Biomedical subjects

P Williams

Publications and source records attributed to P Williams.

At least 37 records · Page 2Linked to original sources

PubMed2004

Deterministic and stochastic modelling of endosome escape by Staphylococcus aureus: "quorum" sensing by a single bacterium.

Deterministic and stochastic models describing quorum sensing by Staphylococcus aureus within an endosome, and the subsequent escape via the production of virulence factors, are developed and analysed. Particular attention is given to a biologically-relevant asymptotic limit of the problem, for which the solutions, including the endosome escape time, can be explicitly characterised in terms of the model parameters.

Computer Simulation↗

PubMed2004

Biocatalytic scrubbing of gaseous acrylonitrile using Rhodococcus ruber immobilized in synthetic silicone polymer (ImmobaSil) rings.

Microbial detoxification of acrylonitrile vapor was performed using Rhodococcus ruber immobilized into rings of a synthetic silicone polymer (ImmobaSil ) sponge. The immobilization matrix was used as both the cell support material and also as the trickle-bed column packing. The elimination capacity of the biocatalytic scrubber was determined for different influent concentrations of gaseous acrylonitrile. The working life of the nongrowing biocatalyst was also examined under test conditions and was found to be at least 70 days before biocatalyst replacement was required. An elimination capacity of 4.0 kg m(-3) h(-1) was achieved with a 95% removal efficiency, and an elimination capacity of over 7.2 kg m(-3) h(-1) acrylonitrile was achieved with a removal efficiency of 90%. This elimination capacity is 10 times that previously published in the literature.

Acrylonitrile↗

PubMed2004

Orthodontics. Part 7: Fact and fantasy in orthodontics.

Clinical research has previously lacked good methodology and much opinion was based on anecdote which is widely regarded as the weakest form of clinical evidence. There are few randomised control trials in orthodontics which support or refute areas of dogma. The number of randomised control trials is increasing significantly. There is currently however no good evidence that orthodontics causes or cures temporomandibular joint dysfunction, that appropriate extractions in orthodontics ruin patients' profiles, or that the orthodontist is able to significantly influence facial growth with appliances.

Evidence-Based Medicine↗

PubMed2004

Mathematical modelling of therapies targeted at bacterial quorum sensing.

Bacteria commonly use diffusible signal molecules to synchronise their behaviour by facilitating population dependent co-ordination. This cell-to-cell signalling mechanism is known as quorum sensing (QS) and provides a way of ensuring that certain genes are 'switched on' only when a certain signal concentration (typically corresponding to a large population density) has been reached. In this paper we focus on the QS system of the human pathogen Pseudomonas aeruginosa, which employs a complex hierarchy of QS signalling systems, which regulate the formation of multiple exoproducts, swarming and biofilm differentiation. In P. aeruginosa, the signal molecules are N-acylated homoserine lactones (AHLs; e.g., N-(3-oxododecanoyl)-homoserine lactone [3-oxo-C12-HSL]), which bind to transcriptional regulator proteins (LasR in the case of 3-oxo-C12-HSL) to activate the expression of target genes including lasI, which codes for the 3-oxo-C12-HSL synthase. Since the virulence of P. aeruginosa is controlled by QS, agents (QSBs) designed to block this cell-to-cell communication have potential as novel antibacterials. By drawing on existing models for the reaction kinetics of this system, we model a growing population subject to treatment with two kinds of QSB, together with a conventional antibiotic. The first kind of QSB is assumed to act by diffusing through the cell membrane and then destabilising/sequestering LasR, while the second kind remains outside the cell and degrades the AHL signal molecule itself. Numerical and mathematical analysis of the resulting systems of ordinary differential equations reveals in particular that, while a sufficiently high dose of QSB is, in all cases considered, able to reduce the AHL concentration (and hence virulence) to a negligible level, the qualitative response to treatment is sensitive to parameter values.

4-Butyrolactone↗

PubMed2004

Cell-signalling repression in bacterial quorum sensing.

In this paper we expand on two mathematical models for investigating the role of three distinct repression mechanisms within the so-called quorum sensing (QS) cell-signalling process of bacterial colonies growing (1) in liquid cultures and (2) in biofilms. The repression mechanisms studied are (i) reduction of cell signalling molecule (QSM) production by a constitutively produced agent degrading the messenger RNA of a crucial enzyme (QSE), (ii) lower QSM production rate due to a negative feedback process and (iii) loss of QSMs by binding directly to a constitutively produced agent; the first two mechanisms are known to be employed by the pathogenic bacterium Pseudomonas aeruginosa and the last is relevant to the plant pathogen Agrobacterium tumefaciens. The modelling approach assumes that the bacterial colony consists of two sub-populations, namely down- and up-regulated cells, that differ in the rates at which they produce QSMs, while QSM concentration governs the switching between sub-populations. Parameter estimates are obtained by curve-fitting experimental data (involving P. aeruginosa growth in liquid culture, obtained as part of this study) to solutions of model (1). Asymptotic analysis of the model (1) shows that mechanism (i) is necessary, but not sufficient, to predict the observed saturation of QSM levels in an exponentially growing colony; either mechanism (ii) or (iii) also needs to be incorporated to obtain saturation. Consequently, only a fraction of the population will become up-regulated. Furthermore, only mechanisms (i) and (iii) affect the main timescales for up-regulation. Repression was found to play a less significant role in a biofilms, but mechanisms (i)-(iii) were nevertheless found to reduce the ultimate up-regulated cell fraction and mechanisms (i) and (iii) to increase the timescale for substantial up-regulation and to decrease the wave speed of an expanding front of QS activity.

Biofilms↗

PubMed2004

Potato plants genetically modified to produce N-acylhomoserine lactones increase susceptibility to soft rot erwiniae.

Many gram-negative bacteria employ N-acylhomoserine lactones (AHL) to regulate diverse physiological processes in concert with cell population density (quorum sensing [QS]). In the plant pathogen Erwinia carotovora, the AHL synthesized via the carI/expI genes are responsible for regulating the production of secreted plant cell wall-degrading exoenzymes and the antibiotic carbapen-3-em carboxylic acid. We have previously shown that targeting the product of an AHL synthase gene (yenI) from Yersinia enterocolitica to the chloroplasts of transgenic tobacco plants caused the synthesis in planta of the cognate AHL signaling molecules N-(3-oxohexanoyl)-L-homoserine lactone (3-oxo-C6-HSL) and N-hexanoylhomoserine lactone (C6-HSL), which in turn, were able to complement a carI-QS mutant. In the present study, we demonstrate that transgenic potato plants containing the yenI gene are also able to express AHL and that the presence and level of these AHL in the plant increases susceptibility to infection by E. carotovora. Susceptibility is further affected by both the bacterial level and the plant tissue under investigation.

Carboxylic Ester Hydrolases↗

PubMed2004

The effect of propranolol on glyceryltrinitrate-induced headache and arterial response.

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 microg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.

Adult↗

PubMed2004

TRIPSTAR: prioritizing oral triptan treatment attributes in migraine management.

Migraine can be associated with severe pain and is often very disabling. Optimal treatment should provide rapid and sustained, complete pain relief, be well tolerated and restore normal function. The seven commercially available triptans show differences in performance on individual treatment attributes. The TRIPSTAR multiattribute decision model compares the profiles of the oral triptans, using efficacy and tolerability data weighted for importance, to identify if measurable differences are clinically relevant. Application of the TRIPSTAR model was demonstrated at the Migraine Trust International Symposium 2002, where delegates collectively prioritized treatment attributes according to the needs of a specific patient case history. The TRIPSTAR model identified the preferred triptans for this patient. These three triptans, almotriptan 12.5 mg, eletriptan 80 mg and rizatriptan 10 mg, standout in a triptan meta-analysis, three TRIPSTAR surveys and in a demonstration of the TRIPSTAR model at a symposium in the USA. Taken together the findings suggest that some differences amongst triptans may be relevant in clinical practice.

Administration, Oral↗

PubMed2004

Real-time monitoring of intracellular Staphylococcus aureus replication.

A high-throughput system to rapidly assess the intracellular replication of Staphylococcus aureus has been developed utilizing S. aureus transformed with a dual gfp-luxABCDE reporter operon under the control of a growth-dependent promoter. Replication of tagged bacteria internalized into bovine mammary epithelial cells (MAC-T) could be measured by monitoring fluorescence and bioluminescence from the reporter operon following removal of extracellular bacteria from the plates. Bacterial replication inside cells was confirmed by a novel ex vivo time-lapse confocal microscopic method. This assay of bacterial replication was used to evaluate the efficacy of antibiotics which are commonly used to treat staphylococcal infections. Not all antibiotics tested were able to prevent intracellular replication of S. aureus and some were ineffective at preventing replication of intracellular bacteria at concentrations above the MIC determined for bacteria in broth culture. Comparison of the fluorescence and bioluminescence signals from the bacteria enabled effects on protein synthesis and metabolism to be discriminated and gave information on the entry of compounds into the eukaryotic cell, even if bacterial replication was not prevented. Elevated resistance of S. aureus to antibiotics inside host cells increases the likelihood of selecting S. aureus strains which are resistant to commonly used antimicrobial agents within the intracellular niche. The approach presented directly assesses intracellular efficacy of antibiotics and provides an evidence-based approach to antibiotic selection for prescribing physicians and medical microbiologists.

Animals↗

PubMed2004

Eczema and early solid feeding in preterm infants.

AIMS: To establish whether development of eczema is influenced by feeding practices in preterm infants, while taking account of confounding factors. METHODS: Data were assembled from 257 infants born prematurely and studied to 12 months post-term. Logistic regression analysis was performed to establish the association between feeding practices and eczema, allowing for potential confounding factors including the infants' gender, parental atopic status, social background, and parental smoking habits. RESULTS: For the development of eczema (with or without other symptoms) by 12 months post-term, the introduction of four or more solid foods by or before 17 weeks post-term was a significant risk (odds ratio 3.49). Male infants were at significantly higher risk (odds ratio 1.84). In addition, having non-atopic parents who introduced solid foods before 10 weeks post-term or having at least one atopic parent represented a significant risk scenario (odds ratio 2.94). CONCLUSIONS: Early introduction of a diverse range of solid foods may predispose the preterm infant to eczema development by 12 months post-term. Furthermore, non-atopic parents who practice early as opposed to late introduction of solid foods may be exposing preterm infants to a greater risk of eczema by 12 months post-term.

Adolescent↗

PubMed2004

The use of osseointegrated implants in orthodontic patients: I. Implants and their use in children.

Implants have been used successfully for the rehabilitation of edentulous adults. However, their use in children is limited because of the special problems of implants relating to continuing growth and development. This, the first of two articles, provides a review of the use of osseointegrated implants in the context of facial growth, and the role of the orthodontist in the management of implant-supported prosthodontic structures. A second article will discuss the role of implants in orthodontics in providing what has been termed 'absolute anchorage'.

Anodontia↗

PubMed2003

Development of a conductimetric biosensor using immobilised Rhodococcus ruber whole cells for the detection and quantification of acrylonitrile.

A conductimetric biosensor for the detection of acrylonitrile in solution was designed and characterised using whole cells of Rhodococcus ruber NCIMB 40757, which were immobilised into a disc of dimethyl silicone sponge (ImmobaSil). The biosensor described was capable of the detection and quantification of acrylonitrile in aqueous solution, having a linear response to concentrations between 2 and 50 mM (106-2650 ppm) acrylonitrile. The biosensor has been shown to be reproducible with respect to the data obtained over a number of days, and retains stability for a minimum period of at least 5 days before recalibration of the biosensor is required.

Acrylonitrile↗

PubMed2003

Clinical and simulator wear study of alumina ceramic THR to 17 years and beyond.

Three THAs with cementless monolithic alumina ceramic sockets and cementless Co-alloy stems were retrieved because of aseptic loosening after 17 and 24 years. At revision heads and cups were marked for orientation. Maps were drawn of wear patterns with the use of light microscopy and surveyed by SEM. In a simulator experiment 28-mm-diameter alumina heads and liners were used. The cups were mounted inverted in a hip simulator and run with calf serum as the lubricant. The hip loads were 2 kN maximum and a 1-Hz frequency for 20 million cycles. Wear severity was classified into five grades. In retrieved implants, SEM analysis showed that the main wear zones (MWZ) had Grade 4 wear. The peripheral wear zones (PWZ) showed grain pull-out regions (Grade 5 wear). These corresponded to neck-socket impingement and head-acetabular cup separation. Gray was due to transferred CoCr particles from the stem. In the simulator study, the MWZ had only localized areas of grain pull out surrounded by polished surface regions (Grade 4 wear) at 20 million cycles; stripe wear was not seen. The alumina ceramic bearings proved excellent up to 22 years in simulator studies and clinical studies. However, microseparation kinematics would be necessary in the simulator to duplicate the more peripheral wear zones.

Adult↗

PubMed2003

A dog's life.

Explore the source record for details and available documents.

Animals↗

PubMed2003

Thai mothers and children and the home observation for measurement of the environment (home inventory): pilot study.

The HOME Inventory is a measure of home stimulation available to children. The purposes of the study were to: (a) examine the psychometric properties of a Thai-translated HOME (Infant/Toddler), (b) compare Thai mean HOME scores with three groups (Hmong, Eskimo, HOME normative sample in the state of Washington) reported in the literature. A convenience sample from Mahasarakham public health centers in northeastern Thailand was assessed using 36 dyads of mothers and toddlers, 13-35 months. The internal consistency was 0.81 for the total scale; F-tests of the HOME total scale and subscale means showed significant differences between Thai and three other groups. Scheffe tests which showed Thai means on three subscales (Maternal Involvement, Responsivity, Restriction) were not significantly different from the Washington sample, but were significantly lower on three subscales (Play, Organization, Stimulation). Further study is needed on the use of home assessment instruments by nurses and others working in multicultural settings.

Child↗

PubMed2003

White cell count and intensive care unit outcome.

A high white cell count on admission to the intensive care unit (ICU) is generally perceived to be associated with severe illness and poor outcome, but the implications of a low white cell count are less well recognised. We retrospectively analysed data on 4,165 patients. The white cell count on admission was split into four categories, leucopenic (< 4.0 x 10(9).l(-1)), normal (4.001-10.0 x 10(9).l(-1)), leucemoid (10.001-25.0 x 10(9).l(-1)) and an exaggerated leucemoid response (> 25.001 x 10(9).l(-1)). The mortality of patients with leucopenia on admission to the intensive care unit was higher than those with normal or moderately raised white cell count (37.5% vs. 18.9% and 23.9%, respectively). A leucopenic response, as well as an exaggerated leucemoid response, is associated with an increased mortality.

APACHE↗

PubMed2003

Trend to better nutrition on Australian hospital menus 1986-2001 and the impact of cook-chill food service systems.

OBJECTIVE: To assess trends in the nutritional quality of hospital menus and examine differences between menus used in hospitals with cook-chill or cook-fresh food services. DESIGN: Standard patient menus were analysed against 28 criteria to assess nutritional standards and compared with results from similar studies in 1986 and 1993. SETTING: Menus were collected from 80 hospitals in New South Wales (NSW), Australia, including 36 using cook-chill food service systems. STATISTICAL ANALYSIS: Chi-squared analysis was used to assess differences between the proportions of hospitals meeting the criteria in 1993 and 2001, and between different types of hospitals. RESULTS: In 2001, compared with 1993, significantly many hospitals offered more than one hot choice at the evening meal, more menus highlighted low fat items and more calcium-rich foods were available. More than 90% of hospitals allowed patients to select their own menu, offered wholemeal breads and high-fibre breakfast cereals, fresh fruit, polyunsaturated margarine, a milk dessert at least once a day and two or more hot options at the midday meal. Hospitals with cook-chill food services had menus that were more likely to meet nutritional recommendations, although they were less likely to offer a choice of serving size. A high proportion of unpopular choices were offered in menus, especially meat dishes and desserts. APPLICATIONS/CONCLUSION: Since 1986, NSW hospital menus have improved to offer choices that conform better to dietary guidelines. Cook-chill food services may have positive and negative impacts on meal choices. The assessment criteria are useful in hospitals to assess their menus.

Australia↗

PubMed2003

Effect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects.

GR79236 is a highly potent and selective adenosine A1 receptor agonist that has analgesic and anti-inflammatory actions in humans and animals. In animal models it inhibits trigeminal nerve firing and calcitonin gene-related peptide release which play a pivotal role in migraine pathophysiology. Thus GR79236 may have therapeutic potential in migraine. Although there are no validated human models of migraine, the trigeminal nociceptive pathways may be studied with a novel electrode to elicit nociception-specific blink reflex responses. Twelve healthy female volunteers were randomized in a double-blind, placebo-controlled, cross-over trial to investigate the effect of GR79236 on trigeminal nociceptive pathways, as measured by the blink reflex. A secondary objective was to compare the use of two types of electrode, the standard (SE) and nociception-specific electrodes (NE), to investigate human trigeminal pharmacology. Blink reflexes were elicited with SE and NE before and 30 min after GR79236 (10 microg/kg i.v.) or placebo. The median area under the curve of repeated sweeps of the R2 component of the blink reflex was analysed using analysis of covariance with baseline as covariate. Using NE, GR79236 produced a non-significant reduction of the ipsilateral R2 compared with placebo (P = 0.097) and a significant reduction contralaterally (P = 0.008). No significant changes were observed using SE. There were no significant adverse events. The results suggest that NE is more sensitive than SE to detect pharmacological effects in the trigeminal nociceptive system. Furthermore, the adenosine A1 receptor agonist GR79236 inhibits trigeminal nociception in humans. These results support a possible therapeutic role for GR79236 in primary headache disorders.

Adenosine↗