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Richard Smith

Publications and source records attributed to Richard Smith.

At least 109 records · Page 6Linked to original sources
PubMed2002

Too much medicine?

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Delivery of Health Care↗
PubMed2002

Molecular classification of head and neck squamous cell carcinoma using cDNA microarrays.

Squamous cell carcinomas of the head and neck constitute an anatomically heterogeneous group of neoplasms that share in common a causal association with tobacco and alcohol exposure. The clinical course of these neoplasms is difficult to predict based on established prognostic clinicopathological criteria. Given the genetic complexity of head and neck cancers, it is not surprising that correlations with individual genetic abnormalities have also been disappointing. Several authors have suggested that global gene expression patterns can be used to subgroup patients with cancer. Here we report the use of cDNA microarrays containing 9216 clones to measure global patterns of gene expression in these neoplasms. We have used a statistical algorithm to identify 375 genes, which divide patients with head and neck tumors into two clinically distinct subgroups based on gene expression patterns. Our results demonstrate that gene expression profiling can be used as a predictor of outcome.

Adult↗
PubMed2002

Homogeneous quasispecies in 16 out of 17 individuals during very early HIV-1 primary infection.

OBJECTIVE: To measure HIV-1 quasispecies diversity in very recently infected male and female plasma donors. METHODS: HIV-1 RNA testing of blood and plasma donations was used to select anti HIV-1 antibody negative, HIV-1 RNA positive plasma samples from 13 males and four females undergoing primary infection. To determine whether these early viral populations were clonal or oligoclonal, heteroduplex mobility assays were performed on multiple independently generated envelope PCR products. Genetically heterogeneous quasispecies where subcloned and their divergent envelope variants sequenced. RESULTS: Because of frequent plasma donations in this population, HIV-1 RNA quasispecies could be studied during very early primary infection. Heteroduplex mobility assays detected the presence of genetically distinct variants in four of the 17 plasma donors. DNA sequence analysis showed that one case was due to a G to A hyper-mutation event and that two cases were caused by the presence of in-frame insertions/deletions resulting in DNA heteroduplex mobility shifts. The early plasma quasispecies of one female contained highly divergent variants differing by up to 6% substitution and multiple insertions/deletions, a level of divergence unlikely to have been generated de novo following transmission. V3 loop sequences analysis indicated the presence of non-syncitium inducing genotypes in 14 out of 17 primary infection cases. CONCLUSION: Plasma viremia is generally genetically homogeneous even during the very early phase of primary infection when viremia is first detected and still rising exponentially. Evidence for the transmission of multiple variants was detected in only one out of four women and none of 13 men undergoing primary infection with subtype B HIV-1.

Base Sequence↗
PubMed2002

Superbugs II: how should economic evaluation be conducted for interventions which aim to contain antimicrobial resistance?

To date, there has been little examination of the problems associated with conducting economic evaluation for interventions designed to contain antimicrobial resistance. There are two quite different types of intervention aimed at containing antimicrobial resistance: interventions which are designed to avoid the emergence of resistant organisms; and interventions that are designed to avoid the transmission of resistance organisms. Four aspects of economic evaluation where the ease of assessment might be expected to differ across evaluations for these different types of intervention are examined: problems associated with the identification of diffuse impacts, problems associated with comparing current and future impacts, problems associated with uncertainty, and problems associated with difficulties in measurement and valuation. The paper suggests that it may be much easier to conduct rigorous economic evaluations for interventions designed to avoid transmission of resistance, than for those intended to avoid emergence. Unfortunately, the transmission policies, which are likely to be the easiest to evaluate, are not likely to produce an optimal long-term outcome given the apparent irreversibility of much resistance and the potentially severe harms which could be imposed as a result. Given the desirability of avoiding a scenario where, in the evidence-based medicine culture, the most rigorously evaluated policies are followed even though they may be less important, there is the need to consider carefully what, and how, economic evaluation should be conducted in the area of antimicrobial resistance. It is suggested that research should focus on the use of modelling as a means of evaluating optimal policy responses and on trying to resolve some of the difficulties associated with measurement and valuation.

Anti-Infective Agents↗
PubMed2002

Initiation of eukaryotic DNA replication: regulation and mechanisms.

The accurate and timely duplication of the genome is a major task for eukaryotic cells. This process requires the cooperation of multiple factors to ensure the stability of the genetic information of each cell. Mutations, rearrangements, or loss of chromosomes can be detrimental to a single cell as well as to the whole organism, causing failures, disease, or death. Because of the size of eukaryotic genomes, chromosomal duplication is accomplished in a multiparallel process. In human somatic cells between 10,000 and 100,000 parallel synthesis sites are present. This raises fundamental problems for eukaryotic cells to coordinate the start of DNA replication at each origin and to prevent replication of already duplicated DNA regions. Since these general phenomena were recognized in the middle of the 20th century the regulation and mechanisms of the initiation of eukaryotic DNA replication have been intensively investigated. These studies were carried out to find the essential factors involved in the process and to determine their functions during DNA replication. These studies gave rise to a model of the organization and the coordination of DNA replication within the eukaryotic cell. The elegant experiments carried out by Rao and Johnson (1970) (1), who fused cells in different phases of the cell cycle, showed that G1 cells are competent for replication of their chromosomes, but lack a specific diffusible factor required to activate their replicaton machinery and showed that G2 cells are incompetent for DNA replication. These findings suggested that eukaryotic cells exist in two states. In G1 phase, cells are competent to initiate DNA replication, which is subsequently triggered in S phase. After completion of S phase, cells in G2 are no longer able to initiate DNA replication and they require a transition through mitosis to reenable initiation of DNA replication to take place in the next S phase. The Xenopus cell-free replication system has proved a good model system in which to study DNA replication in vitro as well as the mechanism preventing rereplication within a single cell cycle (2). Studies using this system resulted in the development of a model postulating the existence of a replication licensing factor, which binds to chromatin before the G1-S transition and which is displaced during replication (2, 3). These results were supported by genetic and biochemical experiments in Saccharomyces cerevisiae (budding yeast) and Schizosaccharomyces pombe (fission yeast) (4, 5). The investigation of cell division cycle mutants and the budding yeast origin of replication resulted in the concept of a prereplicative and a postreplicative complex of initiation proteins (6-9). These three individual concepts have recently started to merge and it has become obvious that initiation in eukaryotes is generally governed by the same ubiquitous mechanisms.

Animals↗
PubMed2002

Effect of pregnancy on trunk range of motion when sitting and standing.

BACKGROUND: During pregnancy, apposition of body segments and changes in trunk mobility and motion control due to increased mass and dimensions may reduce the functional range of motion of the trunk segments. Although static postures have been investigated, dynamic trunk motion during pregnancy in sitting and standing has had very limited investigation. METHODS: Included in the study was a volunteer sample of convenience of nine primiparous and multiparous women. Twelve nulliparous females formed a control group. The subjects were filmed while performing maximum seated and standing trunk forward flexion, side-to-side flexion and seated axial rotation. A repeated measures anova was used to investigate systematic changes in the motion of the pelvic and thoracic segments and the thoracolumbar spines during pregnancy. RESULTS: As pregnancy progressed, there was no significant decrease in the range of side-to-side flexion. For forward flexion and axial rotation, motion of the thoracic segment and the thoracolumbar spine was significantly reduced. Movement of the pelvis was less affected. Base of support width was increased for forward flexion and side-to-side flexion. CONCLUSIONS: In late pregnancy, strategies such as increasing the width of the base of support and reducing obstruction from other body parts were used to minimize the effects of increased trunk mass and girths. Not all trunk segment motion was affected equally. The differing effect on individual trunk segment motion may lead to altered movement patterns during functional tasks.

Adult↗
PubMed2002

Static trunk posture in sitting and standing during pregnancy and early postpartum.

OBJECTIVE: To investigate the postural alignment of the upper body in the sagittal plane during sitting and standing postures as pregnancy progressed and then in the postpartum period. DESIGN: Longitudinal, repeated-measures design. SETTING: Biomechanics laboratory in an Australian university. PARTICIPANTS: A volunteer convenience sample of 9 primiparous and multiparous women and 12 nulliparous women serving as a control group. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Subjects were filmed while sitting and during quiet standing at intervals throughout pregnancy and at 8 weeks postpartum. A repeated-measures analysis of variance was used to assess systematic changes in the alignment of the pelvic, thoracic, and head segments, and the thoracolumbar and cervicothoracic spines. Student t tests were used to compare the postpartum and nulliparous control groups. RESULTS: There was no significant effect of pregnancy on the upper-body posture, although there was a tendency in some subjects for a flatter thoracolumbar spinal curve in sitting as pregnancy progressed. Postpartum during standing, the pelvic segment had a reduced sagittal plane anterior orientation, and the thoracolumbar spine was less extended, indicating a flatter spinal curve compared with the control group. CONCLUSIONS: There was no significant effect of pregnancy on upper-body posture during sitting and standing, although individuals varied in their postural response. A flatter spinal curve was found during standing postpartum.

Adult↗
PubMed2002

Consultant assessment and appraisal: an outline in practice.

AIMS: To demonstrate a practical method to address new Department of Health requirements for assessment and appraisal. METHOD: This process was developed within the department to incorporate workload, clinical incidents and 360 degrees questionnaires to assess performance and working with departmental staff as preliminaries to an appraisal interview. CONCLUSION: Review of 2 years' process has resulted in minor amendments but there was general agreement that the parameters encompassed were practical and useful.

Clinical Competence↗
PubMed2002

Strategies to contain the emergence of antimicrobial resistance: a systematic review of effectiveness and cost-effectiveness.

OBJECTIVES: To conduct a systematic review of the literature to describe and critically appraise studies reporting on the cost and/or effectiveness of interventions proposed to control the emergence of antimicrobial resistance (AMR). METHODS: The search for relevant studies encompassed consultation with world experts in AMR, and electronic bibliographic database search of: Medline (1960-2000); ISI (1981-2000); EMBASE (1988-2000); Grey Literature (1999-2000); Database of Reviews of Effectiveness (DARE) and the NHS Health Economic Evaluation Database (HEED) at York University's Centre for Reviews and Dissemination (CRD) (numerous years); OPAC (1975-2000); and the Cochrane Library Online (1990-2000). Only studies that concerned the effectiveness or cost-effectiveness of measures specifically designed to contain the emergence of AMR were reviewed. Standardised data extraction sheets, based on existing checklists for effectiveness and cost-effectiveness, were used to assess the validity of each study using the 'risk of bias criteria' suggested in the Cochrane Handbook. Only studies categorised as being at low or moderate risk of bias were reported fully. The reliability of the data review process was monitored by comparison of several, random, independent assessments by all authors. The mix of study methods (i.e. including studies based on non-randomised controlled trials) meant that formal meta-analysis was not possible, and thus a qualitative review was performed. RESULTS: In total, 43 studies were reviewed, with 21 classed as being at moderate or low risk of bias and therefore reported in the paper. These studies covered policies on: restricting the use of antimicrobials (five studies, suggesting that restriction policies can alter prescriber behaviour, although with limited evidence of subsequent effect on AMR); prescriber education, feedback and use of guidelines (six studies, with no clear conclusion); combination therapies (seven studies, showing the potential to lower drug-specific resistance, although for an indeterminate time period); vaccination (three studies showing cost/effectiveness). Most of these studies were: from the developed world, principally the USA; hospital-based, with few community level interventions; and concerned with effectiveness, not cost-effectiveness. CONCLUSIONS: Overall, there is an absence of good evidence concerning what is effective, and especially cost-effective, in reducing the emergence of AMR. However, in addition to more research concerning these forms of intervention, the paper highlights four specific areas for further investigation: validating intermediate or surrogate outcome measures to enable better use to be made of the literature on intermediate measures; development and evaluation of 'macro' strategies; research into specific aspects of AMR in developing countries; and empirical and methodological research concerning the economic evaluation of interventions.

Anti-Bacterial Agents↗
PubMed2002

Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour.

Consumption of cycad seed products (Cycas circinalis) is one of the strongest epidemiological links to the Guamian neurological disorder amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), however, the putative toxin which causes neurodegeneration has never been identified definitively. To reexamine this issue, 6-7-mo-old, male CD-1 mice were assessed for motor and cognitive behaviours during and following feeding with pellets made from washed cycad flour. Cycad-fed animals showed early evidence of progressive motor and cognitive dysfunctions. Neurodegeneration measured using TUNEL and caspase-3 labeling was found in neocortex, various hippocampal fields, substantia nigra, olfactory bulb, and spinal cord. In vitro studies using rat neocortex have identified toxic compounds in washed cycad flour that induce depolarizing field potentials and lead to release of lactate dehydrogenase (LDH), both blocked by AP5. High-performance liquid chromatography (HPLC)/mass spectrometry of cycad flour samples failed to show appreciable amounts of other known cycad toxins, cycasin, MAM, or BMAA; only trace amounts of BOAA were present. Isolation procedures employing these techniques identified the most toxic component as beta-sitosterol beta-D-glucoside (BSSG). The present data suggest that a neurotoxin, or a toxic metabolite, not previously identified in cycad, is able to gain access to central nervous system (CNS) resulting in neurodegeneration of specific neural populations and in motor and cognitive dysfunctions. These data are consistent with a number of major features of ALS-PDC in humans.

Amyotrophic Lateral Sclerosis↗