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Biomedical subjects

G Thomson

Publications and source records attributed to G Thomson.

At least 19 recordsLinked to original sources
PubMed2007

HLA-A, -B, -C, -DRB1 allele and haplotype frequencies in an African American population.

Sequence-based typing was used to identify human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 alleles from 564 consecutively recruited African American volunteers for an unrelated hematopoietic stem cell registry. The number of known alleles identified at each locus was 42 for HLA-A, HLA-B 67, HLA-C 33, and HLA-DRB1 44. Six novel alleles (A*260104, A*7411, Cw*0813, Cw*1608, Cw*1704, and DRB1*130502) not observed in the initial sequence-specific oligonucleotide probe testing were characterized. The action of balancing selection, shaping more 'even' than expected allele frequency distributions, was inferred for all four loci and significantly so for the HLA-A and DRB1 loci. Two-, three-, and four-locus haplotypes were estimated using the expectation maximization algorithm. Comparisons with other populations from Africa and Europe suggest that the degree of European admixture in the African American population described here is lower than that in other African American populations previously reported, although HLA-A:B haplotype frequencies similar to those in previous studies of African American individuals were also noted.

Black or African American↗
PubMed2005

D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus.

AIMS/HYPOTHESIS: The HLA class II DQB1*0602 allele confers strong dominant protection against type 1 diabetes but protection is not absolute. The aim of this study was to identify markers within the HLA region that differentiate DQB1*0602 haplotypes and show different associations with disease risk. METHODS: We defined alleles at eight microsatellite markers spanning the HLA region in a case-control cohort from Sweden. RESULTS: We found that allele 15 at marker D6S265 (109 kb centromeric of HLA-A) was over-represented among patients carrying DRB1*15, DQB1*0602. A detailed haplotype analysis showed that DRB1*15, DQB1*0602 haplotypes carrying D6S265*15 have a ten-fold higher odds ratio (OR) than those carrying other alleles and thus confer reduced protection [OR D6S265*15=0.186 (95% CI 0.074, 0.472) vs OR D6S265*15-=0.017 (95% CI 0.005, 0.062), p<0.001]. CONCLUSIONS/INTERPRETATION: Our data support the existence of a locus that modifies the protective effect associated with DQB1*0602. Typing for allele D6S265*15 can identify a less protective DQB1*0602 haplotype, thereby allowing a more accurate prediction of type 1 diabetes risk.

Adult↗
PubMed2005

A model of contagious bovine pleuropneumonia transmission dynamics in East Africa.

The dynamics of contagious bovine pleuropneumonia (CBPP) transmission vary widely between livestock production systems. This paper describes the development of a homogeneous, stochastic, compartmental model for CBPP transmission in pastoral herds of East Africa. The model was built using parameter estimates based on data published in the literature and on observations of livestock owners obtained through participatory research. The basic reproduction number for CBPP in southern Sudan was estimated to range from 3.2 to 4.6. The homogeneous model indicates that the critical community size for the persistence of CBPP falls within the typical herd sizes for pastoral communities in East Africa suggesting that individual isolated herds are capable of maintaining infection indefinitely. Vaccination alone with currently available vaccines was unlikely to eradicate the disease.

Africa, Eastern↗
PubMed2005

A heterogeneous population model for contagious bovine pleuropneumonia transmission and control in pastoral communities of East Africa.

Pastoral cattle live in highly structured communities characterized by complex contact patterns. The present paper describes a spatially heterogeneous model for the transmission of contagious bovine pleuropneumonia (CBPP) developed specifically for pastoral communities of East Africa. The model is validated against serological data on the prevalence of CBPP infection in several communities of southern Sudan and against livestock owner information on community structure, livestock contact and cattle exchange. The model is used to assess the impact of alternative control strategies including mass and elective vaccination programmes, potential treatment regimes and the combination of vaccination and treatment in a single unified strategy. The results indicate that the eradication of CBPP using mass vaccination with currently available vaccines is unlikely to succeed. On the other hand, elective control programmes based on herd level vaccination, treatment of clinical cases or a combination of both vaccination and treatment enabled individual livestock owners to capture a large benefit in terms of reduced animal-level prevalence and mortality experience. The most promising intervention scenario was a programme which combined the vaccination of healthy animals with treatment of clinical cases.

Africa, Eastern↗
PubMed2005

The effect of ultraviolet (UV) A1, UVB and solar-simulated radiation on p53 activation and p21.

BACKGROUND: High-dose ultraviolet (UV) A1 therapy (doses in the order of 130 J cm(-2)) is effective for atopic dermatitis and scleroderma. UVA1 has been shown to induce a dose-dependent increase in p53 expression in keratinocytes. OBJECTIVES: To examine the effect of UVA1 on the activation of p53 by phosphorylation, which has not yet been studied. METHODS: Five adult volunteers were exposed to dose series of UVA1 (10-100 J cm(-2)) and, for comparison, narrowband UVB (TL-01) (25-550 mJ cm(-2)) and solar-simulated radiation (SSR) (5.6-30 J cm(-2)) on photoprotected buttock skin and the minimal erythema dose (MED) for each was determined at 24 h. Separate sites on the buttock were subsequently irradiated with a 3-MED dose of UVA1, TL-01 and SSR. At 24 h, punch biopsies (4 mm) were taken from each irradiated site and from an adjacent unirradiated control site, and immunohistochemical staining for p53 (Do-1), activation of p53 (assessed by phosphorylation at serine 15 and serine 392) and p21 was performed. Cell staining was expressed as the mean number of cells stained per three high-power fields (HPFs) and as a percentage of 1000 cells. Sunburn cells (SBCs) were also counted per HPF. RESULTS: UVA1 produced negligible numbers of SBCs, relatively little p53 (Do-1) staining (mean +/- SD cell count per HPF 16 +/- 10), no p53 activation and very little evidence of p21 expression (mean +/- SD cell count per HPF 5.3 +/- 7), in contrast to TL-01 (mean +/- SD cell count per HPF of 11.83 +/- 2.1 SBCs, 146.3 +/- 38 for Do-1, 26.6 +/- 15 for serine 15, 14.9 +/- 12 for serine 392 and 77.9 +/- 30 for p21) or SSR irradiation (mean +/- SD cell count per HPF of 3.5 +/- 1.2 SBCs, 147.5 +/- 62 for Do-1, 54 +/- 50 for serine 15, 38.9 +/- 18 for serine 392 and 56.7 +/- 30 for p21). CONCLUSIONS: These data indicate that there are fundamental differences in the effects of UVA1 on p53 and its activation pathways compared with TL-01 and SSR, and may in part explain the differential effects of these phototherapies.

Adult↗
PubMed2005

Differential effects of 5-aminolaevulinic acid photodynamic therapy and psoralen + ultraviolet A therapy on p53 phosphorylation in normal human skin in vivo.

BACKGROUND: Phosphorylation of the tumour suppressor p53 by the CK2/FACT pathway plays a central role in suppressing ultraviolet (UV)-induced skin cancer in animal models. Although p53 protein stabilization is induced after solar-simulated irradiation of human skin in vivo, p53 phosphorylation has not been defined. OBJECTIVES: To investigate the effects of clinically effective treatments for skin diseases including psoralen + UVA (PUVA) and photodynamic therapy (PDT) on p53 phosphorylation to determine whether the tumour-suppressing p53 kinase pathways are activated upon use of these therapies. METHODS: We used antibodies to the ATM/ATR and CK2/FACT phosphorylation sites on p53. RESULTS: We found that p53 activation was induced selectively by PUVA treatment, while 8-oxo-7,8-dihydroguanine DNA damage was induced selectively by 5-aminolaevulinic acid (ALA)-PDT treatment. Importantly, PUVA treatment resulted in p53 kinase activation, as defined by p53 modification at AT (serine-15) and CK2/FACT (serine-392) sites within the proliferative compartment. CONCLUSIONS: These data demonstrate that PUVA provokes accumulation and phosphorylation of p53 by AT and CK2/FACT within critical proliferative focal points (as determined by p63 colocalization studies) where DNA damage may lead to tumorigenesis. PDT is mechanistically distinct in that there is a lower level of induction of p53 expression with no evidence of AT- or CK2/FACT-mediated phosphorylation. This suggests that the type of DNA damage created by the reactive oxygen species generated by ALA-PDT does not induce the p53 pathway classically required for the repair of DNA photoadducts induced by UV.

Aminolevulinic Acid↗
PubMed2005

Extended DR3-D6S273-HLA-B haplotypes are associated with increased susceptibility to type 1 diabetes in US Caucasians.

Human leukocyte antigen (HLA)-DR3 haplotypes are associated with susceptibility to type 1 diabetes (T1D). Reports from Northern European populations show that an allele (D6S273*2) at a microsatellite mapping to HLA class III marks an extended DR3-B18 haplotype associated with increased susceptibility to T1D. Consistent with previous reports, D6S273*2 marked a highly predisposing DR3 haplotype in European origin, multiplex families from the USA. Furthermore, we observed on DR3 haplotypes that other D6S273 alleles were also significantly associated with both increased transmission (D6S273*5; P < 0.02) and decreased transmission (D6S273*7; P < 0.05) to affected individuals. The differential transmission was most evident among DR3-B8 haplotypes. Neither HLA-B*1801 nor any alleles of D6S273 were associated with increased T1D predisposition on DR4 haplotypes. These data indicate that multiple alleles of D6S273 mark a susceptibility locus whose effect we were able to detect only among DR3 haplotypes but not limited to DR3-B18 haplotypes.

Diabetes Mellitus, Type 1↗
PubMed2005

MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies.

Twenty-two human major histocompatibility complex (MHC) region microsatellite (Msat) markers were studied for diversity and linkage disequilibrium (LD) with HLA loci in hematopoietic cell transplant recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donors. These Msats showed highly significant LD over much of the MHC region. The Msat diversity of five common Caucasian haplotypes (HLA-A1-B8-DR3, A3-B7-DR15, A2-B44-DR4, A29-B44-DR7, and A2-B7-DR15) was examined using a new measure called 'haplotype specific heterozygosity' (HSH). Each of the five haplotypes had at least one Msat marker with an HSH value of zero indicating that only one Msat allele was observed for the particular HLA haplotype. In addition, the ability of Msats to predict HLA-A-B-DRB1 haplotypes was studied. Over 90% prediction probability of two common haplotypes (HLA-A1-B8-DR3 and HLA-A3-B7-DR15) was achieved with information from three Msats (D6S265/D6S2787/D6S2894 and D6S510/D6S2810/D6S2876, respectively). We demonstrate how the HSH index can be used in the selection of informative Msats for transplantation and disease association studies. Markers with low HSH values can be used to predict specific HLA haplotypes or multilocus genotypes to supplement the screening of HLA-matched donors for transplantation. Markers with high HSH values will be most informative in studies investigating MHC region disease-susceptibility genes where HLA haplotypic effects are known to exist.

Gene Frequency↗
PubMed2005

Deaths from international terrorism compared with road crash deaths in OECD countries.

OBJECTIVE: To estimate the relative number of deaths in member countries of the Organisation for Economic Co-operation and Development (OECD) from international terrorism and road crashes. METHODS: Data on deaths from international terrorism (US State Department database) were collated (1994-2003) and compared to the road injury deaths (year 2000 and 2001 data) from the OECD International Road Transport Accident Database. RESULTS: In the 29 OECD countries for which comparable data were available, the annual average death rate from road injury was approximately 390 times that from international terrorism. The ratio of annual road to international terrorism deaths (averaged over 10 years) was lowest for the United States at 142 times. In 2001, road crash deaths in the US were equal to those from a September 11 attack every 26 days. CONCLUSIONS: There is a large difference in the magnitude of these two causes of deaths from injury. Policy makers need to be aware of this when allocating resources to preventing these two avoidable causes of mortality.

Accidents, Traffic↗
PubMed2004

Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci.

The allelic and haplotypic diversity of the HLA-A, HLA-B, and HLA-C loci was investigated in 852 subjects from five sub-Saharan populations from Kenya (Nandi and Luo), Mali (Dogon), Uganda, and Zambia. Distributions of genotypes at all loci and in all populations fit Hardy-Weinberg equilibrium expectations. There was not a single allele predominant at any of the loci in these populations, with the exception of A*3002 [allele frequency (AF) = 0.233] in Zambians and Cw*1601 (AF = 0.283) in Malians. This distribution was consistent with balancing selection for all class I loci in all populations, which was evidenced by the homozygosity F statistic that was less than that expected under neutrality. Only in the A locus in Zambians and the C locus in Malians, the AF distribution was very close to neutrality expectations. There were six instances in which there were significant deviations of allele distributions from neutrality in the direction of balancing selection. All allelic lineages from each of the class I loci were found in all the African populations. Several alleles of these loci have intermediate frequencies (AF = 0.020-0.150) and seem to appear only in the African populations. Most of these alleles are widely distributed in the African continent and their origin may predate the separation of linguistic groups. In contrast to native American and other populations, the African populations do not seem to show extensive allelic diversification within lineages, with the exception of the groups of alleles A*02, A*30, B*57, and B*58. The alleles of human leukocyte antigen (HLA)-B are in strong linkage disequilibrium (LD) with alleles of the C locus, and the sets of B/C haplotypes are found in several populations. The associations between A alleles with C-blocks are weaker, and only a few A/B/C haplotypes (A*0201-B*4501-Cw*1601; A*2301-B*1503-Cw*0202; A*7401-B* 1503-Cw*0202; A*2902-B*4201-Cw*1701; A*3001-B*4201-Cw*1701; and A*3601-B*5301-Cw*0401) are found in multiple populations with intermediate frequencies [haplotype frequency (HF) = 0.010-0.100]. The strength of the LD associations between alleles of HLA-A and HLA-B loci and those of HLA-B and HLA-C loci was on average of the same or higher magnitude as those observed in other non-African populations for the same pairs of loci. Comparison of the genetic distances measured by the distribution of alleles at the HLA class I loci in the sub-Saharan populations included in this and other studies indicate that the Luo population from western Kenya has the closest distance with virtually all sub-Saharan population so far studied for HLA-A, a finding consistent with the putative origin of modern humans in East Africa. In all African populations, the genetic distances between each other are greater than those observed between European populations. The remarkable current allelic and haplotypic diversity in the HLA system as well as their variable distribution in different sub-Saharan populations is probably the result of evolutionary forces and environments that have acted on each individual population or in their ancestors. In this regard, the genetic diversity of the HLA system in African populations poses practical challenges for the design of T-cell vaccines and for the transplantation medical community to find HLA-matched unrelated donors for patients in need of an allogeneic transplant.

Africa South of the Sahara↗
PubMed2004

How much downside? Quantifying the relative harm from tobacco taxation.

OBJECTIVE: To estimate the loss of life expectancy attributable to tobacco taxation (via financial hardship and flow-on health effect) in New Zealand. DESIGN: Data were used on the gradients in life expectancy and smoking by neighbourhood socioeconomic deprivation and survey data on tobacco expenditure. Three estimates were modelled of the percentage of the crude association of neighbourhood deprivation with life expectancy that might be mediated via financial hardship: 100%, 50%, and 25% (best estimate). From this information the impact of tobacco taxation on life expectancy was estimated. MAIN RESULTS: For the total population, the estimated loss of life expectancy due to tobacco tax ranged from 0.005 years to 0.027 years. For people living in the most deprived 30% of neighbourhoods, the range was 0.009 to 0.044 years (that is, 3 to 16 days of lost life expectancy). For the total population the loss of life expectancy attributable to tobacco tax ranged from 119 to 460 times less than that attributable to deprivation. The loss of life expectancy attributable to tobacco tax was 42 to 257 times less than that attributable to smoking. CONCLUSIONS: The estimated harm to life expectancy from tobacco taxation (via financial hardship) is orders of magnitude smaller than the harm from smoking. Although the analyses involve a number of simplistic assumptions, this conclusion is likely to be robust. Policy makers should be reassured that tobacco taxation is likely to be achieving far more benefit than harm in the general population and in socioeconomically deprived populations.

Aged↗
PubMed2004

The decline of smoking in British portraiture.

OBJECTIVE: To examine time trends in the portrayal of smoking in a national collection of portraiture and to compare this with the similar trends for television and film. METHODS: A compact disc produced by the National Portrait Gallery in London, UK, was systematically searched for artworks produced in the years 1950 to 1999. A "smoking portrayal" in an artwork was defined as having a cigarette, cigar or pipe in the mouth or hand of a named individual. RESULTS: Out of 1063 artworks included in the analysis, 53 portrayed smoking by identifiable individuals (5.0%). The rate of portrayal was highest in the 1950s (10%) and 1960s (11%) and then declined sharply thereafter (p value for trend < 0.00001). Smoking virtually disappeared from portraiture in the 1990s (at 0.6%). The median age of the smokers portrayed was significantly higher in the 1970 to 1999 period when compared to the 1950 to 1969 period. CONCLUSIONS: The decline of smoking in this collection of portraiture is consistent with the decline in smoking in the UK over these decades, but contrasts with trends for increasing smoking portrayal described elsewhere for film and television.

Art↗
PubMed2001

Modeling of HLA class II susceptibility to Type I diabetes reveals an effect associated with DPB1.

In this report, we present evidence that the HLA class II DPB1 locus (or a locus with alleles in linkage disequilibrium with DPB1) contributes to Type I diabetes (IDDM) susceptibility in addition to the contribution of the HLA DR and DQ loci. The marker association segregation chi-square (MASC) method, which fits both genotype frequency and affected sib-pair identity-by-descent (IBD) distributions, was applied to 257 sib pairs affected with IDDM. Fitting DR-DQ as the sole HLA susceptibility loci was strongly rejected. Next, we considered the DPB1 contribution to disease susceptibility. Published reports indicate a predisposing role for alleles DPB1*0301 and DPB1*0202, including our previous stratification analyses of association data on this sample. IDDM probands were stratified into those not carrying the alleles DPB1*0301 and DPB1*0202 (group DPB1-A), and those carrying at least one copy of either allele (group DPB1-B). Both groups of probands have almost identical frequencies of DR and DQ haplotypes but significantly different IBD distributions in the subset of families with probands who do not carry the highly predisposing DR3/DR4 genotype. In these data, DPB1 (or a locus in linkage disequilibrium), in addition to DR-DQ, is involved in IDDM susceptibility and affects IBD in the HLA region. Addition of DPB1 in a genetic model of IDDM gives a better fit to the data than consideration of DR-DQ alone. Our results are consistent with previous reports implicating DPB1 in IDDM susceptibility.

Alleles↗