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Biomedical subjects

L J Walker

Publications and source records attributed to L J Walker.

At least 19 recordsLinked to original sources
PubMed2004

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations.

Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0.001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0.0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD.

Adolescent↗
PubMed2001

The consolidation/transition model in moral reasoning development.

The consolidation/transition model conceptualizes development as entailing a cyclical pattern of alternating consolidation and transition phases and posits that stage advance is predicted by a specific distribution of reasoning across stages indicative of disequilibrium (more reasoning above than below the mode, with a high degree of mixture). The validity of this model was examined in the context of moral reasoning development with the use of standard statistical techniques as well as Bayesian techniques that can better account for classification error. In this longitudinal study. 64 children and adolescents participated in 5 annual administrations of the Moral Judgment Interview. The distribution of their reasoning across stages was used to predict subsequent development. The results support the hypotheses regarding cyclical patterns of change and predictors of stage transition and demonstrate the utility of Bayesian techniques for evaluating developmental change.

Adolescent↗
PubMed2001

College students' attitudes about AIDS: 1986 to 2000.

College students' attitudes about AIDS and people with AIDS (PWAs) were measured over a 15-year period. The AIDS Attitude Scale, designed by Shrum, Turner, and Bruce (1989; AIDS Education and Prevention, 1, 222-230), was administered to introductory psychology students (n = 1,571) at one midsized southeastern university, thus allowing direct comparison of attitudes over time. Overall tolerance about AIDS and PWAs has increased from 1986 to 2000 and robust gender differences in attitudes have been apparent over time, with females expressing more tolerant attitudes. Concerns about contagion from casual contact are diminishing as well and perceived knowledge about AIDS has increased over time. Perceptions about personal susceptibility to HIV remain low and show little relationship to attitudes about AIDS and PWAs. These data may be used to help refine HIV prevention programs for college students and provide an example of a useful approach to monitor changes in attitudes over time.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Naturalistic conceptions of moral maturity.

By examining naturalistic conceptions of moral maturity, this project sought a more comprehensive understanding of moral excellence than is evident in dominant theories of moral development. Studies 1 and 2 involved different samples of 120 adults (17-25, 35-55, and 65+ years). Study 3 involved a sample of 180 undergraduates. In Study 1, a free-listing procedure was used to generate the attributes of a highly moral person as well as those for two related person-concepts. In Study 2, a rating procedure for these attributes was used to generate a prototype of the moral person-concept. In Study 3, a similarity-sorting task was used to uncover people's implicit typology of moral maturity. The findings indicate that naturalistic notions of moral excellence not only contain themes of principled reasoning but also reference aspects of moral character and virtue that enlarge our understanding of the psychological functioning of the mature moral agent.

Adolescent↗
PubMed1995

Site-directed mutagenesis of the human DNA repair enzyme HAP1: identification of residues important for AP endonuclease and RNase H activity.

HAP1 protein, the major apurinic/apyrimidinic (AP) endonuclease in human cells, is a member of a homologous family of multifunctional DNA repair enzymes including the Escherichia coli exonuclease III and Drosophila Rrp1 proteins. The most extensively characterised member of this family, exonuclease III, exhibits both DNA- and RNA-specific nuclease activities. Here, we show that the RNase H activity characteristic of exonuclease III has been conserved in the human homologue, although the products resulting from RNA cleavage are dissimilar. To identify residues important for enzymatic activity, five mutant HAP1 proteins containing single amino acid substitutions were purified and analysed in vitro. The substitutions were made at sites of conserved amino acids and targeted either acidic or histidine residues because of their known participation in the active sites of hydrolytic nucleases. One of the mutant proteins (replacement of Asp-219 by alanine) showed a markedly reduced enzymatic activity, consistent with a greatly diminished capacity to bind DNA and RNA. In contrast, replacement of Asp-90, Asp-308 or Glu-96 by alanine led to a reduction in enzymatic activity without significantly compromising nucleic acid binding. Replacement of His-255 by alanine led to only a very small reduction in enzymatic activity. Our data are consistent with the presence of a single catalytic active site for the DNA- and RNA-specific nuclease activities of the HAP1 protein.

Amino Acid Sequence↗
PubMed1995

Identification of critical active-site residues in the multifunctional human DNA repair enzyme HAP1.

All organisms express dedicated repair enzymes for counteracting the cytotoxic and mutagenic potential of apurinic/apyrimidinic (AP) lesions, which would otherwise pose a serious threat to genome integrity. We present the predicted three-dimensional structure of the major human AP site-specific DNA repair endonuclease, HAP1, and show that an aspartate/histidine pair, in conjunction with a metal ion-coordinating glutamate residue, are critical for catalyzing the multiple repair activities of HAP1. We suggest that this catalytic mechanism is conserved in certain reverse transcriptases, but is distinct from the two metal ion-mediated mechanism defined for other hydrolytic nucleases.

Amino Acid Sequence↗
PubMed1994

A role for the human DNA repair enzyme HAP1 in cellular protection against DNA damaging agents and hypoxic stress.

The HAP1 protein (also known as APE/Ref-1) is a bifunctional human nuclear enzyme required for repair of apurinic/apyrimidinic sites in DNA and reactivation of oxidized proto-oncogene products. To gain insight into the biological roles of HAP1, the effect of expressing antisense HAP1 RNA in HeLa cells was determined. The constructs for antisense RNA expression consisted of either a full-length HAP1 cDNA or a genomic DNA fragment cloned downstream of the CMV promoter in pcDNAneo. Stable HeLa cell transfectants expressing HAP1 antisense RNA were found to express greatly reduced levels of the HAP1 protein compared to equivalent sense orientation and vector-only control transfectants. The antisense HAP1 transfectants exhibited a normal growth rate, cell morphology and plating efficiency, but were hypersensitive to killing by a wide range of DNA damaging agents, including methyl methanesulphonate, hydrogen peroxide, menadione, and paraquat. However, survival after UV irradiation was unchanged. The antisense transfectants were strikingly sensitive to changes in oxygen tension, exhibiting increased killing compared to controls following exposure to both hypoxia (1% oxygen) and hyperoxia (100% oxygen). Consistent with a requirement for HAP1 in protection against hypoxic stress, expression of the HAP1 protein was found to be induced in a time-dependent manner in human cells during growth under 1% oxygen. The possible involvement of a depletion of cellular glutathione being linked to the hypoxic stress-sensitive phenotype of the antisense HAP1 transfectants came from the finding that they also exhibited hypersensitivity to buthionine sulphoximine, an inhibitor of glutathione biosynthesis. We conclude that the HAP1 protein is a key factor in cellular protection against a wide variety of cellular stresses, including DNA damage and a change in oxygen tension.

Buthionine Sulfoximine↗
PubMed1993

Identification of residues in the human DNA repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding.

The DNA binding activity of the c-jun proto-oncogene product is inhibited by oxidation of a specific cysteine residue (Cys-252) in the DNA binding domain. Jun protein inactivated by oxidation of this residue can be efficiently reactivated by a factor from human cell nuclei, recently identified as a DNA repair enzyme (termed HAP1 or Ref-1). The HAP1 protein consists of a core domain, which is highly conserved in a family of prokaryotic and eukaryotic DNA repair enzymes, and a 61-amino-acid N-terminal domain absent from bacterial homologs such as Escherichia coli exonuclease III. The eukaryote-specific N-terminal domain was dispensable for the DNA repair functions of the HAP1 protein but was essential for reactivation of the DNA binding activity of oxidized Jun protein. Consistent with this finding, exonuclease III protein could not reactive Jun. A minimal 26-residue region of the N-terminal domain proximal to the core of the HAP1 enzyme was required for redox activity. By site-directed mutagenesis, cysteine 65 was identified as the redox active site in the HAP1 enzyme. In addition, it is proposed that cysteine 93 interacts with the redox active site, probably via disulfide bridge formation. It is concluded that the HAP1 protein has evolved a novel redox activation domain capable of regulating the DNA binding activity of a proto-oncogene product which is not essential for its DNA repair functions. Identification of a putative active site cysteine residue should facilitate analysis of the mechanism by which the HAP1 protein may alter the redox state of a wide range of transcription factors.

Base Sequence↗
PubMed1989

A longitudinal study of moral reasoning.

Several issues concerning Gilligan's model of moral orientations and Kohlberg's models of moral stages and moral orientations were examined in a longitudinal study with 233 subjects (from 78 families) who ranged in age from 5 to 63 years. They participated in 2 identical interviews separated by a 2-year interval. In each interview, they discussed hypothetical dilemmas and a personally generated real-life dilemma, which were scored for both moral stage and moral orientation (both Gilligan's and Kohlberg's typologies). Results revealed few violations of the stage sequence over the longitudinal interval, supporting Kohlberg's moral stage model. Sex differences were almost completely absent for both Gilligan's and Kohlberg's moral orientations, although there were clear developmental trends. Hypothetical and real-life dilemmas elicited different moral orientations, especially in terms of Kohlberg's typology. The interrelations between the 2 models of moral orientations were generally weak, indicating that they are not synonymous.

Adolescent↗
PubMed1988

Self-reported stress symptoms in farmers.

The self-reported incidence of stress-related symptoms was studied in 817 farm men and women and 109 urban residents. Close to 50% of the farm sample reported the frequent to constant occurrence of the symptoms of trouble relaxing, loss of temper, and fatigue. Over 30% of the farmers reported similar occurrence rates for six additional symptoms. Self-reported symptom rates were significantly higher in farm women than in farm men, higher in younger farmers, higher in mixed farming operations, and higher in farmers who were holding off-farm employment. Symptom scores were significantly higher in the farmers compared to the urban sample. A stepwise discriminant analysis showed that scores on five symptoms were able to distinguish meaningfully between farm and urban groups. It was suggested that the chronic stress associated with the current farm financial crisis may be causing a high self-reported incidence of symptoms among farmers.

Adult↗
PubMed1988

Effect of nifedipine on arrhythmias in the acute phase of myocardial infarction.

In a double-blind placebo-controlled trial to study the effect of nifedipine on ventricular arrhythmias among patients with acute myocardial infarction, 434 patients with suspected myocardial infarction were randomized within 6 h from the onset of chest pain to treatment with nifedipine (p = 217) or placebo (p = 217). During the 48-h treatment period, a 10-mg capsule containing active drug or placebo was administered sublingually every 4 h for 24 h, then orally every 4 h for the next 24 h. Acute myocardial infarction was confirmed in 295 patients (146 in the nifedipine group and 149 in the placebo group). Twenty-four hour ECG tape analysis during 1-5 h from onset of chest pain showed that there was no significant difference in the number of patients with ventricular ectopics, ventricular couplets, ventricular tachycardia (3-9 beats), self terminating or sustained ventricular tachycardia between the two treatment groups. Also during the greater than 5-24 h from onset of chest pain, the numbers of patients with ventricular ectopics, multifocal, bigeminal or couplets, self-terminating ventricular tachycardia or sustained ventricular tachycardia did not differ significantly. However, there was a significant reduction in the number of patients with short runs of ventricular tachycardia (3-9 beats) in the nifedipine-treated group. There was no significant difference among patients with ventricular fibrillation between the two treatment groups.

Adult↗
PubMed1988

Disseminated infection caused by urease-negative Cryptococcus neoformans.

We report a case of fungemia and disseminated disease caused by a urease-negative strain of Cryptococcus neoformans in a patient with the acquired immune deficiency syndrome. Except for failure to hydrolyze urea, the microbiological characteristics of the isolate were typical of C. neoformans. Laboratory specialists should be aware of the occurrence of atypical strains of C. neoformans, particularly those recovered from patients with the acquired immune deficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Effect of nifedipine on enzymatically estimated infarct size in the early phase of acute myocardial infarction.

In a double blind placebo controlled trial, 434 patients with suspected myocardial infarction were randomised to treatment with nifedipine (n = 217) or placebo (n = 217) within six hours from the onset of chest pain. During the treatment period of 48 hours, a 10 mg capsule containing nifedipine or placebo was given sublingually every four hours for 24 hours, then orally every four hours for the next 24 hours. Acute myocardial infarction was confirmed in 295 patients (146 in the nifedipine group and 149 in the placebo group). The median delay time to intervention with nifedipine in patients with acute myocardial infarction was 111 minutes. Infarct size was assessed by the estimation of release of creatine kinase isoenzyme MB and creatine kinase from blood samples taken every four hours for 48 hours. The total mean (SEM) creatine kinase MB released was 406.4 (27.2) IU/l in the nifedipine group and 345.7 (20.5) IU/l in the placebo group. Total mean (SEM) creatine kinase released was 2749.6 (165.1) IU/l in the nifedipine group and 2698.4 (145.9) IU/l in the placebo group. In hospital mortality was similar for both the nifedipine and placebo groups (6.6% and 5.8% respectively). Treatment with nifedipine in the early phase of acute myocardial infarction seems to have no effect on enzymatically measured infarct size.

Aged↗
PubMed1987

Intravenous catheter-associated Malassezia furfur fungemia.

Malassezia furfur, a lipophilic yeast that is the etiologic agent of tinea versicolor, has not been considered as a cause of serious illness in adults in the past. Two adults are described in whom Malassezia furfur fungemia developed while receiving total parenteral nutrition supplemented with lipids. The organism was identified in blood cultures from both patients only after isolation media were supplemented with a source of fatty acids. Because M. furfur will grow only in media supplemented with fatty acids, clinicians should alert the laboratory whenever a lipophilic organism is suspected to be present in blood cultures.

Catheters, Indwelling↗