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Biomedical subjects

R J White

Publications and source records attributed to R J White.

At least 19 recordsLinked to original sources
PubMed2006

The prevalence of Barrett's oesophagus in a cohort of 1040 Canadian primary care patients with uninvestigated dyspepsia undergoing prompt endoscopy.

BACKGROUND: The prevalence of Barrett's oesophagus in patients undergoing gastroscopy may be influenced by possible referral bias. AIM: To present the prevalence of Barrett's oesophagus from the the Canadian Adult Dyspepsia Empirical Therapy Prompt Endoscopy study and to explore potential risk factors for its presence. METHODS: Patients had not been on treatment for dyspepsia for 2-4 weeks prior to endoscopy, which was performed within 10 working days of presentation. RESULTS: Barrett's oesophagus was endoscopically suspected in 53 of 1040 cases (5%) and histologically confirmed by the presence of intestinal metaplasia in 25 (2.4%). The prevalence of biopsy-proven Barrett's oesophagus was 4% in patients with dominant reflux-like symptoms. Sixty-four percent with confirmed Barrett's oesophagus had dominant reflux-like symptoms compared with 37% without Barrett's oesophagus. Barrett's oesophagus was more common in patients >50 years of age; 68% of cases were males. The mean duration of symptoms was 10 years, yet 16% had symptoms of <1-year duration. Endoscopic reflux oesophagitis was present in 68% of confirmed Barrett's oesophagus patients. CONCLUSIONS: Barrett's oesophagus is confirmed on biopsy in about half of endoscopically suspected Barrett's oesophagus patients. Barrett's oesophagus is more common in males, in those with dominant reflux-like symptoms, and in patients with a longer symptom history.

Aged↗
PubMed2005

Heartburn-dominant, uninvestigated dyspepsia: a comparison of 'PPI-start' and 'H2-RA-start' management strategies in primary care--the CADET-HR Study.

BACKGROUND: There are few data on empiric, stepped therapy for heartburn relief or subsequent relapse in primary care. AIMS: To compare heartburn relief produced by a proton pump inhibitor-start or an H(2)-receptor antagonist-start with step-up therapy, as needed, followed by a treatment-free period to assess relapse. METHODS: Heartburn-dominant uninvestigated dyspepsia patients from 46 primary care centres were randomized to one of two active treatment strategies: omeprazole 20 mg daily (proton pump inhibitor-start) or ranitidine 150 mg bid (H2-receptor antagonist-start) for the first 4-8 weeks, stepping up to omeprazole 40 or 20 mg daily, respectively, for 4-8 weeks for persistent symptoms. Daily diaries documented heartburn relief (score < or = 3/7 on < or = of 7 prior days) and relapse (score > or = 4 on > or = 2 of 7 prior days). RESULTS: For 'proton pump inhibitor-start' (n = 196) vs. 'H2-receptor antagonist-start' (n = 194), respectively, heartburn relief occurred in 55.1% vs. 27.3% (P < 0.001) at 4 weeks and in 88.3% vs. 87.1% at 16 weeks. After therapy, 308 patients were heartburn-free (159 vs. 149); median times to relapse were 8 vs. 9 days and cumulative relapse rates were 78.6% vs. 75.8%, respectively. CONCLUSIONS: An empiric 'proton pump inhibitor-start' strategy relieves heartburn more effectively than an 'H2-receptor antagonist-start' strategy up to 12 weeks but has no effect on subsequent relapse, which is rapid in most patients.

Adolescent↗
PubMed2005

Bacterial Peptide deformylase inhibitors: a new class of antibacterial agents.

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth but is not required by mammalian cells. Thus, it represents a selective and promising target for the development of new antibacterial agents. Since deformylase inhibitors have yet to be used clinically as antibacterial drugs, compounds targeting this enzyme should avoid cross-resistance with currently used antibacterial agents. The PDF enzyme is a ferrous ion-containing metallohydrolase, but a nickel-containing surrogate is routinely used in the laboratory for testing inhibitors due to its better stability. Enzymes from several bacterial species have been cloned and both their three-dimensional structures and co-crystal structures with bound inhibitor have been determined. As a metallo enzyme, PDF lends itself to the well-precedented mechanism-based rational drug design approach. Using structural and mechanistic information together with high throughput screening, several types of potent PDF inhibitors have been identified. PDF inhibitors identified to date share a common structural feature of a "chelator + peptidomimetic" scaffold. Although compounds with many different chelators inhibit the cell free enzyme, only compounds containing hydroxamic acid or N-formyl hydroxylamine exhibit appreciable antibacterial activity. Several lead inhibitors have demonstrated in vivo efficacy and an excellent safety profile. Two PDF inhibitors, VIC-104959 (LBM415) and BB-83698, have progressed to Phase I clinical trials. In this review, different PDF inhibitors are compared and their biological activities are discussed. Structure-activity relationships have been established and the implications of this work in the design of future PDF inhibitors are considered.

Amidohydrolases↗
PubMed2004

RNA polymerase III transcription--a battleground for tumour suppressors and oncogenes.

This review provides a summary of the European Association for Cancer Research Award Lecture, presented at the ECCO12 meeting in Copenhagen in September 2003. It describes what we have learnt about the mechanisms responsible for deregulating RNA polymerase III transcription in transformed cells. A network has been discovered of unanticipated links to key tumour suppressors and oncogenes. Novel functions have been revealed for RB, p53 and c-Myc, that may help explain their profound biological effects.

Cell Division↗
PubMed2004

EACR-18: the best of European cancer research.

EACR-18 was the 18th biennial meeting of the European Association for Cancer Research (EACR). It attracted more than 700 delegates, providing a pivotal European forum for basic scientists, translational researchers and clinical oncologists alike. It covered most of the key areas and recent developments in cancer research. This Review presents a meeting report.

Biomedical Research↗
PubMed2004

Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach.

Peptide deformylase (PDF), a metallohydrolase essential for bacterial growth, is an attractive target for use in the discovery of novel antibiotics. Focused chelator-based chemical libraries were constructed and screened for inhibition of enzymatic activity, inhibition of Staphylococcus aureus growth, and cytotoxicity. Positive compounds were selected based on the results of all three assays. VRC3375 [N-hydroxy-3-R-butyl-3-(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl)propionamide] was identified as having the most favorable properties through an integrated combinatorial and medicinal chemistry effort. This compound is a potent PDF inhibitor with a K(i) of 0.24 nM against the Escherichia coli Ni(2+) enzyme, possesses activity against gram-positive and gram-negative bacterial pathogens, and has a low cytotoxicity. Mechanistic experiments demonstrate that the compound inhibits bacterial growth through PDF inhibition. Pharmacokinetic studies of this drug in mice indicate that VRC3375 is orally bioavailable and rapidly distributed among various tissues. VRC3375 has in vivo activity against S. aureus in a murine septicemia model, with 50% effective doses of 32, 17, and 21 mg/kg of body weight after dosing by intravenous (i.v.), subcutaneous (s.c.), and oral (p.o.) administration, respectively. In murine single-dose toxicity studies, no adverse effects were observed after dosing with more than 400 mg of VRC3375 per kg by i.v., p.o., or s.c. administration. The in vivo efficacy and low toxicity of VRC3375 suggest the potential for developing this class of compounds to be used in future antibacterial drugs.

Algorithms↗
PubMed2003

The prevalence of clinically significant endoscopic findings in primary care patients with uninvestigated dyspepsia: the Canadian Adult Dyspepsia Empiric Treatment - Prompt Endoscopy (CADET-PE) study.

BACKGROUND: Uninvestigated dyspepsia is common in family practice. The prevalence of clinically significant upper gastrointestinal findings (CSFs) in adult uninvestigated dyspepsia patients, and their predictability based on history, is unknown. METHODS: Prompt endoscopy was performed within 10 days of referral, in 1040 adult patients presenting with uninvestigated dyspepsia at 49 Canadian family practitioner centres. Subsequent management strategies during a 6-month follow-up period were determined by the individual family practitioners. RESULTS: CSFs were identified in 58% (603/1040) of patients. Erosive oesophagitis was most common (43%; N = 451); peptic ulcer was uncommon (5.3%; N = 55). Alarm symptoms were uncommon (2.8%; N = 29). Most patients had at least three dyspepsia symptoms, more than 80% had at least six, and approximately half had eight or more. Based on the dominant symptom, 463 (45%) patients had ulcer-like, 393 (38%) had reflux-like and 184 (18%) had dysmotility-like dyspepsia. The patients' dominant symptom was not predictive of endoscopic findings. Oesophagitis was more common in those with dominant reflux-like symptoms and was the most common finding in all subgroups. The prevalence of gastroduodenal findings was similar in all symptom subgroups. Helicobacter pylori (H. pylori) infection (30%; 301/1013) was associated with gastroduodenal findings. CONCLUSIONS: Dyspepsia subclassifications, based on dominant symptom, are of limited value in predicting the presence and nature of CSFs. Oesophagitis was by far the most common diagnosis (43% of patients). CSFs were common in uninvestigated dyspepsia patients and their nature suggests patients could be initially treated effectively, without endoscopy, using empirical acid suppressive therapy.

Adolescent↗
PubMed2003

Issues of exploration: human health and wellbeing during a mission to Mars.

Today, the tools are in our hands to enable us to travel away from our home planet and become citizens of the solar system. Even now, we are seriously beginning to develop the robust infrastructure that will make the 21st century the Century of Space Travel. But this bold step must be taken with due concern for the health, safety and wellbeing of future space explorers. Our long experience with space biomedical research convinces us that, if we are to deal effectively with the medical and biomedical issues of exploration, then dramatic and bold steps are also necessary in this field. We can no longer treat the human body as if it were composed of muscles, bones, heart and brain acting independently. Instead, we must lead the effort to develop a fully integrated view of the body, with all parts connected and fully interacting in a realistic way. This paper will present the status of current (2000) plans by the National Space Biomedical Research Institute to initiate research in this area of integrative physiology and medicine. Specifically, three example projects are discussed as potential stepping stones towards the ultimate goal of producing a digital human. These projects relate to developing a functional model of the human musculoskeletal system and the heart.

Adaptation, Physiological↗
PubMed2003

Myotonic dystrophy and paediatric anaesthesia.

Myotonic dystrophy is a neuromuscular condition inherited in an autosomal dominant fashion, and is most commonly diagnosed in the neonatal period. With improving levels of care, these patients are now presenting more commonly for anaesthesia. We review the clinical features of the condition, and then discuss the steps in the anaesthetic process, outlining the anaesthetic implications of myotonic dystrophy at each stage.

Anesthesia↗
PubMed2003

Quantitative description and discrimination of butterfly wing patterns using moment invariant analysis.

Studies examining and using pattern variation in insects for identification and characterization of individuals and populations have been limited by the methods available for quantifying wing patterns objectively. In this paper, differences in wing pattern are demonstrated statistically using moment invariant data sets generated automatically from digitized images of the speckled wood butterfly, Pararge aegeria (Linnaeus). Studies with other biological subjects have already shown moment invariants to work well with outline shapes and silhouettes. A pilot study with replicated monochrome photographs of a single butterfly showed the method could detect pattern differences between wing surfaces, even in the presence of simulated wing fading and damage. In a further study of the wings of 228 specimens, multivariate analyses of variance using the moment data reliably detected differences between groups of butterflies according to sex, geographical origin and culture history. Potential applications and future improvements of the moment methodology are considered.

Analysis of Variance↗
PubMed2002

Direct and indirect regulation of derrière, a Xenopus mesoderm-inducing factor, by VegT.

One candidate for an endogenous mesoderm-inducing factor in Xenopus is derrière, a member of the TGFbeta family closely related to Vg1. In this paper we first show that derrière is able to exert long-range effects in the early Xenopus embryo, reinforcing the view that it functions as a secreted factor required for proper formation of posterior structures. Analysis of the derrière promoter shows that expression of the gene is controlled through a complex inductive network involving VegT and TGFbeta-related molecules and also, perhaps, FGF family members. The work confirms that derrière plays an important role in mesoderm formation and it illustrates the complex regulation to which inducing factors are subject.

Activins↗
PubMed2001

Humans in space.

Many successful space missions over the past 40 years have highlighted the advantages and necessity of humans in the exploration of space. But as space travel becomes ever more feasible in the twenty-first century, the health and safety of future space explorers will be paramount. In particular, understanding the risks posed by exposure to radiation and extended weightlessness will be crucial if humans are to travel far from Earth.

Extraterrestrial Environment↗
PubMed2001

Regulation of RNA polymerase III transcription during cell cycle entry.

Increased rates of RNA polymerase (pol) III transcription constitute a central feature of the mitogenic response, but little is known about the mechanism(s) responsible. We demonstrate that the retinoblastoma protein RB plays a major role in suppressing pol III transcription in growth-arrested fibroblasts. RB knockout cells are compromised in their ability to down-regulate pol III following serum withdrawal. RB binds and represses the pol III-specific transcription factor TFIIIB during G(0) and early G(1), but this interaction decreases as cells approach S phase. Full induction of pol III coincides with mid- to late G(1) phase, when RB becomes phosphorylated by cyclin D- and E-dependent kinases. TFIIIB only associates with the underphosphorylated form of RB, and overexpression of cyclins D and E stimulates pol III transcription in vivo. The RB-related protein p130 also contributes to the repression of TFIIIB in growth-arrested fibroblasts. These observations provide insight into the mechanisms responsible for controlling pol III transcription during the switch between growth and quiescence.

3T3 Cells↗
PubMed2001

Impairment of deglutition reflex by acid-induced esophageal mucosal injury.

Swallowing is an important defense mechanism against reflux esophagitis as it helps clear refluxed gastric contents from the esophagus, while bicarbonate in the saliva acts to neutralize acid. The purpose of the present study was to examine the effect of esophagitis on the deglutition reflex in anesthetized opossums. Animals perfused with either an acidified pepsin solution for 45 min or with 100 mM hydrochloric acid for 45 min on each of three consecutive days exhibited a significantly impaired deglutition reflex in comparison to baseline. Control animals perfused with 0.9% saline showed no impairment. Bilateral cervical vagotomy in animals perfused with acidified pepsin attenuated the impaired deglutition reflex. Taken together, these results suggest that esophagitis causes an impairment in the deglutition reflex that is mediated by vagal afferent pathways.

Animals↗
PubMed2001

Transposable B2 SINE elements can provide mobile RNA polymerase II promoters.

Short interspersed elements (SINEs) are highly abundant components of mammalian genomes that are propagated by retrotransposition. SINEs are recognized as a causal agent of human disease and must also have had a profound influence in shaping eukaryotic genomes. The B2 SINE family constitutes approximately 0.7% of total mouse genomic DNA (ref. 2) and is also found at low abundance in humans. It resembles the Alu family in several respects, such as its mechanism of propagation. B2 SINEs are derived from tRNA and are transcribed by RNA polymerase (pol) III to generate short transcripts that are not translated. We find here, however, that one B2 SINE also carries an active pol II promoter located outside the tRNA region. Indeed, a B2 element is responsible for the production of a mouse Lama3 transcript. The B2 pol II promoters can be bound and stimulated by the transcription factor USF (for upstream stimulatory factor), as shown by transient transfection experiments. Moreover, this pol II activity does not preclude the pol III transcription necessary for retrotransposition. Dispersal of B2 SINEs by retrotransposition may therefore have provided numerous opportunities for creating regulated pol II transcription at novel genomic sites. This mechanism may have allowed the evolution of new transcription units and new genes.

Animals↗
PubMed2001

Anaesthetic management of a patient with myotonic dystrophy.

A 13-year-old boy with myotonic dystrophy underwent insertion of a percutaneous gastrostomy feeding tube under general anaesthesia. We used a laryngeal mask airway and a spontaneously breathing technique with propofol total intravenous anaesthesia. Postoperative vomiting and aspiration, 12 h after the procedure, subsequently required intubation and ventilation. We discuss the anaesthetic management of this case and review the features of the disease to be considered when contemplating anaesthesia in such patients.

Adolescent↗
PubMed2001

Remission and relapse of chronic plaque psoriasis treated once a week with clobetasol propionate occluded with a hydrocolloid dressing versus twice daily treatment with clobetasol propionate alone.

BACKGROUND: Many studies have shown the clinical efficiency of occlusion therapy for psoriasis, particularly corticosteroids used under hydrocolloid dressings. However, there are no data from comparative clinical studies evaluating the remission and relapse characteristics of such occlusion therapy compared with orthodox topical steroid monotherapy. METHODS: In a randomised, open-label, parallel group study from three centres, the remission and relapse characteristics were investigated for the use of a hydrocolloid dressing (HCD) over clobetasol propionate 0.05% lotion once a week compared with the same steroid in ointment formulation used unoccluded twice a day in 61 patients with stable chronic plaque psoriasis. RESULTS: There was a pronounced treatment difference in favour of the HCD + clobetasol propionate lotion group with respect to time to clearance, but there was little evidence for a difference with respect to time to relapse. CONCLUSION: The combination of the HCD + clobetasol propionate lotion provides a fast and highly effective remission induction.

Administration, Topical↗