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Biomedical subjects

G E Wright

Publications and source records attributed to G E Wright.

At least 19 recordsLinked to original sources
PubMed2001

Effects of stress management on pain behavior in rheumatoid arthritis.

OBJECTIVE: To examine the effects of stress management training on pain behavior exhibited by persons with rheumatoid arthritis (RA) and the relationship of change in pain behavior with certain patient characteristics as well as change in self-reported levels of pain. METHODS: Patients with RA (n = 131) were randomly assigned to 1 of 3 groups: a stress management group, an attention control group, or a standard care control group. The stress management and attention control groups received a 10-week intervention followed by a 15-month maintenance phase. RESULTS: The 3 groups did not differ significantly in the change in pain behavior at any of the assessment periods. However, persons with RA who had less disease activity tended to exhibit positive changes in pain behavior over time. Changes in self-reported pain were not significantly related to changes in pain behavior. CONCLUSION: The results indicate that stress management interventions do not reduce total pain behaviors exhibited by persons with RA. Changes in pain behaviors appear to be related to disease activity, age, and disease duration, but not to changes in self-reported measures of pain.

Arthritis, Rheumatoid↗
PubMed2001

Improving the quality of outpatient care for older patients with diabetes: lessons from a comparison of rural and urban communities.

OBJECTIVE: Our goal was to compare the quality of diabetic care received by patients in rural and urban communities. STUDY DESIGN: We performed a retrospective analysis of claims data captured by the Medicare program. POPULATION: We included all fee-for-service Medicare patients 65 years and older living in the state of Washington who had 2 or more physician encounters for diabetes care during 1994. OUTCOME MEASURES: The outcomes were the extent to which patients received 3 specific recommended services: glycated hemoglobin determination, cholesterol measurement, and eye examination. RESULTS: A total of 30,589 Medicare patients (8.4%) were considered to have diabetes; 29.1% lived in rural communities. Generalists provided most diabetic care in all locations. Patients living in small rural towns received almost half their outpatient care in larger communities. Patients living in large rural towns remote from metropolitan areas were more likely to have received the recommended tests than patients in all other groups. Patients who saw an endocrinologist at least once during the year were more likely to have received the recommended tests. CONCLUSIONS: Large rural towns may provide the best conditions for high-quality care: They are vibrant, rapidly growing communities that serve as regional referral centers and have an adequate-but not excessive-supply of both generalist and specialist physicians. Generalists provide most diabetic care in all settings, and consultation with an endocrinologist may improve adherence to guidelines.

Aged↗
PubMed2000

Novel nonsubstrate inhibitors of human thymidine phosphorylase, a potential target for tumor-dependent angiogenesis.

Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) is an enzyme involved in thymidine metabolism and homeostasis, and its catalytic activity appears to play an important role in angiogenesis. Here we describe the cloning and expression of a His-tagged human TP/PD-ECGF and its assay with uracil and thymine analogues. We present the design, synthesis, and biological evaluation of novel 6-(phenylalkylamino)uracil derivatives which, at micromolar concentrations, inhibit both catabolic and anabolic reactions of human TP in vitro. These base analogues are not converted by the enzyme into the nucleoside form, thus representing pure nonsubstrate inhibitors of the enzyme.

Amino Acid Sequence↗
PubMed2000

In vitro antimicrobial activities of novel anilinouracils which selectively inhibit DNA polymerase III of gram-positive bacteria.

The 6-anilinouracils are novel dGTP analogs that selectively inhibit the replication-specific DNA polymerase III of gram-positive eubacteria. Two specific derivatives, IMAU (6-[3'-iodo-4'-methylanilino]uracil) and EMAU (6-[3'-ethyl-4'-methylanilino]uracil), were substituted with either a hydroxybutyl (HB) or a methoxybutyl (MB) group at their N3 positions to produce four agents: HB-EMAU, MB-EMAU, HB-IMAU, and MB-IMAU. These four new agents inhibited Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Time-kill assays and broth dilution testing confirmed bactericidal activity. These anilinouracil derivatives represent a novel class of antimicrobials with promising activities against gram-positive bacteria that are resistant to currently available agents, validating replication-specific DNA polymerase III as a new target for antimicrobial development.

Anti-Bacterial Agents↗
PubMed2000

The effect of the doctor-patient relationship on emergency department use among the elderly.

OBJECTIVES: This study sought to determine the rate of emergency department use among the elderly and examined whether that use is reduced if the patient has a principal-care physician. METHODS: The Health Care Financing Administration's National Claims History File was used to study emergency department use by Medicare patients older than 65 years in Washington State during 1994. RESULTS: A total of 18.1% of patients had 1 or more emergency department visits during the study year; the rate increased with age and illness severity. Patients with principal-care physicians were much less likely to use the emergency department for every category of disease severity. After case mix, Medicaid eligibility, and rural/urban residence were controlled for, the odds ratio for having any emergency department visit was 0.47 for patients with a generalist principal-care physician and 0.58 for patients with a specialist principal-care physician. CONCLUSIONS: The rate of emergency department use among the elderly is substantial, and most visits are for serious medical problems. The presence of a continuous relationship with a physician--regardless of specialty--may reduce emergency department use.

Aged↗
PubMed2000

Stress management in rheumatoid arthritis: what is the underlying mechanism?

OBJECTIVE: To test whether change in cognitive-behavioral variables (such as self-efficacy, coping strategies, and helplessness) is a mediator in the relation between cognitive behavior therapy and reduced pain and depression in persons with rheumatoid arthritis (RA). METHODS: A sample of patients with RA who completed a stress management training program (n = 47) was compared to a standard care control group (n = 45). A path analysis testing a model including direct effects of comprehensive stress management training on pain and depression and indirect effects via change in cognitive-behavioral variables was conducted. RESULTS: The path coefficients for the indirect effects of stress management training on pain and depression via change in cognitive-behavioral variables were statistically significant, whereas the path coefficients for the direct effects were found not to be statistically significant. CONCLUSION: Decreases in pain and depression following stress management training are due to beneficial changes in the arenas of self-efficacy (the belief that one can perform a specific behavior or task in the future), coping strategies (an individual's confidence in his or her ability to manage pain), and helplessness (perceptions of control regarding arthritis). There is little evidence of additional direct effects of stress management training on pain and depression.

Adaptation, Psychological↗
PubMed1999

Molecular modeling and synthesis of inhibitors of herpes simplex virus type 1 uracil-DNA glycosylase.

We recently reported the properties of the first selective inhibitors of herpes simplex virus type 1 (HSV1) uracil-DNA glycosylase (UDG), an enzyme of DNA repair that has been proposed to be required for reactivation of the virus from latency. 6-(4-Octylanilino)uracil (octAU) was the most potent inhibitor among a series of 6-(4-alkylanilino)uracils, acting in the micromolar range and without effect against human UDG. A 28.5-kDa catalytic fragment of HSV1 UDG has been crystallized in the presence of uracil, and the structure was recently solved. We have used the coordinates of this structure in order to study interaction of our inhibitors with the enzyme, and a model of binding between octAU and UDG has been derived. Starting with the optimized model, the activity of several octAU analogues was predicted, and the values compared favorably with experimental results found for the synthetic compounds. Several hydrophilic derivatives were predicted and found to be active as UDG inhibitors. These compounds will be useful to determine if UDG, like the viral thymidine kinase, is required for reactivation of HSV1 from latency in nerve cells.

Aniline Compounds↗
PubMed1999

6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III: antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3.

6-Anilinouracils (6-AUs) are dGTP analogues which selectively inhibit the DNA polymerase III of Bacillus subtilis and other Gram-positive bacteria. To enhance the potential of the 6-AUs as antimicrobial agents, a structure-activity relationship was developed involving substitutions of the uracil N3 position in two 6-AU platforms: 6-(3,4-trimethyleneanilino)uracil (TMAU) and 6-(3-ethyl-4-methylanilino)uracil (EMAU). Series of N3-alkyl derivatives of both 6-AUs were synthesized and tested for their ability to inhibit purified B. subtilis DNA polymerase III and the growth of B. subtilis in culture. Alkyl groups ranging in size from ethyl to hexyl enhanced the capacity of both platforms to bind to the polymerase, and with the exception of hexyl, they also significantly enhanced their antimicrobial potency. N3 substitution of the EMAU platform with more hydrophilic hydroxyalkyl and methoxyalkyl groups marginally enhanced anti-polymerase III activity but enhanced antibacterial potency severalfold. In sum, the results of these studies indicate that the ring N3 of 6-anilinouracils can tolerate substituents of considerable size and structural variety and, thus, can be manipulated to significantly enhance the antibacterial potency of this novel class of polymerase III-specific inhibitors.

Anti-Bacterial Agents↗
PubMed1999

A confirmatory factor analysis of the Center for Epidemiologic Studies Depression Scale in rheumatoid arthritis patients: additional evidence for a four-factor model.

OBJECTIVE: To examine the factor structure of the Center for Epidemiologic Studies Depression Scale (CES-D) in a sample of patients with rheumatoid arthritis (RA), testing all of the alternative models suggested by the previous evidence. METHODS: The CES-D was administered to a group of RA patients (n = 685) during a structured telephone interview. The telephone interview was repeated 6 months later (n = 537) and 12 months later (n = 453). Confirmatory factor analyses were conducted to test alternative models. RESULTS: The correlated 4-factor model and the second-order 4-factor model were the best fitting models. CONCLUSION: The factor structure of the CES-D previously found in the general population was replicated in an RA sample. The results are consistent with previous evidence of criterion contamination in the CES-D when used in an RA sample and provide support for the view that a single summary score may not be the most informative index of the CES-D.

Arthritis, Rheumatoid↗
PubMed1999

Sensitivity of bacteriophage RB69 DNA polymerase to N2-(p-n-butylphenyl)-2'-deoxyguanosine nucleotides.

The response of bacteriophage RB69 DNA polymerase to N2-(p-n-butylphenyl)-2'-deoxyguanosine 5'-triphosphate (BuPdGTP), related nucleotides and non-nucleoside inhibitors was measured and compared to values obtained for the closely related DNA polymerase from bacteriophage T4. Both enzymes showed similar responses to inhibitors in terms of Ki values and the ability to utilize BuPdGTP as a substrate. These results provide the relevance of using the recent crystal structure of RB69 DNA polymerase for analysis of BuPdGTP/B family DNA polymerase interactions.

Bacteriophage T4↗
PubMed1999

Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria.

6-Anilinouracils are selective inhibitors of DNA polymerase III, the enzyme required for the replication of chromosomal DNA in gram-positive bacteria (N. C. Brown, L. W. Dudycz, and G. E. Wright, Drugs Exp. Clin. Res. 12:555-564, 1986). A new class of 6-anilinouracils based on N-3 alkyl substitution of the uracil ring was synthesized and analyzed for activity as inhibitors of the gram-positive bacterial DNA polymerase III and the growth of gram-positive bacterial pathogens. Favorable in vitro properties of N-3-alkyl derivatives prompted the synthesis of derivatives in which the R group at N-3 was replaced with more-hydrophilic methoxyalkyl and hydroxyalkyl groups. These hydroxyalkyl and methoxyalkyl derivatives displayed K(i) values in the range from 0.4 to 2.8 microM against relevant gram-positive bacterial DNA polymerase IIIs and antimicrobial activity with MICs in the range from 0.5 to 15 microg/ml against a broad spectrum of gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. Two of these hydrophilic derivatives displayed protective activity in a simple mouse model of lethal staphylococcal infection.

Aniline Compounds↗
PubMed1998

The role of leucine residues in the structure and function of a leucine zipper peptide inhibitor of paramyxovirus (NDV) fusion.

To investigate the molecular mechanisms involved in paramyxovirus-induced cell fusion, the function and structure of synthetic peptide analogs of the sequence from the leucine zipper region (heptad repeat region 2) of the Newcastle disease virus fusion protein (F) were characterized. As previously reported (Young et al., Virology, 238, 291), a peptide with the sequence ALDKLEESNSKLDKVNVKLT (amino acids 478-497 of the F protein) inhibited syncytia formation after transfection of Cos cells with the hemagglutinin-neuraminidase and F protein cDNAs. A peptide analog which had an alanine residue in place of the first leucine residue in the zipper motif (ALDKAEESNSKLDKVNVKLT) retained inhibitory activity but less than the original peptide. Further loss in activity was observed in a peptide in which two of the leucine residues were replaced with alanine (ALDKAEESNSKADKVNVKLT), and a peptide which had all leucine residues in the zipper motif replaced with alanine (ALDKAEESNSKADKVNVKLT) had no inhibitory activity. The three-dimensional conformations of these peptides in aqueous solution were determined through the use of nuclear magnetic spectroscopy and molecular modeling. Results showed that while the wild-type peptide formed a helix with properties between an alpha-helix and a 3(10) helix with leucine residues aligned along one face of the helix, progressive substitution of leucine residues with alanine resulted in the progressive loss of helical structure. The results suggest that alterations of leucine residues in the zipper motif disrupt secondary structure of the peptide and that this structure is critical to the inhibitory activity of the peptide.

Amino Acid Sequence↗
PubMed1998

Age, depressive symptoms, and rheumatoid arthritis.

OBJECTIVE: To examine the relationship between age and depression in persons with rheumatoid arthritis (RA). METHODS: Two separate outpatient cohorts of persons with RA were studied. In both studies, the Center for Epidemiological Studies Depression Scale was administered to all subjects, and the prevalence of depressive symptoms was determined by age group. In the second study, data on additional measures of disease activity, pain, life stress, and coping were collected for use in multiple linear regression analyses. RESULTS: In both samples, a significant correlation between age and depression was found; younger persons (age < or = 45 years) with RA were significantly more depressed, even after controlling for potentially confounding variables such as sex, marital status, antidepressant medication, arthritis medication, functional class, and disease duration. CONCLUSION: The findings show that younger persons with RA are at higher risk for depressive symptoms than their older counterparts.

Adaptation, Psychological↗
PubMed1998

Synthesis and biochemical study of N2-(p-n-butylphenyl)-2'-deoxyguanosine 5'-(alpha,beta-imido)triphosphate (BuPdGMPNHPP): a non-substrate inhibitor of B family DNA polymerases.

BuPdGMPNHPP was synthesized and assayed as a non-incorporable inhibitor of B family DNA polymerases. The derivative was synthesized by preparation of the imidophosphorane of BuPdG followed by reaction with orthophosphate using the imidazolide method. BuPdGMPNHPP inhibited human DNA polymerase alpha and T4 DNA polymerase 10 and 3.5-times more potently than BuPdGTP, respectively, and was not a substrate for either enzyme. BuPdGMPNHPP acts as an active site affinity probe that could find use in co-crystallization trials of B family DNA polymerases.

DNA Polymerase beta↗
PubMed1997

Analysis of a peptide inhibitor of paramyxovirus (NDV) fusion using biological assays, NMR, and molecular modeling.

To investigate the molecular mechanisms involved in paramyxovirus-induced cell fusion, the function and structure of a peptide with a 20-amino-acid sequence from the leucine zipper region (heptad repeat region 2) of the Newcastle disease virus fusion protein (F) were characterized. A peptide with the sequence ALDKLEESNSKLDKVNVKLT (amino acids 478-497 of the F protein) was found to inhibit syncytia formation after virus infection and after transfection of Cos cells with the HN (hemagglutinin-neuraminidase) and F protein cDNAs. Using an F protein gene that requires addition of exogenous trypsin for cleavage, it was shown that the peptide exerted its inhibitory effect prior to cleavage. The three-dimensional conformation of the peptide in aqueous solution was determined through the use of NMR and molecular modeling. Results showed that the peptide formed a helix with properties between an alpha-helix and a 3(10)-helix and that leucine residues aligned along one face of the helix. Side chain salt bridges and hydrogen bonds likely contributed to the stability of the peptide secondary structure. Analysis of the aqueous solution conformation of the peptide suggested mechanisms for specificity of interaction with the intact F protein.

Amides↗
PubMed1997

The importance of enhancing self-efficacy in rheumatoid arthritis.

OBJECTIVE: To examine relationships among changes in self-efficacy and changes in other clinically relevant outcome measures. METHOD: Subjects (n = 44) were participants in a prospective, randomized stress-management study followed over 15 months. Outcome measures included self-efficacy, depression, pain, health status, and disease activity. RESULTS: Correlational analyses revealed significant associations between changes in self-efficacy (particularly total self-efficacy) and changes in selected measures of depression, pain, health status, and disease activity. The observed associations were not due to changes in medication regimen or to nonadherence to the stress-management program. CONCLUSIONS: Evidence is provided that induced changes in self-efficacy following a stress-management program were significantly related to other clinically important outcome measures.

Activities of Daily Living↗
PubMed1997

Structural studies by 1H NMR of a prototypic alpha-helical peptide (LYQELQKLTQTLK) and homologs in trifluoroethanol/water and on sodium dodecyl sulfate micelles.

The 1H NMR-determined structure and dynamics of a synthetic, amphiphilic alpha-helical peptide, PH-1.0 (LYQELQKLTQTLK), and several homologs were compared in 50% trifluoroethanol-d2 (TFE-d2)/H20 and in sodium dodecyl-d25 sulfate (SDS-d25) micelles. The peptides were designed to test the influence on secondary structure of placement of favored and disfavored residues relative to a "longitudinal, hydrophobic strip-of-helix" defined by the repeating leucines. PH-1.0 was highly ordered as an alpha-helix in 50% TFE-d2/H20 and in SDS-d25 micelles. Homologs PH-1.1, in which L1 was replaced by T, and PH-1,4, in which L12 was replaced by T. were found to be partially helical in both media. Calculated structures in SDS-d25 revealed that the helix of PH-1.1 was slightly disordered at the N-terminus, but that of PH-1.4 was completely disordered at the C-terminus. Examination of distributions of hydrophobic residues in protein structures revealed that, when [symbol: see text] = LIVFM and [symbol: see text] = nonLIVFM, the pattern [symbol: see text] is favored and [symbol: see text] is disfavored in alpha-helices. Several analogs of PH-1.0 incorporating these patterns were studied. Peptide PH-1.12 (LYQELQKLLQTLK) retained alpha-helical structure in both 50% TFE-d2/H20 and in SDS-d25 micelles. However, although PH-1.13 (LYQELQKLTLTLK) was fully helical in 50% TFE, it was helical only through residue 6 in SDS micelles. Two homologs containing an additional loop of the helix and repeats of favored (PH-5.0, NYLQTLLETLKTLLQK) or suppressed LL patterns (PH-5.11, NYLQTLETLKLTQK) gave similar results, i.e. the latter peptide was helical only through residue 6 in SDS micelles. The degree of local order in these SDS micelle-adsorbed peptides correlates to placement of hydrophobic residues in motifs which are favored or disfavored in proteins in general and in alpha-helices specifically.

Amino Acid Sequence↗