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Biomedical subjects

Andrew Jones

Publications and source records attributed to Andrew Jones.

At least 19 recordsLinked to original sources
PubMed2006

Inhibitors of Plasmepsin II-potential antimalarial agents.

In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.

Animals↗
PubMed2006

Council tax valuation bands, socio-economic status and health outcome: a cross-sectional analysis from the Caerphilly Health and Social Needs Study.

UNLABELLED: Council tax valuation bands (CTVBs) are a categorisation of household property value in Great Britain. The aim of the study was to assess the CTVB as a measure of socio-economic status by comparing the strength of the associations between selected health and lifestyle outcomes and CTVBs with two measures of socio-economic status: the National Statistics Socio-Economic Classification (NS-SEC) and the 2001 UK census-based Townsend deprivation index. METHODS: Cross-sectional analysis of data on 12,092 respondents (adjusted response 62.7%) to the Caerphilly Health and Social Needs Study, a postal questionnaire survey undertaken in Caerphilly county borough, south-east Wales, UK. The CTVB was assigned to each individual by matching the sampling frame to the local authority council tax register. Crude and age-gender adjusted odds ratios for each category of CTVB, NS-SEC and fifth of the ward distribution of Townsend scores were estimated for smoking, poor diet, obesity, and limiting long-term illness using logistic regression. Mean mental (MCS) and physical (PCS) component summary scores of the Short-Form SF-36 health status questionnaire were estimated in general linear models. RESULTS: There were significant trends in odds ratios across the CTVB categories for all outcomes, most marked for smoking and mental and physical health status. The adjusted odds ratio for being a smoker in the lowest versus highest CTVB category was 3.80 (95% CI: 3.06, 4.71), compared to 3.00 (95% CI: 2.30, 3.90) for the NS-SEC 'never worked and long-term unemployed' versus 'higher managerial and professional' categories, and 1.61 (95% CI: 1.42, 1.83) for the most deprived versus the least deprived Townsend fifth. The difference in adjusted mean MCS scores was 5.9 points on the scale for CTVB, 9.2 for NS-SEC and 3.2 for the Townsend score. The values for the adjusted mean PCS scores were 6.3 points for CTVB, 11.3 for NS-SEC, and 2.5 for the Townsend score. CONCLUSION: CTVBs assigned to individuals were strongly associated with the health and lifestyle outcomes modelled in this study. CTVBs are readily available for all residential properties and deserve further consideration as a proxy for socio-economic status in epidemiological studies in Great Britain.

Adolescent↗
PubMed2006

Replacement of isobutyl by trifluoromethyl in pepstatin A selectively affects inhibition of aspartic proteinases.

Two bis-trifluoromethyl pepstatin A analogues, carboxylic acid 1 and its methyl ester 2, have been synthesised in order to probe the properties and size of the trifluoromethyl (Tfm) group and compare it to the "bigger" isobutyl that is present in pepstatin A. The results demonstrate that Tfm can effectively replace the isobutyl chain as far as inhibitory activity against plasmepsin II (PM II), an aspartic proteinase from Plasmodium falciparum, is concerned. On the other hand, replacement of isobutyl by Tfm selectively affected activity against other aspartic proteinases tested. Two lines of evidence led to these conclusions. Firstly, compounds 1 and 2 retained single-digit nanomolar inhibitory activity against PM II, but were markedly less active against PM IV, cathepsin D and cathepsin E. Secondly, the X-ray crystal structures of the three complexes of PM II with 1, 2 and pepstatin A were obtained at 2.8, 2.4 and 1.7 A resolution, respectively. High overall similarity among the three complexes indicated that the central Tfm was well accommodated in the lipophilic S1 pocket of PM II, where it was involved in tight hydrophobic contacts. The interaction of PM II with Phe111 appeared to be crucial. Comparison of the crystal structures presented here, with X-ray structures or structural models of PM IV and cathepsin D, allowed an interpretation of the inhibition profiles of pepstatin A and its Tfm variants against these three enzymes. Interactions of the P1 side chain with amino acids that point into the S1 pocket appear to be critical for inhibitory activity. In summary, Tfm can be used to replace an isobutyl group and can affect the selectivity profile of a compound. These findings have implications for the design of novel bioactive molecules and synthetic mimics of natural compounds.

Animals↗
PubMed2006

Visualisation and analysis of proteomic data from the procyclic form of Trypanosoma brucei.

We have undertaken a large scale study of the proteins expressed in the procyclic form of the parasite Trypanosoma brucei, which causes African sleeping sickness, using 2-DE and MS. The complete data set encompasses over 2000 identifications, of which 770 are distinct proteins. We have discovered that multiple protein isoforms appear to be common in T. brucei, as most proteins have been matched to more than one gel spot. We have developed visualisation software to investigate the differences between isoforms, based on the information from the results of database searches with MS data. We are able to highlight instances where PTMs are the most likely cause of variant forms. In other cases, spots that appear reproducibly across replicates contain fragments of proteins, arising either as experimental artefacts or as part of protein degradation. We are also able to classify clusters of gel spots into different groups based on the pattern of peptides that have been matched from MS data. The entire data set is stored within a relational database system that allows complex queries ( http://www.gla.ac.uk/functionalgenomics). Using specific proteins as examples, we demonstrate how the visualisation software and the database query facilities can be used.

Animals↗
PubMed2005

Identification of DNA markers for a transmissible Pseudomonas aeruginosa cystic fibrosis strain.

A number of transmissible Pseudomonas aeruginosa strains have been identified which potentially constitute an emerging threat to patients with cystic fibrosis (CF). We sought to identify DNA markers that were specific to a transmissible P. aeruginosa CF clone and evaluate these probes on a large collection of genotypically distinct P. aeruginosa strains. Using subtractive DNA hybridization, in combination with analysis using the P. aeruginosa PAO1 genome chip, DNA markers specific for or absent from the Manchester transmissible CF strain (MA) were identified. Five subtractive DNA hybridization markers (MA15, MA18, MA21, MA22, and MA30) were found to be specific to strain MA and were located within a novel 13,318-bp genomic island, designated the MA island. The MA island encoded 18 genes and consisted of two bacteriophage-like regions; one region encoded the MA-specific subtractive hybridization markers, while the other bacteriophage-like region contained a Vibrio cholera-like toxin gene. Probes MA15, MA18, MA21, MA22, and MA30 were all found to be specific to strain MA when a collection of 141 P. aeruginosa strains was examined by hybridization with each DNA marker. In contrast, a previously isolated DNA marker for the Liverpool transmissible CF strain, PS21, was not found to be specific, detecting two additional strain types in the collection screened. Both the Manchester and Liverpool strain types were not encountered in CF populations outside the United Kingdom. The MA genomic island and Vibrio cholera-like toxin gene within it constitute novel genetic factors associated with a transmissible P. aeruginosa strain and their role in pathogenesis remains to be determined.

Blotting, Southern↗
PubMed2005

The index of multiple deprivation 2000 access domain: a useful indicator for public health?

The access domain of the UK index of multiple deprivation (IMD) 2000 was designed to identify populations in small areas with poor geographical access to certain local key services. The measure is a composite of straight line distances to post offices, large food shops, primary schools and general practice surgeries for population sub-groups. Using the region of East Anglia as a case study area, this research evaluated the utility of the IMD2000 as an indicator of access to primary care. IMD2000 access scores for electoral wards were compared with a range of more detailed indicators of travel times and bus availability for visiting a general practitioner generated in a geographical information system (GIS). A range of easy-to-calculate surrogate variables was developed and tested as possible candidates to improve the explanatory power of the IMD2000 access score. The access domain was negatively correlated with the other five deprivation domains that comprise the overall index, suggesting that access should not be combined with the other measures of deprivation into a composite single score. The access domain was also found to predict access to primary care only with moderate accuracy. Two additional indicators of accessibility calculated in a GIS (road kilometres per thousand population and the presence of a major road in each ward) were found to add slightly to the power of the index. The predictive power of the index was best in urban areas, although it is in rural areas that access to primary care is a more important public health issue. The IMD2000 should be therefore used with caution as a measure of health service accessibility in rural areas.

Catchment Area, Health↗
PubMed2005

Geographical distribution of road traffic deaths in England and Wales: place of accident compared with place of residence.

BACKGROUND: There are two sources of information on road traffic mortality in England and Wales: ONS records giving the place of residence and police records giving the place of the accident. Use of the police records has been limited by the lack of an obvious denominator to control for population at risk. This study compares the two measures and explores the implications of using the same population denominator for both. METHODS: The number of road traffic deaths occurring in 403 local authority districts in England and Wales during 1995-1999 was compared to the number of deaths to residents in the same period. Both numbers were related to the expected number of deaths to residents and selected environmental risk factors using regression techniques. RESULTS: Large differences were found between the number of deaths in each district and the number of deaths to residents. The expected number of deaths to residents was the strongest predictor of both observed totals. The number of deaths in the district and the number divided by expected deaths of residents were highly predictable from road accident risk factors, but the number of deaths to residents and the conventional SMR were not. CONCLUSION: Information on the place of residence of road traffic accident fatalities does not show true variations in accident risk. Police records are better for this purpose. The expected number of deaths to residents estimate provides a partial but effective and unbiased control for population effects.

Accidents, Traffic↗
PubMed2004

Three cases of Q fever osteomyelitis in children and a review of the literature.

Q fever is a common zoonosis worldwide. Awareness of the disease and newer diagnostic modalities have resulted in increasing recognition of unusual manifestations. We report 3 cases of Q fever osteomyelitis in children and review the literature on 11 other reported cases. The cases demonstrate that Coxiella burnetii can cause granulomatous osteomyelitis that presents without systemic symptoms and frequently results in a chronic, relapsing, multifocal clinical course. Optimal selection and duration of antimicrobial therapy and methods of monitoring therapy are currently uncertain.

Adult↗
PubMed2004

An object model and database for functional genomics.

MOTIVATION: Large-scale functional genomics analysis is now feasible and presents significant challenges in data analysis, storage and querying. Data standards are required to enable the development of public data repositories and to improve data sharing. There is an established data format for microarrays (microarray gene expression markup language, MAGE-ML) and a draft standard for proteomics (PEDRo). We believe that all types of functional genomics experiments should be annotated in a consistent manner, and we hope to open up new ways of comparing multiple datasets used in functional genomics. RESULTS: We have created a functional genomics experiment object model (FGE-OM), developed from the microarray model, MAGE-OM and two models for proteomics, PEDRo and our own model (Gla-PSI-Glasgow Proposal for the Proteomics Standards Initiative). FGE-OM comprises three namespaces representing (i) the parts of the model common to all functional genomics experiments; (ii) microarray-specific components; and (iii) proteomics-specific components. We believe that FGE-OM should initiate discussion about the contents and structure of the next version of MAGE and the future of proteomics standards. A prototype database called RNA And Protein Abundance Database (RAPAD), based on FGE-OM, has been implemented and populated with data from microbial pathogenesis. AVAILABILITY: FGE-OM and the RAPAD schema are available from http://www.gusdb.org/fge.html, along with a set of more detailed diagrams. RAPAD can be accessed by registration at the site.

Abstracting and Indexing↗
PubMed2002

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Case-Control Studies↗
PubMed2002

Differing pathways of lower airway colonization and infection according to mode of ventilation (endotracheal vs tracheotomy).

OBJECTIVES: To determine whether the pathogenesis of lower airway colonization and infection was endogenous (via the oropharynx) or exogenous (via the endotracheal tube or tracheotomy) during the 2 modes of ventilation in the same subset of children requiring long-term ventilation. DESIGN: Prospective, observational cohort study. SETTING: A pediatric intensive care unit and a respiratory ward. PATIENTS: Consecutive admissions between September 1, 1993, and August 30, 1998. MEASUREMENTS AND MAIN RESULTS: Cultures were obtained simultaneously from the oropharynx and tracheobronchial tree on admission to the pediatric intensive care unit, at placement of the tracheotomy, and afterward twice weekly. Forty-five patients were studied. Lower airways were always sterile in 6 children, 39 children (87%) developed a total of 82 episodes of colonization, and 17 (38%) progressed to 25 episodes of infection. The number of infected children was halved once they had a tracheotomy (7 children [16%]). Of the 107 episodes of colonization and infection, 41 and 66 occurred during endotracheal ventilation and via a tracheotomy, respectively. Primary endogenous episodes of colonization and infection due to bacteria present in the admission flora in the pediatric intensive care unit were significantly more common with endotracheal ventilation than during ventilation via a tracheotomy (31/41 [76%] vs 36/66 [55%]; P =.03). Secondary endogenous and exogenous episodes of colonization and infection due to bacteria associated with the respiratory ward were significantly more frequent when ventilation was continued through a tracheotomy than during endotracheal ventilation (30/66 [45%] vs 10/41 [24%]; P =.02). CONCLUSIONS: Surveillance samples allow the distinction between primary endogenous ("imported" bacteria) from secondary endogenous and exogenous ("nosocomial" microorganisms) colonization and infection. This classification permits the development of preventive strategies to control both endogenous and exogenous pathways.

Adolescent↗