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Biomedical subjects

W Yuan

Publications and source records attributed to W Yuan.

At least 55 records · Page 3Linked to original sources
PubMed2000

Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-beta involves functional cooperation with p300/CBP transcriptional coactivators.

Transforming growth factor-beta (TGF-beta) stimulation of Type I collagen gene (COL1A2) transcription involves the Smad signal transduction pathway, but the mechanisms of Smad-mediated transcriptional activation are not fully understood. We now demonstrate that the ubiquitous transcriptional coactivators p300 and CREB-binding protein (CBP) enhanced basal as well as TGF-beta- or Smad3-induced COL1A2 promoter activity, and stimulated the expression of endogenous Type I collagen. The adenoviral E1A oncoprotein abrogated stimulation of COL1A2 activity in transfected fibroblasts, and reduced the basal level of collagen gene expression. This effect was due to specific interaction of E1A with cellular p300/CBP because (a) a mutant form of E1A defective in p300 binding failed to abrogate stimulation, and (b) forced expression of p300/CBP restored the ability of TGF-beta to stimulate COL1A2 promoter activity in the presence of E1A. The effect of p300 on COL1A2 transcription appeared to be due, in part, to its intrinsic acetyltransferase activity, as stimulation induced by a histone acetyltransferase-deficient mutant p300 was substantially reduced. Transactivation of COL1A2 by p300 involved the Smad signaling pathway, as Smad4-deficient cells failed to respond to p300, and stimulation was rescued by overexpression of Smad4. Furthermore, minimal constructs containing only the Smad-binding CAGACA element of COL1A2 were transactivated by p300 in the presence of TGF-beta. These results indicate, for the first time, that the multifunctional p300/CBP coactivators play a major role in Smad-dependent TGF-beta stimulation of collagen gene expression in fibroblasts. Oncogene (2000) 19, 3546 - 3555

Adenovirus E1A Proteins↗
PubMed2000

Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group.

BACKGROUND: Galantamine is a reversible, competitive cholinesterase inhibitor that also allosterically modulates nicotinic acetylcholine receptors. These mechanisms of action provided the rationale for a therapeutic trial of galantamine in AD. METHODS: A 6-month, multicenter, double-blind trial was undertaken in 636 patients with mild to moderate AD. Patients were randomly assigned to placebo or galantamine and escalated to maintenance doses of 24 or 32 mg/d. Eligible patients then entered a 6-month, open-label study of the 24 mg/d dose. Primary efficacy measures were the 11-item AD Assessment Scale cognitive subscale (ADAS-cog/11) and the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). The Disability Assessment for Dementia (DAD) scale was a secondary efficacy variable. RESULTS: Galantamine significantly improved cognitive function relative to placebo; the treatment effects were 3.9 points (lower dose) and 3.8 points (higher dose) on the ADAS-cog/11 scale at month 6 (p < 0.001 in both cases). Both doses of galantamine produced a better outcome on CIBIC-plus than placebo (p < 0.05). Therapeutic response to galantamine was not affected by APOE genotype. At 12 months, mean ADAS-cog/11 and DAD scores had not significantly changed from baseline for patients who received galantamine 24 mg/d throughout the 12 months. The most common adverse events, which were predominantly gastrointestinal, decreased in frequency during long-term treatment. There was no evidence of hepatotoxicity. CONCLUSIONS: Galantamine is effective and safe in AD. At 6 months, galantamine significantly improved cognition and global function. Moreover, cognitive and daily function were maintained for 12 months with the 24 mg/d dose.

Aged↗
PubMed2000

Comparison of two single-chain antibodies that neutralize canine parvovirus: analysis of an antibody-combining site and mechanisms of neutralization.

We cloned the heavy- and light-chain variable domains of two monoclonal antibodies that recognize each of the two major neutralizing antigenic sites of the canine parvovirus (CPV) capsid. After expression in Escherichia coli as single-chain variable domains (scFv) with glycine-serine linker sequences, both scFv bound CPV capsids with the same specificity as the intact IgG, but with 10- to 20-fold lower avidity. Both scFvs neutralized CPV infectivity with efficiency similar to that of the IgG. Although both IgGs inhibited hemagglutination by CPV, only one scFv was inhibiting. The binding of one of the antibodies has previously been analyzed by cryoelectron microscopic reconstruction and the epitope-binding residues predicted. Mutagenesis of predicted contact residues in three heavy-chain complementarity-determining regions (CDR) showed that mutants of CDR1 or CDR3 reduced the binding of the scFv by about 10-fold compared with the wild-type scFv, while no effect was seen for one mutant of CDR2. The levels of neutralization of CPV and of hemagglutination inhibition by the scFv mutants were proportional to their reduction in binding affinity compared with the wild type. Neither scFv blocked virus binding to host cells, but they both caused aggregation of the capsids and appeared to affect the process of infection after virus uptake into the cells.

Amino Acid Sequence↗
PubMed2000

Intron 1 rather than 5' flanking sequence mediates cell type-specific expression of c-myb at level of transcription elongation.

Previous studies have shown that expression of steady-state c-myb mRNA was regulated primarily by a block in intron 1 during transcription elongation. This study shows that the block site maps approximately 1700 bp from the start of the intron. Studies based on a reporter construct containing c-myb flanking region and intron 1 suggest that the flanking region is not important in the regulation of the cell type-specific expression of c-myb. RNA splicing of intron 1 may enhance the expression in a non-cell type-specific manner. A conserved intron domain comprising the block site is required for defining this site, but this function of the domain is independent of cell type. The cell type-specific regulation of c-myb transcription elongation is mediated by a 5' intron sequence. A mechanism for down regulation of c-myb gene expression by the block to transcription elongation has been proposed.

3T3 Cells↗
PubMed2000

Interaction of smad3 with a proximal smad-binding element of the human alpha2(I) procollagen gene promoter required for transcriptional activation by TGF-beta.

Transcription of the alpha2(I) collagen gene (COL1A2) in fibroblasts is potently induced by transforming growth factor-beta (TGF-beta). Smad family proteins function as intracellular signal transducers for TGF-beta that convey information from the cell membrane to the nucleus. In the present study, we establish the functional requirement for endogenous Smad3 and Smad4 in TGF-beta-stimulated COL1A2 transcription in human skin fibroblasts in vitro. Furthermore, using transfections with a series of 5' deletions of the human COL1A2 promoter, we identify a proximal region between -353 and -148 bp, which is required for full stimulation of transcription by a constitutively active TGF-beta type I receptor. This region of the COL1A2 promoter contains a CAGA motif also found in the promoter of the plasminogen activator inhibitor-1. Substitutions disrupting this sequence decreased the binding of nuclear extracts or recombinant Smad3 to the CAGACA oligonucleotide, and markedly reduced the transcriptional response to TGF-beta or overexpressed Smad3 in transient transfection assays. The insertion of tandem repeats of CAGACA conferred TGF-beta stimulation to a heterologous minimal promoter-reporter construct. Inhibition of endogenous Smad expression in fibroblasts by antisense oligonucleotides or cDNA against Smad3 or Smad4, and transfection of COL1A2 promoter constructs into Smad4-deficient breast adenocarcinoma cells, indicated the critical role of Smads for the full TGF-beta response. The importance of Smad binding to the CAGACA box of COL1A2 was further established by transcriptional decoy oligonucleotide competition. Taken together, the results identify a functional Smad-binding element of the COL1A2 promoter harboring a CAGACA consensus sequence that is both necessary and sufficient for stimulation by TGF-beta, and demonstrate that interaction of this Smad-binding element with endogenous Smads is required for the full TGF-beta response in fibroblasts.

Adenocarcinoma↗
PubMed2000

Surgical treatment of nonunited fractures of the odontoid process, with special reference to occipitocervical fusion for unreducible atlantoaxial subluxation or instability.

Fifty-seven consecutive patients treated surgically for nonunited fractures of the odontoid process were reviewed. All patients presented late, exhibiting neurological deficits subsequent to nonunion. Delay in presentation was between 6 and 120 months (mean 32 months) after the original injury, due to missed diagnosis or inappropriate management. Seven patients who were reduced in traction underwent a Gallie atlantoaxial fusion. In the remaining 50 patients who were unreducible, an occipitocervical arthrodesis was performed. They were followed up for a minimum of 2 years, except one who died from postoperative respiratory failure. All patients obtained a solid bony union, including two in whom nonunion occurred following atlantoaxial fusion, and occipitocervical fusion was added as a rescue. Thirty-eight patients achieved excellent neurological recovery, nine still had some disability, five retained their neurological deficits and two reported a deterioration. In two patients, a recurrence in a traumatic episode was experienced long after a resolution. Our findings demonstrate that occipitocervical arthrodesis is preferable for unreducible subluxation or instability of atlantoaxial articulation in nonunion of odontoid fractures.

Adolescent↗
PubMed2000

The effectiveness of the 'ride-bright' legislation for motorcycles in Singapore.

This paper examines the effectiveness of the 'ride-bright' legislation implemented in Singapore in November 1995. The odds ratio test is used to investigate if there is any significant difference in the number of daytime motorcycle accidents by severity before and after the implementation of the legislation. The findings indicate that although there is insignificant change in the number of slight injury accidents, the legislation is effective in reducing the number of fatal and serious injury accidents.

Accidents, Traffic↗
PubMed2000

A population-based cohort study of birth and neonatal outcome in older primipara.

OBJECTIVES: To examine the risk of adverse birth outcome in older primiparous women. METHODS: We identified 14,676 primiparae of 20 years of age or more from 1991 to 1996 using the Birth Registry in the North Jutland County, Denmark. We evaluated the risk of adverse birth outcome in the primiparous women aged 30-34 years and above 35 years using the primiparae aged 20-29 years at time of birth as reference. RESULTS: The risks of induced labor, perineotomy, stimulating contraction and vacuum extraction were significantly higher (adjusted odds ratio: 1.3 to 1.7) in the primiparae of 35 years or more. The odds ratio for cesarean section delivery was 2.1 (95% confidence interval: 1.7-2.6) and the odds ratio for delivering a low birth weight child among the primiparae of 35 years or more was 2.2 (95% confidence interval: 1.4-3.3) compared with the primiparae of 20-29 years of age. These risk estimates were independent of women's infertility treatment history. CONCLUSIONS: A negative effect of maternal age on birth and neonatal outcome may be seen even after 30 years of age and is partly related to chronic diseases. However, it is impossible to rule out selection bias, but the actual risk must be taken into consideration in antenatal care.

Adult↗
PubMed2000

The influence of repetitive eye movements on vergence performance.

We measured the peak velocity of convergence eye movement responses in four normal subjects before and after a large number of either repetitive vergence or repetitive saccadic eye movements. A 20% decrease in the mean value of peak velocity was observed in vergence responses after 100 repetitive step vergence eye movements. However, 100 cycles of slow sinusoidal vergence tracking did not induce any notable change in vergence dynamics. Five hundred repetitive saccadic eye movements also caused an approximately 20% decrease in peak velocity. The reduction in peak velocity was related to the number of repetitions for both vergence and saccadic fatiguing stimuli. The frequency of occurrence of double-vergences was also used as an index to monitor the influence of repetitive eye movements on convergence performance. Results showed that repetitive step convergence movements could double, or even triple, the frequency of the occurrence of double-vergence responses, while slow sinusoidal vergence tracking or repetitive saccades had no influence on the frequency of response doubles.

Convergence, Ocular↗
PubMed2000

Disparity vergence double responses processed by internal error.

Disparity vergence eye movements occasionally exhibit two high-velocity components to a single step stimulus (Alvarez, T. L., Semmlow, J. L. & Yuan, W. (1998). Journal of Neurophysiology, 79, 37-44). This research investigates the neural strategy used to trigger the second component of double high-velocity vergence eye movements. Vergence doubles evoked by an experimental protocol that induces post-movement visual error were compared to doubles that occur normally. The second component of a visually evoked response double occurred later, and with slower dynamics, than that of a naturally occurring double. These differences in timing and dynamics indicate that natural double responses are mediated, at least in part, by a mechanism other than visual feedback. The faster dynamics and timing of natural doubles suggest that an internal monitoring process triggers these movements.

Adolescent↗
PubMed2000

Os odontoideum: etiology, diagnosis, and management.

BACKGROUND: There have been few reports of os odontoideum since the initial description. METHODS: Forty-four patients with os odontoideum treated during the period 1980 through 1996 were reviewed. There were 33 males and 11 females. Their ages ranged from 7 to 56 years, with an average of 24.6 years. Five patients with no symptoms were treated conservatively. Thirty-nine patients underwent operative treatment including nine posterior atlantoaxial fusions and 33 occipitocervical fusions. RESULTS: The patients were followed up for one to 16 years, with an average of 6.5 years. Five patients treated conservatively have remained stable. All 39 treated patients achieved solid arthrodesis. The results were satisfactory. CONCLUSIONS: We conclude that fusion is indicated if atlantoaxial instability or clinical symptoms are significant, and that occipitocervical fusion should be considered in the operative management of os odontoideum if atlantoaxial arthrodesis is impossible.

Adolescent↗
PubMed2000

Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions.

The melanocortin system is involved in the regulation of several diverse physiological pathways, including energy homeostasis. Several synthetic peptide analogs have been designed, synthesized, and pharmacologically characterized at the mouse melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119. Analogs containing DNal(2') at position 7 resulted in partial agonist and antagonistic activities at the mMC3R while possessing full antagonistic activities at the mMC4R. Recently, the melanocortin-5 receptor (MC5R) has been demonstrated to have a role in the regulation of exocrine gland function. This study has characterized the following analogs of SHU9119 that possess antagonist activity at the MC5R: Ac-Nle-c[Asp-(1-Me)His(6)-DNal(2')(7)-Arg-Trp-Lys]-NH(2), pA(2) = 7. 1; Ac-Nle-c[Asp-(1-Me)His(6)-DNal(2')(7)-Arg-Nal(2')(9)-Lys]-NH(2), pA(2) = 7.2; and Ac-Nle-c[Asp-Trp(6)-DNal(2')(7)-Arg-Nal(2')(9)-Lys]-NH(2), pA(2) = 6. 6.

Amino Acid Sequence↗
PubMed2000

Cytoplasmic trafficking of the canine parvovirus capsid and its role in infection and nuclear transport.

To begin a successful infection, viruses must first cross the host cell plasma membrane, either by direct fusion with the membrane or by receptor-mediated endocytosis. After release into the cytoplasm those viruses that replicate in the nucleus must target their genome to that location. We examined the role of cytoplasmic transport of the canine parvovirus (CPV) capsid in productive infection by microinjecting two antibodies that recognize the intact CPV capsid into the cytoplasm of cells and also by using intracellular expression of variable domains of a neutralizing antibody fused to green fluorescence protein. The two antibodies tested and the expressed scFv all efficiently blocked virus infection, probably by binding to virus particles while they were in the cytoplasm and before entering the nucleus. The injected antibodies were able to block most infections even when injected 8 h after virus inoculation. In control studies, microinjected capsid antibodies did not interfere with CPV replication when they were coinjected with an infectious plasmid clone of CPV. Cytoplasmically injected full and empty capsids were able to move through the cytosol towards the nuclear membrane in a process that could be blocked by nocodazole treatment of the cells. Nuclear transport of the capsids was slow, with significant amounts being found in the nucleus only 3 to 6 h after injection.

Animals↗
PubMed2000

The N-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding protein and mediates transcriptional activation and apoptosis.

The newly identified p53 homolog p73 mimics the transcriptional function of p53. We have investigated the regulation of p73's transcriptional activity by p300/CREB binding protein (CBP). p73-p300 complexes were identified in HeLa cell extracts by cofractionation and coimmunoprecipitation assays. The p73-p300 interaction was confirmed in vitro by glutathione S-transferase-protein association assays and in vivo by coimmunoprecipitating the overexpressed p300 and p73 in human p53-free small-cell lung carcinoma H1299 or osteosarcoma Saos-2 cells. The N terminus but not the N-terminal truncation of p73 bound to the CH1 domain (amino acids [aa] 350 to 450) of p300/CBP. Accordingly, this p73 N-terminal deletion was unable to activate transcription or to induce apoptosis. Overexpression of either p300 or CBP stimulated transcription mediated by p73 but not its N-terminally deleted mutant in vivo. The N-terminal fragment from aa 19 to 597, but not the truncated fragment from aa 242 to 1700 of p300, reduced p73-mediated transcription markedly. p73-dependent transcription or apoptosis was partially impaired in either p300- or CBP-deficient human breast carcinoma MCF-7 or H1299 cells, suggesting that both coactivators mediate transcription by p73 in cells. These results demonstrate that the N terminus of p73 directly interacts with the N-terminal CH1 domain of p300/CBP to activate transcription.

Apoptosis↗
PubMed2000

The optimal analgesic dose of rofecoxib: Overview of six randomized controlled trials.

BACKGROUND: Rofecoxib, which specifically inhibits cyclooxygenase-2, is indicated for relief of the signs and symptoms of osteoarthritis and for the management of acute pain in adults. The authors present an overview of six placebo-controlled trials designed to evaluate the single-dose analgesic efficacy of a range of doses of rofecoxib in the treatment of postoperative dental pain. METHODS: The six studies included doses of rofecoxib ranging from 7.5 to 500 milligrams. Maximal analgesic doses of a nonsteroidal anti-inflammatory drug, or NSAID, either naproxen sodium (550 mg) or ibuprofen (400 mg), were used as active comparators in each study. Analgesic efficacy was assessed with the use of validated self-administered questionnaires. The primary endpoint in each study was the total pain relief over the eight-hour postdose period. Additional endpoints were used to characterize the onset of analgesia and peak analgesic effect. RESULTS: The results of these studies demonstrated that the efficacy of rofecoxib was dose-related, with 50 mg being consistently more effective than placebo for all measures of analgesic efficacy. Moreover, 50 mg was the lowest dose that reproducibly demonstrated an analgesic effect comparable to the effect of maximum single analgesic doses of NSAIDs. CONCLUSION: The results of these studies support the recommended dose of 50 mg of rofecoxib once daily for the management of pain. CLINICAL IMPLICATIONS: Rofecoxib, at a dose of 50 mg, is effective in the management of postoperative dental pain.

Adolescent↗
PubMed2000

[Information behavior of microsatellite loci in genome scanning].

OBJECTIVE: To determine the heterozygosity and polymorphism information content of 139 microsatellite loci in Han population. METHODS: Multiplex approach was used to analyze the 139 loci. The amplified fragments were subjected to electrophoresis in PAGE gel and analyzed with Genescan( TM) and Genotyper(TM). RESULTS: The heterozygosities are between 0.35 to 0.89, with the heterozygosities of 88% loci >0.60. PICs are in the range of 0.32 and 0.88, with PICs of 95% loci >0.50. CONCLUSION: The polymorphism information content of microsatellite loci is very high and their distribution varies in different races and populations.

Aged↗