Biomedical subjects

Chris Williams

Publications and source records attributed to Chris Williams.

17 recordsLinked to original sources

PubMed2006

Reverse fingerprinting, similarity searching by group fusion and fingerprint bit importance.

Recent research has shown that using data fusion rules in fingerprint-based similarity searching can improve results over traditional searches. Group fusion scores, which use multiple reference compounds, have in particular been shown to be quite effective in increasing enrichment rates over single reference structure based searches. In this paper, the effectiveness of using data fusion with multiple reference compounds to increase similarity search recall rates was investigated using 44 biological targets and four different 2D fingerprinting systems, including a new 2D typed triangle fingerprinting system introduced here. Scaffold-hopping abilities using data fusion rules were investigated using eight (8) different classes of scaffolds active against cGMP phosphodiesterase isoform 5 (PDE5). An approach to using the reference group for ranking and visualizing important fingerprints bits, or reverse fingerprinting, was presented, and used to score and visualize important pharmacophore features within sample active molecules. Finally, similarity statistics within the reference groups were investigated and compared to recall rates.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

Pex13p: docking or cargo handling protein?

The Src homology 3 (SH3) domain-containing peroxisomal membrane protein Pex13p is an essential component of the import machinery for matrix proteins and forms a binding site for the peroxisomal targeting type I (PTS1) receptor Pex5p. The interaction between these two proteins can be described as novel in several ways. In the yeasts Saccharomyces cerevisiae and Pichia pastoris, the SH3 domain itself is responsible for the interaction but not via the typical P-x-x-P motifs that are common to SH3 ligands as Pex5p lacks such a motif. Instead, a region of Pex5p containing a W-x-x-x-F/Y motif is crucial for this binding. In mammals, again W-x-x-x-F/Y motifs appear to be important for the interaction but the SH3 domain seems not to be the site for Pex5p binding, this being located in the N-terminus of Pex13p. Despite these differences in the details of the Pex13p-Pex5p interaction, the association of the two proteins is a crucial step in Pex5p-mediated protein import into peroxisomes in both yeasts and mammals.

Amino Acid Motifs↗

PubMed2006

Going home from hospital: the postdischarge experience of patients and carers in rural and remote Queensland.

OBJECTIVE: This paper reports on a study of the experiences of patients and carers discharged from the Townsville General Hospital into rural and remote communities in North Queensland. DESIGN: The findings presented in this paper are drawn from post-discharge in-depth, qualitative interviews of both patients and carers. RESULTS: The findings indicate the importance of examining the lived experience of both patients and carers in attempting to understand the impact of current discharge practices. CONCLUSION: We conclude that carers are providing the bulk of post-discharge care of patients - a difficult role in which the difficulties are exacerbated when the patient or the carer or both is a long way from the home community.

Caregivers↗

PubMed2005

Early evidence of a regulated response to hypoxaemia in sheep that preserves the brain cortex.

Hypoxaemia consequent to inspired carbon monoxide (CO), and to other causes, often does not injure the brain cortex. At least five types of brain and heart protective cardiovascular response to hypoxaemia have been reported. The underlying mechanism is unknown. The present study was designed to test the hypothesis that the reaction to inspired CO involves the amygdala as this structure is thought to be central to stress responsivity; involvement would support the additional hypothesis that the somatic response to CO-hypoxaemia is regulated. Eighteen ewes were randomly allocated to control and two CO groups. The CO groups were exposed to 1% CO for 120 min and killed either 5 or 15 days later. This exposure caused isolated white matter brain injury and a transient increase in protein-kinase C (gamma) activity in the pyramidal neurons in the nuclei of the central and basal-lateral amygdala and in the neurons of the audio-cortex (p < 0.05). This was associated with evidence of a sympathetic response. It would seem reasonable to hypothesise both that the amygdala is important in the processes by which the hypoxaemic effects of CO on the brain are prevented, delayed and/or mitigated and that these processes are regulated.

Amygdala↗

PubMed2005

Saccharomyces cerevisiae Pex14p contains two independent Pex5p binding sites, which are both essential for PTS1 protein import.

Pex14p is a peroxisomal membrane-associated protein involved in docking of both Pex5p and Pex7p to the peroxisomal membrane. Previous studies have shown that, in humans, the N-terminal region of Pex14p interacts with WxxxF/Y motifs in Pex5p. Here, we report that Saccharomyces cerevisiae Pex14p contains two independent Pex5p binding sites, one in the N- and one in the C-terminus. Using deletion analysis we show that, in vivo, both of these interactions are needed for PTS1 import. Furthermore, we show that the characterized WxxxF/Y motifs of Pex5p are not essential for binding to the N-terminus of Pex14p but do play a role in the interaction with the Pex14 C-terminus. Thus, the data suggest that the mechanism of the Pex14p-Pex5p interaction in yeast is different from that previously reported for humans.

Amino Acid Motifs↗

PubMed2005

Blockade of haem oxygenase and nitric oxide synthetase causes cortical dysfunction in sheep exposed to carbon monoxide.

Twenty adult ewes underwent common surgery and following recovery were exposed to 1% carbon monoxide (CO) for 2 h. Ten of these sheep were randomly selected for treatment with haem oxygenase (HO) and nitric oxide synthetase (NOS) blockers. All sheep were killed 5 days later. The CO exposure was narcotic and EEG frequency was suppressed. The EEG recovery was rapid in the control sheep and both slow and incomplete in the treated sheep. This difference was statistically significant (P<0.05). For the first time in our CO studies in sheep, one showed multiple cortical infarcts. This sheep was blocked for HO and NOS function. No significant differences were seen in peri-ventricular white matter infarction distribution and frequency. We have previously shown brain protection against CO- and inert diluent-hypoxemia by way of an increase in brain blood flow (BBF) that maintains adequate brain O2 uptake, and by an increase in circulating red blood cells. From this study, we propose that the induction of neuronal and glial HO and NOS in sheep exposed to CO is protective, especially for the cortex. We intend to study this further by both selective and collective enzyme blockade and by measuring regional BBF changes.

Animals↗

PubMed2005

A clinical pathway for bronchiolitis is effective in reducing readmission rates.

OBJECTIVE: To examine the use of a clinical pathway in the management of infants hospitalized with acute viral bronchiolitis. STUDY DESIGN: A clinical pathway with specific management and discharge criteria for the care of infants with bronchiolitis was developed from pathways used in tertiary care pediatric institutions in Australia. Two hundred and twenty-nine infants admitted to hospital with acute viral bronchiolitis and prospectively managed using a pathway protocol were compared with a retrospective analysis of 207 infants managed without a pathway in 3 regional and 1 tertiary care hospital. RESULTS: Readmission to hospital was significantly lower in the pathway group (P = .001), as was administration of supplemental fluids (P = .001) and use of steroids (P = .005). There were no differences between groups in demographic factors or clinical severity. The pathway had no overall effect on length of stay or time in oxygen. CONCLUSIONS: A clinical pathway specifying local practice guidelines and discharge criteria can reduce the risk of readmission to hospital, the use of inappropriate therapies, and help with discharge planning.

Acute Disease↗

PubMed2005

Assessment of public health workforce bioterrorism and emergency preparedness readiness among tribes in Washington State: a collaborative approach among the Northwest Center for Public Health Practice, the Northwest Portland Area Indian Health Board, and the Washington State Department of Health.

This article examines the collaboration, methodology, results, and lessons learned stemming from the experience of a unique university, state, and tribal collaborative model for public health emergency preparedness assessment activities. This collaborative model may be applicable to other public health preparedness efforts, as well as the broader range of general public health or workforce development partnerships between state, local, and tribal health departments and academic institutions.

Adult↗

PubMed2005

Self-help books for depression: how can practitioners and patients make the right choice?

BACKGROUND: Depression is a common and important public health problem most often treated by GPs. A self-help approach is popular with patients, yet little is known about its effectiveness. AIM: Our primary aim was to review and update the evidence for the clinical effectiveness of bibliotherapy in the treatment of depression. Our secondary aim was to identify which of these self-help materials are generally available to buy and to examine the evidence specific to these publications. METHOD: Medline, CINAHL, EMBASE, PsycINFO, CCTR, PsiTri and the National Research Register were searched for randomised trials that evaluated self-help books for depression which included participants aged over 16 years with a diagnosis or symptoms of depression. Clinical symptoms, quality of life, costs or acceptability to users were the required outcome measures. Papers were obtained and data extracted independently by two researchers. A meta-analysis using a random effects model was carried out using the mean score and standard deviation of the Hamilton Rating Scale for Depression at the endpoint of the trial. RESULTS: Eleven randomised controlled trials were identified. None fulfilled CONSORT guidelines and all were small, with the largest trial having 40 patients per group. Nine of these evaluated two current publications, Managing Anxiety and Depression (UK) and Feeling Good (US). A meta-analysis of 6 trials evaluating Feeling Good found a large treatment effect compared to delayed treatment (standardised mean difference = -1.36; 95% confidence interval [CI] = -1.76 to -0.96). Five self-help books were identified as being available and commonly bought by members of the public in addition to the two books that had been evaluated in trials. CONCLUSION: There are a number of self-help books for the treatment of depression readily available. For the majority, there is little direct evidence for their effectiveness. There is weak evidence that suggests that bibliotherapy, based on a cognitive behavioural therapy approach is useful for some people when they are given some additional guidance. More work is required in primary care to investigate the cost-effectiveness of self-help and the most suitable format and presentation of materials.

Adolescent↗

PubMed2004

Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease.

We report four siblings showing features of a pontobulbar palsy, a mixed spinal and upper motor neuropathy and variable deafness. The observation of affected males and females born to consanguineous first cousin parents suggests autosomal recessive inheritance. Two children presented in the first 16 months of life with stridor and died of respiratory failure by the age of 2 years. Hearing loss was not apparent in these infants. In contrast, 2 further siblings developed a bulbar palsy in their sixth year followed by the onset of deafness and features of an anterior horn neuropathy with corticospinal tract involvement. They exhibited a relatively slow but relentless decline over a period of several years. These cases highlight the phenotypic overlap of Brown-Vialetto-Van Laere syndrome with Fazio-Londe disease. Rather than representing two separate disorders, our findings suggest the possibility of a single disease entity which may usefully be considered a form of juvenile amyotrophic lateral sclerosis.

Adolescent↗

PubMed2003

Selective cortical alteration after hypoxic-ischemic injury in the very immature rat brain.

Distinctive cerebral lesions with disruptions to the developing white matter are found in very low birth weight (VLBW) infants. Although hypoxia-ischemia (HI) is a causal pathway, the pathogenesis of cerebral white matter injury in the VLBW infant is not fully understood. Pertinent murine models would facilitate the investigation of the processes leading to these cerebral lesions and enable the evaluation of therapeutic strategies. Postnatal d 3 (P3) rats are at a stage of cortical oligodendroglial maturation and axonal outgrowth similar to very preterm infants. Our aim was to characterize the effects of a focal hypoxic-ischemic injury at P3 on subsequent cerebral development. Three groups of P3 Wistar rats were investigated: group I underwent right carotid ligation followed by 6% hypoxia for 30 min (HI), group 2 had carotid ligation only, and group 3 had no intervention. At P21, in the HI group, the right cortical area was reduced compared with controls (p < 0.01). There were no significant alterations in the size of the dorsal hippocampus, striatum, and thalamus. The cortical myelinated area was reduced in the HI animals compared with controls (p < 0.01). There was a corresponding loss of myelinated axons extending up into the cortex, with deep cortical neuronal and axonal architecture markedly disrupted. Glial fibrillary acidic protein immunohistology showed a reactive gliosis in the deep parietal cortex (p < 0.01). Moderate HI injury in the immature rat brain compromised cortical growth and led to a selective alteration of cortical myelinated axons with persistent gliosis. These alterations induced at P3 by unilateral HI share neuropathological similarities with the diffuse white matter lesions found in VLBW infants.

Age Factors↗

PubMed2003

Using the expected survival to explain differences between the results of randomized trials: a case in advanced ovarian cancer.

PURPOSE: A meta-analysis of randomized trials in advanced ovarian cancer showed a longer survival with cyclophosphamide, doxorubicin, and cisplatin (CAP) than with cyclophosphamide and cisplatin (CP; P =.009). In contrast, the results of the large International Collaborative Ovarian Neoplasm Study (ICON2) showed no survival difference between CAP and carboplatin (P =.98). In this article, we show how these discrepant results can be reconciled through the estimation of expected survival curves. MATERIALS AND METHODS: A proportional hazards model, fitted to the meta-analysis data, was used to construct the expected survival curve for each treatment arm of the ICON2 trial. Expected survival curves were compared with observed survival curves in the ICON2 trial at all time points using a nonparametric test. RESULTS: The prognostic model for survival obtained in the meta-analysis included extent of residual disease, age, histologic grade, and International Federation of Gynecology and Obstetrics stage. When this model was applied to the ICON2 data, there was no difference between the expected and observed curves in the CAP arm. In contrast, the observed survival curve for carboplatin was far superior to the expected survival curve for CP (P <.01). CONCLUSION: These analyses provide indirect evidence that better results are achieved with carboplatin alone at an optimally tolerated dose, compared with the CP combination at a cisplatin dose of 50 to 60 mg/m2. The expected survival may provide valuable insight when direct comparisons between randomized groups yield discrepant results across different studies.

Adult↗

PubMed2003

A lignocaine infusion worsens the leukoencephalopathy due to a carbon monoxide exposure in sheep.

Poisoning by carbon monoxide (CO) is common and conventional treatment of affected people is frequently unsuccessful. Lignocaine was identified as a potential therapy in this context because of the benefit shown for it in other brain injuries for which the received toxic mechanisms are similar. Twelve Romney ewes were exposed to 1% CO for 120 min were then infused intravenously with either lignocaine (N=6) or saline for 72 h, and were killed 5 days after the exposure for histological and immunohistochemical examination. This dose of CO was narcotic and caused white matter brain infarcts, with associated glial cell activation, axonal dysfunction and induction of both neuronal and glial haeme oxygenase and nitric oxide synthetase. The frequency of the white matter infarcts was significantly greater in the lignocaine-treated group. The mechanism of this adverse interaction is neither established here nor is it deducible from other published data; alternative antidotes to CO clearly need to be tested.

Animals↗

PubMed2003

PHASE: a randomised, controlled trial of supervised self-help cognitive behavioural therapy in primary care.

BACKGROUND: Common mental health problems account for up to 40% of all general practitioner (GP) consultations. Patients have limited access to evidence-based psychological therapies. Cognitive behavioural therapy self-help strategies offer one potential solution. AIM: To determine differences in clinical outcome, patient satisfaction and costs, between a cognitive behavioural-based self-help package facilitated by practice nurses compared to ordinary care by GPs for mild to moderate anxiety and depression. DESIGN OF STUDY: Randomised controlled trial. SETTING: Seventeen primary healthcare teams. METHOD: Patients presenting to their GP with mild to moderate anxiety and/or depression were recruited to the study and randomised to receive either a self-help intervention facilitated by practice nurses or ordinary care. The self-help intervention consisted of up to three appointments: two 1 week apart and a third 3 months later. There were no restrictions on ordinary care. RESULTS: Intention-to-treat analysis showed that patients treated with practice nurse-supported cognitive behavioural therapy self-help attained similar clinical outcomes for similar costs and were more satisfied than patients treated by GPs with ordinary care. On-treatment analysis showed patients receiving the facilitated cognitive behavioural therapy self-help were more likely to be below clinical threshold at 1 month compared to the ordinary care group (odds ratio [OR] = 3.65, 95% confidence interval [CI] = 1.87 to 4.37). This difference was less well marked at 3 months (OR = 1.36, 95% CI = 0.52 to 3.56). CONCLUSION: Facilitated cognitive behavioural self-help may provide a short-term cost-effective clinical benefit for patients with mild to moderate anxiety and depression. This has the potential to help primary care provide a choice of effective psychological as well as pharmacological treatments for mental health problems.

Adolescent↗

PubMed2002

Informed consent: patients listen and read, but what information do they retain?

AIM: To determine the percentage of knowledge retained immediately following an outpatient consultation for total hip and knee joint arthroplasty, and whether any improvement in that knowledge occurred after reading an information leaflet about the operation. METHODS: Patients on the waiting list for joint replacement surgery were given verbal information during the consultation about basic operative details, post-operative programme, and potential complications. A questionnaire was completed asking them to recall these details. They were then given information leaflets to read. Six weeks later, they were contacted again and asked the same questions. RESULTS: Immediately following a consultation, patients recall only a small percentage of information. In particular, retention of post-operative recovery time frames, and possible operative complications is poor. Despite an information booklet, patients' level of knowledge deteriorates from the initial consultation. CONCLUSIONS: Verbal and written information supplied to a patient may be understood, but it is easily and quickly forgotten. In an increasingly medicolegal environment, it is essential to gain informed consent from a patient when performing interventions. The provision of an information booklet may provide nothing more than proof for the surgeon of information provision to the patient.

Aged↗

PubMed2002

A narcotic dose of carbon monoxide induces neuronal haeme oxygenase and nitric oxide synthetase in sheep.

Twelve Romney ewes were exposed to either 1% carbon monoxide (CO) in air (n=6) or room air alone for 120 min and were killed 15 days later for histological and immunohistochemical examination. This dose of CO was narcotic and induced both haeme oxygenase and nitric oxide synthetase in brain neurons, but not in endothelial cells. The mechanism of the induction is not established here, but cellular theories of CO toxicity will need to be re-examined given these results.

Animals↗

PubMedDate not supplied

Effect of in ovo vaccine delivery route on herpesvirus of turkeys/SB-1 efficacy and viremia.

A study was designed to ascertain the influence of in ovo site of inoculation and embryonic fluid type on the development of Marek's disease (MD) vaccine viremia and efficacy against MD challenge. The experiments were divided into in vitro and in vivo phases. In the in vitro phase, herpesvirus of turkeys/SB-1 vaccine was combined with basal medium eagle (BME) medium (control), amniotic fluid, or allantoic fluid and subsequently titrated on secondary chick embryo fibroblast cultures. There were no significant differences in titer between the virus inoculum carried in BME and the virus inoculum combined with either the allantoic fluid or the amniotic fluid. In the in vivo phase, five routes of inoculation, amniotic, intraembryonic, allantoic, air cell, and subcutaneous at hatch, were compared for generation of protection against virulent MD challenge. Comparisons were made in both specific-pathogen-free and commercial broiler embryos/chicks and, for the amniotic and allantoic routes, injection at either day 17 or day 18 of embryonation. Reisolation of the vaccine virus at day 3 of age was also done for all routes with the exception of the air cell route. Vaccine virus was recovered from all birds tested that were injected in ovo via the amniotic and intraembryonic routes and the subcutaneously at hatch route but was isolated only sporadically from birds inoculated via the allantoic route. Vaccination protective efficacy against virulent MD for all birds vaccinated in ovo via the amniotic or intraembryonic routes and birds vaccinated subcutaneously at hatch was over 90% regardless of day of in ovo injection or bird type. Protective efficacy for vaccines delivered in ovo by either the allantoic or the air cell routes was less than 50% regardless of day of injection or bird type. Therefore, in ovo MD vaccines must be injected either via the amniotic route or the intraembryonic route for optimal performance.

Allantois↗