bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sum statistics for the joint detection of multiple disease loci in case‐control association studies with SNP markers
Authors: Wille Anja , Hoh Josephine , Ott Jurg 
Published: November 2003

AbstractIn complex traits, multiple disease loci presumably interact to produce the disease. For this reason, even with high‐resolution single nucleotide polymorphism (SNP) marker maps, it has been difficult to map susceptibility loci by conventional locus‐by‐locus methods. Fine mapping strategies are needed that allow for the simultaneous detection of interacting disease loci while handling large numbers of densely spaced markers. For this purpose, sum statistics were recently proposed as a first‐stage analysis method for case‐control association studies with SNPs. Via sums of single‐marker statistics, information over multiple disease‐associated markers is combined and, with a global significance value α, a small set of “interesting” markers is selected for further analysis. Here, the statistical properties of such approaches are examined by computer simulation. It is shown that sum statistics can often be successfully applied when marker‐by‐marker approaches fail to detect association. Compared with Bonferroni or False Discovery Rate (FDR) procedures, sum statistics have greater power, and more disease loci can be detected. However, in studies with tightly linked markers, simple sum statistics can be suboptimal, since the intermarker correlation is ignored. A method is presented that takes the correlation structure among marker loci into account when marker statistics are combined. Genet Epidemiol 25:350–359, 2003. © 2003 Wiley‐Liss, Inc.
Rank truncated product of P‐values, with application to genomewide association scans
Authors: Dudbridge Frank , Koeleman Bobby P.C. 
Published: November 2003

AbstractLarge exploratory studies are often characterized by a preponderance of true null hypotheses, with a small though multiple number of false hypotheses. Traditional multiple‐test adjustments consider either each hypothesis separately, or all hypotheses simultaneously, but it may be more desirable to consider the combined evidence for subsets of hypotheses, in order to reduce the number of hypotheses to a manageable size. Previously, Zaykin et al. ([2002] Genet. Epidemiol. 22:170–185) proposed forming the product of all P‐values at less than a preset threshold, in order to combine evidence from all significant tests. Here we consider a complementary strategy: form the product of the K most significant P‐values. This has certain advantages for genomewide association scans: K can be chosen on the basis of a hypothesised disease model, and is independent of sample size. Furthermore, the alternative hypothesis corresponds more closely to the experimental situation where all loci have fixed effects. We give the distribution of the rank truncated product and suggest some methods to account for correlated tests in genomewide scans. We show that, under realistic scenarios, it provides increased power to detect genomewide association, while identifying a candidate set of good quality and fixed size for follow‐up studies. Genet Epidemiol 25:360–366, 2003. © 2003 Wiley‐Liss, Inc.
Multipoint linkage disequilibrium mapping for complex diseases
Authors: Liang Kung‐Yee , Hsu Fang‐Chi , Beaty Terri H. 
Published: November 2003

AbstractLinkage disequilibrium (LD) or association studies using case‐parent trios have become a common approach to locate unobserved susceptibility genes underlying complex diseases. With the availability of ever more dense marker maps, how to utilize the information carried by multiple markers simultaneously remains challenging. Recently, Liang et al. ([2001a] Am. J. Hum. Genet. 68: 937–950) proposed a multipoint LD method to estimate the location of a susceptibility gene within a framework map along with its sampling uncertainty. Two important features of this method are that 1) it uses all trios whether parents are heterozygous for a given marker or not, and 2) it provides a single test statistic for the null hypothesis of no linkage or no LD to the region, avoiding the multiple testing problem encountered when performing individual transmission disequilibrium tests (TDT) for each marker individually. In this paper, we discuss how this method can be expanded to address important issues pertaining to complex diseases in a unified fashion. These issues include, among others, gene‐gene and gene‐environment interactions, genetic heterogeneity, phenotypic refinement, and paternal vs. maternal transmission. We applied this method to asthmatic case‐parent trios from the Collaborative Study on the Genetics of Asthma (CSGA), and found that the previous evidence for linkage and LD in a 13.6 cM region of chromosome 11 can be attributed to maternal transmission, while there was no evidence of excess paternal transmission. Furthermore, such discrepancy in preferential transmission was most evident among probands with early onset age (6 years old or younger).Genet Epidemiol25:285–292, 2003. © 2003 Wiley‐Liss, Inc.
Genistein treatment protects mice from ionizing radiation injury
Authors: Landauer Michael R. , Srinivasan Venkataraman , Seed Thomas M. 
Published: November 2003

AbstractThe radioprotective and behavioral effects of an acute administration of the isoﬂavone genistein (4′,5,7‐trihydroxyﬂavone) were investigated in adult CD2F1 male mice. Mice were administered a single subcutaneous (s.c.) dose of genistein either 24 h or 1 h before a lethal dose of gamma radiation (9.5‐Gy of cobalt‐60 at 0.6 Gy min−1). Mice received saline, PEG‐400 vehicle or genistein at 3.125, 6.25, 12.5, 25, 50, 100, 200, or 400 mg kg−1 body weight. For mice treated 24 h before irradiation there was a signiﬁcant increase in 30‐day survival for animals receiving genistein doses of 25 to 400 mg kg−1 (p < 0.001). In contrast, the 30‐day survival rates of mice treated with genistein 1 h before irradiation were not signiﬁcantly different from those of the vehicle control group. Additionally, the acute toxicity of genistein was evaluated in non‐irradiated male mice administered a single s.c. injection of saline, vehicle, or genistein at 100, 200 or 400 mg kg−1. At these genistein doses there were no adverse effects, compared with controls, on locomotor activity, grip strength, motor coordination, body weight, testes weight, or histopathology. These results demonstrate that a single s.c. administration of the ﬂavonoid genistein at non‐toxic doses provides protection against acute radiation injury. Published in 2003 by John Wiley & Sons, Ltd.
Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats
Authors: Welsch Frank , Elswick Barbara , Arden James R. , Marr Melissa C. , Myers Christina B. , Tyl Rochelle W. 
Published: November 2003

AbstractThis evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identiﬁcation study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed‐pregnant CD®(Sprague‐Dawley) rats and CD‐1® mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6–16 (mice) or 6–19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no‐observable‐adverse‐effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near‐term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, signiﬁcantly reduced fetal body weights per litter and increased incidences of cleft palate (classiﬁed as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study. Copyright © 2003 John Wiley & Sons, Ltd.
Phosphoric and boric acid activation of pine sawdust
Authors: Muñoz Yuvisa , Arriagada Renán , Soto‐Garrido G , García Rafael 
Published: November 2003

AbstractChemical activation of pine sawdust using aqueous solutions of phosphoric and boric acid was studied. Thermogravimetric analyses of the impregnated lignocellulosic precursor as well as their reactivities are presented. The role of the activating agents in the thermal decomposition of the precursor and their effects on the development of porosity in activated carbons is discussed. The use of boric acid as activating agent and a final heat treatment temperature (HTT) of 600 °C produced some porosity and activated carbons with a surface area of 600 m2 g−1. With a HTT of 450 °C, molecular sieve‐like materials were produced. In contrast, phosphoric acid activation produced activated carbons with high surface areas. The amount of phosphoric acid retained in the precursor was, as expected, a function of the initial concentration as well as the impregnation time and temperature. The fact that the activated carbon porosity increases with the phosphoric acid content per gram of precursor was confirmed. The use of 6 M phosphoric acid solution and HTT of 450 °C produced the activated carbon with the highest surface area, about 1600 m2 g−1. The high degree of microporosity which developed in phosphoric acid‐activated carbons is related to the low reactivity during the thermal treatment of chemical activation. The presence of up to 10% oxygen during HTT with phosphoric acid activation caused only small textural changes. Copyright © 2003 Society of Chemical Industry
Direct filtration of Procion dye bath wastewaters by nanofiltration membranes: flux and removal characteristics
Authors: Koyuncu Ismail 
Published: November 2003

AbstractThe treatment and reuse of industrial wastewaters by membrane processes has become more attractive in the last few years due to constraints on water usage. The aim of this study was to investigate the direct filtration of reactive dye house wastewaters by nanofiltration membranes based on permeate flux, and sodium chloride and colour removal. Experiments were performed using both synthetic and industrial dye bath wastewaters with the fluxes of the industrial dye bath wastewaters lower than those of the synthetic solutions. The effects of operating conditions such as pressure and pH were assessed. Studies with DS5 DK type (polysulfone–polyamide) membranes showed that nanofiltration membranes are suitable for direct treatment of wastewaters and the permeate quality was appropriate for reuse in the dyeing process. Pre‐treatment and neutralisation were important for recovery of large amounts of salt and water from the permeate stream. Neutralisation of the solution with HCl rather than H2SO4 gave a better permeate from the point of view of the reuse. The highest permeate flux and colour removal and the lowest salt removal were achieved with the HCl neutralisation. Copyright © 2003 Society of Chemical Industry
Mineralization improvement of phenol aqueous solutions through heterogeneous catalytic ozonation
Authors: Beltrán Fernando J , Rivas Francisco J , Montero‐de‐Espinosa Ramón 
Published: November 2003

AbstractTo assess the mineralization level achieved, aqueous solutions of phenol have been treated with ozone in the presence of different solid catalysts. Activated carbon was the principal catalyst investigated, although some additional experiments were carried out by utilizing metal oxide‐based catalysts (ie Ti, Co and Fe) supported onto alumina. Usage of Co/Al2O3 led to the highest values of phenol byproduct mineralization, nevertheless some metal leaching was experienced in the process. The operating variables studied when using activated carbon as the catalyst were ozone gas concentration, amount of catalyst added and temperature. Regardless of the catalyst type used, two different ozonation kinetic regimes were observed: (I) an initial period, corresponding to the presence of phenol in solution, characterized by small amounts of dissolved ozone and no improvement of the mineralization degree if comparing catalytic and non‐catalytic runs; (II) a second period, free of phenol, in which dissolved ozone accumulated in water and the beneficial effects of catalysts on mineralization were noticed. Experimental data also demonstrated the improvement in oxalic acid elimination in the presence of heterogeneous catalysts. Finally, consumption of ozone per mass of carbon removed, reaction factors and Hatta numbers were also calculated. Copyright © 2003 Society of Chemical Industry
Fluorine‐18‐ and iodine‐125‐labelling of spiegelmers
Authors: Kuhnast B. , Klussmann S. , Hinnen F. , Boisgard R. , Rousseau B. , Fürste J. P. , Tavitian B. , Dollé F. 
Published: November 2003

AbstractSpiegelmers are high‐affinity l‐enantiomeric oligonucleotide ligands (aptamers) that display high resistance to enzymatic degradation compared to d‐oligonucleotides. Spiegelmers belong to the third generation of aptamers, and are currently extensively investigated as potential therapeutic agents. We have previously developed an original method to label natural oligonucleotides with radiohalogens and particularly with fluorine‐18, the most widely used positron‐emitter, t1/2: 109.8 min. Using the same strategy, we herein report the labelling of Spiegelmers, both with fluorine‐18 for positron emission tomography imaging and iodine‐125 for high resolution autoradiography. Three 25‐mer l‐oligonucleotides have been used, differing (a) by the position of the terminal phosphorothioate monoester group (3′‐ or 5′‐end, and therefore differing by the position of the labelling on the macromolecule) and (b) by the nature of the backbone sugar moiety (2′‐OH or 2′‐H, therefore covering the RNA and DNA series, respectively). N‐(4‐[18F]fluorobenzyl)‐2‐bromoacetamide was synthesized in three radiochemical steps from 4‐cyano‐N,N,N‐trimethylanilinium trifluoromethanesulfonate and HPLC‐purified in 90 min (typical production: 2.2–2.4 GBq starting from a batch of 22–24 GBq of [18F]fluoride). N‐(4‐[125I]iodobenzyl)‐2‐bromoacetamide was synthesized from the corresponding trimethylsilyl derivative (one pot, two radiochemical steps) and HPLC‐purified in 60 min (typical production: 24 MBq starting from 37 MBq of Na[125I]I). Coupling of the Spiegelmers with the appropriate HPLC‐purified [radiolabelled]‐halobenzyl‐2‐bromoacetamide (MeOH/PBS (0.1 M, pH 8), 10 min, 120°C) gave the corresponding labelled conjugated Spiegelmers after RP‐HPLC purification. For fluorine‐18, the whole synthetic procedure yields up to 1.1 GBq of pure labelled Spiegelmers in 160 min with a specific radioactivity of 37–74 GBq/μmol at the end of synthesis starting from 22–24 GBq of [18F]fluoride. For iodine‐125, the whole synthetic procedure allows producing up to 7.4 MBq of pure labelled Spiegelmers in 100 min with a specific radioactivity of 11–37 GBq/μmol starting from 37 MBq of Na[125I]I. Copyright © 2003 John Wiley & Sons, Ltd.
Synthesis of [3H] vardenafil, Levitra®, using a new labeling technique
Authors: Pleiss U. 
Published: November 2003

AbstractTritium was introduced into the new orally active, selective phosphodiesterase type V (PDE V) inhibitor vardenafil (Levitra®), by reduction of a suitable amide precursor with freshly prepared lithium aluminum tritide. A specific activity of 52.7 Ci/mmol (1.95 TBq/mmol) was achieved. In order to overcome the usual technical difficulties during the preparation of complex tritides a new and easy labeling technique which has considerable potential for various tritia‐tion procedures, was developed. Copyright © 2003 John Wiley & Sons, Ltd.
Radiosynthesis of 3‐(2′‐[18F]fluoro)‐flumazenil ([18F]FFMZ)
Authors: Wadsak Wolfgang , Mitterhauser Markus , Mien Leonhard‐Key , Tögel Stefan , Keppler Bernhard , Dudczak Robert , Kletter Kurt 
Published: November 2003

AbstractRecently, two fluorine‐18 labelled derivatives of flumazenil were described: 5‐(2′‐[18F]fluoroethyl)‐5‐desmethylflumazenil (ethyl 8‐fluoro‐5‐[18F]fluoroethyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylate; [18F]FEFMZ) and 3‐(2′‐[18F]fluoro)‐flumazenil (2′‐[18F]fluoroethyl 8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a]‐[1,4]diazepine‐3‐carbo‐ xylate; [18F]FFMZ). Since the biodistribution data of the latter were superior to those of the former we developed a synthetic approach for [18F]FFMZ starting from a commercially available precursor, thereby obviating the need to prepare a precursor by ourselves. The following two‐step procedure was developed:First, [18F]fluoride was reacted with 2‐bromoethyl triflate using the kryptofix/acetonitrile method to yield 2‐bromo‐[18F]fluoroethane ([18F]BFE). In the second step, distilled [18F]BFE was reacted with the tetrabutylammonium salt of 3‐desethylflumazenil (8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylic acid) to yield [18F]FFMZ. The synthesis of [18F]FFMZ allows for the production of up to 7 GBq of this PET‐tracer, enough to serve several patients. [18F]FFMZ synthesis was completed in less than 80 min and the radiochemical purity exceeded 98%. Copyright © 2003 John Wiley & Sons, Ltd.
Measurement of single‐kidney glomerular filtration rate using a contrast‐enhanced dynamic gradient‐echo sequence and the Rutland‐Patlak plot technique
Authors: Hackstein Nils , Heckrodt Jan , Rau Wigbert S. 
Published: November 2003

AbstractPurposeTo determine the accuracy of single‐kidney glomerular filtration rate (GFR) determination using contrast‐enhanced dynamic magnetic resonance imaging (MRI) and the Rutland‐Patlak plot technique.Materials and MethodsTwenty‐eight adult patients were included. As reference method, the GFR was measured by plasma clearance using a small bolus injection of iopromide. A three‐dimensional gradient‐echo (GRE) sequence with a flip angle of 50° was used for MRI; this showed a good linear relationship between gadolinium (Gd)‐DTPA concentration and signal change when measured up to a Gd‐DTPA concentration of 10 mmol/liter. A slab containing both kidneys and the abdominal aorta was measured 30 times in approximately 3.5 minutes. During this measurement, 15 mL of Gd‐DTPA, 0.5 mol/liter diluted to a volume of 60 mL, was injected over 60 seconds. A Rutland‐Patlak plot was calculated from the signal changes in the aorta and the renal parenchyma. Single‐kidney GFR was calculated for different time windows from the Rutland‐Patlak plot slope.ResultsThe best correlation compared to the reference method was found with the GFR calculated from the slope of the Rutland‐Patlak plot 40–110 seconds postaortic rise. Pearson's correlation coefficient was r = 0.86, SD was 14.8 mL/minute. In many of the patients, a decrease of the renal signal was observed in the excretory phase, which was probably caused by very high Gd‐DTPA concentrations in the collecting tubules.ConclusionSingle‐kidney GFR can be calculated from dynamic contrast‐enhanced MRI. We found a promising correlation of global GFR calculated by MRI compared to the reference method. In any future study, the amount of Gd‐DTPA should by reduced to avoid artificial signal drop in the excretory phase induced by the T2* effect. J. Magn. Reson. Imaging 2003;18:714–725. © 2003 Wiley‐Liss, Inc.
Multislice T1 relaxation time measurements in the brain using IR‐EPI: Reproducibility, normal values, and histogram analysis in patients with multiple sclerosis
Authors: van Walderveen Marianne A.A. , van Schijndel Ronald A. , Pouwels Petra J.W. , Polman Chris H. , Barkhof Frederik 
Published: November 2003

AbstractPurposeTo perform T1 measurements using inversion recovery (IR) echoplanar imaging (EPI) to evaluate reproducibility, normal values, and T1 histogram analysis as a measure of disease progression in multiple sclerosis (MS) patients.Materials and MethodsMultislice IR‐EPI was performed in 10 controls and 36 MS patients. Region‐of‐interest (ROI) and T1 histogram analysis were performed on T1 maps and compared to hypointense T1 lesions and brain atrophy in MS patients.ResultsCoefficient of variation (COV) varied from 1.6% to 4.9%. Callosal normal (appearing) white matter (N(A)WM) showed the lowest and cortical gray matter the highest T1 values. T1 histogram analysis in controls showed a sharp WM peak centered on a T1 value of 729 msec (range = 679–765) with extension into a shoulder of higher T1 values. In MS patients, a shift toward higher T1 values (mean = 788 msec, range = 700–957) with a lower relative peak amplitude was present, predominantly resulting from T1 prolongation in NAWM. T1 histogram parameters strongly related to hypointense T1 lesion volume and brain atrophy in MS patients.ConclusionsIR‐EPI provides a reproducible method to obtain T1 values in the brain. Regional variation in T1 values is present in N(A)WM of volunteers and MS patients. Since T1 histogram parameters reflect changes in NAWM and correlate with conventional measures of disease burden in MS patients, T1 histogram analysis may provide a global measure of disease progression in MS. J. Magn. Reson. Imaging 2003;18:656–664. © 2003 Wiley‐Liss, Inc.
DTI‐based three‐dimensional tractography detects differences in the pyramidal tracts of infants and children with congenital hemiparesis
Authors: Glenn Orit A. , Henry Roland G. , Berman Jeffrey I. , Chang Patrick C. , Miller Steven P. , Vigneron Daniel B. , Barkovich A. James 
Published: November 2003

AbstractPurposeTo test the hypothesis that there is greater asymmetry in diffusion properties between right and left pyramidal tracts in patients with congenital hemiparesis than in patients with normal motor function.Materials and MethodsFour congenitally hemiparetic patients and four age‐matched controls underwent magnetic resonance diffusion tensor imaging (DTI)‐based three‐dimensional tractography of the pyramidal tracts. Relative anisotropy, individual eigenvalues, and directionally averaged apparent diffusion coefficient were measured and degree of asymmetry was calculated.ResultsCompared with age‐matched controls, congenitally hemiparetic patients had greater asymmetry in all measured diffusion properties. The asymmetry was characterized primarily by lower anisotropy, lower parallel diffusion, higher transverse diffusion, and slightly higher mean diffusivity in the pyramidal tract contralateral to the hemiparesis (i.e., affected pyramidal tract) compared with the unaffected pyramidal tract.ConclusionsThere appears to be greater diffusion asymmetry between the pyramidal tracts in congenitally hemiparetic patients compared to controls. These differences suggest that there are alterations in the microstructure of the pyramidal tract that controls the motor function of the hemiparetic side. Our results suggest that DTI‐based three‐dimensional tractography is potentially useful in the assessment of motor dysfunction in infants and children with congenital hemiparesis. J. Magn. Reson. Imaging 2003;18:641–648. © 2003 Wiley‐Liss, Inc.