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Biomedical subjects

Jonathan Smith

Publications and source records attributed to Jonathan Smith.

17 recordsLinked to original sources
PubMed2007

Recombinant protein-based assays for detection of antibodies to severe acute respiratory syndrome coronavirus spike and nucleocapsid proteins.

Recombinant severe acute respiratory syndrome (SARS) nucleocapsid and spike protein-based immunoglobulin G immunoassays were developed and evaluated. Our assays demonstrated high sensitivity and specificity to the SARS coronavirus in sera collected from patients as late as 2 years postonset of symptoms. These assays will be useful not only for routine SARS coronavirus diagnostics but also for epidemiological and antibody kinetic studies.

Antibodies, Viral↗
PubMed2006

Genetic susceptibility to myocardial infarction and coronary artery disease.

Atherosclerotic involvement in the coronary arteries, which can result in heart attack and sudden death, is a common disease and prototypic of a complex human trait. To understand its genomic basis, eight linkage studies of sibling pairs have been performed. Although there was limited inter-study concordance of important loci, two gene variants in the leukotriene pathway (ALOX5AP and LTA4) have emerged as susceptibility factors for myocardial infarction (MI). Genome-wide association studies have also been undertaken, and the pro-inflammatory cytokine lymphotoxin-alpha (LTA), and its key ligand galectin-2 (LGALS2) have been identified as genes implicated in predisposition for heart attack. By cueing into the genomic basis for low serum LDL cholesterol levels, much work has been done to advance the importance of the serine protease PCSK9, which modulates LDL receptor function. Lifelong lowered LDL cholesterol associated with PCSK9 point mutations in 2-3% of individuals have been shown to provide marked protection from coronary artery disease (CAD). Most of the success in this field has been with the phenotype of MI, which is considerably more restrictive than CAD. Four principal and interdependent processes--lipoprotein handling, endothelial integrity, arterial inflammation, and thrombosis--have been supported as important via the clustering of genes, thus far implicated in CAD susceptibility. Of note, connecting genes in a single pathway (leukotriene), of a protein and its ligand (LTAalpha) or from one disease to another [age-related macular degeneration (AMD); complement factor H (CFH)], or even three disease characterized by inflammation (MHC2) have now been reported. Although the population attributable risk for any of the genes identified to date is limited, such discovery is likely to be accelerated in the future.

5-Lipoxygenase-Activating Proteins↗
PubMed2006

'I was like a wild wild person': understanding feelings of anger using interpretative phenomenological analysis.

This paper is concerned with illuminating how emotion (anger) and emotion-related phenomena such as feelings, thoughts and expressions appear to the individual person. In particular, it focuses on the role of feelings in emotion experience. It does this through the qualitative analysis of interview material from a single person case study using interpretative phenomenological analysis. The paper examines how the participant feels and experiences anger, the defining characteristics of anger episodes, and how the typical pattern of these episodes is disrupted by life-changes. The findings are examined in light of phenomenological ideas and the utility of these ideas for psychology's understanding of emotion argued for.

Adult↗
PubMed2006

An international comparative study on the use of the Cohort Component Method for estimating national populations.

This comparative study explores the use of the Cohort Component Method (CCM) to produce national level population estimates. This method is used annually to calculate mid-year population estimates for England and Wales by the Office for National Statistics (ONS). Initially the article considers recent population change in England and Wales, with particular emphasis on the growing importance and challenges faced by migration estimation. Comparisons are then made between how population estimates are produced in England and Wales and other countries, with a particular focus on differences in the way the CCM is applied. Recent changes in methods used to estimate population are then reviewed along with a discussion of alternative approaches such as those described in academic literature.

Adolescent↗
PubMed2005

Review of pediatric airway malacia and its management, with emphasis on stenting.

Malacia of the pediatric airway presents itself in a variety of clinical circumstances. Pediatric airway stenting is a more recent treatment modality. Complications may necessitate stent removal. This is usually performed bronchoscopically. We were forced to surgically remove a complicated airway stent. The Palmaz stent had been inserted for bronchomalacia presenting after interrupted aortic arch surgery in a 4-month old child with DiGeorge syndrome. This prompted us to review pediatric airway malacia, its management options and long-term outcomes, in an attempt to crystallize the current status of this relatively uncommon and difficult issue. The role of stents is analysed.

Cardiac Surgical Procedures↗
PubMed2005

Monoclonal antibodies to SARS-associated coronavirus (SARS-CoV): identification of neutralizing and antibodies reactive to S, N, M and E viral proteins.

Monoclonal antibodies (Mabs) against the Urbani strain of the SARS-associated coronavirus (SARS-CoV) were developed and characterized for reactivity to SARS-CoV and SARS-CoV S, N, M, and E proteins using enzyme-linked immunoabsorbent (ELISA), radioimmunoprecipitation, immunofluorescence, Western Blot and microneutralization assays. Twenty-six mAbs were reactive to SARS-CoV by ELISA, and nine were chosen for detailed characterization. Five mAbs reacted against the S protein, two against the M protein, and one each against the N and E proteins. Two of five S protein mAbs neutralized SARS-CoV infection of Vero E6 cells and reacted to an epitope within amino acids 490-510 in the S protein. While two of the three non-neutralizing antibodies recognized at second epitope within amino acids 270-350. The mAbs characterized should prove useful for developing SARS-CoV diagnostic assays and for studying the biology of infection and pathogenesis of disease.

Animals↗
PubMed2005

Cellular localization and antigenic characterization of crimean-congo hemorrhagic fever virus glycoproteins.

Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the genus Nairovirus of the family Bunyaviridae, causes severe disease with high rates of mortality in humans. The CCHFV M RNA segment encodes the virus glycoproteins G(N) and G(C). To understand the processing and intracellular localization of the CCHFV glycoproteins as well as their neutralization and protection determinants, we produced and characterized monoclonal antibodies (MAbs) specific for both G(N) and G(C). Using these MAbs, we found that G(N) predominantly colocalized with a Golgi marker when expressed alone or with G(C), while G(C) was transported to the Golgi apparatus only in the presence of G(N). Both proteins remained endo-beta-N-acetylglucosaminidase H sensitive, indicating that the CCHFV glycoproteins are most likely targeted to the cis Golgi apparatus. Golgi targeting information partly resides within the G(N) ectodomain, because a soluble version of G(N) lacking its transmembrane and cytoplasmic domains also localized to the Golgi apparatus. Coexpression of soluble versions of G(N) and G(C) also resulted in localization of soluble G(C) to the Golgi apparatus, indicating that the ectodomains of these proteins are sufficient for the interactions needed for Golgi targeting. Finally, the mucin-like and P35 domains, located at the N terminus of the G(N) precursor protein and removed posttranslationally by endoproteolysis, were required for Golgi targeting of G(N) when it was expressed alone but were dispensable when G(C) was coexpressed. In neutralization assays on SW-13 cells, MAbs to G(C), but not to G(N), prevented CCHFV infection. However, only a subset of G(C) MAbs protected mice in passive-immunization experiments, while some nonneutralizing G(N) MAbs efficiently protected animals from a lethal CCHFV challenge. Thus, neutralization of CCHFV likely depends not only on the properties of the antibody, but on host cell factors as well. In addition, nonneutralizing antibody-dependent mechanisms, such as antibody-dependent cell-mediated cytotoxicity, may be involved in the in vivo protection seen with the MAbs to G(C).

Animals↗
PubMed2004

Conformational heterogeneity of an equilibrium folding intermediate quantified and mapped by scanning mutagenesis.

It is challenging to experimentally define an energy landscape for protein folding that comprises multiple partially unfolded states. Experimental results are often ambiguous as to whether a non-native state is conformationally homogeneous. Here, we tested an approach combining systematic mutagenesis and a Brønsted-like analysis to reveal and quantify conformational heterogeneity of folding intermediate states. Using this method, we resolved an otherwise apparently homogeneous equilibrium folding intermediate of Borrelia burgdorferi OspA into two conformationally distinct species and determined their relative populations. Furthermore, we mapped the structural differences between these intermediate species, which are consistent with the non-native species that we previously proposed based on native-state hydrogen exchange studies. When treated as a single state, the intermediate ensemble exhibited fractional Phi-values for mutations and Hammond-type behaviors that are often observed for folding transition states. We found that a change in relative population of the two species within the intermediate ensemble explains these properties well, suggesting that fractional Phi-values and Hammond-type behaviors exhibited by folding intermediates and transition states may arise more often from conformational heterogeneity than from a single partial structure. Our results are consistent with the presence of multiple minima in a rugged energy landscape predicted from theoretical studies. The method described here provides a promising means to probe a complex folding energy landscape.

Antigens, Surface↗
PubMed2004

Evidence into practice: a theory based study of achieving national health targets in primary care.

RATIONALE, AIMS AND OBJECTIVES: This study investigates reasons why general practices achieve nationally set milestones to different extents. It compares the beliefs, self-reported behaviours and organizational context of general practitioners (GPs) who have been successful in achieving milestones set out in the UK's National Service Framework (NSF) for Coronary Heart Disease (CHD) with those who have been less successful. METHODS: Sixteen London GPs were interviewed, eight 'high implementers' (having met five or more of six CHD NSF milestones) and eight 'low implementers' (having met one or two milestones). Practices were matched for practice size across the groups as far as possible. The interview consisted of open-ended questions, based on theoretical constructs identified as key to implementation research in a previous project. Interviews were transcribed and analysed with Interpretative Phenomenological Analysis (IPA). RESULTS: There were three main areas that differentiated high and low implementers: beliefs about evidence-based practice, control over professional practice and consequences of achieving the milestones. Low implementers: (i) expressed less belief in evidence-based guidelines as the basis of their practice; (ii) were more concerned about their lack of control over the development and implementation of the guidelines (lack of ownership), and over their own practice (lack of autonomy); and (iii) perceived more negative consequences and fewer positive consequences, both for themselves and for patient care. CONCLUSIONS: This study demonstrates the application of psychological theory in trying to understand and improve professional practice. The results suggest areas that could be targeted in developing interventions to increase guideline implementation in primary care.

Coronary Disease↗
PubMed2003

Quantitative trait locus mapping for atherosclerosis susceptibility.

PURPOSE OF REVIEW: Atherosclerosis is a complex trait with both environmental and genetic aspects. Although some progress has been made in defining genes associated with atherosclerosis in humans, animal models have been useful in learning about pathways and genes involved in atherogenesis. This review describes an unbiased genetic mapping method called quantitative trait locus mapping and progress in using this method to identify genes that alter atherosclerosis susceptibility in mice. RECENT FINDINGS: Approximately 10 well defined genetic loci have been described that are associated with lesion severity in diet-induced or gene knockout mouse models of atherosclerosis. Recently, two of these genetic loci were narrowed considerably by analysis of genetic recombinants within these loci. In addition, a computational method to discover quantitative trait loci has been applied to atherosclerosis. However, none of the genes responsible for these atherosclerosis quantitative trait loci has been definitively identified. The recent completion of the mouse draft genome should facilitate the task of identifying these genes. SUMMARY: Quantitative trait locus mapping studies in mouse models of atherosclerosis have defined genetic regions that alter lesion severity. The identification of the responsible genes may lead to insights into the pathogenesis of atherosclerosis as well as to candidates for human genetic association studies.

Animals↗
PubMed2003

Implications of 2001 Census for local authority district mid-year population estimates.

ONS published mid-2001 population estimates for England and Wales based on the 2001 Census in October 2002. Mid-2001 estimates were also produced, but not published, rolled forward from the 1991 Census. By considering the differences between these two estimates, ONS is able to assess how accurate estimates of population change have been between mid-1991 and mid-2001. Results of this comparison at national and regional levels have already been published on the National Statistics website. This article concentrates on the differences at local authority district level. Analyses of these differences within the article are in three parts-basic descriptive statistics, comparison of the local authority districts as a proportion of their national totals, and more complex multiple regression analysis. The implications of these results are then assessed and recommendations put forward to help improve the mid-year estimates in the following decade. Improvements will also come through other studies such as the National Statistics Quality Review on international migration.

Censuses↗
PubMed2002

Eastern equine encephalomyelitis virus infection in a horse from California.

A yearling quarter horse, which was raised in southern California, received routine vaccinations for prevention of infection by Eastern equine encephalomyelitis virus (EEEV). One week later, severe neurologic signs developed, and the horse was humanely destroyed. A vaccine-related encephalomyelitis was later suspected. A final diagnosis of EEEV infection was established on the basis of acute onset of the neurologic signs, histopathologic and serologic testing, and isolation and molecular characterization of EEEV from brain tissue. The vaccine was extensively tested for viral inactivation. Nucleotide sequences from the vaccine and the virus isolated in the affected horse were also compared. In California, arboviral encephalomyelitides are rarely reported, and EEEV infection has not previously been documented. This report describes the occurrence of EEEV infection in the horse and the investigation to determine the source of infection, which was not definitively identified.

Animals↗
PubMed2002

Evaluation in nonhuman primates of vaccines against Ebola virus.

Ebola virus (EBOV) causes acute hemorrhagic fever that is fatal in up to 90% of cases in both humans and nonhuman primates. No vaccines or treatments are available for human use. We evaluated the effects in nonhuman primates of vaccine strategies that had protected mice or guinea pigs from lethal EBOV infection. The following immunogens were used: RNA replicon particles derived from an attenuated strain of Venezuelan equine encephalitis virus (VEEV) expressing EBOV glycoprotein and nucleoprotein; recombinant Vaccinia virus expressing EBOV glycoprotein; liposomes containing lipid A and inactivated EBOV; and a concentrated, inactivated whole-virion preparation. None of these strategies successfully protected nonhuman primates from robust challenge with EBOV. The disease observed in primates differed from that in rodents, suggesting that rodent models of EBOV may not predict the efficacy of candidate vaccines in primates and that protection of primates may require different mechanisms.

Animals↗
PubMed2002

Rebasing the annual mid-year population estimates for England and Wales.

The ONS produces mid-year population estimates annually, which are based on updating from the most recent census. Therefore, whenever results become available from a census, a new base is created for the population estimates. This has implications for historic series, which need to be revised to be consistent with both the past and the most recent census. This article describes the methodology that will be used for this rebasing of the mid-year population estimates following the availability of results from the 2001 Census. Census results also provide a unique opportunity to assess the accuracy of the population estimates that are based on the previous census and this article also describes the approach that will be taken to the assessment of accuracy.

Censuses↗