Biomedical subjects
Publications and source records attributed to G Gallagher.
We provide characterization of a highly polymorphic dinucleotide repeat in the human TNF-receptor 1 gene (TNFR1, TNFRp55, CD120a). We have observed 11 alleles at this locus in individuals from the West of Scotland. In a panel of healthy, unrelated individuals from the West of Scotland (n = 143), the overall heterozygosity was 68%, indicating the potential usefulness of these markers in immunogenetic studies.
We have examined four polymorphic elements in the human interleukin-6 (IL-6) locus and described their allele distribution in 73 unrelated, healthy individuals from the West-of-Scotland. These comprised three single nucleotide polymorphisms (SNP) in the 5' promoter region of the gene and one VNTR in the 3' region of IL-6. A statistical consideration of the relationship between alleles at each locus was carried out. Of a total of 12 possible haplotypes observed in the population, the analysis suggested that four were prominent. These accounted for 41.1%, 28.1%, 14.4% and 3.4% respectively; in total, 87% of the haplotypes present. Frequently, these proposed haplotypes were supported by homozygosity across all four loci within individuals. We propose that these haplotypes be identified as IL6.0103, IL6.0204, IL6.0207 and IL6.0307, in recognition of their frequency in this population and the alleles that they contain.
Interleukin-10 (IL-10) is a pleiotropic cytokine with important immunoregulatory functions whose actions influence activities of many of the cell-types in the immune system. We report here identification and cloning of a gene and corresponding cDNAs encoding a novel homologue of IL-10, designated IL-19. IL-19 shares 21% amino acid identity with IL-10. The exon/intron structure of IL-19 is similar to that of the human IL-10 gene, comprising five exons and four introns within the coding region of the IL-19 cDNA. There are at least two distinct IL-19 mRNA species that differ in their 5'-sequences, suggesting the existence of an intron in the 5'-sequences of coding portion of the IL-19 gene. The longer 5'-sequence contains an alternative initiating ATG codon that is in-frame with the rest of the coding sequence. The expression of IL-19 mRNA can be induced in monocytes by LPS-treatment. The appearance of IL-19 mRNA in LPS-stimulated monocytes was slightly delayed compared to expression of IL-10 mRNA: significant levels of IL-10 mRNA were detectable at 2 h post-stimulation, whereas IL-19 mRNA was not detectable until 4 h. Treatment of monocytes with IL-4 or IL-13 did not induce de novo expression of IL-19, but these cytokines did potentiate IL-19 gene expression in LPS-stimulated monocytes. In addition, GM-CSF was capable of directly inducing IL-19 gene expression in monocytes. IL-19 does not bind or signal through the canonical IL-10 receptor complex, suggesting existence of an IL-19 specific receptor complex, the identity of which remains to be discovered.
Burn dressing changes require profound analgesia for a short duration. This study aimed to determine whether an operator-adjusted target-controlled infusion of alfentanil could provide effective analgesia for burn dressing changes. Ten patients with a burn of between 5 and 50% of body surface area were studied. Pain scoring was performed before, during and following the dressing change. Target and effect site concentrations of alfentanil were recorded during and for 15 min after the dressing change. Median baseline visual analogue pain score (VAS) was 22 mm. Median (range) duration of dressing change was 35 (20-75) min. Median (range) VAS during the dressing change was 30 (14-66) mm. All patients were satisfied with their pain relief. There was no respiratory depression or cardiovascular instability. No patient became sedated and there were no episodes of nausea or vomiting. Median (range) total dose of alfentanil was 2.6 (1-10.7) mg. This study supports the efficacy of an operator-adjusted target-controlled infusion of alfentanil to provide analgesia for burn dressing changes.
In order to prescribe appropriate analgesia for burns dressing changes the pain experienced by 30 burned patients during this procedure was recorded. Patients received analgesia prior to their dressing changes according to the current protocol in the burns unit. During the same period the medical and nursing staff in the unit who were involved in prescribing and administering the analgesia for the dressing change, were asked to assess the severity of pain that they thought patients experienced during dressing changes. Patients recorded their worst pain as none or mild in 64% of procedures. In contrast, no surgeon and only one nurse, rated pain as none or mild. The discrepancy between severity of pain recorded by patients and the pain predicted by staff prescribing and administering analgesia has clinical implications.
OBJECTIVES: To determine the frequency of use of irrigation amongst head and neck surgeons in the U.K. and Ireland, the range of fluids in use; to identify differences in practice in benign and malignant surgery, and ascertain common theories about irrigation, wound infection and tumour recurrence. METHOD: A postal survey of 695 members of the B.A.O.L. Head and Neck Surgeons (348/695 returned). Eight questions with tick box replies and space for free text. Members were asked about their practice of wound irrigation and opinions on its effect(s). Of 348 returned questionnaires 301 were used, 47 discarded as members had retired. RESULTS: 203 of 301 carried out head and neck tumour surgery (67.44%). 67.98% routinely perform wound irrigation. A variety of fluids are used, the most common being sterile water, then saline (table II). Reducing wound infection and tumour recurrence were reasons for irrigating by 47.1%, reducing infection alone, 15.22%, and reducing tumour recurrence alone, 31.16%. 59.42% believe that irrigation prevents wound seeding by benign tumour cells, 70.29% by malignant cells. Irrigation was performed by 70% of surgeons who did more than 5 head and neck tumour procedures per year and by 56% of surgeons who did less than five. CONCLUSIONS: There is little evidence for the putative effects of wound irrigation as noted from literature. Most studies have been performed on animals. There is a need for further research into wound irrigation, types of fluid used and its effects on head and neck cancer patients.
The pathologies of many infectious, autoimmune and malignant diseases are influenced by the profiles of cytokine production in pro-inflammatory (TH1) and anti-inflammatory (TH2) T cells. Interindividual differences in cytokine profiles appear to be due, at least in part, to allelic polymorphism within regulatory regions of cytokine gene. Many studies have examined the relationship between cytokine gene polymorphism, cytokine gene expression in vitro, and the susceptibility to and clinical severity of diseases. A review of the findings of these studies is presented. An on-line version featuring appropriate updates is accessible from the World Wide Web site, http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm.
Interleukin-10 (IL-10) is a pivotal immunoregulatory cytokine, influencing many aspects of the immune response. The IL-10 gene is located on chromosome 1 at 1q31-32 and is highly polymorphic. One microsatellite and three single nucleotide polymorphisms (SNPs) have been recorded within the 1.2 kb immediately upstream of the gene, with an additional microsatellite present at 4 kb upstream. The relationship between these two classes of polymorphism is poorly defined in the IL-10 gene. Haplotypes have been presented comprising alleles from the two microsatellite loci, and independently from the three SNPs, but these have not yet been brought together to define unified halpotypes. In the present report we describe the 29 IL-10 haplotypes found in 56 Dutch European families and show that they fall into four major haplotype groups, each of which spans the 4 kb upstream of the IL-10 gene and has a different distribution of IL10.G alleles. In addition, we describe three novel single nucleotide polymorphisms in the human IL-10 gene and suggest how they relate to these four haplotype families.
Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci.
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Stimulation of human blood cultures with bacterial lipopolysaccharide (LPS) shows large inter-individual variation in interleukin 10 (IL-10) secretion, which has been shown to have a genetic component of over 70%. Alleles at two microsatellite loci in the 4 kb immediately upstream of the human IL-10 transcription initiation site in 132 individuals from 56 Dutch families were defined and assigned as haplotypes. LPS-induced IL-10 secretion was measured by ELISA and related to the IL-10 promoter haplotypes present in 78 unrelated individuals obtained from these families. Analysis showed that LPS-induced IL-10 secretion from unrelated individuals varied with IL-10 promoter haplotypes (P = 0.024; Kruskal-Wallis test). Two observations were made in relation to secreted IL-10 levels and promoter haplotypes; first, those haplotypes containing the allele IL10.R3 were associated with lower IL-10 secretion than haplotypes containing any other IL10.R allele. Second, the haplotype IL10.R2/IL10.G14 was associated with highest IL-10 secretion overall, whereas the haplotype IL10.R3/IL10.G7 was associated with lowest IL-10 secretion. These data demonstrate that the ability to secrete IL-10 can vary in man according to the genetic composition of the IL-10 locus.
We examined the distribution of polymorphic elements within the tumor necrosis factor (TNF) gene cluster in 105 unrelated individuals and determined their relationship to class I and class II major histocompatibility complex (MHC) antigens, and to the highly polymorphic microsatellites TNFa and TNFb. The data demonstrate the contribution of elements within the TNF cluster to two extended haplotypes which are recognized to straddle the MHC. The A1.B8.DR3 haplotype appears to contain the TNF alleles TNFa2, TNFb3, LT.Nco-1.B*1, and TNF-308.2, while the A3.B7.DR2 haplotype is associated with the TNF alleles TNFa11, TNFb6, TNFc1, LT.Nco-1.B*2, LT.AspH1.1, TNF-308.1, and TNFe1. The presence of other extended associations which covered smaller parts of the MHC was also suggested. In most cases, the associations described here were in keeping with previously described extended haplotypes which dominate the structure of the MHC, but these did not always match completely. Taken together, these data suggest that the structure of the TNF locus is well integrated into the rest of the MHC but that important ethnic differences may exist.
Interleukin-10 (IL-10) is an important regulatory cytokine whose involvement extends into diverse areas of the human immune system. Recent characterization of the promoter and 5' flanking regions has demonstrated the presence of positive and negative regulatory segments in the promoter. In addition, the characterization of two dinucleotide repeat elements immediately upstream of the gene has shown that there is considerable polymorphism directly associated with the human IL10 gene. In the present report, we describe the mapping of the human IL10 gene to a discrete area of chromosome 1, the definition of a potential cytokine-responsive segment 3 - 4 kilobases upstream of the transcription initiation site, and the identification of two new point mutations in the immediate promoter region with their distribution in a panel of 75 unrelated healthy individuals. These data should further the understanding of how the IL10 gene is controlled in humans and how its function may vary between individuals.
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Temporal arteritis (TA) is an acute vasculitis characterised by destruction of arterial architecture following infiltration of the arterial wall by macrophages, giant cells and lymphocytes. Using immunohistochemical techniques, tumour necrosis factor (TNF) was demonstrated in up to 60% of the cells in all areas of inflamed arteries. More cells staining for TNF were detected in the intima and media of inflamed vessels than control uninflamed arteries (P < 0.003 and P < 0.001, respectively). In TA, TNF was localised to giant cells and macrophages, suggesting that its predominant source is from the monocyte lineage, but, occasionally, TNF staining was found in areas infiltrated by T cells. Many endothelial cells also contained TNF, but there were no differences between the number of endothelial cells staining in inflamed and normal blood vessels. Of the two TNF receptors, the p75 receptor was sparsely represented in the inflamed vessels in TA. By comparison, the p55 receptor was widely detected on endothelial cells and infiltrating mononuclear cells close to the internal elastic lamina (IEL). Endothelial cells from normal vessels also stained for both TNF receptors, but normal smooth muscle cells in the vessel media expressed the p55 receptor, indicating that they are capable of responding to locally secreted TNF. Localisation of TNF receptors and TNF in close proximity to the IEL suggests that TNF could be involved in the leucocyte infiltration and arterial wall destruction characteristic of TA.
Recent studies have shown elevated IL-10 levels in several rheumatic autoimmune diseases, and particularly in systemic lupus erythematosus (SLE). Such changes may have a genetic basis. We studied two novel polymorphic dinucleotide repeats in the IL-10 promoter region (IL10.G and IL10.R) in order to investigate their possible significance in association with this condition in a group of 56 Caucasian SLE patients compared with 102 ethnically matched controls. The results show that there is an allelic imbalance between SLE patients and controls at the IL10.G microsatellite; this observation is supported by a significant difference in genotype distribution. The nature of autoantibody production and the presence or absence of renal involvement also appeared to be associated with certain IL10.G microsatellite alleles, although the small size of individual clinical sub-groupings may have influenced this result. No association with the IL10.R microsatellite was observed. Overall, the differences observed at the IL10.G microsatellite between SLE patients and controls suggest that the IL-10 locus contributes to the genetic background important for the development of this disease. Although the moderate sample size described in this study requires that the results be interpreted carefully, they provide an interesting and useful framework for future study.
Independently, our two groups collaborating in this report performed association studies to consider the influence of the TNF region within the human MHC on the presence of colorectal cancer. In the Glasgow Study, 84 colorectal cancer patients were compared with 91 controls at the TNFa microsatellite locus. Analysis of individual alleles by Fisher's exact test revealed a significant overrepresentation of the TNFa2 allele in the colorectal cancer group, after correcting for multiple comparisons. In the Essen Study, 47 colorectal cancer patients were compared with 117 matched controls, and the hypothesis of TNFa2 overrepresentation in colorectal cancer was confirmed. These data provide evidence for the involvement of the TNF locus in the pathogenetic etiology of colorectal cancer.
We examined six polymorphic elements in the tumor necrosis factor (TNF) locus and determined their allelic distribution in 98 Caucasian rheumatoid arthritis patients in comparison with 91 ethnically-matched controls. Polymorphic elements at four biallelic sites were distributed similarly between patients and controls, irrespective of the presence or absence of DR4. Differences were observed between the two groups at the TNFa and TNFe loci, but these were consistent with extended MHC haplotypes known to be present in rheumatoid arthritis patients. Therefore, this study suggests that there is little, if any, independent contribution of the TNF locus to the genetic background for rheumatoid arthritis susceptibility.