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Biomedical subjects

P Williams

Publications and source records attributed to P Williams.

At least 91 records · Page 5Linked to original sources
PubMed2001

Initiation of apoptosis by actin cytoskeletal derangement in human airway epithelial cells.

Changes in epithelial cell shape can lead to cell death and detachment. Actin filaments are cleaved during apoptosis, but whether disruption in the actin cytoskeletal network, as one manifestation of cell shape change, can itself induce apoptosis is not known. We tested this hypothesis in the airway epithelial cell line 1HAEo(-) and in primary airway epithelial cells by preventing actin filament elongation with cytochalasin D or by aggregating actin filaments with jasplakinolide. Disruption of actin filament integrity promptly induced apoptosis in adherent epithelial cells within 5 h. Jasplakinolide-induced apoptosis did not disrupt focal adhesions, whereas cytochalasin D-induced apoptosis decreased focal adhesion protein expression and occurred despite ligation of the fibronectin receptor. Death induction was abrogated by the caspase inhibitors z-VAD-fmk and Ac-DEVD-cho but not by blocking the Fas (CD95) receptor. Whereas cytochalasin D--induced apoptosis was associated with cleavage of pro-caspase-8, jasplakinolide-induced apoptosis was not. Both agents induced formation of a death-inducing signaling complex. These data demonstrate that disruption of actin filament integrity with either cytochalasin D or jasplakinolide induces apoptosis in airway epithelial cells but by different mechanisms, and suggest that actin may be an early modulator of apoptotic commitment.

Actins↗
PubMed2001

The process of knowledge discovery from large pharmacokinetic data sets.

The advent of statistical software with powerful graphical and modeling capabilities has revolutionized the manner in which pharmacokinetic and pharmacodynamic analyses are performed. Knowledge discovery from a large (population) pharmacokinetic data set incorporates all steps taken from data assembly to the development of a population pharmacokinetic model and the communication of the results thereof. The process can be formalized into a number of steps: (1) creation of a data set for pharmacokinetic knowledge discovery, (2) data quality analysis, (3) data structure analysis (exploratory examination of raw data), (4) determination of the basic pharmacokinetic model that best describes the data and generating post hoc empiric individual Bayesian parameter estimates, (5) the search for patterns and relationships between parameters and parameters and covariates by visualization, (6) the use of modern statistical modeling techniques for data structure revelation and covariate selection, (7) consolidation of the discovered knowledge into irreducible form (i.e., developing a population pharmacokinetic model), (8) the determination of model robustness (determination of the reliability of model parameter estimates), and (9) the communication and integration of the discovered pharmacokinetic knowledge. This process is discussed, and a motivating example is presented. The use of modern graphical, modeling, and statistical techniques for knowledge discovery from large pharmacokinetic data sets has given the data analyst the freedom to choose statistical methodology appropriate to the problem at hand with the maximization of information extraction, rather than on the basis of mathematical/statistical tractability.

Adolescent↗
PubMed2001

Some difficulties in the analysis of a withdrawn patient.

The author discusses some difficulties that arose in the analysis of a seriously disturbed patient who found talking about himself extremely problematical. He defended against awareness of conflicts, ideas and affects while being tormented and overwhelmed by them. He seemed to have acquired an inhibited character that was not, however, schizoid. He related to others in a wary, quarrelsome, yet passive way. It became apparent that his sense of identity was confused. Attention to archaic fantasies led to the uncovering of a parthenogenetic unconscious fantasy involving identification with his mother and the attempted eradication of the mental function of his father. Experiences of differentiation led to extreme anxiety including risk of failure of ego functions with the arousal of latent psychotic anxieties. Interpretation of the content of sessions became possible only after several years: until then interpretation of defensive processes aimed at preventing contact or change predominated. Disclosure of 'unofficial' communications by the patient, expressed as lapses of vigilance by his severe superego, revealed his crises and feelings. These idiosyncratic, muted appeals for help became a vehicle through which interpretation of content and its transference meaning became possible. Some confusing transference and countertransference experiences in the analysis are described.

Adult↗
PubMed2001

The cost effectiveness of stratified care in the management of migraine.

OBJECTIVE: To examine the cost effectivess of a stratified-care regimen for patients with migraine--in which patients are stratified by severity of illness, and then prescribed differing treatments according to level of severity--compared with a conventional stepped-care approach. DESIGN AND METHODS: A decision analytic model was constructed to simulate a controlled clinical trial in which patients with migraine receiving primary medical care were randomly assigned to treatment under a stepped-care or a stratified-care regimen. A health service payer perspective was adopted and the time horizon was 1 year. Data inputs were: (i) the frequency and disability of migraine, derived from population-based studies; (ii) disability level-specific treatment response rates for over-the-counter analgesics,aspirin/metoclopramide and zolmitriptan as the representative of high-end therapy obtained from an international consensus opinion enquiry; and (iii) unit costs of healthcare obtained from UK health service sources. MAIN OUTCOME MEASURES AND RESULTS: The estimated 1-year direct healthcare costs per primary care patient with migraine were pound sterling 156.82 for stepped care and sterling pound 151.57 for stratified care. Estimates of treatment response rates were 40 and 71% for stepped and stratified care, respectively. The cost per successfully treated attack was sterling pound 23.43 for stepped care and sterling pound 12.60 for stratified care. Stratified care remained cost effective when tested in a wide range of one-way sensitivity analyses, and probabilistic sensitivity analysis showed the cost effectiveness of stratified care to be significant at the 3% level. Conditional confidence analysis showed that the level of confidence in the cost effectiveness of stratified care varied positively with the case mix, i.e. in populations where the proportion of moderate and severely disabled patients with migraine was greater than 25%, the cost effectiveness of stratified care remained statistically significant. CONCLUSION: A stratified-care treatment strategy (including zolmitriptan as the representative of high-end therapy) is a highly cost-effective method of managing migraine in the primary care setting compared with stepped care, delivering improved clinical outcomes at no additional cost.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Evaluation of inspiratory rise time and inspiration termination criteria in new-generation mechanical ventilators: a lung model study.

INTRODUCTION: Inspiratory rise time adjustment during pressure ventilation and inspiration termination criteria adjustment during pressure support ventilation are available on some of the newest mechanical ventilators. Both are designed to improve patient-ventilator synchrony. However, the function of these adjuncts during pressure ventilation on these ventilators has not been evaluated. METHODS: Three inspiratory rise times (minimum, medium, and maximum) were evaluated in 5 new-generation mechanical ventilators (Hamilton Galileo, Siemens 300A, Puritan Bennett 840, BEAR 1000, and Dräger Evita 4) during pressure support and pressure assist/control. Three inspiration termination criteria settings (minimum, medium, and maximum) were also evaluated in 2 mechanical ventilators (Hamilton Galileo and Puritan Bennett 840) during pressure support. All evaluations were performed with a spontaneous breathing lung model (compliance 50 mL/cm H2O, resistance 8.2 cm H2O/L/s, respiratory rate 12 breaths/min, inspiratory time 1.0 s, and lung model peak inspiratory flow 60 L/min). Throughout the evaluation, inspiratory pressure was set at 15 cm H2O and positive end-expiratory pressure at 5 cm H2O, resulting in a peak airway pressure of 20 cm H2O. RESULTS: Significant (p < 0.05) and important (> 10%) differences were found among the ventilators at similar rise times (minimum, medium, and maximum) and for each ventilator as rise time was varied. Also, significant (p < 0.05) and important (> 10%) differences were observed between ventilators and within each ventilator when inspiration termination criteria were varied. There were significant (p < 0.05) differences between pressure support and pressure assist/control, but most were < 10%, except those associated with expiration. CONCLUSIONS: Major differences exist for each ventilator as rise time or inspiration termination criteria are varied and among ventilators at similar settings. Inspiration termination criteria adjustment markedly affects transition to exhalation in the Puritan Bennett 840.

Calibration↗
PubMed2001

Extrusion of actin-positive strands from Hep-2 and Int 407 cells caused by outer membrane preparations of enteropathogenic Escherichia coil and specific attachment of wild type bacteria to the strands.

Enteropathogenic Escherichia coli (EPEC) causes persistent infantile diarrhoea. This nontoxigenic E. coli exhibits a complicated pathogenic mechanism in which its outer membrane proteins and type III secretory proteins damage intestinal epithelium and cause diarrhoea. In accordance with this, our previous study using HEp-2 cells demonstrated cytopathic effects caused by cell-free outer membrane preparations of EPEC. In this study, we report the extrusion of actin-positive strands from HEp-2 and Int 407 cells when treated with outer membrane preparations. An interesting observation of this work, perhaps relevant to the characteristic localized three-dimensional colony formation of EPEC, is the attachment of a wild type EPEC strain to these actin-positive strands.

Actin Cytoskeleton↗
PubMed2001

Impact evaluation of a folate education campaign with and without the use of a health claim.

OBJECTIVE: To measure the impact of a Kellogg/Northcott Society multimedia folate education campaign, run nationally from July 1998 to June 1999, with and without the use of health claims. METHOD: Three national telephone surveys of more than 500 Australian women aged 18-44 in July and November 1998 and May 1999. RESULTS: Awareness of the role of folate in the prevention of birth defects rose from 21% at baseline to 29% in November 1998 and 44% in May 1999. Awareness of the recommendation to take folate before pregnancy rose by 8% in the first six months of the campaign (without health claims) and by 22% in the second half (when health claims were incorporated). At the end of the campaign, the foods most commonly cited as sources of folate were leafy green vegetables (72%), breakfast cereals (70%), fruit (41%) and bread (40%). CONCLUSION: Inclusion of a specific health claim explaining the role of folate in preventing birth defects appeared to increase the impact of the folate education campaign. IMPLICATIONS: Changing food regulations to permit health claims may increase the impact of health promotion campaigns involving industry partnerships. Future folate programs should target young women (aged 18-24), those in rural areas and those on lower incomes.

Adolescent↗
PubMed2001

Mathematical modelling of quorum sensing in bacteria.

The regulation of density-dependent behaviour by means of quorum sensing is widespread in bacteria, the relevant phenomena including bioluminescence and population expansion by swarming, as well as virulence. The process of quorum sensing is regulated by the production and monitoring of certain molecules (referred to as QSMs); on reaching an apparent threshold concentration of QSMs (reflecting high bacterial density) the bacterial colony in concert 'switches on' the density-dependent trait. In this paper a mathematical model which describes bacterial population growth and quorum sensing in a well mixed system is proposed and studied. We view the population of bacteria as consisting of down-regulated and up-regulated sub-populations, with QSMs being produced at a much faster rate by the up-regulated cells. Using curve fitting techniques for parameter estimation, solutions of the resulting system of ordinary differential equations are shown to agree well with experimental data. Asymptotic analysis in a biologically relevant limit is used to investigate the timescales for up-regulation of an exponentially growing population of bacteria, revealing the existence of bifurcation between limited and near-total up-regulation. For a fixed population of cells steady-state analysis reveals that in general one physical steady-state solution exists and is linearly stable; we believe this solution to be a global attractor. A bifurcation between limited and near-total up-regulation is also discussed in the steady-state limit.

Bacteria↗
PubMed2000

Anti antibiotics?

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Anti-Bacterial Agents↗
PubMed2000

Structural characterization of the pectic polysaccharide rhamnogalacturonan II: evidence for the backbone location of the aceric acid-containing oligoglycosyl side chain.

Monomeric rhamnogalacturonan II (mRG-II) was isolated from red wine and the reducing-end galacturonic acid of the backbone converted to L-galactonic acid by treatment with NaBH4. The resulting product (mRG-II'ol) was treated with a cell-free extract from Penicillium daleae, a fungus that has been shown to produce RG-II-fragmenting glycanases. The enzymatically generated products were fractionated by size-exclusion and anion-exchange chromatographies and the quantitatively major oligosaccharide fraction isolated. This fraction contained structurally related oligosaccharides that differed only in the presence or absence of a single Kdo residue. The Kdo residue was removed by acid hydrolysis and the resulting oligosaccharide then characterized by 1- and 2D 1H NMR spectroscopy, ESMS, and by glycosyl-residue and glycosyl-linkage composition analyses. The results of these analyses provide evidence for the presence of at least two structurally related oligosaccharides in the ratio approximately 6:1. The backbone of these oligosaccharides is composed of five (1-->4)-linked alpha-D-GalpA residues and a (1-->3)-linked L-galactonate. The (1-->4)-linked GalpA residue adjacent to the terminal non-reducing GalpA residue of the backbone is substituted at O-2 with an apiosyl-containing side chain. Beta3-L-Araf-(1-->5)-beta-D-DhapA is likely to be linked to O-3 of the GalpA residue at the non-reducing end of the backbone in the quantitatively major oligosaccharide and to O-3 of a (1-->4)-linked GalpA residue in the backbone of the minor oligosaccharide. Furthermore, the results of our studies have shown that the enzymically generated aceryl acid-containing oligosaccharide contains an alpha-linked aceryl acid residue and a beta-linked galactosyl residue. Thus, the anomeric linkages of these residues in RG-II should be revised.

Carbohydrate Conformation↗
PubMed2000

Quorum sensing and the population-dependent control of virulence.

One crucial feature of almost all bacterial infections is the need for the invading pathogen to reach a critical cell population density sufficient to overcome host defences and establish the infection. Controlling the expression of virulence determinants in concert with cell population density may therefore confer a significant survival advantage on the pathogen such that the host is overwhelmed before a defence response can be fully initiated. Many different bacterial pathogens are now known to regulate diverse physiological processes including virulence in a cell-density-dependent manner through cell-cell communication. This phenomenon, which relies on the interaction of a diffusible signal molecule (e.g. an N-acylhomoserine lactone) with a sensor or transcriptional activator to couple gene expression with cell population density, has become known as 'quorum sensing'. Although the size of the 'quorum' is likely to be highly variable and influenced by the diffusibility of the signal molecule within infected tissues, nevertheless quorum-sensing signal molecules can be detected in vivo in both experimental animal model and human infections. Furthermore, certain quorum-sensing molecules have been shown to possess pharmacological and immunomodulatory activity such that they may function as virulence determinants per se. As a consequence, quorum sensing constitutes a novel therapeutic target for the design of small molecular antagonists capable of attenuating virulence through the blockade of bacterial cell-cell communication.

4-Butyrolactone↗
PubMed2000

The staphylococcal transferrin receptor: a glycolytic enzyme with novel functions.

To obtain iron from the host for growth, staphylococci have evolved sophisticated iron-scavenging systems including siderophores and a cell surface receptor for transferrin, the mammalian iron-transporting glycoprotein. The staphylococcal transferrin receptor has been identified as a member of a newly emerging family of multifunctional, cell-surface-associated glyceraldehyde-3-phosphate dehydrogenases, which not only retain their glycolytic enzyme activities but also bind diverse human serum proteins and possess NAD-ribosylating activity. These multiple functions suggest a potential contribution to virulence far beyond iron acquisition.

Cell Wall↗
PubMed2000

Efficacy and safety of amphotericin B lipid complex injection (ABLC) in solid-organ transplant recipients with invasive fungal infections.

BACKGROUND: Fungal infections following solid-organ transplantation are a major source of morbidity and mortality. This report describes the efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients. METHODS: Three open-label, second-line treatment studies evaluated ABLC as a treatment for severe, life-threatening mycoses in patients who were refractory to or intolerant to conventional antifungal (mostly amphotericin B [AmB]) therapy or had pre-existing renal disease. RESULTS: The 79 solid-organ transplant recipients (25 heart, 20 liver, 17 kidney, 11 lung, 5 multiple, 1 pancreas) who received ABLC in these studies had the following fungal infections: aspergillosis (n = 39); candidiasis (n = 20); zygomycosis (n = 8); cryptococcosis and histoplasmosis (n = 3 each); and blastomycosis, cladosporiosis, fusariosis, Bipolaris hawaiiensis, Dactylaria gallopava, and an unspecified fungal infection (n = 1 each). The median duration of ABLC therapy was 28 d (1-178 d). The daily dose ranged between 1.6 and 7.4 mg/kg (median, 4.6 mg/kg). The clinical response rate for the patients who could be assessed was 58% (39/67). Clinical response rates for heart, liver, kidney, and lung recipients were 59, 60, 67, and 40%, respectively; response rates for aspergillosis and candidiasis were 47 and 71%, respectively. Forty-six of the 79 patients (58%) survived for more than 28 d after the last dose of ABLC. Mean baseline serum creatinine was 3.2 mg/dL; 64 patients (81%) had stable (n = 37) or improved (n = 27) serum creatinine at the end of treatment. CONCLUSIONS: ABLC is safe and effective treatment for fungal infections in solid-organ transplant recipients. Its renal-sparing properties are particularly suited for this high-risk population for renal failure.

Adolescent↗
PubMed2000

Asking questions can change choice behavior: does it do so automatically or effortfully?

The present research uses a technique that permits unique estimation of both automatic and effortful processes in the question-behavior link. Results show that individuals asked to report behavioral intent (vs. those not asked) are more likely to choose options that are highly accessible and positively valenced, regardless of cognitive resources available at the time of processing. This suggests that the effect of intent questions on subsequent behavior is primarily the result of automatic, as opposed to effortful, processing. Practically, this suggests that efforts to debias this robust effect need to affect nonconscious processes and adjust for the automatic impact of being asked an intention question on respondents' behavior.

Automatism↗
PubMed2000

The regulatory locus cinRI in Rhizobium leguminosarum controls a network of quorum-sensing loci.

N-(3-hydroxy-7-cis-tetradecenoyl)-L-homoserine lactone (3OH, C14:1-HSL) is a quorum-sensing signalling molecule produced by Rhizobium leguminosarum. It is unusual in that it inhibits the growth of several strains of R. leguminosarum and was previously known as 'small bacteriocin'. The cinRI locus responsible for the production of 3OH,C14:1-HSL has been characterized; it is predicted to be on the chromosome, based on DNA hybridization. The cinR and cinI genes are in different transcriptional units, separated by a predicted transcription terminator. CinR regulates cinI expression to a very high level in a cell-density dependent manner, and cinI expression is positively autoregulated by 3OH,C14:1-HSL, the only identified N-acyl homoserine lactone (AHL) produced by CinI. No other AHLs were identified that strongly induced cinI expression. Mutation of cinI or cinR abolishes the production of 3OH,C14:1-HSL and also reduces the production of several other AHLs. This is thought to result from the expression of three other AHL production loci being affected by the absence of 3OH,C14:1-HSL. AHLs produced by these other loci include N-hexanoyl- and N-octanoyl-L-homoserine lactones and, unexpectedly, N-heptanoyl-L-homoserine lactone (C7-HSL). The expression of the rhiI gene on the symbiotic plasmid is greatly reduced in a cinI mutant, and the major regulatory effect appears to be mediated at least in part as a result of an effect on expression of RhiR, the regulator of rhiI. Thus, cinR and cinI appear to be at the top of a regulatory cascade or network that influences several AHL-regulated quorum-sensing loci. The expression of cinI-lacZ fusions is significantly reduced (but not abolished) when the symbiosis plasmid pRL1JI is present, resulting in a reduction in the level of 3OH,C14:1-HSL produced. Mutation of cinI had little effect on growth or nodulation. However, plasmid transfer was affected, and the results obtained indicate that 3OH,C14:1-HSL produced by either the donor or the recipient in mating experiments can stimulate transfer of pRL1JI.

4-Butyrolactone↗