bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for the recognition of non‐nucleotide antagonists within the transmembrane domains of the human P2Y1 receptor
Authors: Guo Danping , Kügelgen Ivar von , Moro Stefano , Kim Yong‐Chul , Jacobson Kenneth A. 
Published: January 2003

AbstractSite‐directed mutagenesis was used to search for amino acid residues of the human P2Y1 receptor involved in the binding of the P2 receptor antagonists pyridoxal‐5′‐phosphate‐6‐azophenyl‐2,4‐disulfonate (PPADS), its analogue 6‐(2′‐chloro‐phenylazo)‐pyridoxal‐α5‐phosphate (MRS 2210), the suramin analogue 8‐8′‐[carbonylbis(imino‐3,1‐phenylene)]bis(1,3,5‐naphthalene‐trisulfonate) (NF023), and Reactive blue 2. Receptors containing single amino acid replacements at positions in transmembrane helical domains (TMs) 3, 5, 6, and 7 critical for the activation of the receptor by nucleotide agonists were expressed in COS‐7 (African green monkey kidney) cells. Inositol phosphate accumulation was induced by 2‐methylthioadenosine 5′‐diphosphate (2‐MeSADP). In wild type human P2Y1 receptors, PPADS (10 to 60 µM), MRS 2210 (10 µM), NF023 (100 µM), and Reactive blue 2 (10 µM) shifted the concentration‐response curve of 2‐MeSADP in a parallel manner to the right. For PPADS, a pA2 value of 5.2 was estimated. The shifts caused by MRS 2210, NF023, and Reactive blue 2 corresponded to apparent pKB values of 5.6, 5.0, and 5.8, respectively. In K280A mutant receptors, the affinities of PPADS, MRS 2210, NF023, and Reactive blue 2 were about 6‐ to 60‐fold lower than those observed at wild type receptors. The K280A mutation also caused an approximately 1,000‐fold increase in the EC50 value of the agonist 2‐MeSADP, similar to previous observations. In contrast, no major change in antagonistic potency was observed at receptors with other mutations in TMs 3, 5, 6, and 7. Thus, the residue Lys280 (6.55), which is located within the upper third of TM 6 of the human P2Y1 receptor, is not only critical for the activation of the receptor but also plays an important role in the binding of pyridoxal derivatives and a number of other chemically unrelated P2 receptor antagonists. Lys280 seems to belong to an overlapping region of the respective binding sites. Drug Dev. Res. 57:173–181, 2002. Published 2003 Wiley‐Liss, Inc.
Suppression of experimental zymosan‐induced arthritis by intraperitoneal administration of adenosine
Authors: Baharav Ehud , Dubrosin Anatoly , Fishman Pnina , Bar‐Yehuda Sara , Halpren Marisa , Weinberger Abraham 
Published: January 2003

AbstractThe anti‐inflammatory effect of methotrexate (MTX) is mediated by the increasing extracellular concentration of adenosine. The response of the immune system to activation of cell membrane subclass receptors for adenosine initiates intracellular signaling pathways, which causes immunomodulatory responses. To test the direct immunomodulatory effects of systemic administration of adenosine on animal model of inflammation, zymosan induced arthritis (ZIA) in mice was employed. Sterile zymosan (30 µg) was injected directly into the knee cleft of 60 mice, divided into 3 equal groups. The experimental groups received, every second day, 0, 0.25, and 0.5 mg/kg adenosine intraperitoneally. Inflammatory intensity was evaluated clinically by knee swelling measurement, histology, the total white blood cell (WBC) count, and serum tumor necrosis factor‐alpha (TNF‐α) levels served as markers of systemic inflammatory reaction. As observed, only the mice that received the higher dose of 0.5 mg/kg adenosine developed a significantly milder arthritis. A 23.9% reduction (P < 0.004) of the mean knee diameter swelling was noted. The histological inflammatory parameters and WBC count in the 0.5 mg/kg adenosine‐treated mice were also decreased (6,555 ± 510/mm3 vs. 9,250 ± 530 WBC/mm3 in the untreated mice, P > 0.006; 9,188 ± 588 WBC/mm3 in the 0.25 mg/kg adenosine‐treated group). Serum TNF‐α levels were significantly reduced (78.1 pg/ml in the 0.5 mg/kg adenosine‐treated group vs. 124.3 pg/ml, in the control group, P < 0.004). The data indicate a remarkable clinical beneficial effect, as well as a local and systemic anti‐inflammatory response that was noted on administration of 0.5 mg/kg adenosine every alternate day to mice with inflammatory arthritis. Drug Dev. Res. 57:182–186, 2002. © 2003 Wiley‐Liss, Inc.
Age‐related susceptibility to brain ischemia in mice
Authors: Fuentes‐Vargas Monica , Santiago‐Mejia Jacinto , Pinzon Enrique , Rodriguez Rodolfo 
Published: January 2003

AbstractIn this study, we evaluated the effect of age on survival and on neurological alterations produced by bilateral sequential common carotid artery (CCA) sectioning in mice. Male mice, 3–4 (young), 20–30 (adult), and 40–60 (aged) weeks old, underwent sequential CCA sectioning at an interval of 32 days. After the second surgery, mortality was registered continuously over a period of 24 h and thereafter every 24 h up to 3 days. Neurological assessment was performed 24 h after the second surgery. The influence of age on survival was analyzed using a log‐rank test, and survival curves were generated by the Kaplan‐Meier method. In mice with previous left CCA sectioning, sectioning of the contralateral artery induced a wide range of neurological alterations and a high mortality rate. Young and aged animals had a significantly lower (P < 0.05) survival rate as compared to adults (3, 6, 9, and 12 h after the second surgery), thus confirming that young and aged animals are, in fact, less resistant to brain ischemia. In contrast, the percentage of mice showing severe neurological alterations increased with age. This observation coincides with clinical evidence showing that elderly tend to have a worse outcome than younger patients do. These findings indicate that, besides morphological changes, studies of influence of age on the susceptibility to brain ischemia should include mortality and functional endpoints. Drug Dev. Res. 57:161–166, 2002. © 2003 Wiley‐Liss, Inc.
Effects of ReN1869, a CNS‐available antihistamine, on capsaicin‐ and histamine‐induced neurogenic inflammation in healthy subjects
Authors: Thomsen Mikael S. , Hansen Anker J. , Olsen Uffe B. , Reeh Peter , Ingwersen Steen , Schaffler Klaus , Seibel Klaus 
Published: January 2003

AbstractReN1869 (elsewhere referred to as NNC 05‐1869) is a new tricyclic compound which is chemically related to amitriptyline, but is without any significant interaction with other receptors except for the histamine H1‐receptor, where it functions as an antagonist. The compound exhibits antinociceptive effects in rodent models of chronic pain and is effective against inflammation of neurogenic origin. The present trial was designed to assess the effect of a single dose of ReN1869 in humans on neurogenic inflammation induced by capsaicin and histamine and on the concomitant itch and pain sensation. Twenty‐four healthy male subjects were enrolled in this randomized, double‐blind, two‐period, crossover trial consisting of a single oral dose of 95 mg ReN1869 and matching placebo. Thirty minutes after dosing the participants received, in a randomized order, either histamine (on the skin of the palmar forearm, prick test) before capsaicin (on the skin of the back) in both trial periods and capsaicin before histamine in both periods. Several pharmacodynamic tests were performed after the capsaicin/histamine application: laser somatosensory‐evoked potentials (Laser‐SEP), sensory and pain threshold to laser stimuli of increasing intensity, planimetry of areas of wheal and flare, pinprick hyperalgesia, brush‐evoked pain, allodynia, skin reflection spectrometry (colorimetry), and visual analog scale of itch. ReN1869 had significant effects on the histamine‐induced phenomena. No wheal could be evoked in 14/21 evaluated subjects in contrast to all placebo‐treated subjects. The area of flare was reduced by 80% and itching by 65%. The flare induced by capsaicin was only slightly (not significantly) reduced by ReN1869. However, ReN1869 strongly influenced Laser‐SEP evoked by nociceptive stimuli from the capsaicin‐treated skin area by a 25% reduction of the amplitude of the P2 component, whereas the N1 component was not affected. This observation reflects a central analgesic effect without a peripheral component. The dosing was well tolerated and no particular adverse events were related to the trial drug. Conclusively, ReN1869 represents a new class of antihistamines that has antiinflammatory properties (related to antihistaminergic effects) as well as central analgesic effects (probably mediated centrally through histamine H1 receptors). Drug Dev. Res. 57:193–199, 2002. © 2003 Wiley‐Liss, Inc.
Effects of Ginkgo biloba extract (EGb 761) on gene expression: Possible relevance to neurological disorders and age‐associated cognitive impairment
Authors: DeFeudis Francis V. 
Published: January 2003

AbstractGinkgo biloba leaf extract (EGb 761), which contains many constituents, including flavonoid glycosides and terpenoids (ginkgolides, bilobalide), is used to treat cerebrovascular and peripheral vascular insufficiency, as well as cognitive impairment and other symptoms of dementia. Recent studies have indicated that these therapeutic effects of EGb 761 probably involve modification of the expression of many genes by actions involving several of its active constituents. As examples: EGb 761 and its ginkgolide B constituent inhibit the expression of the peripheral benzodiazepine receptor in the adrenal cortex and decrease circulating levels of corticosterone in the rat, effects that provide a mechanism for explaining the “antistress” action of the extract. Both the flavonoid and terpenoid constituents of EGb 761 decrease the expression of inducible nitric oxide synthase (iNOS), supporting an action of the extract of opposing the deleterious effects of excessive formation of NO. EGb 761 upregulates several genes that encode vital antioxidant enzymes, including heme oxygenase‐1 and the regulatory and catalytic subunits of γ‐glutamyl‐cysteinyl synthetase. Dietary treatment of mice with EGb 761 upregulates the expression of genes encoding neuronal tyrosine/threonine phosphatase 1 and microtubule‐associated tau in the cerebral cortex, findings that are of interest since these proteins are associated with the intracellular neurofibrillary tangles found in the brain in Alzheimer's disease. Bilobalide upregulates two mitochondrial‐DNA‐encoded genes, subunit III of cytochrome c oxidase and subunit ND1 of NADH dehydrogenase, indicating a fundamental mechanism that may underlie EGb 761‐induced neuroprotection. Collectively, such results indicate that the therapeutic effects of EGb 761 on cognitive impairment (dementia) may involve its action of altering gene expression. Drug Dev. Res. 57:214–235, 2002. 2003 Wiley‐Liss, Inc.
Development of CDD‐0102 as a selective M1 agonist for the treatment of Alzheimer's disease
Authors: Messer William S. , Bachmann Kenneth A. , Dockery Colleen , El‐Assadi Afif A. , Hassoun Ezdihar , Haupt Nicola , Tang Bin , Li Xuemei 
Published: January 2003

AbstractSelective muscarinic agonists might be useful in the treatment of Alzheimer's disease. To help characterize the activity and functional selectivity of two M1 muscarinic agonists, secretion of amyloid precursor protein, brain penetration, side effect profiles, cognition‐enhancing properties, oral bioavailability, and acute toxicity were evaluated. CDD‐0102 stimulated the secretion of APP from CHO‐K1 cells expressing M1 receptors and penetrated into the brain following i.p. administration in rodents. CDD‐0102 produced relatively few cholinergic side effects (e.g., diarrhea, salivation) following i.p. administration in mice. The effects of muscarinic agonists on memory function were examined following bilateral injections of 192 IgG‐saporin into the diagonal band of rats to lesion basal forebrain cholinergic pathways. 192 IgG‐saporin produced decreases in cortical and hippocampal choline acetyltransferase activity and impaired performance of a paired‐run, delayed‐alternation task in a T‐maze relative to vehicle‐injected controls. Toxin‐treated rats performed significantly better following i.p. injections (1 mg/kg) of either xanomeline or CDD‐0102 as compared with saline. Prominent cholinergic side effects (e.g., diarrhea) were apparent only following xanomeline treatments. In separate studies, oral administration of CDD‐0102 (10 mg/kg) reversed the memory deficits induced by 192 IgG‐saporin in the T‐maze task. Rats achieved 54 ± 4.2% correct choices with saline, but 94 ± 1.2% following CDD‐0102 injection. In acute toxicity studies in mice, the LD50 of CDD‐0102 was greater than 1,000 mg/kg orally; 190 mg/kg i.p. The LD50 of xanomeline was 100 mg/kg p.o. and 75 mg/kg i.p. In summary, both xanomeline and CDD‐0102 displayed beneficial effects on memory function, while CDD‐0102 also exhibited a low side effect profile and low toxicity. CDD‐0102 warrants further evaluation as a therapeutic agent for the treatment of Alzheimer's disease. Drug Dev. Res. 57:200–213, 2002. © 2003 Wiley‐Liss, Inc.
Monitoring dyslexics' intelligence and attainments: A follow‐up study
Authors: Thomson Michael 
Published: January 2003

AbstractIntelligence (Wechsler Intelligence Scale for Children R and III, 1992) and written language attainment (BAS Word Reading, Neale Analysis of Reading, Vernon Graded Word Spelling) data for around 250 children attending a specialist school for dyslexics are presented. The Wechsler scales data show some evidence for ‘ACID’ and ‘SCAD’ profile effects on the subtests, with specifically weak Index scores on Freedom from Distractibility and Processing Speed. The relationship between intelligence and reading development is also examined, with evidence for significant correlations between intelligence and written language and a longitudinal study showing that there is no ‘Matthew’ or drop‐off effect in intelligence. The attainments tests demonstrate that the widening gap between a dyslexic's chronological age and his/her attainments can be closed, and how attainments may be monitored within the context of ‘growth curves’. The results are discussed in relation to recent reports (e.g. B.P.S. on Dyslexia, Literacy and Psychological Assessment) on the relationship between intelligence and attainments and it is concluded that this report could be seriously misleading for practising educational psychologists. Copyright © 2003 John Wiley & Sons, Ltd.
Age‐related improvements in auditory temporal resolution in reading‐impaired children
Authors: Hautus Michael J. , Setchell Gregory J. , Waldie Karen E. , Kirk Ian J. 
Published: January 2003

AbstractIndividuals with developmental dyslexia show impairments in processing that require precise timing of sensory events. Here, we show that in a test of auditory temporal acuity (a gap‐detection task) children ages 6–9 years with dyslexia exhibited a significant deficit relative to age‐matched controls. In contrast, this deficit was not observed in groups of older reading‐impaired individuals (ages 10–11 years; 12–13 years) or in adults (ages 23–25 years). It appears, therefore, that early temporal resolution deficits in those with reading impairments may significantly ameliorate over time. However, the occurrence of an early deficit in temporal acuity may be antecedent to other language‐related perceptual problems (particularly those related to phonological processing) that persist after the primary deficit has resolved. This result suggests that if remedial interventions targeted at temporal resolution deficits are to be effective, the early detection of the deficit and early application of the remedial programme is especially critical. Copyright © 2003 John Wiley & Sons, Ltd.
Evaluation of an exercise‐based treatment for children with reading difficulties
Authors: Reynolds David , Nicolson Roderick I. , Hambly Helen 
Published: January 2003

AbstractAn evaluation is reported of an exercise‐based approach to remediation of dyslexia‐related disorders. Pupils in three years of a Warwickshire junior school were screened for risk of literacy difficulty using the Dyslexia Screening Test (DST). The 35 children scoring 0.4 or over on the DST were divided randomly into two groups matched for age and DST score. One quarter of the participants had an existing diagnosis of dyslexia, dyspraxia or ADHD. Both groups received the same treatment at school but the intervention group used the DDAT exercise programme daily at home. Performance on the DST and specialist cerebellar/vestibular and eye movement tests were assessed initially and after six months. Cerebellar/vestibular signs were substantially alleviated following the exercise treatment whereas there were no significant changes for the control group. Even after allowing for the passage of time, there were significant improvements for the intervention group in postural stability, dexterity, phonological skill, and (one‐tailed) for naming fluency and semantic fluency. Reading fluency showed a highly significant improvement for the intervention group, and nonsense passage reading was also improved significantly. Significantly greater improvements for the intervention group than the control group occurred for dexterity, reading, verbal fluency and semantic fluency. Substantial and significant improvements (compared with those in the previous year) also occurred for the exercise group on national standardized tests of reading, writing and comprehension. It is concluded that, in addition to its direct effects on balance, dexterity and eye movement control, the benefits of the DDAT exercise treatment transferred significantly to cognitive skills underlying literacy, to the reading process, and to standardized national literacy attainment tests. Copyright © 2003 John Wiley & Sons, Ltd.
Long‐time constants of irregular AC losses in a large superconducting coil
Authors: Hamajima Takataro , Yoshida Motonobu , Shimamura Hiroshi , Harada Naokara , Tsuda Masa , Takahata Kazuya , Satow Takashi 
Published: January 2003

AbstractA large superconducting coil wound with a Cable‐in‐Conduit (CIC) conductor caused an additional AC loss, which cannot be estimated from the short conductor sample test results. It was confirmed that the additional AC loss was generated by long current loops in the CIC conductor. Magnetic field decays of the loops with various long‐time constants were observed through Hall probes. We propose a mechanism for the formation of the long loops. The CIC conductor is composed of several staged subcables. If one strand on the surface of a subcable contacts the other strand on the surface of the adjacent subcable, the two strands must encounter each other again at the LCM (Least Common Multiplier) distance of all staged cable pitches and thereby form a pair of long loops. We numerically traced each strand in the CIC according to a method in which the subcables at all substages rotate around the center of inertia. The calculated long‐time constants of the long loops were slightly shorter than the observed ones. We labeled all strands by order in a real CIC conductor, disassembling the cable carefully after peeling the conduit. It was found that the strands in a triplex were widely displaced from their original positions, so that their contacting lengths became longer than the calculated ones. This fact makes the time constant of the loop longer and hence can explain the observed long‐time constants. The proposed mechanism is effective for estimating the long loops causing additional AC losses in the coil. © 2003 Wiley Periodicals, Inc. Electr Eng Jpn, 143(1): 50–57, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.10064
A speed control method for a PM motor using a speed observer and a low‐resolution encoder
Authors: Ohishi Kiyoshi , Ogawa Yasuaki , Dohmaki Hideo 
Published: January 2003

AbstractThis paper proposes a new speed control method for a PM motor using a low‐resolution encoder and a speed observer. The servo system should be economical and simple. For this purpose, this paper realizes the high‐performance speed control system using a low‐resolution encoder, whose performance is nearly equal to the performance of speed servo system using a conventional optical encoder. The speed observer uses the information of motor current and motor voltage. The rotor position is calculated by the estimated value of speed observer. This observer has the influence of electrical parameter variation. This paper proposes the correction algorithm of both the voltage error of PWM inverter and the electrical parameter variation. The experimental results and numerical simulation results point out that the proposed speed control system has the desired speed response with respect to parameter variations and load torque perturbation. © 2003 Wiley Periodicals, Inc. Electr Eng Jpn, 143(1): 66–75, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.10121
Analysis of TOF transient currents affected by circuit time constants
Authors: Kikuchi Yoshiaki , Wakamatsu Takashi , Takahashi Hideaki , Endo Isao 
Published: January 2003

AbstractTime‐of‐flight (TOF) transient currents affected by circuit time constants of RC at the measurements are calculated. The one‐dimensional carrier distributions by diffusion and drift transport are used in the calculations, and the strong drift and weak drift transport induces the typical TOF currents, the nondispersive and the dispersive types, respectively. For these waveforms, it is examined whether we should choose the current or the voltage measurements from RC and the observation time scale. The simulation results here pointed out that in the case of either TOF type, the TOF current method required the setting of RC value less than 1/100 of the transit time Tr, and that the voltage method required RC be more than 100 times Tr and in addition at the voltage measurements the circuit time constants have no influence on the TOF waveforms in the initial time. © 2003 Wiley Periodicals, Inc. Electr Eng Jpn, 143(1): 1–7, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.10139
Influence of common XPD and XRCC1 variant alleles on p53 mutations in lung tumors
Authors: Hou Sai‐Mei , Ryk Charlotta , Kannio Annamaria , Angelini Sabrina , Fält Susann , Nyberg Fredrik , Husgafvel‐Pursiainen Kirsti 
Published: January 2003

AbstractThe DNA repair proteins XPD and XRCC1 are involved in the nucleotide and base excision repair of DNA lesions induced by many tobacco and environmental carcinogens. Common variant alleles at the XPD (312Asn, 751Gln) and XRCC1 (399Gln) loci have been identified and associated with increased risk for lung cancer. We therefore investigated a possible effect of these variant alleles on the frequency and spectrum of p53 mutations in the tumors of 97 Swedish lung cancer patients (56 never‐smokers and 41 age‐, gender‐, and hospital‐matched ever‐smokers). The p53 gene was mutated in 4 never‐smokers (7%) and 11 ever‐smokers (27%). Smoking‐related transversion‐type mutations predominated over transitions among smokers (8:3), but not among never‐smokers (1:3). None of the variant alleles altered the overall frequency of p53 mutation. Transversions, however, were marginally increased among patients with at least one XPD variant allele compared with patients who were wild‐type homozygotes (73% vs. 25% for the Asp312Asn polymorphism, P = 0.095; 78% vs. 33% for Lys751Gln, P = 0.085). Five of six women or six of seven smokers who carried at least one XPD 751Gln allele had p53 transversion. The XRCC1 variant allele did not show any effect on the p53 mutation. We conclude that the XPD variant alleles may be associated with an increased frequency of smoking‐related p53 mutations in lung tumors, presumably due to reduced DNA repair proficiency. Environ. Mol. Mutagen. 41:37–42, 2003. © 2003 Wiley‐Liss, Inc.