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Biomedical subjects

Richard Smith

Publications and source records attributed to Richard Smith.

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

Does home based medication review keep older people out of hospital? The HOMER randomised controlled trial.

OBJECTIVE: To determine whether home based medication review by pharmacists affects hospital readmission rates among older people. DESIGN: Randomised controlled trial. SETTING: Home based medication review after discharge from acute or community hospitals in Norfolk and Suffolk. PARTICIPANTS: 872 patients aged over 80 recruited during an emergency admission (any cause) if returning to own home or warden controlled accommodation and taking two or more drugs daily on discharge. INTERVENTION: Two home visits by a pharmacist within two weeks and eight weeks of discharge to educate patients and carers about their drugs, remove out of date drugs, inform general practitioners of drug reactions or interactions, and inform the local pharmacist if a compliance aid is needed. Control arm received usual care. MAIN OUTCOME MEASURE: Total emergency readmissions to hospital at six months. Secondary outcomes included death and quality of life measured with the EQ-5D. RESULTS: By six months 178 readmissions had occurred in the control group and 234 in the intervention group (rate ratio = 1.30, 95% confidence interval 1.07 to 1.58; P = 0.009, Poisson model). 49 deaths occurred in the intervention group compared with 63 in the control group (hazard ratio = 0.75, 0.52 to 1.10; P = 0.14). EQ-5D scores decreased (worsened) by a mean of 0.14 in the control group and 0.13 in the intervention group (difference = 0.01, -0.05 to 0.06; P = 0.84, t test). CONCLUSIONS: The intervention was associated with a significantly higher rate of hospital admissions and did not significantly improve quality of life or reduce deaths. Further research is needed to explain this counterintuitive finding and to identify more effective methods of medication review.

Aftercare↗
PubMed2005

Spray irrigation of landfill leachate: estimating potential exposures to workers and bystanders using a modified air box model and generalised source term.

Generalised source term data from UK leachates and a probabilistic exposure model (BPRISC(4)) were used to evaluate key routes of exposure from chemicals of concern during the spraying irrigation of landfill leachate. Risk estimates secured using a modified air box model are reported for a hypothetical worker exposed to selected chemicals within a generalised conceptual exposure model of spray irrigation. Consistent with pesticide spray exposure studies, the key risk driver is dermal exposure to the more toxic components of leachate. Changes in spray droplet diameter (0.02-0.2 cm) and in spray flow rate (50-1000 l/min) have little influence on dermal exposure, although the lesser routes of aerosol ingestion and inhalation are markedly affected. The risk estimates modelled using this conservative worst case exposure scenario are not of sufficient magnitude to warrant major concerns about chemical risks to workers or bystanders from this practice in the general sense. However, the modelling made use of generic concentration data for only a limited number of potential landfill leachate contaminants, such that individual practices may require assessment on the basis of their own merits.

Aerosols↗
PubMed2005

Assessment of municipal waste compost as a daily cover material for odour control at landfill sites.

The ability of municipal waste compost as a daily cover material to reduce the odorous emissions associated with landfill surfaces was investigated. Trials were carried out using landfill gas, a certified sulphurous gas mix and ambient air as a control. Odorous gas was passed through portable test column filled with compost at different densities (590 kg/m3 and 740 kg/m3). Gas samples were taken from the inlet, outlet and at varying column depths and examined using a combination of sensory analysis (olfactometry) and a novel analytical method (Transportable Selected Ion Flow Tube--TSIFT). Results for the trials using landfill gas showed a 69% odour reduction (OU/m3) through the column for compost with a bulk density of 590 kg/m3, and a reduction of 97% using compost with a bulk density of 740 kg/m3. TSIFT analysis showed an overall decrease in the concentration of terpenes, and sulphurous compounds in the outlet gas from the column for both bulk densities. No significant trend could be identified for the concentrations at different depths within the column. Results show the ability of compost to reduce landfill odours under differing conditions. The inconclusive data provided by TSIFT analysis may be due to the analysis of compounds that are not contributing to odour, and thus highlights the potential for synergetic effects and the importance of sensory measurement when examining odorous emissions.

Odorants↗
PubMed2005

Efficient elutriation of monocytes within a closed system (Elutra) for clinical-scale generation of dendritic cells.

Dendritic cells (DC) are promising tools for the immunotherapy of cancer. The induction of tumor-specific T cells and clinical regressions have already been observed in early phase I/II vaccination trials. As DC vaccination is now facing trials with larger patient collectives it becomes increasingly important to obtain large numbers of cells suitable for therapeutic applications under labor- and cost-effective conditions. We describe here a procedure that uses a novel cell separator (Elutra, Gambro BCT) to enrich monocytes from an entire apheresis product within one hour. Cells are separated on the basis of size and to a lesser extent density, by elutriation in a 40-ml conical chamber. The total monocyte recovery following elutriation (n = 6) was 98.53% (+/-8.07%), the recovery in the monocyte-rich fraction 75.45% (+/-11.31%), and the mean purity 82.95% (+/-6.01%). These monocytes can be cultured either in conventional culture dishes or in closed cell culture bags and differentiated, by using GM-CSF+IL-4 followed by a maturation cocktail composed of IL-1beta+IL-6+TNF-alpha+PGE2, into fully mature DC. The Elutra separator allows for fast and easy enrichment of monocytes within a closed system. Subsequently, elutriated monocytes can be successfully cultured into phenotypically and functionally mature DC for immunotherapeutic approaches. The method neither requires a density gradient step to enrich PBMC from leucapheresis products nor does it apply (xenogeneic) antibodies to target monocytes. Isolation of monocytes with Elutra may greatly facilitate future DC-based vaccination approaches.

Cell Differentiation↗
PubMed2005

Dynamics of viremia in early hepatitis C virus infection.

BACKGROUND: It is important to characterize viral dynamics in early hepatitis C virus (HCV) infection to further our understanding of viral pathogenesis and the potential for secondary transmission in acute infection through blood transfusion or other routes. STUDY DESIGN AND METHODS: Serial units given by 77 source plasma donors who had evolved from HCV RNA-negative to HCV RNA-positive by nucleic acid amplification technology (NAT) screening with 512-unit pool-NAT or were followed from RNA detection to antibody conversion were tested by individual NAT and quantitative RNA assays. RESULTS: During the ramp-up phase when exponential growth occurs, HCV viral load doubled every 10.8 hours (95% confidence interval [CI], 9.9-12.0). Intermittent viremia was observed before the ramp-up phase in 37 of 50 panels with the earliest detectable viremic bleed occurring 63 days before the estimated onset of ramp-up. The plateau phase or high-titer viremic period that occurs between ramp-up and seroconversion was estimated to last 56.3 days (95% CI, 44.8-67.8). CONCLUSIONS: Intermittent low-level HCV viremia can occur as much as 2 months before the periods of exponential increase in viral load and the high-titer plateau-phase viremia that usually precede seroconversion. Animal inoculation studies are in progress to evaluate if transfusion of low-level viremic plasma can transmit HCV infection.

Blood Donors↗
PubMed2004

Expression and functional characterization of recombinant human HDAC1 and HDAC3.

Histone deacetylases (HDACs) are a family of enzymes involved in transcription regulation. HDACs are known to play key roles in the regulation of cell proliferation; consequently, inhibition of HDACs has become an interesting approach for anti-cancer therapy. However, expression of mammalian HDACs has proven to be difficult. All attempts to express these HDACs in E.coli, Pichia and baculovirus systems were unsuccessful. Here we present the stable expression of human recombinant His-tagged HDAC1 and HDAC3 in mammalian cells. Full-length human genes for HDAC1 and HDAC3 were cloned into the pcDNA 3.1 vector containing a N-terminal His-tag with an enterokinase cleavage site. Recombinant HDAC enzyme activity was only detected after nickel affinity purification due to high activity of endogenous HDACs; and removal of the His-tag increased activity 2-4 fold. Western blots demonstrated the nickel affinity purified rhHDAC1 preparation also contained endogenous HDAC2 and HDAC3; likewise, rhHDAC3 preparation contained endogenous HDAC1 and HDAC2. Therefore, the active HDAC preparation is actually a multi-protein and a multi-HDAC containing complex. This provides one explanation for the similar IC50 values exhibited by SAHA and MS-275 against nuclear HDACs and rhHDAC1 and 3 preparations. These results demonstrate that recombinant forms of the HDACs can be over-expressed in mammalian cells, isolated as active multi-protein complexes that contain multiple HDAC enzymes, and caution must be used when determining HDAC inhibitor in vitro selectivity.

Blotting, Western↗
PubMed2004

Effects of training on quality of peer review: randomised controlled trial.

OBJECTIVE: To determine the effects of training on the quality of peer review. DESIGN: Single blind randomised controlled trial with two intervention groups receiving different types of training plus a control group. SETTING AND PARTICIPANTS: Reviewers at a general medical journal. Interventions Attendance at a training workshop or reception of a self taught training package focusing on what editors want from reviewers and how to critically appraise randomised controlled trials. MAIN OUTCOME MEASURES: Quality of reviews of three manuscripts sent to reviewers at four to six monthly intervals, evaluated using the validated review quality instrument; number of deliberate major errors identified; time taken to review the manuscripts; proportion recommending rejection of the manuscripts. RESULTS: Reviewers in the self taught group scored higher in review quality after training than did the control group (score 2.85 v 2.56; difference 0.29, 95% confidence interval 0.14 to 0.44; P = 0.001), but the difference was not of editorial significance and was not maintained in the long term. Both intervention groups identified significantly more major errors after training than did the control group (3.14 and 2.96 v 2.13; P < 0.001), and this remained significant after the reviewers' performance at baseline assessment was taken into account. The evidence for benefit of training was no longer apparent on further testing six months after the interventions. Training had no impact on the time taken to review the papers but was associated with an increased likelihood of recommending rejection (92% and 84% v 76%; P = 0.002). CONCLUSIONS: Short training packages have only a slight impact on the quality of peer review. The value of longer interventions needs to be assessed.

Education, Professional↗
PubMed2004

Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion.

Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761-774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2-1 mM) activated AMPK in both human islets and MIN6 beta-cells in parallel with an inhibition of insulin secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal beta-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.

AMP-Activated Protein Kinases↗
PubMed2004

Protein kinase A phosphorylation characterized by tandem Fourier transform ion cyclotron resonance mass spectrometry.

A microelectrospray ionization tandem Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS(n)) approach for structural characterization of protein phosphorylation is described. Identification of proteolytic peptides is based solely upon mass measurement by high field (9.4 Tesla) FT-ICR MS. The location of the modification within any phosphopeptide is then established by FT-ICR MS(2) and MS(3) experiments. Structural information is maximized by use of electron capture dissociation (ECD) and/or infrared multiphoton dissociation (IRMPD). The analytical utility of the method is demonstrated by characterization of protein kinase A (PKA) phosphorylation. In a single FT-ICR MS experiment, 30 PKA tryptic peptides (including three phosphopeptides) were mass measured by internal calibration to within an absolute mean error of |0.7 ppm|. The location of each of the three sites of phosphorylation was then determined by MS(2) and MS(3) experiments, in which ECD and IRMPD provide complementary peptide sequence information. In two out of three cases, electron irradiation of a phosphopeptide [M + nH](n+) ion produced an abundant charge-reduced [M + nH]((n-1)+*) ion, but few sequence-specific c and z(*) fragment ions. Subsequent IRMPD (MS(3)) of the charge-reduced radical ion resulted in the detection of a large number of ECD-type ion products (c and z ions), but no b or y type ions. The utility of activated ion ECD for the characterization of tryptic phosphopeptides was then demonstrated.

Amino Acid Sequence↗
PubMed2004

Giant cell formation through fusion of cells derived from a human giant cell tumor of tendon sheath.

Although the mechanism of multinucleation in giant cell tumors of tendon sheath (GCTTS) remains unknown, two mechanisms have been proposed: one is cell fusion and the other amitotic division. The purpose of this study was to clarify the multinucleation process of cultured cells from GCTTS using an in vitro fluorescent cell membrane labeling technique. Cultured GCTTS cells obtained from a 7-year-old Japanese girl were divided into two groups, one for PKH-2 (green) staining and the other for PKH-26 (red) staining. After staining with the dyes, the cell populations were mixed and observed with a fluorescent microscope on the 4th and 14th days after mixing. On both the 4th and 14th days, the cultured GCTTS giant cells showed a mosaic of green and red colors, thus indicating cell membrane fusion. Images of double fluorescent labeled giant cells indicated cell fusion of mononucleated stromal cells that lead to multinucleated giant cells in these GCTTS cell cultures. These findings suggest that multinucleation in GCTTS results from the fusion of mononuclear stromal cells in vitro.

Animals↗
PubMed2004

A common open representation of mass spectrometry data and its application to proteomics research.

A broad range of mass spectrometers are used in mass spectrometry (MS)-based proteomics research. Each type of instrument possesses a unique design, data system and performance specifications, resulting in strengths and weaknesses for different types of experiments. Unfortunately, the native binary data formats produced by each type of mass spectrometer also differ and are usually proprietary. The diverse, nontransparent nature of the data structure complicates the integration of new instruments into preexisting infrastructure, impedes the analysis, exchange, comparison and publication of results from different experiments and laboratories, and prevents the bioinformatics community from accessing data sets required for software development. Here, we introduce the 'mzXML' format, an open, generic XML (extensible markup language) representation of MS data. We have also developed an accompanying suite of supporting programs. We expect that this format will facilitate data management, interpretation and dissemination in proteomics research.

Database Management Systems↗
PubMed2004

Communicable disease control: a 'Global Public Good' perspective.

Despite the increasing 'globalization' of health, the responsibility for it remains primarily national, generating a potential mismatch between global health problems and current institutions and mechanisms to deal with them. The 'Global Public Good' (GPG) concept has been suggested as a framework to address this mismatch in different areas of public policy. This paper considers the application of the GPG concept as an organizing principle for communicable disease control (CDC), considering in particular its potential to improve the health and welfare of the developing world. The paper concludes that there are significant limitations to the GPG concept's effectiveness as an organizing principle for global health priorities, with respect to CDC. More specifically, there are few areas of CDC which qualify as GPG, and even among those that can be considered GPGs, it is not necessarily appropriate to provide everything which can be considered a GPG. It is therefore suggested that it may be more useful to focus instead on the failure of 'collective action', where the GPG concept may then: (1) provide a rationale to raise funds additional to aid from developed countries' domestic budgets; (2) promote investment by developed countries in the health systems of developing countries; (3) promote strategic partnerships between developed and developing countries to tackle major global communicable diseases; and (4) guide the political process of establishing, and mechanisms for providing and financing, global CDC programmes with GPG characteristics, and GPGs which have benefits for CDC. In short, the GPG concept is not without limitations and weaknesses as an organizing principle, but does provide, at least in some areas, guidance in improving collective action at the international level for the improvement of global CDC.

Communicable Disease Control↗