). A masked rater that was blind to the group allocation, assessed patients in order to rate anxiety symptoms and medication side effects. Relapse was defined as the occurrence of a single panic attack after remission of panic symptoms. The instruments were administered at baseline and also at the 4, 8 and 12 weeks visits and at the 1 year visit.

Results

The two groups responded equally well to paroxetine treatment as measured at the 8 weeks and 12 months follow‐up visits. There were no significant effects of age, sex and duration of illness as covariates with response rates between the two groups. Also PD or PDA diagnosis did not affect the treatment response in either group. There were no significant differences in weight gain, sexual side effects or relapse rates between patients according to gender or comorbid diagnosis.

Acute cannabis use can be associated with the onset of panic attacks and panic disorder, and panic disorder which develops after cannabis use is responsive to pharmacotherapy. Copyright © 2004 John Wiley & Sons, Ltd.
A randomized clinical trial comparing doses and efficacy of lormetazepam tablets or oral solution for insomnia in a general practice setting
Authors: Ancolio C. , Tardieu S. , Soubrouillard C. , Alquier C. , Pradel V. , Micallef J. , Blin O.
Published: February 2004

Lormetazepam is a short‐acting benzodiazepine hypnotic which is beneficial in shortening the time to onset of sleep. The aim of the study was to assess a new formulation of lormetazepam (oral solution) in comparison with lormetazepam tablets in out‐patients with insomnia. This trial was an open randomized parallel group study conducted by 30 general practitioners. One hundred and eight patients took 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg (for oral solution) and 0.5 mg (for tablets), respectively, each day and every 2 days. The patients assessed the efficacy, acceptability and tolerance of lormetazepam using a diary card and a set of visual analogue scales assessing their sleep. Over 14 days of treatment, the mean daily dose of lormetazepam was lower in the oral solution group than in the tablets group (0.78 mg versus 0.97 mg). The cumulated dose of lormetazepam was lower with the oral solution (18% reduction). No significant difference between the two groups was found in the assessment of sleep characteristics. The occurrence of side effects did not differ between the two groups. These results suggest that a unitary dose as achieved by an oral solution of lormetazepam allows easier determination of the minimal individual effective dose. Copyright © 2004 John Wiley & Sons, Ltd.
Maintenance treatment for schizophrenia with quetiapine
Authors: Buckley Peter F.
Published: February 2004

With the majority of current information being derived from short‐term clinical trials, the impact of atypical antipsychotics during maintenance treatment of schizophrenia is of considerable interest, although only limited data are available at present. The present report is an analysis of data that are available up to 156 weeks after the start of an open‐label extension (OLE) phase of three, double‐blind randomized trials in quetiapine‐treated patients who responded to an initial 6‐week treatment period. The mean daily quetiapine dose (range 150–750 mg) was 439.5 mg for patients included in the brief psychiatric rating scale (BPRS) and 438.5 mg for patients included in the clinical global impression (CGI) analyses. The initial mean acute phase BPRS total score (40.67; n=258) and CGI severity of illness score (4.81; n=259) were reduced at the start of the OLE to 13.94 and 3.00, respectively. After 156 weeks, endpoint scores were 9.04 for BPRS and 2.43 for CGI severity of illness. Although limited by patient attrition, these OLE data suggest that an initial beneficial response with quetiapine treatment can be maintained over a long‐term period. Copyright © 2004 John Wiley & Sons, Ltd.
Dosage finding and outcome in the treatment of schizophrenic inpatients with amisulpride. Results of a drug utilization observation study
Authors: Linden Michael , Scheel Tabea , Xaver Eich Franz
Published: February 2004

Objectives

Amisulpride is an unique neuroleptic drug insofar as it has a dual pharmacodynamic effect. At low doses it blocks selectively presynaptic autoreceptors, and at high doses it blocks postsynaptic D2/D3 receptors. This allows the dosage to be adjusted and the treatment tailored to various clinical situations. It is unknown whether this pharmacological property has any bearing for routine treatment. The questions are: which dosages of amisulpride are chosen by physicians in the treatment of schizophrenic inpatients and does this dosage handling deviate from prescription guidelines?; which factors can explain dosage selection, and what is the treatment outcome with different dosages? The study pertains to drug management and dosage finding as principal factors in explaining positive and negative medication results.

Methods

In a drug utilization observation study the prescribing of amisulpride for 811 schizophrenic inpatients from 240 psychiatric hospitals was monitored for 8 weeks. Standardized assessment included dosage, the positive and negative symptom scale (PANSS), the clinical global impression rating (CGI), the patients' subjective reaction to amisulpride, psychosocial functioning, EPS and other adverse events. The mean observation period was 49 days.

Results

The mean initial daily dose of amisulpride was 361 mg/day. The mean daily dose at day 56 was on average 550 (SD 266) mg/d, ranging from 100 mg to 1600 mg. 17.9% of patients received a maximum dose up to 399 mg/d, 48.1% between 400 and 799 mg/d, and 25.5% 800 mg/d and higher. Higher doses were preferably prescribed for males, patients with involuntary admission, patients with paranoid schizophrenia with acute exacerbation, high CGI and high PANSS‐positive scores. Patients with higher doses of amisulpride at the same time received higher rates of additional other neuroleptic drugs. Higher doses yield better results in very severe cases.

Conclusions

Prescribed dosages were in the lower range of what is recommended for acute cases. Dosage was significantly influenced by the severity of the illness. Polypharmacy was the rule rather than the exception. Efficacy rates under conditions of routine care were similar to the results from controlled clinical trials, which speaks for their generalizability. Very severe cases profit from higher doses. Copyright © 2004 John Wiley & Sons, Ltd.
NK and CD8+ T cell‐mediated eradication of poorly immunogenic B16‐F10 melanoma by the combined action of IL‐12 gene therapy and 4‐1BB costimulation
Authors: Xu Dongping , Gu Peidi , Pan Ping‐Ying , Li Qingsheng , Sato Alice I. , Chen Shu‐Hsia
Published: February 2004

In previous reports, systemic administration of a stimulatory monoclonal antibody directed against the 4‐1BB receptor had no effect on survival or tumor burden in mice inoculated with the poorly immunogenic B16‐F10 melanoma. We combined IL‐12 gene transfer with 4‐1BB costimulation to explore a previously noted cooperative anti‐tumor effect against this model tumor. We hypothesize that the innate immune response mediated by IL‐12‐activated natural killer (NK) cells initiates the activation of the immune system, leading to the priming of T cells, whereas 4‐1BB costimulation enhances the function of primed tumor‐specific T cells. The effect of the combination therapy on the growth of subcutaneous (s.c.) tumors and pulmonary metastasis was examined. The combination therapy significantly retarded the growth of subcutaneously‐inoculated tumors, and 50% of tumor‐bearing mice survived with complete tumor regression. In contrast, neither IL‐12 gene transfer nor anti‐4‐1BB antibody administration alone was as effective. Enhanced CTL activity against both B16‐F10 tumor cells and TRP‐2‐pulsed EL4 syngeneic tumor cells was observed in tumor‐bearing animals treated with the combination therapy 2 weeks after treatment and, in long‐term survivors from this combination therapy, at >120 days. In a pulmonary metastatic model, only the combination therapy generated significant protection against metastasis. In vivo depletion of NK or CD8+ but not CD4+ subsets eliminated the protective immunity. Furthermore, NK cell depletion significantly reduced both tumor‐specific CTL activity and the number of tumor‐specific IFN‐γ‐producing cells, suggesting that this synergistic effect requires the participation of both NK and CD8+ T cells. © 2004 Wiley‐Liss, Inc.
Bladder cancer risk and personal hair dye use
Authors: Andrew Angeline S. , Schned Alan R. , Heaney John A. , Karagas Margaret R.
Published: February 2004

Several cohort and case‐control studies have found an increased risk of bladder cancer among hairdressers and barbers who are occupationally exposed to hair dyes. However, the carcinogenic risk associated with personal use of hair dyes remains uncertain since several large case‐control and cohort studies did not find an association between personal hair dye use and bladder cancer. To address this question, the authors used data collected on 459 bladder cancer cases and 665 controls who were interviewed as part of a case‐control study conducted in New Hampshire between 1994 and 1998. Participants underwent a structured personal interview with regard to history of hair dye use and bladder cancer risk factors. Unconditional logistic regression analysis was used to compute odds ratios that were associated with hair dye use, while controlling for potential confounding factors. A history of any hair dye use was inversely associated with bladder cancer incidence in men [adjusted odds ratio (OR) = 0.5; 95% confidence interval (CI)=0.3–0.8], although risk reductions were not statistically significant for individual dye types. In women, use of permanent (adjusted OR = 1.5; 95%CI = 0.8–2.7) and rinse‐type hair dye (adjusted OR = 1.7; 95%CI = 0.8–3.6) were associated with a modestly elevated risk of bladder cancer but with limited statistical precision; no association was found with use of semi‐permanent dyes (adjusted OR = 0.7; 95%CI = 0.3–1.4). For permanent hair dye use, odds ratios were most pronounced for younger age at first use, higher frequency and prolonged time since first use; however there were no clear trends in risk by these factors. In light of the prevalence of hair dye use, further studies are needed that address the effects of specific colors and types of hair dyes along with the possible role of individual susceptibility. © 2004 Wiley‐Liss, Inc.