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Biomedical subjects

M Chang

Publications and source records attributed to M Chang.

At least 19 recordsLinked to original sources
PubMed2006

The 620W allele is the PTPN22 genetic variant conferring susceptibility to RA in a Dutch population.

OBJECTIVES: A missense SNP, C1858T, in PTPN22 has been identified as a genetic risk factor for rheumatoid arthritis (RA). Subsequent work has suggested that other variants in this gene, in particular a haplotype marked by the minor allele of rs3789604, are associated with RA in white North Americans independent of C1858T. We tested this hypothesis in an independent white Dutch study. METHODS: A total of 667 RA patients and 286 controls were genotyped for 13 PTPN22 single nucleotide polymorphisms (SNPs) by allele-specific kinetic polymerase chain reaction. rs3789604 was genotyped in an additional 410 RA and 270 UA patients participating in the Leiden early arthritis inception cohort. We conducted single-marker and haplotype association tests. RESULTS: The sole haplotype strongly associated with RA in our Dutch population carries the PTPN22 1858T allele. A second haplotype identical at all other SNPs tested except 1858 was not associated with disease. No significant association of the haplotype tagged by the 3' PTPN22 SNP, rs3789604, with RA susceptibility (P = 0.134) was observed in our sample set. CONCLUSION: We conclude that C1858T is the sole PTPN22 variant predisposing to RA in our white Dutch sample set.

Adult↗
PubMed2006

Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency.

Tetrahydrobiopterin (BH(4)) deficiency is an autosomal recessive disorder caused by enzyme defects in the biosynthesis or recycling of BH(4). Patients with BH(4) deficiency present with severe neurological signs and symptoms and require a different treatment from classical phenylketonuria. During the last 12 years, 31 cases of BH(4) deficiency were identified in our department. They were all classified as 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. They were diagnosed at the ages of 2.5-48 months and treated with BH(4), L-dopa and 5-hydroxytryptophan immediately after diagnosis. The average development quotients (DQ) at diagnosis and after treatment for more than 3 years were 53+/- 16, and 78+/- 15, respectively. A significant negative correlation was observed between the level of the DQ and the age at which treatment was commenced (r = -0.751, p = 0.002). Developmental profiles were uneven. Language, adaptability and at later age mathematics were particularly weak areas. Only two patients achieved a good performance in mathematics. Eleven patients who were treated with drugs from ages of 2.9-48 months had neuroradiological scanning. Computed tomography disclosed calcification in lentiform nuclei in one patient and magnetic resonance imaging disclosed delayed myelination and abnormal high intensity signal in cerebral white matter in all of them. Even though most of abnormalities were reversible, small patchy or spotted areas were still present on these regions after treatment for 10-46 months. In summary, our study supports the substantial efficacy of the current therapeutic approach in PTPS deficiency of normalizing amine neurotransmitters with three drugs as early as possible. For the first time, calcifications could be detected in patients with PTPS deficiency. Abnormalities in white matter on magnetic resonance imaging were not related to clinical manifestations and most were reversible.

Brain↗
PubMed2006

Human cytomegalovirus pp65 lower matrix protein: a humoral immunogen for systemic lupus erythematosus patients and autoantibody accelerator for NZB/W F1 mice.

Both the infection of human cytomegalovirus (HCMV) and the immunization of its recombinant glycoprotein (gB) in mice have been known to induce autoimmunity, resulting in symptoms similar to those of human systemic lupus erythematosus (SLE). Research has also found that the murine cytomegalovirus (MCMV)-specific monoclonal antibody (mAb) is able to react with a human U1-70K-like autoantigen. To investigate HCMV involvement in autoimmunity, we analysed the humoral responses to HCMV by autoimmune patients and normal adults. Our studies show unambiguously that sera from SLE patients exhibited an elevated IgG titre to HCMV when compared with those observed in controls and other connective tissue disease (CTD) patients (P < 0.001). The IgM titres to HCMV and IgG to HBV were evaluated, and no significant differences were noted among all testing groups. In addition to initiating T cell activity, as reported by many investigators, we found that the HCMV pp65 antigen (also known as lower matrix protein) was able to induce humoral responses in SLE patients. Immunoblot assays showed that 82.56% of sera from SLE patients reacted with the HCMV pp65 antigen, but only 11.11%, 23.53% and 31.17% of patients from normal control, rheumatoid arthritis (RA) and CTD patients, respectively, reacted to it. Unlike HCMV pp65, HCMV pp150 induced B cell activity in most collected sera (92.22%-98.04%). Finally, female NZB/W F1 mice immunized with plasmids encoding HCMV pp65 open reading frame (pcDNApp65) developed an early onset of autoantibody activity and more severe glomerulonephritis. Thus, we conclude that the HCMV pp65 antigen triggers humoral immunity in SLE patients and autoimmune-prone mice and that it could very well exacerbate the autoimmune responses in susceptible animals.

Adolescent↗
PubMed2005

Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000.

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36+/-4.7%) and for the group that received only intensive chemotherapy (35+/-4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63+/-5.4%) and of children with Down's syndrome (5-year EFS estimate, 66+/-8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42+/-8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.

Acute Disease↗
PubMed2004

Spatio-temporal distribution and characteristics of PAHs in sediments from Masan Bay, Korea.

The distribution of polycyclic aromatic hydrocarbons (PAHs) has been investigated in the surface and core sediments from Masan Bay, Korea. Total PAHs in the surface sediments ranged from 207 to 2670 ng/g dry weight with a mean value of 680 ng/g. Qualitative similarity and quantitative difference between inner and outer bay indicate that the main sources of PAHs are located in the inner bay and outer bay is also affected by the same sources. Vertical distribution of PAHs revealed that three distinctive stages could be differentiated with the help of PCA analysis. The highest concentration (industrialization stage) appeared between late 1950s and 1980, which was 10 years later than other developed countries. A strong pyrolytic source fingerprint has been detected with slight influence of petrogenic sources, and diagenetic PAH, perylene also contributed. Total organic carbon normalized PAHs (sum of 13 PAHs, 8.85-88.0 microg/g OC) were under the threshold effects concentration (TEC, 290 microg/g OC).

Environmental Monitoring↗
PubMed2003

Pro-Leu-glycinamide and its peptidomimetic, PAOPA, attenuate haloperidol induced vacuous chewing movements in rat: A model of human tardive dyskinesia.

In the present experimental paradigm, we examine the effect of L-prolyl-L-leucyl-glycinamide (PLG) co-administration with haloperidol on vacuous chewing movements (VCM) in rats-a model of tardive dyskinesia (TD) in humans. We examined the dose dependent induction of VCM through both injected and orally administered PLG (MIF-1). Our results show significant levels of VCM attenuation (P<0.05) in rats treated with 10mg/kg of PLG. Doses of 1 and 100mg/kg were ineffective. Reductions were present in both orally treated and injected rats. We also examined the therapeutic effect of a peptidomimetic of PLG-PAOPA. PAOPA was able to produce similar behavioral effects to PLG at a dose, which was 100-fold lower than the effective dose of PLG. These results suggest that PLG may play a role in D2 receptor expression and function, as well as providing a therapy for neuroleptic induced TD.

Administration, Oral↗
PubMed2003

Pharmacokinetics, metabolism and excretion of an inhibitor of inducible nitric oxide synthase, L-NIL-TA, in dog.

1. The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog. 2. The dose of [14C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5 mg kg-1), with Cmax of radioactivity of 6.45-7.07 microg equivalents g-1 occurring at 0.33-0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively. 3. Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [14C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%. 4. Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.

Administration, Oral↗
PubMed2003

Short-term temporal variation in PM2.5 mass and chemical composition during the Atlanta Supersite Experiment, 1999.

Measurements in urban Atlanta of transient aerosol events in which PM2.5 mass concentrations rapidly rise and fall over a period of 3-6 hr are reported. The data are based on new measurement techniques demonstrated at the U.S. Environmental Protection Agency (EPA) Atlanta Supersite Experiment in August 1999. These independent instruments for aerosol chemical speciation of NO3-, SO4(2-), NH4+, and organic and elemental carbon (OC and EC), reconstructed the observed hourly dry PM2.5 mass to within 20% or better. Data from the experiment indicated that transient PM2.5 events were ubiquitous in Atlanta and were typically characterized by a sudden increase of EC (soot) and OC in the early morning or SO4(2-) in the late afternoon. The frequent temporal decoupling of these events provides insights into their origins, suggesting mobile sources in metro Atlanta as the main contributor to early morning PM2.5 and more regionally located point SO2 sources for afternoon PM2.5 events. The transient events may also have health implications. New data suggest that short-term PM2.5 exposures may lead to adverse health effects. Standard integrated filter-based techniques used in PM2.5 compliance monitoring networks and in most past PM2.5 epidemiologic studies collect samples over 24-hr periods and thus are unable to capture these transient events. Moreover, health-effects studies that focus on daily PM2.5 mass alone cannot evaluate the health implications of the unique and variable chemical properties of these episodes.

Aerosols↗
PubMed2003

The androgen receptor in spermatogenesis.

Androgens are steroid hormones that are necessary for normal male phenotype expression, including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis. Many physiological actions of androgens are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. AR functions as a ligand-dependent transcription factor, regulating expression of an array of target genes that are important in male pubertal development and fertility. In this review, the expression and necessity of AR in specific testicular cell types that are important in spermatogenesis will be discussed, and recent information obtained through the study of complete and cell type-specific AR null mouse models will be presented.

Animals↗
PubMed2002

Phenotypic analysis of Paf1/RNA polymerase II complex mutations reveals connections to cell cycle regulation, protein synthesis, and lipid and nucleic acid metabolism.

Paf1 is an RNA polymerase II-associated protein in yeast, which defines a complex that is distinct from the Srb/Mediator holoenzyme. The Paf1 complex, which also contains Ctr9, Cdc73, Hpr1, Ccr4, Rtf1 and Leo1, is required for full expression of a subset of yeast genes, particularly those responsive to signals from the Pkc1/MAP kinase cascade. We have extensively characterized the pleiotropic phenotypes of deletion mutants for factors present in the Paf1 complex, identifying more than a dozen new phenotypes, and, in some cases, establishing possible molecular explanations for the growth defects. For example, paf1 Delta causes sensitivity to hydroxyurea; this phenotype correlates with a reduction in RNR1 transcript abundance and is suppressed by over-expression of RNR1. In contrast, the resistance of paf1 Delta cells to the transcription elongation inhibitors 6-azauracil and mycophenolic acid correlates with its ability to derepress the IMD2 transcript. We tested the hypothesis that Paf1 communicates with some promoters through the DNA-binding factors Swi4, Mbp1 or Rlm1. The phenotypes of mutations in Paf1 complex components are exacerbated in the swi4 Delta background, suggesting that the complex acts in a pathway parallel to that controlled by Swi4. Conversely, the fact that mbp1 Delta and rlm1 Delta mutations do not enhance the phenotypes suggests that the Paf1 complex may function in the same regulatory pathway(s) with Mbp1 and Rlm1.

Cell Cycle↗
PubMed2002

[Nphe1]nociceptin(1-13)-NH2 antagonizes nociceptin-induced hypotension, bradycardia, and hindquarters vasodilation in the anesthetized rat.

The purpose of this study was to investigate the effects of [Nphe1]nociceptin(1-13)-NH2 on nociceptin-induced decreases in mean arterial pressure (MAP), heart rate (HR), and hindquarters vascular bed resistance (HVBR) of the anesthetized rat. The results showed that i.c.v. or i.v. [Nphe1]nociceptin(1-13)-NH2 (1.5-12 nmol/kg and 5-120 nmol/kg, respectively) could antagonize the depressor effects of i.c.v. or i.v. nociceptin (3 and 30 nmol/kg, respectively) on MAP and HR. Furthermore, [Nphe1]nociceptin(1-13)-NH2 (5-120 nmol/kg) could reverse nociceptin (30 nmol/kg)-induced decrease of HVBR. However, [Nphe1]nociceptin(1-13)-NH2 had no significant effects on similar effects induced by morphine. Our results suggest that [Nphe1]nociceptin(1-13)-NH2 acts as a selective antagonist of the nociceptin receptor in the cardiovascular system of the rat.

Anesthesia↗
PubMed2001

Lignification induced by pseudomonads harboring avirulent genes on Arabidopsis.

The responses of Arabidopsis thaliana ecotypes to the bacterial pathogen Pseudomonas syringae pv. maculicola 4326 (Psm4326) harboring cloned avirulence genes avrB and avrRpt2 from P. syringae pv. glycinea were examined. Psm4326 containing avirulent genes, avrB and avrRpt2 induced lignification and peroxidase activities in the bacteria infiltrated leaves of Col-O only and not in Mt-O, Bla-2 and Po-1. However, Arabidopsis ecotypes infiltrated with Psm4326 harboring with and without avirulent genes all showed differential induction of mRNA for peroxidase gene and lignin accumulation up to 24 h after infiltration. Only avrB gene in Col-O showed strong corelationship between peroxidase mRNA expression as well as lignification gradually up to 36 h after infiltration. These results extend previous observations that avirulence genes from pathogens of one host plant can be recognized by non-host plants and provide the genetic framework for analysis of the plant-specific response to the bacterial avirulent gene products in A. thaliana.

Arabidopsis↗
PubMed2001

Structural and functional consequences of inactivation of human glutathione S-transferase P1-1 mediated by the catechol metabolite of equine estrogens, 4-hydroxyequilenin.

The inactivation mechanism(s) of human glutathione S-transferase P1-1 (hGST P1-1) by the catechol metabolite of Premarin estrogens, 4-hydroxyequilenin (4-OHEN), was (were) studied by means of site-directed mutagenesis, electrospray ionization mass spectrometric analysis, titration of free thiol groups, kinetic studies of irreversible inhibition, and analysis of band patterns on nonreducing sodium dodecyl sulfate--polyacrylamide gel electrophoresis (SDS-PAGE). The four cysteines (Cys 14, Cys 47, Cys 101, and Cys 169 in the primary sequence) in hGST P1-1 are susceptible to electrophilic attack and/or oxidative damage leading to loss of enzymatic activity. To investigate the role of cysteine residues in the 4-OHEN-mediated inactivation of this enzyme, one or a combination of cysteine residues was replaced by alanine residues (C47A, C101A, C47A/C101A, C14A/C47A/C101A, and C47A/C101A/C169A mutants). Mutation of Cys 47 decreased the affinity for the substrate GSH but not for the cosubstrate 1-chloro-2,4-dinitrobenzene (CDNB). However, the Cys 47 mutation did not significantly affect the rate of catalysis since V(max) values of the mutants were similar or higher compared to that of wild type. Electrospray ionization mass spectrometric analyses of wild-type and mutant enzymes treated with 4-OHEN showed that a single molecule of 4-OHEN-o-quinone attached to the proteins, with the exception of the C14A/C47A/C101A mutant where no covalent adduct was detected. 4-OHEN also caused oxidative damage as demonstrated by the appearance of disulfide-bonded species on nonreducing SDS--PAGE and protection of 4-OHEN-mediated enzyme inhibition by free radical scavengers. The studies of thiol group titration and irreversible kinetic experiments indicated that the different cysteines have distinct reactivity for 4-OHEN; Cys 47 was the most reactive thiol group whereas Cys 169 was resistant to modification. These results demonstrate that hGST P1-1 is inactivated by 4-OHEN through two possible mechanisms: (1) covalent modification of cysteine residues and (2) oxidative damage leading to proteins inactivated by disulfide bond formation.

Amino Acid Substitution↗
PubMed2001

Degree of antigen adsorption in the vaccine or interstitial fluid and its effect on the antibody response in rabbits.

The effect of the degree of adsorption of lysozyme by aluminium hydroxide adjuvant on the immune response in rabbits was studied. The surface charge of the adjuvant was modified by pretreatment with phosphate anion to produce five vaccines having degrees of adsorption ranging from 3 to 90%. The degree of adsorption of vaccines exhibiting 3, 35 or 85% adsorption changed to 40% within 1 h after each vaccine was mixed with sheep interstitial fluid to simulate subcutaneous administration. The mean anti-lysozyme antibody titers produced by the vaccines were the same and were four times greater than that produced by a lysozyme solution. Thus, the degree of adsorption of lysozyme in sheep interstitial fluid rather than the degree of adsorption in the vaccine correlated with the immune response.

Adjuvants, Immunologic↗
PubMed2001

Nitric oxide donors regulate nitric oxide synthase in bovine pulmonary artery endothelium.

This study examined the notion that exogenous generation of nitric oxide (NO) modulates NOS gene expression and activity. Bovine pulmonary artery endothelial cells (BPAEC) were treated with the NO donors, 1 mM SNAP (S-nitroso-N-acetylpenicillamine), 0.5 mM SNP (sodium nitroprusside) or 0.2 microM NONOate (spermine NONOate) in medium 199 containing 2% FBS. Controls included untreated cells and cells exposed to 1 mM NAP (N-acetyl-D-penicillamine). NOS activity was assessed using a fibroblast-reporter cell assay; intracellular Ca2+ concentrations were assessed by Fura-2 microfluorometry; and NO release was measured by chemiluminescence. Constitutive endothelial (e) and inducible (i) NOS gene and protein expression were examined by northern and western blot analysis, respectively. Two hours exposure to either SNAP or NONOate caused a significant elevation in NO release from the endothelial cells (SNAP = 51.4 +/- 5.9; NONOate = 23.8 +/- 4.2; control = 14.5 +/- 2.8 microM); but A23187 (3 microM)-stimulated NO release was attenuated when compared to controls. Treatment with either SNAP or NONOate for 2 h also resulted in a significant increase in NOS activity in endothelial homogenates (SNAP = 23.6 +/- 2.5; NONOate= 29.8 +/- 7.7; control = 14.5 +/- 2.5fmol cGMP/microg per 10(6) cells). Exposure to SNAP and SNP, but not NONOate, for 1 h caused an increase in intracellular calcium. Between 4 and 8 h, SNAP and NONOate caused a 2- to 3-fold increase in eNOS, but not iNOS, gene (P < 0.05) and protein expression. NAP had little effect on either eNOS gene expression, activity or NO production. Our data indicate that exogenous generation of NO leads to a biphasic response in BPAEC, an early increase in intracellular Ca2+, and increases in NOS activity and NO release followed by increased expression of the eNOS gene, but not the iNOS gene. We conclude that eNOS gene expression and activity are regulated by a positive-feedback regulatory action of exogenous NO.

Animals↗
PubMed2001

Synthesis and in vitro antibacterial activity of cephalosporins with a pyridinium substituent carrying an isoxazole moiety at the C-3 position.

Several quaternary pyridinium cephalosporin analogues were prepared and evaluated in vitro for antibacterial activity against selected gram-positive and gram-negative organisms. Most of the synthesized analogues were either as effective or less effective against the tested bacterial organisms than the reference compounds, Cefpirome and Ceftazidime.

Cephalosporins↗