bluuebunny/crossref_metadata_2025_split huggingface dataset:
Testing for Dual Brain Processing Routes in Reading: A Direct Contrast of Chinese Character and Pinyin Reading Using fMRI
Authors: Chen Yiping , Fu Shimin , Iversen Susan D. , Smith Steve M. , Matthews Paul M. 
Published: October 2002

Abstract
Chinese offers a unique tool for testing the effects of word form on language processing during reading. The processes of letter-mediated grapheme-to-phoneme translation and phonemic assembly (assembled phonology) critical for reading and spelling in any alphabetic orthography are largely absent when reading nonalphabetic Chinese characters. In contrast, script-to-sound translation based on the script as a whole (addressed phonology) is absent when reading the Chinese alphabetic sound symbols known as pinyin, for which the script-to-sound translation is based exclusively on assembled phonology. The present study aims to contrast patterns of brain activity associated with the different cognitive mechanisms needed for reading the two scripts. fMRI was used with a block design involving a phonological and lexical task in which subjects were asked to decide whether visually presented, paired Chinese characters or pinyin “sounded like” a word. Results demonstrate that reading Chinese characters and pinyin activate a common brain network including the inferior frontal, middle, and inferior temporal gyri, the inferior and superior parietal lobules, and the extrastriate areas. However, some regions show relatively greater activation for either pinyin or Chinese reading. Reading pinyin led to a greater activation in the inferior parietal cortex bilaterally, the precuneus, and the anterior middle temporal gyrus. In contrast, activation in the left fusiform gyrus, the bilateral cuneus, the posterior middle temporal, the right inferior frontal gyrus, and the bilateral superior frontal gyrus were greater for nonalphabetic Chinese reading. We conclude that both alphabetic and nonalphabetic scripts activate a common brain network for reading. Overall, there are no differences in terms of hemispheric specialization between alphabetic and nonalphabetic scripts. However, differences in language surface form appear to determine relative activation in other regions. Some of these regions (e.g., the inferior parietal cortex for pinyin and fusiform gyrus for Chinese characters) are candidate regions for specialized processes associated with reading via predominantly assembled (pinyin) or addressed (Chinese character) procedures.
A survey of violent and threatening behaviours within an in-patient learning disability unit
Authors: Hakeem Az , Fitzgerald Brian 
Published: October 2002

Aims and MethodTo analyse violent and threatening behaviour occurring within an in-patient service. We surveyed recorded incidents over a 6-month period.ResultsNinety-six incidents were recorded. The patients involved were assessed as being aware of their actions. Police were contacted in five cases. No charges were pressed.Clinical ImplicationsWe believe that violence and threatening behaviours are excessively tolerated in learning disability units. Reasons for this include a staff culture of accepting offending behaviour and an unwillingness or inability to involve the police.
Effect of levothyroxine administration on intestinal P‐glycoprotein expression: Consequences for drug disposition*
Authors: Siegmund Werner , Altmannsberger Stephan , Paneitz Andrea , Hecker Ute , Zschiesche Michael , Franke Gerd , Meng Wieland , Warzok Rolf , Schroeder Eike , Sperker Bernhard , Terhaag Bernd , Cascorbi Ingolf , Kroemer Heyo K. 
Published: October 2002

ObjectiveThyroid function alters the pharmacokinetics of many drugs; one example is the cardiac glycoside digoxin. Because digoxin disposition is affected by intestinal expression of P‐glycoprotein, we hypothesized that thyroid hormones may regulate P‐glycoprotein and influence disposition of P‐glycoprotein substrates.MethodsDuodenal expression of P‐glycoprotein measured by reverse transcriptase‐polymerase chain reaction of MDR1 messenger ribonucleic acid (mRNA) and by immunohistochemical examination was studied in 8 healthy volunteers (4 men and 4 women; age range, 22‐29 years; body weight, 59–89 kg) before and after coadministration with levothyroxine (200 μg orally for 17 days), which resulted in suppression of thyroid‐stimulating hormone. The pharmacokinetics of the P‐glycoprotein substrate talinolol was assessed after intravenous (30 mg) and oral (100 mg) administration.ResultsDuodenal MDR1 mRNA expression and immunoreactive P‐glycoprotein were increased 1.4‐fold (not significant; P = .078) and 3.8‐fold (P < .01), respectively, after administration of levothyroxine. The changes in P‐glycoprotein expression were associated with minor alterations in talinolol half‐life after both oral and intravenous administration.ConclusionsExpression of intestinal P‐glycoprotein in humans appears to be influenced by thyroid hormones. The functional consequences need to be addressed in patients with hyperthyroidism.Clinical Pharmacology & Therapeutics (2002) 72, 256–264; doi: 10.1067/mcp.2002.126706
Increased genotype frequency of N‐acetyltransferase 2 slow acetylation in patients with rheumatoid arthritis
Authors: Pawlik Andrzej , Ostanek Lidia , Brzosko Iwona , Gawroska‐Szklarz Barbara , Brzosko Marek , Dąbrowska‐Żamojcin Ewa 
Published: October 2002

ObjectivesAcetylation polymorphism can alter therapeutic responses and toxicity to certain xenobiotics and may also be a factor that influences a patient's susceptibility to certain diseases. We investigated whether patients with rheumatoid arthritis (RA) differed from healthy individuals with regard to genotype of the polymorphic enzyme N‐acetyltransferase 2 (NAT2).MethodsNAT2 polymorphism was compared in 118 healthy subjects and 82 patients with RA. NAT2 alleles (*4, *5, *6, and *7) were determined by polymerase chain reaction‐restriction fragment length polymorphism methods with deoxyribonucleic acid extracted from peripheral blood.ResultsA statistically significant increase in the proportion of homozygous slow acetylators with 2 mutated alleles (84.1%) was found among patients with RA in comparison with healthy subjects (52.5%; P < .0001). The risk of development of RA was almost 5‐fold greater in slow acetylators than in fast acetylators (odds ratio, 4.79; 95% confidence interval, 2.28–10.21). There was no correlation between NAT2 polymorphism and presence of rheumatoid factor, extra‐articular manifestations, and age at first occurrence of disease symptoms.ConclusionsNAT2 slow acetylation genotype may be a risk factor of individual susceptibility to RA.Clinical Pharmacology & Therapeutics (2002) 72, 319–325; doi: 10.1067/mcp.2002.126740
Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: A focus on neuropsychiatric adverse events*
Authors: van Riemsdijk M. M. , Sturkenboom M. C. J. M. , Ditters J. M. , Ligthelm R. J. , Overbosch D. , Stricker B. H. Ch. 
Published: October 2002

ObjectivesWe performed a prospective, double‐blind, randomized study to compare the occurrence of neuropsychiatric adverse events and concentration impairment during prophylactic use of either mefloquine or atovaquone plus chloroguanide (INN, proguanil).MethodsOur potential study population consisted of all persons who were included in the MAL30010 trial at the Travel Clinic, Rotterdam, The Netherlands. All subjects were randomized to receive either active atovaquone (250 mg) plus chloroguanide (100 mg) daily plus a placebo for mefloquine weekly or active mefloquine (250 mg) weekly plus a placebo for atovaquone plus chloroguanide daily. Each subject was followed up from a baseline screening visit up to the index date, 7 days after he or she left the malaria‐endemic area. We measured the interindividual and intraindividual changes in mood disturbance by means of the Dutch shortened Profile of Mood States and 3 domains of the Neurobehavioral Evaluation System, which included sustained attention, coding speed, and visuomotor accuracy between baseline and follow‐up visit.ResultsThe cohort consisted of 119 subjects with a mean age of 35 years. A significant deterioration in depression, anger, fatigue, vigor, and total mood disturbance domains occurred during use of mefloquine but not during use of atovaquone plus chloroguanide. Stratification for sex showed between‐treatment differences in female patients but not in male patients. In both treatment groups, sustained attention deteriorated after travel, especially with increased duration of stay.ConclusionsProphylactic use of mefloquine was associated with significantly higher scores on scales for depression, anger, and fatigue and lower scores for vigor than prophylactic use of atovaquone plus chloroguanide.Clinical Pharmacology & Therapeutics (2002) 72, 294–301; doi: 10.1067/mcp.2002.127113
The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers
Authors: Sanderink Ger‐Jan , Le Liboux Aimé , Jariwala Navin , Harding Neasa , Ozoux Marie‐Laure , Shukla Umesh , Montay Guy , Boutouyrie Bruno , Miro Adelaida 
Published: October 2002

ObjectivesThe objective of this study was to compare the pharmacokinetics of the low‐molecular‐weight heparin enoxaparin in obese and nonobese volunteers, by means of two administration regimens.MethodsEnoxaparin was administered subcutaneously (1.5 mg/kg once daily for 4 days) and in a single 6‐hour infusion (1.5 mg/kg) to 24 obese volunteers and 24 age‐, sex‐, and height‐matched nonobese volunteers in a randomized, open‐label, 2‐way crossover design. Blood plasma was assessed for anti‐Xa and anti‐IIa activity and activated partial thromboplastin time.ResultsAfter subcutaneous administration, steady‐state exposure was achieved after the second dose in nonobese volunteers and after the third dose in obese volunteers. Time to maximum anti‐Xa activity was 1 hour longer in obese volunteers, but maximum anti‐Xa activity was similar in both groups. For anti‐Xa activity, exposure at steady‐state was 16% higher in obese volunteers than in nonobese volunteers (90% confidence interval, 108%‐125%). After intravenous infusion, total body clearance and volume of distribution at steady state were higher in obese volunteers than in nonobese volunteers, but when adjusted for weight, these values were about 10% lower in obese volunteers. Anti‐IIa activity after subcutaneous administration did not differ significantly between obese and nonobese volunteers. Pharmacodynamic analysis of activated partial thromboplastin time showed similar results in obese and nonobese volunteers after both intravenous and subcutaneous administration. No deaths or serious adverse events occurred during the study.ConclusionsEnoxaparin was well tolerated when administered subcutaneously or intravenously, and there appears to be no need to modify the currently recommended dose for obese volunteers.Clinical Pharmacology & Therapeutics (2002) 72, 308–318; doi: 10.1067/mcp.2002.127114
Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype
Authors: Molden Espen , Johansen Per Wiik , Bøe Grethe Helen , Bergan Stein , Christensen Hege , Rugstad Hans Erik , Rootwelt Helge , Reubsaet Leon , Lehne Gustav 
Published: October 2002

ObjectivesRecently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O‐demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes.MethodsNorwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting‐curve analysis of allele‐specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction‐amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6‐metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography‐mass spectrometry.ResultsThe pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N‐demethyldesacetyl diltiazem was ≥5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P < .01).ConclusionsCYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N‐demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.Clinical Pharmacology & Therapeutics (2002) 72, 333–342; doi: 10.1067/mcp.2002.127396
Cytochrome P450 2E1 and 3A activities do not differ between Mexicans and European Americans*
Authors: Poland Russell A. , Lin Keh‐Ming , Nuccio Cenci , Wilkinson Grant R. 
Published: October 2002

ObjectivesPopulation differences in the activity of various cytochrome P450 (CYP) enzymes have been demonstrated on the basis of either genetic or environmental determinants. Hispanics are a large demographic group both worldwide and within the United States; hence the possibility of differences in metabolism between one such group—Mexicans—and a European‐derived population was determined with respect to CYP2E1 and CYP3A.MethodsYoung healthy Mexican immigrants living in Los Angeles, Calif, who had maintained a traditional diet were compared with previously and identically studied groups of age‐, sex‐, and weight‐matched European Americans who resided in middle Tennessee and ate a “western” diet (15 men and 15 women). In one study carried out in 15 women, the disposition of chlorzoxazone after an oral dose (250 mg) was compared. In the other investigation, all of the 15 subjects were men and received intravenous [15N3]‐labeled midazolam (1 mg) and oral midazolam (2 mg) simultaneously to characterize the disposition of benzodiazepine in the two populations.ResultsPlasma concentration‐time profiles of chlorzoxazone and its 6‐hydroxy metabolite and the 0‐ to 24‐hour urinary recovery of the latter were not different between Mexicans and European Americans. This indicates that CYP2E1 activity is similar in the two populations. Similarly, no significant intergroup differences were noted in the plasma concentration‐time profiles of midazolam after either intravenous or oral administration. Accordingly, CYP3A does not appear to be different between Mexicans and European Americans.ConclusionsSimilarity in the metabolism of chlorzoxazone between Mexicans and European Americans suggests that the risk associated with CYP2E1‐mediated activation of procarcinogens is not different between these two populations. Likewise, the absence of any difference in the disposition of midazolam indicates that, from a pharmacokinetic standpoint, dosages of drugs metabolized by CYP3A need not be different between Mexicans and European Americans.Clinical Pharmacology & Therapeutics (2002) 72, 288–293; doi: 10.1067/mcp.2002.127398
Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes
Authors: Niemi Mikko , Cascorbi Ingolf , Timm Ramona , Kroemer Heyo K. , Neuvonen Pertti J. , Kivistö Kari T. 
Published: October 2002

ObjectivesOur objective was to investigate the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 on the pharmacokinetics of glyburide (INN, glibenclamide) and glimepiride, two widely used sulfonylurea antidiabetic drugs.MethodsWe conducted CYP2C9 genotyping for 29 healthy volunteers who had participated in our previous pharmacokinetic studies on glyburide or glimepiride.ResultsThere were 17 subjects (59%) with the CYP2C9*1/*1 (wild‐type) genotype, 8 (28%) with the CYP2C9*1/*2 genotype, 3 (10%) with the CYP2C9*1/*3 genotype, and 1 (3%) with the CYP2C9*2/*3 genotype. The pharmacokinetics of glyburide or glimepiride were not significantly changed among subjects with the CYP2C9*1/*2 genotype. However, in individuals heterozygous for the CYP2C9*3 allele, the median total area under the plasma concentration‐time curve of glyburide (n = 2) was 280% (P ≤ .05) and that of glimepiride (n = 3) was 267% (P ≤ .01) of the respective values in subjects with the CYP2C9*1/*1 genotype (n = 5 and n = 12, respectively). Blood glucose responses to glyburide and glimepiride were not significantly affected by the CYP2C9 genotype.ConclusionsGenetic polymorphisms of CYP2C9 markedly affect the pharmacokinetics of both glyburide and glimepiride. The influence of the CYP2C9*3 variant allele on glyburide and glimepiride pharmacokinetics may be clinically significant.Clinical Pharmacology & Therapeutics (2002) 72, 326–332; doi: 10.1067/mcp.2002.127495
Evaluation of potential losartan‐phenytoin drug interactions in healthy volunteers*
Authors: Fischer Tracy L. , Pieper John A. , Graff Donald W. , Rodgers Jo E. , Fischer Jeffrey D. , Parnell Kimberly J. , Goldstein Joyce A. , Greenwood Robert , Patterson J. Herbert 
Published: October 2002

BackgroundPhenytoin, a cytochrome P450 (CYP) 2C9 substrate, has a narrow therapeutic index and nonlinear pharmacokinetics. Therefore there is the potential for significant concentration‐related adverse effects when phenytoin is coadministered with other CYP2C9 substrates. Losartan, an antihypertensive agent, is also a substrate for CYP2C9.ObjectiveOur objective was to assess the effects of losartan on the pharmacokinetics of phenytoin and the effects of phenytoin on the pharmacokinetics of losartan in a healthy population of volunteers.MethodsA prospective, randomized, 3‐period crossover study was conducted in 16 healthy volunteers with phenytoin alone, phenytoin in combination with losartan, and losartan alone. Each treatment was given for 10 days with a 3‐week washout period between treatments. On day 10, plasma concentrations of phenytoin and plasma and urine concentrations of losartan and its active carboxylic‐acid metabolite E3174 were measured to determine steady‐state pharmacokinetic parameters.ResultsCoadministration of losartan had no effect on the pharmacokinetics of phenytoin. Coadministration of phenytoin increased the mean area under the concentration‐time curve from time zero to 24 hours [AUC(0–24)] of losartan by 17% (355 ± 220 ng · h/mL versus 427 ± 177 ng · h/mL; P = .1), but this difference was not statistically significant. In the 14 CYP2C9*1/*1 subjects, the mean AUC(0–24) of losartan was increased by 29% (284 ± 84 ng · h/mL versus 402 ± 128 ng · h/mL; P = .008). Coadministration of phenytoin significantly reduced the AUC(0–24) of E3174 by 63% (1254 ± 256 ng · h/mL versus 466 ± 174 ng · h/mL; P = .0001) and the formation clearance of losartan to E3174 (1.91 ± 0.8 mL/h per kilogram versus 0.62 ± 0.4 mL/h per kilogram; P = .0001).ConclusionsLosartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9‐mediated conversion of losartan to E3174.Clinical Pharmacology & Therapeutics (2002) 72, 238–246; doi: 10.1067/mcp.2002.127945
Nucleic Acid-Independent Retrovirus Assembly Can Be Driven by Dimerization
Authors: Johnson Marc C. , Scobie Heather M. , Ma Yu May , Vogt Volker M. 
Published: October 2002

ABSTRACT

The Gag protein of retroviruses alone can polymerize into regular virus-like particles (VLPs) both in vitro and in vivo. In most circumstances the capsid (CA) and nucleocapsid (NC) domains of Gag as well as some form of nucleic acid are required for this process. The mechanism by which NC-nucleic acid interaction promotes assembly has remained obscure. We show here that while deletion of the NC domain of Rous sarcoma virus Gag abolishes formation and budding of VLPs at the plasma membranes of baculovirus-infected insect cells
,
replacement of NC with a dimer-forming leucine zipper domain restores budding of spherical particles morphologically similar to wild-type VLPs. The positioning of the dimerization domain appears to be critical for proper assembly, as the insertion of a 5-amino-acid flexible linker upstream of the zipper domain leads to budding of tubular rather than spherical particles. Similar tubular particles are formed when the same linker is inserted upstream of NC. The tubes are morphologically distinct from tubes formed when the p10 domain upstream of CA is deleted. The fact that a foreign dimerization domain can functionally mimic NC suggests that the role of nucleic acid in retroviral assembly is not to serve as a scaffold but rather to promote the formation of Gag dimers, which are critical intermediates in the polymerization of the Gag shell.
Disruption of Epstein-Barr Virus Latency in the Absence of Phosphorylation of ZEBRA by Protein Kinase C
Authors: El-Guindy Ayman S. , Heston Lee , Endo Yoshimi , Cho Myung-Sam , Miller George 
Published: October 2002

ABSTRACTZEBRA protein converts Epstein-Barr virus (EBV) infection from the latent to the lytic state. The ability of ZEBRA to activate this switch is strictly dependent on the presence of serine or threonine at residue 186 of the protein (A. Francis, T. Ragoczy, L. Gradoville, A. El-Guindy, and G. Miller, J. Virol. 72:4543-4551, 1999). We investigated whether phosphorylation of ZEBRA protein at this site by a serine-threonine protein kinase was required for activation of an early lytic cycle viral gene, BMRF1, as a marker of disruption of latency. Previous studies suggested that phosphorylation of ZEBRA at S186 by protein kinase C (PKC) activated the protein (M. Baumann, H. Mischak, S. Dammeier, W. Kolch, O. Gires, D. Pich, R. Zeidler, H. J. Delecluse, and W. Hammerschmidt, J. Virol 72:8105-8114, 1998). Two residues of ZEBRA, T159 and S186, which fit the consensus for phosphorylation by PKC, were phosphorylated in vitro by this enzyme. Several isoforms of PKC (α, β1, β2, γ, δ, and ε) phosphorylated ZEBRA. All isoforms that phosphorylated ZEBRA in vitro were blocked by bisindolylmaleimide I, a specific inhibitor of PKC. Studies in cell culture showed that phosphorylation of T159 was not required for disruption of latency in vivo, since the T159A mutant was fully functional. Moreover, the PKC inhibitor did not block the ability of ZEBRA expressed from a transfected plasmid to activate the BMRF1 downstream gene. Of greatest importance, in vivo labeling with [32P]orthophosphate showed that the tryptic phosphopeptide maps of wild-type ZEBRA, Z(S186A), and the double mutant Z(T159A/S186A) were identical. Although ZEBRA is a potential target for PKC, in the absence of PKC agonists, ZEBRA is not constitutively phosphorylated in vivo by PKC at T159 or S186. Phosphorylation of ZEBRA by PKC is not essential for the protein to disrupt EBV latency.