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Biomedical subjects

Anne Wright

Publications and source records attributed to Anne Wright.

9 recordsLinked to original sources
PubMed2006

Interrelationships of quantitative asthma-related phenotypes in the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy.

BACKGROUND: Delineating asthma subphenotypes is of interest to understand the cause of the disease. Few studies have addressed the interrelationships of quantitative asthma-related traits. OBJECTIVE: We sought to study the interrelationships of allergy markers and FEV(1) in relation to asthma and sex in children and adults. METHODS: Total IgE levels, skin prick test (SPT) positivity, eosinophil counts, and FEV(1) were assessed in 299 asthmatic cases (children and adults) recruited in chest clinics and 309 nonasthmatic population-based control subjects in the French Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy. RESULTS: Allergy parameters were significantly higher in asthmatic cases than in control subjects for children and adults and for both sexes. Sex and age modified the pattern of concordance of high IgE levels, SPT positivity, and eosinophilia among asthmatic cases, with the greatest overlap in male children (64%) and the lowest in male adults (18%). Patterns of change over the lifespan of IgE levels, eosinophil counts, and FEV(1)/height(2) varied, with the acceleration of FEV(1) decrease being particularly evident in asthmatic adults. In adult cases and control subjects, SPT positivity (particularly to indoor allergens) was significantly related to IgE levels but not to eosinophil counts. The association of eosinophil counts with IgE levels was evident only in children. Environmental factors (smoking, pets, and country living) did not alter the patterns observed. CONCLUSIONS: Each allergy-related phenotype showed a distinct relation with asthma, with the role for eosinophils being different than that for IgE levels and SPT responses. CLINICAL IMPLICATIONS: Taking age and sex into account is essential for understanding the interrelationships of the various allergy-related phenotypes to asthma status.

Adult↗
PubMed2006

The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome.

We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism.

Adaptation, Physiological↗
PubMed2006

Direct measurement of in-vivo vaginal microbicide levels of PRO 2000 achieved in a human safety study.

OBJECTIVES: To directly measure the cervico-vaginal lavage (CVL) and plasma PRO 2000 concentrations achieved by vaginal dosing. DESIGN: A sub-study of a prospective randomized, double-blind phase 1 trial of a candidate vaginal microbicide, PRO 2000 gel. METHODS: Thirty-six sexually abstinent women self-administered 4% PRO 2000 gel, 0.5% PRO 2000 gel or placebo gel twice on day 0 and then once daily for a further 12 days. RESULTS: There was no evidence of systemic absorption of PRO 2000. PRO 2000 concentrations in CVL exceeded 25 microg/ml in all women in both the 4 and 0.5% groups at 2 h post-first dose, and in 10 of 12 of the women in the 4% gel group compared with five of 12 of women in the 0.5% group at 12 h post-seventh dose. Single use of both 4 and 0.5% PRO 2000 gels was therefore associated with levels of PRO 2000 in CVL that would be capable of preventing HIV infection in vitro, although the 4% gel gave a greater margin of excess. Levels substantially in excess of the target concentration were present 12 h after repeated dosing in twice as many 4% gel recipients compared with 0.5% gel recipients. CONCLUSIONS: Both PRO 2000 gel strengths provided satisfactory in-vivo HIV inhibitory concentrations. However, our observations show that higher concentrations of PRO 2000 are likely to provide a greater margin of potential efficacy in the context of sexual intercourse provided safety issues are equivalent for differing concentrations of the agent.

Absorption↗
PubMed2005

Proteomic analysis of cell surface proteins from Clostridium difficile.

Clostridium difficile is a bacterium that causes disease of the large intestine, particularly after treatment with antibiotics. The bacterium produces two toxins (A and B) that are responsible for the pathology of the disease. In addition, a number of bacterial virulence factors associated with adhesion to the gut have previously been identified, including the cell wall protein Cwp66, the high-molecular weight surface layer protein (HMW-SLP) and the flagella. As the genome sequence predicts many other cell wall associated proteins, we have investigated the diversity of proteins in cell wall extracts, with the aim of identifying further virulence factors. We have used a number of methods to remove the proteins associated with the cell wall of C. difficile. Two of the resulting extracts, obtained using low pH glycine treatment and lysozyme digestion of the cell wall, have been analysed in detail by two-dimensional electrophoresis and mass spectrometry. One hundred and nineteen spots, comprising 49 different proteins, have been identified. The two surface layer proteins (SLPs) are the most abundant proteins, and we have also found components of the flagellum. Interestingly, we have also determined that a number of paralogs of the HMW-SLP are expressed, and these could represent targets for further investigation as virulence factors.

Bacterial Proteins↗
PubMed2005

Presentation and treatment of asthma among native children in southwest Alaska delta.

Our objective was to determine if a different presentation of asthma among Eskimo children in southwest Alaska influenced treatment for asthma. Data regarding symptoms, medication use, and hospitalization were obtained from the medical records of 58 Eskimo children diagnosed with asthma. Half of the children also had a diagnosis of chronic lung disease (CLD), and 57% had a history of allergies. CLD was associated with significantly more visits for wheeze (P=0.02), asthma (P <0.005), and lower respiratory tract illnesses (P <0.005), and a greater incidence (P <0.005) and frequency (P <0.005) of hospitalizations. Allergy status showed no similar relation with utilization of health services. Inhaled corticosteroids were prescribed for a minority (38%) of these asthmatic children. Allergic children tended to be more likely to receive inhaled steroids, and they received significantly more prescriptions for inhaled steroids compared to children without allergies. Those with CLD only were no more likely to receive inhaled steroids than other children, despite their higher incidence of hospitalization. Although the proportion of children with CLD or allergy did not differ significantly by village, there were significant regional differences in healthcare utilization and medication use. In conclusion, while CLD was the primary determinant of healthcare utilization among these native children with asthma, only allergic children with CLD were more likely to receive inhaled steroids.

Adolescent↗
PubMed2005

Diverse plasmid DNA vectors by directed molecular evolution of cytomegalovirus promoters.

Genetic vaccinations, gene therapy, and manufacturing of therapeutic proteins would benefit from promoter sequences that provide improved or prolonged expression levels. The cytomegalovirus (CMV) promoter is one of the most potent promoters known to date, and no previous examples of improved activity of this promoter by sequence mutagenesis have been reported. This study describes directed molecular evolution of CMV promoters derived from two human and two nonhuman primate strains of CMV by DNA shuffling and screening. Libraries of chimeric promoters were screened and analyzed for expression levels and immune responses, using plasmid DNA vectors encoding luciferase and beta-galactosidase. The results indicate that high functional diversity among CMV promoters can be generated, and the chimeric promoters selected after two rounds of DNA shuffling and particularly designed screening assays provided approximately 2-fold increased luciferase reporter gene expression and anti-beta-galactoside antibody response in vivo when compared with wild-type promoters. Sequence analysis of the shuffled promoters identified several mutations potentially contributing to the observed enhanced or reduced promoter activities and identified a 42-nucleotide region that appears obsolete for the functioning of the CMV promoter. Taken together, these data demonstrate the feasibility of generating diverse promoter sequences by DNA shuffling and screening methods, and provide novel structure- function information about CMV promoters. DNA shuffling and screening technologies provide a new approach to promoter optimization and development of optimal expression vectors for genetic vaccinations, gene therapy, and protein expression.

Animals↗
PubMed2002

Expression, purification, crystallization and preliminary characterization of an HHED aldolase homologue from Escherichia coli K12.

An ORF designated b2245 (yfaU) in the Escherichia coli K12 genome sequence, identified as an HHED aldolase homologue, was cloned into the high-expression plasmid pT7-7 and overexpressed in E. coli B835(DE3). The enzyme was purified in three steps to 95% purity prior to crystallization. Crystals were obtained by the hanging-drop vapour-diffusion method at 277 K from a number of screening conditions. Crystals suitable for structural studies were grown from solutions containing 0.4 M ammonium dihydrogen phosphate and grew to a maximum dimension of approximately 0.5 mm. Diffraction data to 1.7 A were collected using an in-house Cu Kalpha radiation source at 100 K. The crystals belong to space group C222(1), with unit-cell parameters a = 105.1, b = 136.6, c = 123.1 A. A 90% complete data set was collected to 1.78 A from a single native crystal using in-house facilities.

Aldehyde-Lyases↗