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Biomedical subjects

M Warner

Publications and source records attributed to M Warner.

At least 73 records · Page 4Linked to original sources
PubMed2001

Activity of moxifloxacin and other quinolones against pneumococci resistant to first-line agents, or with high-level ciprofloxacin resistance.

The activity of moxifloxacin and other quinolones was assessed against 288 epidemiologically diverse isolates of Streptococcus pneumoniae, many of them resistant to one or more first-line agents and/or with increased ciprofloxacin resistance (minimum inhibitory concentrations, MICs 16- > 64 mg/l compared with 1-2 mg/l for most isolates). Moxifloxacin and grepafloxacin were the most active quinolone analogues, inhibiting about 90% of the isolates at < or = 1 mg/l, whereas levofloxacin inhibited 64% of isolates at < = 1 mg/l and ciprofloxacin inhibited 42%. Moxifloxacin also was the most active agent against isolates with elevated ciprofloxacin resistance (MIC 16- > 64 mg/l): moxifloxacin MICs of around 4 mg/l were seen for most such isolates, compared with 16-32 mg for levofloxacin and grepafloxacin. The activity of moxifloxacin against pneumococci resistant to one or more first-line agent suggests it will have a useful therapeutic role, although its activity against highly ciprofloxacin resistant isolates seems marginal.

Anti-Bacterial Agents↗
PubMed2001

Activity of the ketolide telithromycin (HMR-3647) against erythromycin-susceptible and -resistant pneumococci isolated in the UK.

The novel ketolide telithromycin (formerly HMR-3647) was tested against a collection of pneumococci of varying sensitivity to erythromycin and clindamycin, isolated in geographically diverse UK hospitals. Telithromycin was highly active against erythromycin-susceptible pneumococci, the MIC(90) being 0.015 mg/l. Erythromycin-resistant pneumococci that contained the ermB gene, either alone or together with the mefE gene, were cross-resistant to other macrolides and to clindamycin, while erythromycin-resistant pneumococci that contained only the mefE gene were cross-resistant to azithromycin, clarithromycin and roxithromycin but remained susceptible to josamycin and clindamycin. Telithromycin was active against erythromycin-resistant pneumococci irrespective of their mechanism of macrolide resistance, although the MIC(90) (0.25 mg/l) was higher than that seen with erythromycin-sensitive isolates. Telithromycin thus appears to be a potentially useful drug in settings where pneumococcal resistance to macrolides is prevalent.

Anti-Bacterial Agents↗
PubMed2001

Antibiotic resistance in bacteria from magpies (Pica pica) and rabbits (Oryctolagus cuniculus) from west Wales.

The prevalence of antibiotic-resistant bacteria in wild animal and bird populations is largely unknown, with little consistency among the few published reports. We therefore examined intestinal bacteria from magpies (Pica pica) and rabbits (Oryctolagus cuniculus) collected in rural west Wales. Escherichia coli isolates resistant to multiple antibiotics were grown from eight of 20 magpies trapped in spring, 1999 and one of 17 in spring, 2000; the most prevalent resistance trait among these isolates was to tetracycline, but resistances to ampicillin, chloramphenicol, kanamycin, sulphonamide, tetracycline and trimethoprim were also found. Tetracycline-resistant Enterococcus spp. were found in one of 20 magpies in 1999 and three of 17 in 2000. Only one resistant E. coli isolate was detected among gut bacteria from 13 rabbits, and this strain was resistant only to tetracycline. Differences in the prevalence of resistance between bacteria from rabbits and magpies may reflect differences in diet: rabbits graze field edges, whereas magpies are omnivorous and opportunistic. The resistance genes found in E. coli isolates from magpies mostly corresponded to those common among human isolates, but those conferring tetracycline resistance were unique.

Animals↗
PubMed2001

In vitro activity of ketolides HMR 3004 and HMR 3647 and seven other antimicrobial agents against Corynebacterium diphtheriae.

The in vitro activities of two ketolides, HMR 3004 and HMR 3647 (telithromycin), and the comparator agents erythromycin A, azithromycin, clarithromycin, roxithromycin, levofloxacin, ofloxacin and penicillin G were determined by an agar dilution method against 410 isolates of Corynebacterium diphtheriae. Test isolates originated from diverse geographical locations, including the former USSR, where epidemic diphtheria has re-emerged during the 1990s. All isolates tested were susceptible to penicillin G, ofloxacin and levofloxacin. The two ketolides and four macrolides were highly active against 405 of the 410 isolates. HMR 3004 was the most active of the drugs, followed by HMR 3647, clarithromycin, erythromycin A, roxithromycin and azithromycin. Five isolates showed reduced susceptibility to all macrolides and ketolides tested; three were non-toxigenic isolates from Australia and the remaining two were from cases of diphtheria in Vietnam. Inducible (MLS(B)) resistance was detected in the isolates from Vietnam, but not in the isolates originating from Australia. Significant antimicrobial resistance remains rare amongst C. diphtheriae; nevertheless, new ketolide antimicrobials may have a role to play in the treatment and control of this re-emergent pathogen.

Anti-Bacterial Agents↗
PubMed2001

Activity of moxifloxacin against clinical isolates of Streptococcus pneumoniae from England and Wales.

The activity of moxifloxacin was assessed against 1269 isolates of Streptococcus pneumoniae, comprising 462 isolates referred from UK hospitals, primarily for confirmation of resistance to first line agents, and 807 isolates from an enhanced surveillance of invasive infections. Resistance rates to penicillin, erythromycin, tetracycline and chloramphenicol were 88.7% (32.6% intermediate and 56.1% fully resistant), 50, 48 and 22.7%, respectively, for the former, and 8.0 (4.5% intermediate and 3.5% fully resistant), 14.7, 9.0 and 0.6% for the latter. Ninety-four per cent of the referred isolates and 99% of the surveillance isolates were susceptible to moxifloxacin at <or=1 mg/L. Moxifloxacin may therefore be a useful drug for the treatment of patients with pneumococcal infections due to antibiotic-resistant strains or those with severe invasive disease.

Anti-Infective Agents↗
PubMed2001

Antimicrobial susceptibility of Pseudomonas aeruginosa: results of a UK survey and evaluation of the British Society for Antimicrobial Chemotherapy disc susceptibility test.

A survey was conducted in 1999, first to establish the prevalence of antibiotic resistance among clinical isolates of Pseudomonas aeruginosa in the UK and secondly to test whether the use of the standardized British Society for Antimicrobial Chemotherapy (BSAC) disc testing method improved the accuracy of routine susceptibility testing for this organism. Twenty-five hospitals were each asked to collect up to 100 consecutive, clinically significant isolates of P. aeruginosa and to test their susceptibility to amikacin, gentamicin, ceftazidime, imipenem, meropenem, ciprofloxacin, piperacillin and piperacillin/tazobactam using the new BSAC disc method. A total of 2194 isolate reports were available for analysis and 10% of the isolates represented, plus those with unusual resistances, were re-tested centrally for quality control purposes. The zone distributions were essentially unimodal, indicating the absence of major populations with acquired resistance. The results indicated that resistance rates to the beta-lactam, aminoglycoside and quinolone agents tested in P. aeruginosa in the UK remain low (<12%), and were mostly unchanged since a previous survey conducted in 1993. High resistance rates were nevertheless reported for isolates from cystic fibrosis patients. The accuracy of susceptibility testing using the new BSAC disc testing method was better than in previous studies, when Stokes' method was most frequently used. Critically, the proportion of resistant isolates incorrectly reported as susceptible was reduced significantly; nevertheless, depending on the antibiotic, up to 49% of the isolates reported as intermediate or resistant were found susceptible on central re-testing.

Anti-Bacterial Agents↗
PubMed2001

Localization of oestrogen receptors alpha and beta in human testis.

Cellular localization of oestrogen receptor alpha (ERalpha) and beta (ERbeta) proteins were studied in human testis samples using immunohistochemistry, and the expression of the corresponding mRNA was examined with reverse transcription-polymerase chain reaction (RT-PCR). Seven men, aged 28-48 years, who underwent diagnostic testicular biopsy because of azoospermia or to give spermatozoa for intracytoplasmic injection for infertility treatment, donated tissue for the study. One of them had anejaculation but normally functioning testes, and one was diagnosed as having Sertoli cell-only syndrome (SCOS). In addition, expression of ERbeta protein was examined in one testis sample obtained from a man undergoing a sex change operation. Strong ERbeta immunoreactivity was detected in the nuclei of spermatogonia, spermatocytes and early developing spermatids. Elongating spermatids, mature spermatozoa, Sertoli and Leydig cells were all negative for ERbeta. The presence of ERbeta protein was confirmed in Western analysis. With RT-PCR, both wild-type ERbeta and ERbetacx, the isoform which represses wild-type ER function, were easily detected. In most cases, ERbetacx mRNA was more abundantly expressed than wild-type ERbeta. The patient with SCOS expressed neither ERbeta isoform. Neither ERalpha protein nor ERalpha mRNA was detected in any of the samples. We conclude that in the human testis, ERbeta is likely to be the ER that mediates the effects of oestrogen.

Adult↗
PubMed2001

Activity of ertapenem (MK-0826) versus Enterobacteriaceae with potent beta-lactamases.

Ertapenem (MK-0826; L-749,345), a new carbapenem with a long serum half-life, was tested, in vitro, against beta-lactamase-producing bacteria. The new compound had a MIC at which 90% of the isolates were inhibited of 0.06 microg/ml for extended-spectrum beta-lactamase (ESBL)-producing klebsiellas, compared with 0.5 microg/ml for imipenem, 16 microg/ml for cefepime, and >128 microg/ml for ceftazidime and piperacillin-tazobactam. MICs of ertapenem for AmpC-derepressed mutant Enterobacteriaceae were 0.015 to 0.5 microg/ml, whereas imipenem MICs were 0.25 to 1 microg/ml and those of cefepime were 0.5 to 4 microg/ml, and resistance to ceftazidime and piperacillin-tazobactam was generalized. Despite this good activity, the MICs of ertapenem for ESBL-positive klebsiellas mostly were two- to fourfold above those for ESBL-negative strains, and the MICs for AmpC-hyperproducing Enterobacter cloacae and Citrobacter freundii mutants exceeded those for the corresponding AmpC-basal mutants. These differentials did not increase when the inoculum was raised from 10(4) to 10(6) CFU/spot, contraindicating significant lability. Carbapenemase producers were also tested. The IMP-1 metallo-beta-lactamase conferred substantial ertapenem resistance (MIC, 128 microg/ml) in a porin-deficient Klebsiella pneumoniae strain, whereas a MIC of 6 microg/ml was recorded for its porin-expressing revertant. SME-1 carbapenemase was associated with an ertapenem MIC of 2 microg/ml for Serratia marcescens S6, compared with <0.03 microg/ml for Serratia strains lacking this enzyme. In summary, ertapenem had good activity against strains with potent beta-lactamases, except for those with known carbapenemases.

Bacterial Proteins↗
PubMed2001

Mechanisms of estrogen action.

Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ER alpha and ER beta. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ER alpha and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen receptors with agonists and antagonists have revealed much about how ligand binding influences receptor conformation and how this conformation influences interaction of the receptor with coactivators or corepressors and hence determines cellular response to ligands.

Animals↗
PubMed2001

Quantitative analysis of estrogen receptor proteins in rat mammary gland.

Estrogen receptor alpha and beta proteins (ERalpha and ERbeta) at various stages of development of the rat mammary gland were quantified by Western blotting. ERalpha and ERbeta recombinant proteins were used as standards, and their molar concentrations were measured by ligand binding assays. In 3-week-old pregnant, lactating, and postlactating rats the ERalpha content ranged from 0.30-1.55 fmol/microg total protein (mean values). The ERbeta content of the same samples ranged between 1.06-7.50 fmol/microg total protein. At every developmental stage, the ERbeta content of the mammary gland was higher than that of ERalpha. When receptor levels were normalized against beta-actin, it was evident that ER expression changed during development, with maximum expression of both receptors during the lactation period. With an antibody raised against the 18-amino acid insert of the ERbeta variant, originally called ERbeta2 but named ERbetains in this paper, Western blots revealed that ERbetains protein was up-regulated during the lactation period. RT-PCR showed that the levels of messenger RNA of ERbetains paralleled those of the protein. Double immunohistochemical staining with anti-ERalpha and anti-ERbetains antibodies revealed that ERbetains protein colocalized with ERalpha in 70-80% of the ERalpha-expressing epithelial cells during lactation and with 30% of these cells during pregnancy. These observations indicate that expression of ERbetains is regulated not only quantitatively, but also with regard to its cellular distribution. As ERbetains acts as the dominant repressor of ERalpha, we suggest that its coexpression with ERalpha quenches ERalpha function and may be one of the factors that contribute to the previously described insensitivity of the mammary gland to estrogens during lactation.

Actins↗
PubMed2001

Cytochrome P450 in the brain; a review.

After many frustrating decades of unsuccessful attempts to characterize the isoforms of P450 in the brain, several scientific breakthroughs in the 80s and 90s have resulted in major advances in our understanding of cytochromes P450 (CYP) in brain. We now know that classical CYP inducers, e.g. phenobarbital and pregnenolone 16alpha-carbonitrile, which regulate drug-metabolizing enzymes in the liver, are specific ligands for ligand-activated transcription factors, and that the brain content of many of these transcription factors is low. This explains why these inducers have little effect on brain CYP content. The most effective inducers of brain P450 are some of the CNS active drugs and solvents. The level of CYPs in brain, approximately 0.5-2% of that in liver, is too low to significantly influence the overall pharmacokinetics of drugs and hormones in the body. Instead CYPs appear to have specific functions in brain, e.g. regulation of the levels of endogenous GABAA receptor agonists maintenance of brain cholesterol homeostasis and elimination of retinoids The novel CYPs which catalyse these reactions have recently been characterized. They are abundantly expressed in the brain confirming what has been previously found, i.e. that the major hepatic, adrenal and gonadal CYP isozymes contribute very little to the overall content of CYP in brain. It is not clear what fraction of brain CYP has been characterized, although a complete characterization of constitutive and induced CYPs in brain is essential for understanding the role of these enzymes in brain physiology as well as in age-related and xenobiotic-induced neurotoxicity.

Animals↗
PubMed2001

Teaching evidence-based medical care: description and evaluation.

BACKGROUND AND OBJECTIVES: This paper describes and evaluates several years of a seminar series designed to stimulate residents to seek evidence-based answers to their clinical questions and incorporate this evidence into practice. METHODS: At the first session, 86 of 89 (97%) residents completed a baseline needs assessment questionnaire. Post-course self-assessment questionnaires measured change from the first to the final seminar session in six domains of interest and skill, as well as residents' preferred sources of information for clinical problem solving up to 2 years after the course. RESULTS: Before the seminars, 48% of residents reported that textbooks were their most important source of information for solving clinical problems. A total of 58 of 75 (77%) residents completed the first post-course questionnaire. Residents reported significant increases in skill at formulating clinical questions and searching for evidence-based answers, appraising reviews, and deciding when and how to incorporate new findings into practice. Use of secondary sources of information such as "Best Evidence," moved up in importance from before the course to after the course. CONCLUSIONS: First-year family practice residents who completed our seminar series have reported increased skill at blending consideration of a clinical problem with the use of secondary sources of information to access evidence to support their health care decisions.

Clinical Competence↗
PubMed2001

Drowning-related deaths in New Zealand, 1980-94.

OBJECTIVE: To describe the epidemiology of drowning in New Zealand for the period 1980-94. METHODS: Drowning-related incidents were identified by linking New Zealand Health Information Service and Water Safety New Zealand databases. RESULTS: 2,606 drowning-related incidents were identified. In three-quarters of the incidents, drowning was listed as the immediate cause of death. The majority of drownings were unintentional (85%), involved males (76%), and 0-4 and 15-24 year age groups had the highest rates. Boating was the leading cause of unintentional drowning (28%) followed by swimming and other water sports (19%), motor vehicle drownings (13%) and falls or slips (12%). CONCLUSIONS AND IMPLICATIONS: Although there has been a significant decline in drownings, New Zealand compares poorly internationally. In particular, our unintentional drowning rate is twice that of Australia. For New Zealand to continue to make substantial progress in addressing its overall drowning rate, we need to continue and strengthen our efforts in priority areas, in particular those due to motor vehicle crashes and boating and among pre-schoolers, adolescents and young adults. Motor vehicle traffic crashes warrant closer attention than has been the case to date.

Accidents↗
PubMed2000

Signalling pathways regulating the dephosphorylation of Ser729 in the hydrophobic domain of protein kinase Cepsilon upon cell passage.

We have recently demonstrated that in quiescent fibroblasts protein kinase C (PKC) epsilon(95) is phosphorylated at Ser(729), Ser(703), and Thr(566) and that upon passage of quiescent cells phosphorylation at Ser(729) is lost, giving rise to PKCepsilon(87). Ser(729) may be rephosphorylated later, suggesting cycling between PKCepsilon(87) and PKCepsilon(95). Here we show that the dephosphorylation at Ser(729) is insensitive to okadaic acid, calyculin, ascomycin C, and cyclosporin A, suggesting that dephosphorylation at this site is not mediated through protein phosphatases 1, 2A or 2B. We demonstrate that this dephosphorylation at Ser(729) requires serum and cell readhesion and is sensitive to rapamycin, PD98059, chelerythrine, and Ro-31-8220. These results suggest that the phosphorylation status of Ser(729) in the hydrophobic domain at Ser(729) is regulated independently of the phosphorylation status of other sites in PKCepsilon, by a mTOR-sensitive phosphatase. The mitogen-activated protein kinase pathway and PKC are also implicated in regulating the dephosphorylation at Ser(729).

3T3 Cells↗