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Biomedical subjects

Richard Wise

Publications and source records attributed to Richard Wise.

At least 19 recordsLinked to original sources
PubMed2006

Antimicrobial resistance: paradox, actions and economics.

The threat from antimicrobial-resistant organisms is accumulating and accelerating. One strand of the action that an adequate response to this threat demands is good clinical governance through management and audit of antimicrobial prescribing in hospitals. This is the subject of another article in this issue of the Journal, which describes the guidelines developed by the Scottish Medicines Consortium and Scottish Health Executive to tackle this problem. However, the problems posed by resistant organisms are wider still. In a period of increased threat, innovation (new drugs and technologies) seems to be in decline. There are grounds for serious concern that the current economic model is not capable of responding adequately. Governments need to acknowledge and address this fact. Patient outcomes will suffer increasingly if governments do not act to change the status quo.

Anti-Bacterial Agents↗
PubMed2006

The role of semantics and grammatical class in the neural representation of words.

On the basis of neuropsychological and functional imaging evidence, meaning and grammatical class (particularly the verb-noun distinction) have been proposed as organizational principles of linguistic knowledge in the brain. However, previous studies investigating verb and noun processing have been confounded by the presence of systematic correlations between word meaning and grammatical class. In this positron emission tomography study, we investigated implicit word processing using stimuli that allowed the effects of semantic and grammatical properties to be examined independently, without grammatical-semantic confounds. We found that left hemisphere cortical activation during single-word processing was modulated by word meaning, but not by grammatical class. Motor word processing produced significant activation in left precentral gyrus, whereas sensory word processing produced significant activation in left inferior temporal and inferior frontal regions. In contrast to previous studies, there were no effects of grammatical class in left inferior frontal gyrus (IFG). Instead, we found semantic-based differences within left IFG: anterior, but not posterior, left IFG regions responded preferentially to sensory words. These findings demonstrate that the neural substrates of implicit word processing are determined by semantic rather than grammatical properties and suggest that word comprehension involves the activation of modality-specific representations linked to word meaning.

Adult↗
PubMed2005

Quantitative assessment of the reproducibility of functional activation measured with BOLD and MR perfusion imaging: implications for clinical trial design.

BOLD contrast is the most commonly used functional MRI method for studies of brain activity. However, the underlying physiological processes giving rise to measured BOLD signal changes (which include contribution from changes in cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2)) vary substantially between sessions and subjects. To determine whether direct CBF measurement is a more reliable technique, we compared the localisation of activation and reproducibility of relative signal change measured by optimised BOLD versus CBF measured using the arterial spin labelling (ASL) technique. Data were collected within the primary sensorimotor cortex in normal healthy controls performing a simple finger-tapping task over three imaging sessions (two on same day and one on a different day). The displacement between the foci of BOLD and CBF activation was less than the linear dimension of one voxel (2.4 mm), however, BOLD activation was significantly closer to the nearest draining vein compared to CBF activation (P=0.030). For the relative signal change measurement, we found that CBF has a lower inter-subject variation than BOLD (P<0.05), enabling a smaller sample size for any given effect size, although the intra-subject variation across sessions for CBF was not significantly different from BOLD. BOLD imaging provides the optimal contrast for exploratory brain activation mapping, however, for a single time-point group study, CBF has reduced variance. In addition, the reduction of variance over time using CBF measurements (non-significant) suggests it could potentially provide a more useful approach when assessing longitudinal activation changes.

Adult↗
PubMed2004

Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study.

We obtained [11C](R)-PK11195 PET scans in six patients at different time points between 3 and 150 days after onset of ischemic stroke in order to measure the time course of microglial activation. Increased [11C](R)-PK11195 binding around the lesion was observed as early as 3 days. Scans at later time points showed ongoing changes in the distribution of the [11C](R)-PK11195 signal, involving the area of the primary lesion and areas distant from the primary lesion site. Our data suggest that [11C](R)-PK11195 PET can be used to investigate both the primary lesion and remote pathological changes following Wallerian degeneration.

Adult↗
PubMed2004

The relentless rise of resistance?

Antibiotics have undoubtedly made a major contribution to improvements in both human and animal health and welfare. Recent years have brought alarming rises in the prevalence of resistance to some agents among certain groups of bacteria. Concern is growing that therapeutic options will become increasingly limited if resistance rates continue to rise. There is widespread agreement that action is required to reverse or at least slow this process. Necessary steps to manage the situation include better surveillance to assess accurately the extent of problems, more prudent use of the available antibiotics to conserve valuable therapeutic resources and improved infection control to limit the spread of resistant organisms. Achieving these goals will not be possible without government, the medical profession and the public being better informed and educated. Regulatory bodies and the pharmaceutical industry need to work together to ensure a steady supply of new antimicrobials. Our understanding of the processes driving resistance at both the molecular and population levels is advancing. However, the relative contributions of the various uses of antimicrobials to the resistance problem and which will be the most effective containment measures are still hotly debated. Progress is being made, but continued concerted action is necessary if the usefulness of this most important group of therapeutic agents is to be preserved.

Anti-Bacterial Agents↗
PubMed2004

Molecular and kinetic comparison of the novel extended-spectrum beta-lactamases CTX-M-25 and CTX-M-26.

CTX-M-25 is a novel extended-spectrum beta-lactamase isolated from a single Canadian Escherichia coli isolate. Susceptibility testing demonstrated that this enzyme confers resistance to both cefotaxime and ceftazidime, but the level of resistance was reduced with the addition of beta-lactamase inhibitors. The bla(CTX-M-25) gene was detected on a 111-kb plasmid. It is a member of the CTX-M-8 group and has the closest amino acid identity (99%; three amino acid substitutions) with CTX-M-26. The bla(CTX-M-26) gene was detected on a 100-kb plasmid isolated from a Klebsiella pneumoniae strain from the United Kingdom, and plasmid profiling revealed that it showed some homology to the bla(CTX-M-25)-harboring plasmid. Both CTX-M genes were located downstream of ISEcp1, although the copy upstream of bla(CTX-M-25) was disrupted by IS50-A. Comparative kinetic studies of recombinant CTX-M-25 and CTX-M-26 enzymes showed that CTX-M-25 has a higher level of ceftazidime hydrolysis (kcat values, 33 and 0.005 s(-1) for CTX-M-25 and CTX-M-26, respectively).

Amino Acid Sequence↗
PubMed2003

Intrapulmonary penetration of linezolid.

OBJECTIVE: This study was designed to measure the concentrations of linezolid in bronchial mucosa, pulmonary macrophages and epithelial lining fluid and to compare them with simultaneous blood levels. METHODS: Ten adult patients undergoing bronchoscopy for diagnostic purposes were given oral linezolid at a dosage of 600 mg twice a day for a total of six doses. Patients with active lung infection were excluded from the study. Flexible bronchoscopy was carried out between 2 and 8 h after the last dose of linezolid. Bronchial biopsies and bronchoalveolar lavage were carried out and a simultaneous blood sample obtained. Linezolid levels were measured using high-performance liquid chromatography (HPLC). RESULTS: Mean concentrations of linezolid were 13.4 mg/L in serum, 10.7 mg/kg in mucosa, 8.1 mg/L in alveolar macrophages and 25.1 mg/L in epithelial lining fluid. The mean site/serum concentration ratios were 0.79 for bronchial mucosa, 0.71 for macrophages and 8.35 for epithelial lining fluid. CONCLUSIONS: The MIC90 (< or =4 mg/L) of linezolid for Staphylococcus aureus and Streptococcus pneumoniae was exceeded in serum and bronchial mucosa in all subjects, in epithelial lining fluid in nine subjects and in macrophages in six subjects.

Acetamides↗
PubMed2003

Maximizing efficacy and reducing the emergence of resistance.

An understanding of the pharmacokinetic and pharmacodynamic properties of antimicrobial agents enables better choices to be made in the clinical situation. The fluoroquinolones share several useful pharmacokinetic properties, such as good bioavailability (in most cases >85%) and the ability to penetrate and concentrate intracellularly, giving them activity against pathogens such as Legionella pneumophila and Listeria monocytogenes. Nevertheless, there are some important differences between the fluoroquinolones, and even the newer fluoroquinolones demonstrate a range of pharmacodynamic properties. When considering the area under the inhibition curve (AUIC) and the Cmax/MIC, the comparative figures are: ciprofloxacin and ofloxacin (5-25, 1-5); levofloxacin, grepafloxacin and gatifloxacin (25-75, 5-10); trovafloxacin (75-250, 10-20) and moxifloxacin, clinafloxacin and gemifloxacin (>250, >20). The development of resistance is also a concern, and selecting an agent that reaches an adequate concentration above the MIC will reduce the opportunity for resistance to develop. These properties should be considered when selecting a fluoroquinolone either for inclusion in a formulary, or for use in an individual patient.

Animals↗
PubMed2002

The battle against emerging antibiotic resistance: should fluoroquinolones be used to treat children?

Inappropriate use of antibiotic drugs in humans and animals has led to widespread resistance among microbial pathogens. Resistance is the phenotypic expression corresponding to genetic changes caused by either mutation or acquisition of new genetic information. In some cases, multidrug resistance occurs. Streptococcus pneumoniae is one of the most important respiratory pathogens, playing a major role in both upper and lower respiratory tract infections. Pneumococcal resistance to antimicrobials may be acquired by means of horizontal transfer followed by homologous recombination of genetic material from the normal flora of the human oral cavity or by means of mutation. Resistance to penicillins and macrolides has been increasing for some time, but, recently, fluoroquinolone resistance has become an issue as well. We are concerned that, if fluoroquinolones are approved for use in children, their widespread use will result in rapid emergence of pneumococcal resistance, because children are more often colonized in the nasopharynx with high-density populations of pneumococci than are adults.

Anti-Bacterial Agents↗