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Biomedical subjects

Andrew Smith

Publications and source records attributed to Andrew Smith.

At least 73 records · Page 4Linked to original sources
PubMed2004

How T cells use LFA-1 to attach and migrate.

The T lymphocyte (or T cell) has classically been perceived to be a passive circular cell attaching to other cells or fibrils of the extracellular matrix when its integrins become activated. We now understand that the modus operandi of the T cell is migration. These cells are proving to be impressively fast migrators, clocking up basal speeds of approximately 10-15 microm/min which makes them amongst the fastest movers recorded to date. Therefore, migration is the business of the T cell and in this review we will discuss how its motility is regulated and what functions this activity makes possible.

Animals↗
PubMed2004

Biological variation of the natriuretic peptides and their role in monitoring patients with heart failure.

BACKGROUND: B-type natriuretic peptide (BNP) and the inactive metabolite NT-proBNP are proven tests for diagnosis and staging of severity for patients with heart failure. However, the utility of these biomarkers for monitoring the success of drug therapy remains to be determined. Results of longitudinal studies on serial blood testing must be linked to overall patient morbidity and mortality outcomes. We previously determined the 8-week biological variability (BV) of BNP and NT-proBNP assays in healthy subjects and the 1-day BV for BNP alone in patients with compensated and stable heart failure. From these studies, the percent statistical change in serial samples of approximately 100% difference was estimated (95% confidence). METHODS: We applied the biological variability concepts to the serial results of BNP and NT-proBNP collected from patients with heart failure and compared the performance of these two markers. RESULTS: While there are minor differences in the results between the assays from one time period to another, the overall interpretation of results are essentially identical. Moreover, the majority of individual serial time points are not significantly different from the previous value. CONCLUSION: Frequent testing (e.g. daily) for BNP and NT-proBNP to monitor therapy for patients with CHF is not indicated, as overall changes require several days to become evident.

Biomarkers↗
PubMed2004

Effects of upper respiratory tract illnesses in a working population.

The aim of the present study was to assess the impact of upper respiratory tract illnesses on efficiency at work. This was done using the 'after-effect' technique with measurements being taken before and after work and the difference between these giving an indication of efficiency over the day. All of the volunteers (N = 48) were tested when healthy to provide baseline data for simple reaction time and mood. When volunteers developed an upper respiratory tract illness (URTI) they (N = 16) repeated the procedure. Those who remained healthy over a three month period (N = 32) were recalled as healthy controls. In addition to the performance test and mood ratings the volunteers kept a sleep log and also rated how demanding the day had been and how much effort they had put in. The results showed that those with URTIs had slower reaction times and a more negative mood both before and after work. Illness did not have an effect on ratings of demand and effort. Those who were ill reported greater sleep disturbance but this could not account for the impaired performance or negative mood states. These results suggest that upper respiratory illnesses may impair performance and well-being at work.

Adult↗
PubMed2004

Analytical and clinical evaluation of the Bayer ADVIA Centaur automated B-type natriuretic peptide assay in patients with heart failure: a multisite study.

BACKGROUND: B-Type natriuretic peptide (BNP) is released from the left ventricle of the heart into the circulation in response to ventricular stretching and volume overload. Increased BNP concentrations are associated with heart failure (HF). METHODS: We evaluated the analytical and clinical performance of the Bayer ADVIA Centaur BNP assay. Studies included precision, analytical correlation (against the Shionogi ShionoRIA and Biosite Triage BNP assays), BNP results for blood collected in plastic tubes containing EDTA vs other collection tubes, high-dose hook effect, detection limits, and interferences. The clinical performance was tested on 2243 blood samples collected from 983 apparently healthy individuals, 538 patients with chronic disease but without HF (renal insufficiency, chronic obstructive pulmonary disease, diabetes, and hypertension), and 722 patients with HF (New York Heart Association classes I-IV). RESULTS: The ADVIA Centaur assay had total imprecision (CV) of 3.4%, 2.9%, and 2.4% at BNP concentrations of 48, 461, and 1768 ng/L, respectively. The Passing-Bablok correlations to the ShionoRIA and Triage were as follows: ADVIA Centaur = 1.11(ShionoRIA) - 1.19 ng/L (r = 0.98); ADVIA Centaur = 0.78(Triage) + 5.89 ng/L (r = 0.92), respectively. Of the different blood collection tubes, only EDTA plastic tubes (with and without the barrier gel) were acceptable. The lower detection limit was 0.5 ng/L, and there were no interferences from common analytes, other neuropeptides, or unusual antibodies. BNP exhibited different reference intervals according to age and gender. BNP concentrations increased progressively as the severity of HF increased. CONCLUSIONS: The ADVIA Centaur is the first commercially available BNP assay for use on an automated immunochemistry platform. This assay has good analytical and clinical performance characteristics for diagnosing HF.

Adult↗
PubMed2004

Mining the structural genomics pipeline: identification of protein properties that affect high-throughput experimental analysis.

Structural genomics projects represent major undertakings that will change our understanding of proteins. They generate unique datasets that, for the first time, present a standardized view of proteins in terms of their physical and chemical properties. By analyzing these datasets here, we are able to discover correlations between a protein's characteristics and its progress through each stage of the structural genomics pipeline, from cloning, expression, purification, and ultimately to structural determination. First, we use tree-based analyses (decision trees and random forest algorithms) to discover the most significant protein features that influence a protein's amenability to high-throughput experimentation. Based on this, we identify potential bottlenecks in various stages of the structural genomics process through specialized "pipeline schematics". We find that the properties of a protein that are most significant are: (i.) whether it is conserved across many organisms; (ii). the percentage composition of charged residues; (iii). the occurrence of hydrophobic patches; (iv). the number of binding partners it has; and (v). its length. Conversely, a number of other properties that might have been thought to be important, such as nuclear localization signals, are not significant. Thus, using our tree-based analyses, we are able to identify combinations of features that best differentiate the small group of proteins for which a structure has been determined from all the currently selected targets. This information may prove useful in optimizing high-throughput experimentation. Further information is available from http://mining.nesg.org/.

Algorithms↗
PubMed2004

Rotational muscle flap closure for acute groin wound infections following vascular surgery.

Since 1996, 41 patients have presented to our institution with deep but localized groin infection following bypass (30) or isolated femoral artery surgery (11). These patients were treated with antibiotics, debridement, and rotational muscle flap coverage either immediately or within a few days. Patients had one of three patterns: serous leak from a groin incision within a few days of operation (Acute, n = 10), early serous leak that later became grossly infected (Acute-observed, n = 8), or obvious purulent drainage following an initially normal, healed wound (Delayed, n = 23). Patients with early leak had nearly uniformly polymicrobial infections with a preponderance of gram-negative organisms, whereas most of those with late purulence had monobacterial infection with Staphylococcus aureus. At exploration, 26 of 41 suture lines were exposed. Rectus femoris flaps were used in 35 patients (85% of cases) for coverage, and graft preservation was attempted in all 8 vein grafts and 16 of 23 prosthetic grafts. Only one flap failed and there were no instances of anastomotic bleeding. There were no deaths directly attributable to reexploration and flap coverage, although 10 patients died during the index hospitalization. Durable coverage with no long-term evidence of infection was achieved in 24 patients with mean follow-up of 23 (range 10-66) months and another 12 had no evidence of local problems despite shorter follow-up; only 5 patients (12%) overall had evidence of persistent graft infection or unexplained bacteremia. In patients with attempted graft salvage, limb salvage was 97% at 6 months and 85% at 1 year. Although early mortality is high, deaths are not related to the flap procedure itself, local outcome is excellent, and graft and limb salvage are good; results are much worse if an initially draining wound is treated too late. Local rotational muscle flap closure is an excellent solution for acute infections involving the groin following vascular procedures.

Blood Vessel Prosthesis↗
PubMed2004

The effect of class-specific protease inhibitors on the stabilization of B-type natriuretic peptide in human plasma.

BACKGROUND: B-type natriuretic peptide (BNP) is a cardiac hormone that regulates hemodynamic equilibrium. In the circulation, its activity is controlled by proteolytic factors. Accurate measurement of BNP in a patient's plasma may be affected by degradation due to proteolysis. OBJECTIVE: We report on the identification and performance of classes of protease inhibitors that stabilize BNP in plasma. DESIGN AND METHODS: Using the Bayer ADVIA Centaur BNP assay, we measured the effect of arginine, serine and/or specific kallikrein protease inhibitors (PIs) on exogenous spiked or endogenous BNP in patient plasma. RESULTS: Compared to controls without inhibitor, all PIs were capable, to varying degrees, of retarding the rate of proteolytic degradation. The kallikrein-specific inhibitor, D-Phe-Phe-Arg-chloromethylketone (PPACK II) was most effective as a single constituent and was able to eliminate BNP degradation in patient samples for up to 6-10 days when stored at 2-8 degrees C. CONCLUSIONS: The stability of BNP was markedly increased in the presence of kallikrein-specific PPACK II and a broad spectrum of serine PIs. Use of these compounds offers a simple method of extending sample handling and storage of plasma samples containing BNP.

Amino Acid Sequence↗
PubMed2004

A model of antipsychotic action in conditioned avoidance: a computational approach.

The selective ability of antipsychotic drugs (APDs) to attenuate conditioned avoidance responding (CAR) has been recognized for over 50 years. However, most efforts to account for this finding have been either neurochemically oriented (focusing on the neuromodulator dopamine) or behavioral, with little effort invested in uniting the two within a computational model. In this paper we propose a computational model, based on concepts from formal reinforcement learning theory, which accounts for the basic finding that noncataleptic doses of APDs disrupt avoidance without disrupting escape. The model formally separates out sensory, motor, and reward processes, and makes novel predictions pertaining to the dose- and time-dependent effects of APDs on response latencies--predictions which we verified in experimental studies using four different APDs (haloperidol, chlorpromazine, risperidone, and clozapine). The APD action in this model is most consistent with an effect on 'expected future reward'--an idea closely linked to motivational drives and consistent with several leading theories of dopamine action.

Animals↗
PubMed2004

Antimicrobial susceptibility of viridans group streptococcal blood isolates to eight antimicrobial agents.

A total of 155 viridans group streptococci blood culture isolates identified by the Rapid ID32 Strep system were tested for their minimum inhibitory concentrations (MICs) to penicillin, amoxicillin, ceftriaxone, erythromycin, clindamycin, rifampicin, vancomycin and teicoplanin using the E-test. The following species were identified: S. oralis (n = 67), S. mitis (n = 66), S. sanguis (n = 7), S. salivarius (n = 5), S. parasanguis (n = 4), S. gordonii (n = 3) and S. mutans (n = 3). S. oralis and S. mitis demonstrated the highest levels of resistance to the agents tested. There were 27% of S. oralis isolates resistant to pencillin, 51% resistant to erythromycin and 6% resistant to clindamycin. For S. mitis 11% were resistant to penicillin, 40% resistant to erythromycin and 3% resistant to clindamycin. Penicillin resistant isolates (MIC > or = 2 mg/l) also demonstrated decreased susceptibility to other antimicrobial agents tested in this study. High level resistance (MIC > or = 2 mg/l) to ceftriaxone was found in 12 isolates. The isolates identified as ceftriaxone resistant comprised S. oralis (n = 7), S. mitis (n = 4) and S. parasanguis (n = 1). This study has highlighted the difference in susceptibility between different species of viridans group streptococci. These findings are of concern in the light of spread of antibiotic resistance genes from S. oralis and S. mitis to the more invasive pneumococcus.

Anti-Bacterial Agents↗
PubMed2004

From evidence to policy: reflections on emerging themes in health-enhancing physical activity.

Based on a detailed reading of the six preceding papers, in conjunction with a reflection on the socio-political forces shaping lifestyles in the UK at the turn of the millennium, we come to four interrelated conclusions. First, sport and exercise science needs to move beyond evidence-based practice to evidence-based policy. Second, sport and exercise science needs to make health-enhancing physical activity a political issue at both national and local level. Third, transport, not health policy, may be the key to promoting health-enhancing physical activity. And, fourth, young people deserve our special attention. In reaching these four interrelated conclusions, we attempt both to shape evidence based policy and future research agendas in exercise science. To achieve an international perspective, we also present a short case note from Australia.

Australia↗
PubMed2004

Job strain, effort--reward imbalance, and stress at work: competing or complementary models?

BACKGROUND: The Demand Control Model (DCM) and the Effort Reward Imbalance Model (ERI) offer putative explanations of the relationship between stressful working conditions, job strain, and psychological and physical ill health. AIMS: The aims of this study are to: (a) compare the predictive powers of the two models for explaining perceived job stress and mental distress amongst workers as a whole, (b) identify whether a model which combines dimensions of the DCM and ERI might have more predictive power than either of them separately, and (c) ascertain whether the models make distinct contributions to explaining stress at work in specific occupational settings. METHODS: Statistical analysis was carried out on data collected from a cross-sectional postal survey of a random sample (n = 7,069), of the adult population in an urban area in Southern England. The analysis focused on the 4,135 respondents who were in paid employment. RESULTS: There was little support for combining the models as the combined model was dominated by the predictive power of dimensions from the ERI. However, the results also showed that the models or dimensions of the models made distinct contributions to explaining perceived work stress in different types of occupation. CONCLUSIONS: There is little evidence to support a combined model of work characteristics. The ERI appears to be the stronger of the two models although the DCM has explanatory value for specific occupations.

Cross-Sectional Studies↗
PubMed2004

Temporal gene expression patterns in G93A/SOD1 mouse.

Amyotrophic lateral sclerosis (ALS) is a generally fatal degenerative disorder of motor neurons that has no known cure. Many pathological processes have been implicated. However, the early, initiating events in the disease are poorly understood. We performed multivariate analyses of gene expression of 21 selected genes from categories including glutamate neurotoxicity, oxidative stress, neuroinflammation, aberrant metal ion regulation, apoptosis, and abnormal microglial function on G93A SOD1 mice. These animals develop symptoms of motor neuron dysfunction at about 12 weeks of age, and die at age 18 to 20 weeks. We analyzed animals at both presymptomatic and symptomatic stages. Differential regulation of several genes involved in neuroinflammation, including TNF-alpha, IL- RA, CD86, CD200R and Groalpha, was observed in presymptomatic mice, aged 6-9 weeks, while expression of genes representative of other processes was not altered until the animals reached symptomatic stages. Analysis of expression of inflammatory genes and microglia related genes together also revealed a highly significant change in mutant mice relative to wildtype at 6-9 weeks. These changes were due to the presence of the mutant gene, and not simply to overexpression of a SOD1 gene. These findings are discussed in relation to possible roles of microglia function in the development of ALS.

Age Factors↗
PubMed2004

Characterization of a temperature-sensitive DNA ligase from Escherichia coli.

DNA ligases are essential enzymes in cells due to their ability to join DNA strand breaks formed during DNA replication. Several temperature-sensitive mutant strains of Escherichia coli, including strain GR501, have been described which can be complemented by functional DNA ligases. Here, it is shown that the ligA251 mutation in E. coli GR501 strain is a cytosine to thymine transition at base 43, which results in a substitution of leucine by phenylalanine at residue 15. The protein product of this gene (LigA251) is accumulated to a similar level at permissive and non-permissive temperatures. Compared to wild-type LigA, at 20 degrees C purified LigA251 has 20-fold lower ligation activity in vitro, and its activity is reduced further at 42 degrees C, resulting in 60-fold lower ligation activity than wild-type LigA. It is proposed that the mutation in LigA251 affects the structure of the N-terminal region of LigA. The resulting decrease in DNA ligase activity at the non-permissive temperature is likely to occur as the result of a conformational change that reduces the rate of adenylation of the ligase.

Amino Acid Sequence↗
PubMed2004

Genetic analysis of diverse disease-causing pneumococci indicates high levels of diversity within serotypes and capsule switching.

We have used multilocus sequence typing (MLST) and serotyping to build a phylogenetic framework for pneumococcal disease isolates in Scotland that provides a snapshot of the relationships between capsular type and genotype. The results show that while the MLST type correlates with the serotype, isolates within a serotype can belong to a number of individual clonal complexes or sequence types (STs). We also show that isolates of the same ST can express different capsular polysaccharides, i.e., display capsular switching, and that this phenomenon is observed both for capsular types commonly isolated from patients with invasive disease and for serogroups less commonly isolated from patients with invasive disease but which may commonly be carried asymptomatically in the human nasopharynx.

Adolescent↗
PubMed2004

The effect of time delay on infection in open long-bone fractures: a 5-year prospective audit from a district general hospital.

OBJECTIVES: To determine whether a time delay of greater than 6 h from injury to surgical debridement affected the infection rate in open long-bone fractures in a typical district general hospital in the UK. DESIGN: Prospective audit over 5 years. METHODS: 142 open long-bone fractures in 130 patients were seen over a 5-year period between 1996 and 2001 in our hospital. 115 fractures in 103 patients were available for study. The data were collected prospectively in weekly audit meetings. Patients were followed until clinical or radiological union occurred or until a secondary procedure for non-union or infection was carried out. RESULTS: Surgical debridement was carried out in less than 6 h from injury in 60% of cases and in greater than 6 h from injury in 40% of cases. Infection rates were 10.1% and 10.8%, respectively. CONCLUSIONS: We could not demonstrate a significantly increased infection rate in patients in whom surgical debridement occurred greater than 6 h after injury.

Adolescent↗