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Biomedical subjects

Paul Williams

Publications and source records attributed to Paul Williams.

At least 55 records · Page 3Linked to original sources
PubMed2005

Barriers to the effective management of bipolar disorder: a survey of psychiatrists based in the UK and USA.

OBJECTIVE: To identify and prioritize barriers, challenges, and unmet needs in the management of patients with bipolar disorder, as perceived by their psychiatrists. METHODS: A total of 500 US- or UK-based psychiatrists were surveyed by telephone using a validated, semi-structured questionnaire. Both preidentified and participant-elicited barriers, challenges and unmet needs were ranked on a 0-6 point scale in four phases of management: I, entry into care; II, the manic/hypomanic phase; III, the depressive phase; and IV, the long-term/maintenance phase. RESULTS: Education and support for patients and families as well as earlier referral to specialist care were the highest ranked needs at entry into care. During treatment of acute episodes and long-term management the highest ranked needs were for treatments with improved effectiveness and patient adherence, in addition to improved long-term safety in the maintenance phase. Patients with comorbid alcohol and/or substance use disorders, followed by patients with a rapid-cycling disease course, were rated as having the highest level of unmet need. Similarities were predominantly seen between the overall pattern of responses from UK- and US-based psychiatrists. CONCLUSIONS: The highest priority items across the spectrum of treatment related to the need for clinically effective therapeutic agents with broad efficacy and favorable tolerability. At the time of initial diagnosis, patient education, family support, and earlier referral to specialist care were the highest priority needs.

Bipolar Disorder↗
PubMed2005

Disruption of quorum sensing in seawater abolishes attraction of zoospores of the green alga Ulva to bacterial biofilms.

Zoospores of the eukaryotic green seaweed Ulva respond to bacterial N-acylhomoserine lactone (AHL) quorum sensing signal molecules for the selection of surface sites for permanent attachment. In this study we have investigated the production and destruction of AHLs in biofilms of the AHL-producing marine bacterium, Vibrio anguillarum and their stability in seawater. While wild type V. anguillarum NB10 was a strong attractor of zoospores, inactivation of AHL production in this strain by either expressing the recombinant Bacillus lactonase coding gene aiiA, or by mutating the AHL biosynthetic genes, resulted in the abolition of zoospore attraction. In seawater, with a pH of 8.2, the degradation of AHL molecules was temperature-dependent, indicating that the AHLs produced by marine bacterial biofilms have short half-lives. The Ulva zoospores sensed a range of different AHL molecules and in particular more zoospores settled on surfaces releasing AHLs with longer (>six carbons) N-linked acyl chains. However, this finding is likely to be influenced by the differential diffusion rates of AHLs from the experimental surface matrix. Molecules with longer N-acyl chains, such as N-(3-oxodecanoyl)- L-homoserine lactone, diffused more slowly than those with shorter N-acyl chains such as N-(3-hydroxy-hexanoyl)- L-homoserine lactone. Image analysis using GFP-tagged V. anguillarum biofilms revealed that spores settle directly on bacterial cells and in particular on microcolonies which we show are sites of concentrated AHL production.

4-Butyrolactone↗
PubMed2005

HosA, a member of the SlyA family, regulates motility in enteropathogenic Escherichia coli.

In enteropathogenic and enterohemorraghic Escherichia coli (EPEC and EHEC), two members of the SlyA family of transcriptional regulators have been identified as SlyA. Western blot analysis of the wild type and the corresponding hosA and slyA deletion mutants indicated that SlyA and HosA are distinct proteins whose expression is not interdependent. Of 27 different E. coli strains (EPEC, EHEC, enteroinvasive, enteroaggregative, uropathogenic, and commensal) examined, 14 were positive for both genes and proteins. To investigate hosA expression, a hosA::luxCDABE reporter gene fusion was constructed. hosA expression was significantly reduced in the hosA but not the slyA mutant and was influenced by temperature, salt, and pH. In contrast to SlyA, HosA did not activate the cryptic E. coli K-12 hemolysin ClyA. Mutation of hosA did not influence type III secretion, the regulation of the LEE1 and LEE4 operons, or the ability of E2348/69 to form attaching-and-effacing lesions on intestinal epithelial cells. HosA is, however, involved in the temperature-dependent positive control of motility on swim plates and regulates fliC expression and FliC protein levels. In electrophoretic mobility shift assays, purified HosA protein bound specifically to the fliC promoter, indicating that HosA directly modulates flagellin expression. While direct examination of flagellar structure and the motile behavior of individual hosA cells grown in broth culture at 30 degrees C did not reveal any obvious differences, hosA mutants, unlike the wild type, clumped together, forming nonmotile aggregates which could account for the markedly reduced motility of the hosA mutant on swim plates at 30 degrees C. We conclude that SlyA and HosA are independent transcriptional regulators that respond to different physicochemical cues to facilitate the environmental adaptation of E. coli.

Amino Acid Sequence↗
PubMed2005

The RssAB two-component signal transduction system in Serratia marcescens regulates swarming motility and cell envelope architecture in response to exogenous saturated fatty acids.

Serratia marcescens swarms at 30 degrees C but not at 37 degrees C on a nutrient-rich (LB) agar surface. Mini-Tn5 mutagenesis of S. marcescens CH-1 yielded a mutant (WC100) that swarms not only vigorously at 37 degrees C but also earlier and faster than the parent strain swarms at 30 degrees C. Analysis of this mutant revealed that the transposon was inserted into a gene (rssA) predicted to encode a bacterial two-component signal transduction sensor kinase, upstream of which a potential response regulator gene (rssB) was located. rssA and rssB insertion-deletion mutants were constructed through homologous recombination, and the two mutants exhibited similar swarming phenotypes on LB swarming agar, in which swarming not only occurred at 37 degrees C but also initiated at a lower cell density, on a surface with a higher agar concentration, and more rapidly than the swarming of the parent strain at 30 degrees C. Both mutants also exhibited increased hemolysin activity and altered cell surface topologies compared with the parent CH-1 strain. Temperature and certain saturated fatty acids (SFAs) were found to negatively regulate S. marcescens swarming via the action of RssA-RssB. Analysis of the fatty acid profiles of the parent and the rssA and rssB mutants grown at 30 degrees C or 37 degrees C and under different nutrition conditions revealed a relationship between cellular fatty acid composition and swarming phenotypes. The cellular fatty acid profile was also observed to be affected by RssA and RssB. SFA-dependent inhibition of swarming was also observed in Proteus mirabilis, suggesting that either SFAs per se or the modulation of cellular fatty acid composition and hence homeostasis of membrane fluidity may be a conserved mechanism for regulating swarming motility in gram-negative bacteria.

Bacterial Proteins↗
PubMed2004

The Aeromonas hydrophila LuxR homologue AhyR regulates the N-acyl homoserine lactone synthase, AhyI positively and negatively in a growth phase-dependent manner.

Aeromonas hydrophila is a pathogen of fish, amphibians and humans which produces N-acylhomoserine lactone quorum sensing signal molecules and possesses homologues of the Vibrio fischeri luxI and luxR quorum sensing genes termed ahyI and ahyR, respectively. The ahyI and ahyR genes of A. hydrophila comprise a divergon with a 62 bp intergenic region and control biofilm maturation and extracellular protease production. Stationary phase culture supernatants from an ahyR but not an ahyI mutant contain N-butanoylhomoserine lactone (C4-HSL) which is shown to be required for maximal ahyI expression. To determine whether AhyR regulates ahyI, the expression of AhyI was followed throughout growth by Western blot analysis. This revealed that AhyI can be detected in the exponential phase but appears to be degraded in stationary phase in the parent A. hydrophila strain. In an ahyR mutant however, the AhyI protein is only produced in stationary phase but production is sustained suggesting that AhyR controls the timing of AhyI production and turnover. By using RT-PCR, we mapped the transcriptional start site of ahyI which revealed that the 12 bp symmetrical lux-box like sequence present in the 62 bp ahyRI intergenic region overlaps with the -10 region of the ahyI promoter. To determine whether AhyR could bind to the ahyRI intergenic region, the ahyR gene was expressed and purified as a maltose binding protein (MalE) fusion. Electrophoretic mobility shift assays demonstrated that MalE-AhyR specifically bound to this sequence in both the presence and absence of N-butanoylhomoserine lactone (C4-HSL). Taken together, these data suggest that AhyR acts as both a negative and a positive regulator of ahyI and hence C4-HSL production in a growth phase dependent manner.

4-Butyrolactone↗
PubMed2004

N-hexanoyl-L-homoserine lactone, a mediator of bacterial quorum-sensing regulation, exhibits plant-dependent stability and may be inactivated by germinating Lotus corniculatus seedlings.

The half-life of N-hexanoyl-l-homoserine lactone (C6-HSL) was determined under various pH and temperature conditions, and in several plant environments. C6-HSL was sensitive to alkaline pH, a process that was also temperature-dependent. In addition, C6-HSL disappeared from plant environments, i.e. axenic monocot and dicot plants cultivated under gnotobiotic, hydroponic conditions, albeit with variable kinetics. The disappearance was rapid at the root system of legume plants such as clover or Lotus, and slow or non-existent at the root system of monocots such as wheat or corn. These variable kinetics were not dependent upon pH changes that may have affected the growth media of the plants. Furthermore, C6-HSL did not accumulate in the plant, and the plant did not produce inhibitors of the C6-HSL signal. HPLC analyses revealed that C6-HSL disappeared from the media, and hence, Lotus exhibited a natural C6-HSL inactivating ability. This ability was not specific for C6-HSL and allowed the degradation of other N-acyl-homoserine lactones such as 3-oxo-C6-HSL, 3-oxo-octanoyl-HSL and 3-oxo-decanoyl-HSL. Preliminary investigation revealed that the inactivating ability is temperature-dependant and possibly of enzymatic origin.

4-Butyrolactone↗
PubMed2004

Prioritizing treatment attributes and their impact on selecting an oral triptan: results from the TRIPSTAR Project.

Seven oral triptans, which differ on a range of attributes important for treatment selection, are now available for treating migraine. US neurologists were surveyed to assess the relative importance of treatment attributes, prespecified by clinical relevance and availability of controlled study data, for selecting among oral triptans. Using a multiattribute decision model, we combined these data on the importance of treatment attributes with information on the relative performance of the oral triptans derived from a recent meta-analysis of controlled clinical trials.

Animals↗
PubMed2004

Effect of ion implantation on the tribology of metal-on-metal hip prostheses.

Nitrogen ion implantation (which considerably hardens the surface of the bearing) may represent one possible method of reducing the wear of metal-on-metal (MOM) hip bearings. Currently there are no ion-implanted MOM bearings used clinically. Therefore a physiological hip simulator test was undertaken using standard test conditions, and the results compared to previous studies using the same methods. N2-ion implantation of high carbon cast Co-Cr-Mo-on-Co-Cr-Mo hip prostheses increased wear by 2-fold during the aggressive running-in phase compared to untreated bearing surfaces, plus showing no wear reductions during steady-state conditions. Although 2 specimens were considered in the current study, it would appear that ion implantation has no clinical benefit for MOM.

Arthroplasty, Replacement, Hip↗
PubMed2004

Priorities for triptan treatment attributes and the implications for selecting an oral triptan for acute migraine: a study of US primary care physicians (the TRIPSTAR Project).

BACKGROUND: Physicians treating patients with migraine can now choose from among 7 triptans, which differ on a range of attributes that may be important for treatment selection. OBJECTIVE: The aims of this study were to determine the relative importance of treatment attributes of the available triptans and assess their impact on deciding the most appropriate treatment for a particular patient with migraine. METHODS: As part of the TRIPSTAR project, US primary care physicians were surveyed to elicit their views on the relative importance of a prespecified set of treatment attributes for making treatment choices in clinical practice. The treatment attributes assessed were those for which data from controlled clinical trials were available for subsequent comparison. The resulting attribute-importance weights were then combined with data on the performance of individual triptans across these attributes in a multiattribute decision model to assist selection of an oral triptan. RESULTS: Efficacy attributes were considered more important than tolerability or consistency of effect in selecting an oral triptan. For triptan-naive but not triptan-experienced patients, tolerability was considered significantly more important than consistency (30% [95% CI, 27%-34%] vs 21% [19%-24%]). Sustained pain-free status and freedom from cardiovascular (chest) adverse events were the most important efficacy and tolerability attributes for both patient categories. When the relative importance of the treatment attributes was combined in a multiattribute decision model with meta-analysis data from controlled trials, almotriptan, eletriptan, and rizatriptan were significantly closer to the hypothetical ideal triptan than the reference product, sumatriptan 100 mg. CONCLUSION: Multiattribute decision-making models (such as that used in the TRIPSTAR project) that determine and apply the relative importance of treatment attributes to drug selection have considerable potential value as a decision support tool in the treatment of acute migraine.

Acute Disease↗
PubMed2004

Enteritis-associated myocarditis.

We describe two cases in which myocarditis was associated with a prodromal diarrhoeal illness as a result of bacterial enteritis. Both cases were associated with elevated troponin T and chest pain mimicking myocardial infarction.

Journal Article↗
PubMed2004

Global regulation of virulence and the stress response by CsrA in the highly adapted human gastric pathogen Helicobacter pylori.

Although successful and persistent colonization of the gastric mucosa depends on the ability to respond to changing environmental conditions and co-ordinate the expression of virulence factors during the course of infection, Helicobacter pylori possesses relatively few transcriptional regulators. We therefore investigated the contribution of the regulatory protein CsrA to global gene regulation in this important human pathogen. CsrA was necessary for full motility and survival of H. pylori under conditions of oxidative stress. Loss of csrA expression deregulated the oxidant-induced transcriptional responses of napA and ahpC, the acid induction of napA, cagA, vacA, the urease operon, and fur, as well as the heat shock responses of napA, groESL and hspR. Although the level of napA transcript was higher in the csrA mutant, its stability was similar in the wild-type and mutant strains, and less NapA protein was produced in the mutant strain. Finally, H. pylori strains deficient in the production of CsrA were significantly attenuated for virulence in a mouse model of infection. This work provides evidence that CsrA has a broad role in regulating the physiology of H. pylori in response to environmental stimuli, and may be important in facilitating adaptation to the different environments encountered during colonization of the gastric mucosa. Furthermore, CsrA appears to mediate its effects in H. pylori at the post-transcriptional level by influencing the processing and translation of target transcripts, with minimal effect on the stability of the target mRNAs.

Bacterial Proteins↗
PubMed2004

The Pseudomonas aeruginosa global regulator MvaT specifically binds to the ptxS upstream region and enhances ptxS expression.

Exotoxin A production in Pseudomonas aeruginosa is regulated positively or negatively by several genes. Two such regulatory genes, ptxR and ptxS, which are divergently transcribed from each other, have been described previously. While computer analysis suggested that the ptxR-ptxS intergenic region contains potential binding sites for several regulatory proteins, the mechanism that regulates the expression of either ptxR or ptxS in P. aeruginosa is not known. The presence of a P. aeruginosa protein complex that specifically binds to a segment within this region was determined. In this study the binding region was localized to a 150 bp fragment of the intergenic region and the proteins that constitute the binding complex were characterized as P. aeruginosa HU and MvaT. Recombinant MvaT was purified as a fusion protein (MAL-MvaT) and shown to specifically bind to the ptxR-ptxS intergenic region. A PAO1 isogenic mutant defective in mvaT, PAODeltamvaT, was constructed and characterized. The lysate of PAODeltamvaT failed to bind to the 150 bp probe. The effect of mvaT on ptxS and ptxR expression was examined using real-time PCR experiments. The expression of ptxS was lower in PAODeltamvaT than in PAO1, but no difference was detected in ptxR expression. These results suggest that MvaT positively regulates ptxS expression by binding specifically to the ptxS upstream region.

Bacterial Proteins↗
PubMed2004

Symbols and self preservation in severe disturbance.

The author considers a particular way in which symbolic functioning and the sense of self fail in certain cases of severe disturbance. When containment of the infant fails, the experience is a violent one. If the infant is projected into by an 'invasive object', the infant can incorporate this experience both as a bodily and a proto-mental registration. The experience then remains within the psyche-soma and subsequent development is built 'around' the consequences of the trauma. Clinical illustrations are provided to demonstrate this phenomenon in the analytic setting.

Female↗
PubMed2004

A distinctive dual-channel quorum-sensing system operates in Vibrio anguillarum.

Many bacterial cells communicate using diffusible signal molecules to monitor cell population density via a process termed quorum sensing. In marine Vibrio species, the Vibrio harveyi-type LuxR protein is a key player in a quorum-sensing phosphorelay cascade, which controls the expression of virulence, symbiotic and survival genes. Previously, we characterized Vibrio anguillarum homologues of LuxR (VanT) and LuxMN (VanMN) and, in this study, we have identified homologues of LuxPQ (VanPQ) and LuxOU (VanOU). In contrast to other Vibrio species, vanT was expressed at low cell density and showed no significant induction as the cell number increased. In addition, although the loss of VanO increased vanT expression, the loss of VanU, unexpectedly, decreased it. Both VanN and VanQ were required for repression of vanT even in a vanU mutant, suggesting an alternative route for VanNQ signal transduction other than via VanU. VanT negatively regulated its own expression by binding and repressing the vanT promoter and by binding and activating the vanOU promoter. The signal relay results in a cellular response as expression of the metalloprotease, empA, was altered similar to that of vanT in all the mutants. Consequently, the V. anguillarum quorum-sensing phosphorelay systems work differently from those of V. harveyi and may be used to limit rather than induce vanT expression.

Bacterial Proteins↗
PubMed2004

Differential immune modulatory activity of Pseudomonas aeruginosa quorum-sensing signal molecules.

Pseudomonas aeruginosa releases a spectrum of well-regulated virulence factors, controlled by intercellular communication (quorum sensing) and mediated through the production of small diffusible quorum-sensing signal molecules (QSSM). We hypothesize that QSSM may in fact serve a dual purpose, also allowing bacterial colonization via their intrinsic immune-modulatory capacity. One class of signal molecule, the N-acylhomoserine lactones, has pleiotropic effects on eukaryotic cells, particularly those involved in host immunity. In the present study, we have determined the comparative effects of two chemically distinct and endobronchially detectable QSSM, N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) and 2-heptyl-3-hydroxy-4 (1H)-quinolone or the Pseudomonas quinolone signal (PQS), on human leukocytes exposed to a series of stimuli designed to detect differential immunological activity in vitro. 3-Oxo-C12-HSL and PQS displayed differential effects on the release of interleukin-2 (IL-2) when human T cells were activated via the T-cell receptor and CD28 (a costimulatory molecule). 3-Oxo-C12-HSL inhibited cell proliferation and IL-2 release; PQS inhibited cell proliferation without affecting IL-2 release. Both molecules inhibited cell proliferation and the release of IL-2 following mitogen stimulation. Furthermore, in the presence of Escherichia coli lipopolysaccharide, 3-oxo-C12-HSL inhibited tumor necrosis factor alpha release from human monocytes, as reported previously (K. Tateda et al., Infect. Immun. 64:37-43, 1996), whereas PQS did not inhibit in this assay. These data highlight the presence of two differentially active immune modulatory QSSM from P. aeruginosa, which are detectable endobronchially and may be active at the host/pathogen interface during infection with P. aeruginosa, should the bronchial airway lymphoid tissues prove to be accessible to QSSM.

4-Butyrolactone↗
PubMed2004

The staphylococcal ferritins are differentially regulated in response to iron and manganese and via PerR and Fur.

Staphylococcus aureus and Staphylococcus epidermidis ferritin (FtnA and SefA, respectively) homologues are antigenic and highly conserved. A previous study showed that ftnA is a component of the S. aureus PerR regulon with its transcription induced by elevated iron and repressed by PerR, which functions as a manganese-dependent transcriptional repressor. We have further investigated the role of iron and Fur in the regulation of PerR regulon genes ftnA (ferritin), ahpC (alkyl-hydroperoxidase), and mrgA (Dps homologue) and shown that iron has a major role in the regulation of the PerR regulon and hence the oxidative stress response, since in the presence of both iron and manganese, transcription of PerR regulon genes is induced above the repressed levels observed with manganese alone. Furthermore the PerR regulon genes are differentially regulated by metal availability and Fur. First, there is an additional level of PerR-independent regulation of ftnA under low-iron conditions which is not observed with ahpC and mrgA. Second, there is a differential response of these genes to Fur as ftnA expression is constitutive in a fur mutant, while ahpC expression is constitutive under low-Fe/Mn conditions but some repression of ahpC still occurs in the presence of manganese, whereas mrgA expression is still repressed in the fur mutant as in wild-type S. aureus, although there is a decrease in the overall level of mrgA transcription. These studies have also shown that FtnA expression is regulated by growth phase, but maximal transcription of ftnA differs dependent on the growth medium. Moreover, there are significant regulatory differences between the S. aureus and S. epidermidis ferritins, as sefA expression in contrast to that of ftnA is derepressed under low-Fe/Mn ion conditions.

Amino Acid Sequence↗