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Biomedical subjects

S Conway

Publications and source records attributed to S Conway.

At least 19 recordsLinked to original sources
PubMed2005

Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells.

Platinum-based chemotherapeutic regimens are ultimately unsuccessful due to intrinsic or acquired drug resistance. Understanding the molecular basis for platinum drug sensitivity/resistance is necessary for the development of new drugs and therapeutic regimens. In an effort to identify such determinants, we evaluated the expression of approximately 4000 genes using cDNA microarray screening in a panel of 14 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy. These data were analysed relative to the sensitivities of the cells to four platinum drugs (cis-diamminedichloroplatinum (cisplatin), carboplatin, DACH-(oxalato)platinum (II) (oxaliplatin) and cis-diamminedichloro (2-methylpyridine) platinum (II) (AMD473)) as well as the proliferation rate of the cells. Correlation analysis of the microarray data with respect to drug sensitivity and resistance revealed a significant association of Stat1 expression with decreased sensitivity to cisplatin (r=0.65) and AMD473 (r=0.76). These results were confirmed by quantitative RT-PCR and Western blot analyses. To study the functional significance of these findings, the full-length Stat1 cDNA was transfected into drug-sensitive A2780 human ovarian cancer cells. The resulting clones that exhibited increased Stat1 expression were three- to five-fold resistant to cisplatin and AMD473 as compared to the parental cells. The effect of inhibiting Jak/Stat signalling on platinum drug sensitivity was investigated using the Janus kinase inhibitor, AG490. Pretreatment of platinum-resistant cells with AG490 resulted in significant increased sensitivity to AMD473, but not to cisplatin or oxaliplatin. Overall, the results indicate that cDNA microarray analysis may be used successfully to identify determinants of drug sensitivity/resistance and future functional studies of other candidate genes from this database may lead to an increased understanding of the drug resistance phenotype.

Cell Line, Tumor↗
PubMed2004

'Cepacia syndrome' with Burkholderia multivorans, 9 years after initial colonization.

A 16-year-old boy with cystic fibrosis developed 'cepacia syndrome' 9 years after the first isolation of Burkholderia multivorans. It is important to recognise that 'cepacia syndrome' is not restricted to those infected with genomovar type III strains and that rapid, irreversible clinical decline can occur many years after the 1st isolation of Burkholderia cepacia complex (Bcc).

Adolescent↗
PubMed2002

Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center.

We report on an outbreak of colistin-resistant Pseudomonas aeruginosa (CRPA) that occurred in a United Kingdom pediatric cystic fibrosis (CF) unit and involved six children over a period of 5 years. All CRPA-positive children had received aerosolized colistin therapy before first isolation of resistant organisms (mean duration, 3.1 years). Four of the 6 had also received courses of intravenous colistin in the year before the first isolation of CRPA. No impact of CRPA acquisition on respiratory function, clinical condition, or radiological parameters could be demonstrated. Four of the 6 children carried isolates of CRPA indistinguishable on genotyping. Two of these 4 children were sisters. The other 2 were on the same ward together at time of first isolation, and subsequently shared overlapping admissions with one of the sisters. While there is no conclusive evidence for the route of transmission, the frequency of overlapping in-patient admissions between 3 of these patients is suggestive of patient-to-patient transfer in the nosocomial setting.CF clinicians should be aware that colistin resistance can occur in P. aeruginosa, and some of these strains are capable of spread within CF units.

Anti-Bacterial Agents↗
PubMed2001

Cross cultural differences in health related quality of life in adolescents with cystic fibrosis.

PURPOSE: Quality of Life (QoL) is an important outcome measure in health care and pharmacological trials. The trend towards multinational clinical trials may be problematic because it is unclear as to whether, or to what extent, QoL-measures are comparable across cultures. This study compared QoL between English and German adolescents with Cystic Fibrosis (CF) and their healthy peers. METHOD: The study comprised a cross-sectional design. The English subjects formed two groups; 58 adolescents with CF and 49 healthy controls. The German subjects consisted of 26 adolescents with CF and 75 healthy controls. Quality of life was measured using the English and German versions of the SF-36. Demographic (age and gender) and clinical data (FEV1% predicted and BMI) were also recorded. RESULTS: The English and German CF groups had similar age-adjusted lung function and body mass index. Both the English CF and control groups reported a poorer quality of life than their respective German counterparts across several domains of the SF-36. These were limitations in activities due to physical health problems and emotional difficulties, social functioning, energy and vitality and pain. CONCLUSIONS: The differences in quality of life between English and German adolescents with CF appear to be either culturally determined or due to idiosyncrasies in the translations of the SF-36. rather than a consequence of their disease or its management.

Adolescent↗
PubMed2001

Serine residues 110 and 114 are required for agonist binding but not antagonist binding to the melatonin MT(1) receptor.

Site-directed mutation of serine 110 (Ser(3.35)) and serine 114 (Ser(3.39)) in the human melatonin MT(1) receptor to alanine residues reduced ligand binding affinities of seven known melatonin receptor agonists and partial agonists by 3- to 15-fold. These mutants also displayed a relative reduction in their affinities for melatonin-mediated functional responses of 30- and 14-fold, respectively. In contrast to the observed effects of the agonists and partial agonists, the melatonin receptor antagonist luzindole was found to bind to mutants Ser(3.35)Ala and Ser(3.39)Ala with affinities equivalent to that determined for the wild-type melatonin MT(1) receptor. Luzindole was subsequently confirmed as an antagonist of melatonin-mediated functional responses for both mutant receptors. These studies have identified that in the human melatonin MT(1) receptor, Ser(3.35) and Ser(3.39), in transmembrane domain 3, are critical for the formation of the high-affinity ligand binding site for agonists and partial agonists but not for the antagonist luzindole.

Acetamides↗
PubMed2001

A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period.

BACKGROUND: Chronic endobronchial sepsis and profuse airway secretions dominate pulmonary disease in cystic fibrosis. Recombinant human DNase I (dornase alfa) reduces the viscoelasticity of airway secretions and hence may improve clearance of airway secretions. OBJECTIVES: To evaluate the long-term influence of dornase alfa on disease progression by performing a case-controlled study with dornase alfa over a period of 4 years. METHODS: A cohort of patients with cystic fibrosis who have been treated with dornase alfa were matched with a control group of patients with cystic fibrosis who had not received treatment with dornase alfa. The patients were matched by pulmonary function, age, and then sex. All available measurements of forced expiratory volume in one second (FEV1), height, weight and sputum bacteriology were collected for periods when the patients were free from respiratory exacerbations. RESULTS: Thirty-eight patients were matched. Slopes of median changes in FEV1 were -2.19 (-3.32, -1.06) in the control group and -0.75 (-1.87, 0.36) in the dornase alfa-treated group (p = 0.076). There were more infective exacerbations per patient year in the control group [3.13 (1.25-4.25)] in comparison to the dornase alfa group [1.25 (0.63-3.0), p = 0.035] over the 4-year treatment period. Antibiotic requirements were also greater with a median 43.75 (17.5-60.0) days of intravenous antibiotic use per patient year in the control group and 16.25 (8.5-44.0) days in the dornase alfa group (p = 0.034). CONCLUSIONS: The trends suggest that dornase alfa may have some influence on disease progression but in view of the limitations of the current study the need for further long-term studies in larger cohorts of patients is emphasised.

Adult↗
PubMed2000

Effectiveness of dentist-prescribed, home-applied tooth whitening. A meta analysis.

INTRODUCTION: Common clinical experience suggests that tooth whitening agents are 100% effective. This study uses meta-analysis of data from published randomized controlled clinical trials to determine the efficacy of tooth whitening agents. METHODS: A MEDLINE search strategy was developed and implemented to systematically identify clinical trials on dentist-prescribed, home-applied tooth whitening agents, using 10% carbamide peroxide, published between 1989-1999. Inclusion criteria (e.g., in English, human clinical trials) and exclusion criteria (e.g., not placebo controlled) were established and clinical trials that met these criteria were critically appraised for validity and clinical applicability. Meta-analysis was then used to quantitatively integrate the findings. RESULTS: Seven studies were identified that met the inclusion and validity criteria. These studies indicated that: Whitening results in a significant mean change of 6 4 shade guide units (p < 0.01), while the placebo control group exhibited little change (0.7 0.6, p > 0.05). 93% of the bleached patients exhibited 2 shade guide unit change, while 20% of the placebo control group exhibited this change. The brand of bleaching agent had a significant effect on tooth whitening, but the daily application time and duration of treatment did not. Whitening is maintained for 6 months for 1/2 of the people treated. Neither gingival indices nor plaque indices were adversely or favorably affected by bleaching. CLINICAL APPLICABILITY: The data from the reviewed studies indicate that rather than being 100% effective, on average: 73% (93% for bleached group minus 20% placebo group) of people who whiten their teeth will exhibit a whitening that is 2 shade guide units greater than the placebo. 20% of the people who use dentist-prescribed, home-applied bleaching will achieve a mean whitening effect of 5 shade guide units. Re-treatment for 50% of people may be necessary to maintain this effect longer than 6 months. The methods used here are Internet applicable for other clinical topics.

Adult↗
PubMed2000

Chimeric melatonin mt1 and melatonin-related receptors. Identification of domains and residues participating in ligand binding and receptor activation of the melatonin mt1 receptor.

Melatonin receptors bind and become activated by melatonin. The melatonin-related receptor, despite sharing considerable amino acid sequence identity with melatonin receptors, does not bind melatonin and is currently an orphan G protein-coupled receptor. To investigate the structure and function of both receptors, we engineered a series of 14 chimeric receptor constructs, allowing us to determine the relative contribution of each transmembrane domain to ligand binding and receptor function. Results identified that when sequences encoding transmembrane domains 1, 2, 3, 5, or 7 of the melatonin mt(1) receptor were replaced by the corresponding domains of the melatonin-related receptor, the resultant chimeric receptors all displayed specific 2-[(125)I]iodomelatonin binding. Replacement of sequences incorporating transmembrane domains 4 or 6, however, resulted in chimeric receptors that displayed no detectable 2-[(125)I]iodomelatonin binding. The subsequent testing of a "reverse" chimeric receptor in which sequences encoding transmembrane domains 4 and 6 of the melatonin-related receptor were replaced by the corresponding melatonin mt(1) receptor sequences identified specific 2-[(125)I]iodomelatonin binding and melatonin-mediated modulation of cyclic AMP levels. To further investigate these findings, site-directed mutagenesis was performed on residues within transmembrane domain 6 of the melatonin mt(1) receptor. This identified Gly(258) (Gly(6.55)) as a critical residue required for high affinity ligand binding and receptor function.

Animals↗
PubMed2000

Characterisation of human melatonin mt(1) and MT(2) receptors by CRE-luciferase reporter assay.

A cyclic AMP response element (CRE)-luciferase reporter gene assay was used to characterise the functional responses of human melatonin mt(1) and human melatonin MT(2) receptors, stably expressed in the human embryonic kidney cell line HEK293, to a series of six naphthalenic analogues of melatonin. By comparison to the observed melatonin-mediated inhibition of stimulated luciferase levels the naphthalenic series was identified as comprising agonists, partial agonists and one antagonist of melatonin mt(1) and melatonin MT(2) receptor function. Three of the agonist/partial agonist members of this series were also identified as displaying a functional selectivity for the melatonin MT(2) receptor. Competitive displacement of 2-[125I]iodomelatonin binding to the ovine pars tuberalis melatonin ML(1) receptor demonstrated a close correlation to the observed functional luciferase responses of the human melatonin mt(1) receptor. We conclude that the CRE-luciferase reporter gene assay provides an effective functional screening method for the pharmacological characterisation of human melatonin receptor subtypes.

Acetamides↗
PubMed2000

Perceived body image and eating behavior in young adults with cystic fibrosis and their healthy peers.

Treatment aimed at achieving an ideal nutritional status is an integral part of the management of patients with cystic fibrosis (CF). Emphasis is continually placed upon dietary intake and weight. The effects of this on eating behavior and self-perceptions are unclear. This work compared male and female CF adults with a healthy male and female control population with regard to (a) clinical variables, (b) actual, perceived, and desired body shape/body mass index (BMI), and (c) body satisfaction, eating behaviors and attitudes, and self-esteem. Clinical data were recorded for 221 adults with CF and 148 healthy controls. All subjects completed BMI Charts (perception of body weight/BMI), the Eating Attitudes Test, and scales of body satisfaction and self-esteem. CF patients had poorer lung function and nutritional status than controls. Control males accurately perceived their body shape/BMI and were content with it, whereas CF males viewed their BMI as greater than it actually was and desired to be much heavier. Control females viewed their body shape/BMI as less than it actually was and desired to be even slimmer, in comparison with CF females, who perceived their BMI as less than it actually was but were happy with their perceived shape/weight. Control subjects, especially females, dieted to a greater extent and were more preoccupied with food (with binge eating and intended vomiting) than CF patients. Conversely, those with CF reported greater pressure from others to eat than did controls. More problems with food/eating behavior were associated with less body satisfaction and reduced self-esteem. In comparison with a healthy control population, the perceptions and behaviors of CF adults relating to eating, weight, and body image are not abnormal. Indeed, females with CF have fewer problems than their healthy peers.

Adolescent↗
PubMed2000

Benchmarking the clinical orthodontic evidence on Medline.

The purpose of this study was to identify and quantify the availability of orthodontic literature for evidence-based clinical decision-making (ie, sound clinical studies of etiology, diagnosis, treatment, or prognosis meeting basic methodologic criteria for direct clinical use). This is a first step toward developing online decision analysis systems. A search strategy based on Medical Subject Headings (MeSH) for orthodontics was developed to examine MEDLINE using the Ovid Web Gateway search engine. Sensitive and specific methodologic search filters were then employed to identify the 4 categories of information. The results were then subdivided by year to identify trends and sorted to identify source of publications. In the period 1990 to 1998, the MEDLINE searches identified 6938 English-language articles about orthodontics. The mean number of articles (+/-SD) per year ranged from 42+/-25 for specific searches to 314+/-214 for sensitive searches. The number of articles identified by the specific or sensitive searches increased 14% to 21% annually. When subdivided by clinical category, the mean numbers of articles per year for specific and sensitive searches were respectively: etiology 19+/-15 and 91+/-37, diagnosis 11+/-5 and 80+/-35, therapy 3+/-1 and 50+/-23, and prognosis 10+/-7 and 93+/-33. Five dental journals accounted for nearly half of these publications. These results provide several key findings: (1) there is a substantial literature of clinically relevant information in orthodontics upon which to base clinical decisions; (2) the information appears to be balanced between etiology, diagnosis, treatment, and prognosis; (3) approximately 45% of the articles reside in 5 journals, whereas the remainder reside in approximately 66 other journals, making it difficult to stay current; (4) the number of articles is increasing significantly each year; (5) to stay current, one would need to read between 1 and 6 articles per week, 52 weeks per year; (6) these trends suggest the need for computer-based clinical knowledge systems; and (7) the methods used here can be immediately employed to identify the best and most current clinical orthodontic evidence.

Analysis of Variance↗
PubMed1999

Pharmacokinetic interaction of sparfloxacin and digoxin.

Sparfloxacin, a broad-spectrum, oral fluoroquinolone antimicrobial agent, has a long elimination half-life that permits once-daily administration. Antibiotics may increase the oral bioavailability of digoxin, leading to increases in its plasma concentration. Since patients treated with sparfloxacin may be receiving concurrent treatment with digoxin, the possibility of an interaction between sparfloxacin and digoxin was examined in a double-masked, placebo-controlled, multiple-dose, two-way crossover study in 24 healthy male volunteers between 20 and 49 years of age. All subjects were given digoxin 0.3 mg once daily throughout the 20-day study. Sparfloxacin (or placebo) was given as a 400-mg loading dose on day 1, followed by single 200-mg daily doses for 9 days, with crossover to the alternate treatment on days 11 through 20. Plasma levels of digoxin were analyzed by validated radioimmunoassay, and plasma levels of sparfloxacin were analyzed by validated high-performance liquid chromatography. Concomitant administration of sparfloxacin and digoxin was generally well tolerated. Mean values for steady-state area under the concentration-time curve over 24 hours for the 2 treatments were virtually identical: 28.4 ng/h per mL(-1) for digoxin administered with placebo and 28.9 ng/h per mL(-1) for digoxin administered concomitantly with sparfloxacin. Mean steady-state maximum plasma concentrations were 3.91 and 3.59 ng/mL for digoxin with placebo and digoxin with sparfloxacin, respectively. Mean steady-state trough plasma digoxin concentrations for the 2 treatments were 0.87 and 0.89 ng/mL, respectively. Mean times to steady-state maximum plasma concentrations were identical at 0.89 hours for both treatments. Mean steady-state oral clearance was 10.6 L/h for digoxin alone and 10.4 L/h for digoxin with sparfloxacin. Thus administration of sparfloxacin in combination with digoxin did not alter the pharmacokinetics of digoxin in healthy male volunteers aged 20 to 49 years. Steady-state plasma sparfloxacin concentrations were consistent with those obtained in other multiple-dose phase I studies, suggesting that digoxin does not alter the steady-state pharmacokinetics of sparfloxacin.

Adult↗
PubMed1999

Health information resources: tradition and innovation in a medical school curriculum.

Changes in LCME accreditation for medical colleges fostered the development of Health Information Resources, a required, for-credit course created by the Saint Louis University Health Sciences Center Library Reference Department for the first-year medical school curriculum. Six content areas were developed for inclusion in the syllabus: "Electronic Resources Survival Kit"; "Introduction to Problem Based Resources"; "Introduction to Literature Searching"; "MEDLINE Searching Hands-On/Publishing Pearls & Pitfalls"; "The World Wide Web and Patient Information"; and "Introduction to Electronic Mail." A combination of lectures, hands-on instruction, and active learning techniques were employed in the teaching of this class. Submission of a Health Information Resource Guide and a two-part final exam were required.

Academic Medical Centers↗