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Biomedical subjects

D Burgner

Publications and source records attributed to D Burgner.

At least 19 recordsLinked to original sources
PubMed2005

Cytosine-phosphate-guanine motifs fail to promote T-helper type 1-polarized responses in human neonatal mononuclear cells.

BACKGROUND: The T-helper type 1 (Th1) trophic properties of bacterial cytosine-phosphate-guanine (CpG) motifs have made them logical adjuvants both for the suppression of Th2-mediated allergic disease in early life and for promoting vaccine responses in neonates who have relatively immature Th1 function. However, little is known about their effects on immature immune responses in this period. OBJECTIVES: To compare the effects of CpG on adult and neonatal cellular immune responses to various stimuli. METHODS: The immune responses of mononuclear cells (MC) derived from neonates (n=25) and their mothers (n=25) were compared in vitro. These were stimulated with house dust mite (HDM), CpG B, CpG C, non-CpG oligodeoxynucleotides (ODN) or diphtheria toxoid (DT) in optimized conditions. In parallel cultures, CpGs were combined with HDM or DT antigens to assess the effect of the various ODN on these antigen-specific responses. Lymphoproliferation and cytokine responses IL-13, IFN-gamma, IL-6, IL-10, TNF-alpha) were measured for all of the cultures described above. RESULTS: Although neonates showed attenuated lymphoproliferation to CpG, the production of antigen-presenting cell-derived cytokines such as IL-6 and IL-10 and the up-regulation of major histocompatibility complex class II (HLA-DR) were detected at adult levels. T cell-derived cytokines (IL-13 and IFN-gamma) were not detectable in response to CpG alone. Most neonates also failed to produce detectable IFN-gamma to HDM or DT (unlike adults), but readily produced IL-13 to these stimuli. The addition of CpG resulted in an increase in neonatal IFN-gamma production in response to HDM (P=0.011) and a similar but non-significant trend with DT. However, rather than inhibiting Th2 IL-13 responses, the addition of CpGs was associated with a significant increase in the IL-13 responses to HDM (P=0.016) and DT (P=0.03), effects not seen in adults. CONCLUSIONS: This study provides further evidence that neonatal MC responses to CpG are functionally different from adults, and do not show clear Th1 polarization. The CpG associated increase in Th2 responses may reflect a potentiation of the normal neonatal Th2 propensity, or non-specific activation of neonatal MC.

Adjuvants, Immunologic↗
PubMed2005

The diagnosis and management of Kawasaki disease.

Kawasaki disease (KD) is a systemic vasculitis of childhood with a predilection for the coronary arteries. It is the predominant cause of paediatric acquired heart disease in developed countries. The aetiology of KD remains unknown and consequently there is no diagnostic test. The diagnosis is made using a constellation of clinical criteria that in isolation have poor sensitivity and specificity. Early treatment prevents overt coronary artery damage in the majority of children. The long-term effects of childhood KD on later cardiovascular health remain unknown. A recent study showed that treatment of KD in Australia is suboptimal, with late diagnosis occurring in approximately half of the cases and an unacceptably high incidence of acute cardiac involvement. These guidelines highlight the difficulties in the diagnosis of KD and offer some clues that may assist early recognition of this important paediatric disease. They also detail current treatment recommendations and the evidence on which they are based. Increased awareness of the epidemiology and spectrum of the clinical presentation of KD is essential for early recognition and optimal management.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians.

The region of conserved synteny on mouse chromosome 11/human 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL5/RANTES, CCR7, STAT3 and STAT5A/5B. To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 (Z(lr) score 2.34; P=0.01) and D17S1795 (Z(lr) 2.67; P=0.004) and a single peak for tuberculosis at D17S250 (Z(lr) 2.04; P=0.02). Combined analysis shows significant linkage (peak Z(lr) 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P=0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals (NOS2A-8.4 Mb-CCL18-32.3 kb-CCL4-6.04 Mb-STAT5B) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

Animals↗
PubMed2004

Inducible nitric oxide synthase gene (NOS2A) haplotypes and the outcome of hepatitis C virus infection.

Inducible nitric oxide synthase (iNOS) is an important molecule involved in the host defense against infectious agents. iNOS is encoded by the NOS2A gene and well-defined haplotypes exist with respect to this gene. We examined whether these haplotypes were associated with the outcome of hepatitis C virus (HCV) infection in 619 Caucasian patients from seven European liver centres. We observed five major haplotypes: (-277A)+(-1026G)+(-1659C): haplotype 1; (-277G)+(-1026T)+(-1659C): haplotype 2; (-277G)+(-1026G)+(-1659C): haplotype 3; (-277G)+(-1026T)+(-1659T): haplotype 4; and (-277A)+(-1026T)+(-1659C): haplotype 5. Distributions of these haplotypes are comparable with those of previous studies. Homozygotes for haplotype 2 or those with haplotypes 2/4 were more likely than those with the 1/1 (wild type) combination to have self-limiting infections (odds ratios (OR)=3.43; 95% confidence intervals (95% CI): 1.10-8.0; P=0.0206 and OR=5.15; 95% CI: 1.32-14.32; P=0.0018, respectively). Conversely, carriage of haplotype 1 was associated with the lack of self-limiting disease (OR=0.48; 95% CI: 0.27-0.83; P=0.009). The effect was mainly among males (OR=0.41; 95% CI: 0.182-0.942; P=0.031 for males, and OR=0.55; 95% CI: 0.24-1.37; P=0.136 for women). Carriage of haplotype 1 was not associated with initial response (P=0.268) or sustained response (P>0.171). Combinations of haplotypes 1/4 were more likely to respond to interferon monotherapy in comparison of initial responders to nonresponders (OR=2.25; 95% CI: 1.05-5.68; P=0.0275).

Adult↗
PubMed2003

Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations.

The density of genetic markers required for successful association mapping of complex diseases depends on linkage disequilibrium (LD) between non-functional markers and functional variants. The haplotypic relationship between stable markers and potentially unstable but highly informative markers (e.g. microsatellites) indicates that LD might be maintained over considerable genetic distance in non-African populations, supporting the use of such 'mixed marker haplotypes' in LD-based mapping, and allowing inferences to be drawn about human origins. We investigated sequence variation in the proximal 2.6 kb of the inducible nitric oxide synthase (NOS2A) promoter and the relationship between SNP haplotypes and a pentanucleotide microsatellite (the 'NOS2A(-2.6) microsatellite') in Gambians and UK Caucasians. UK Caucasians exhibited a subset of sequence diversity observed in Gambians, sharing four of 11 SNPs and a similar haplotypic structure. Five SNPs were found in the sequence of interspersed repetitive DNA elements. In both populations, there was dramatic loss of LD between SNP haplotypes and microsatellite alleles across a very short physical distance, suggesting a high intrinsic mutation rate of the NOS2A(-2.6) microsatellite, the SNP haplotypes are relatively ancient, or that this was a region of frequent recombination. Understanding locus- and population-specific LD is essential when designing and interpreting genetic association studies.

Gambia↗
PubMed2002

Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research.

This article proposes a clinical guideline for the diagnosis and treatment of Kawasaki disease in the UK based on the best available evidence to date, and highlights areas of practice where evidence is anecdotal or based on retrospective data. Future research as proposed by the London Kawasaki Disease Research Group is outlined, and clinicians are invited to prospectively enroll their suspected cases into this collaborative research project.

Adrenal Cortex Hormones↗
PubMed2000

Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations: assessment of the NOS2A gene and predisposition to infectious disease.

Allelic frequencies of a (CCTTT)(n) pentanucleotide repeat in the NOS2A promoter region were determined in a total of 1393 unrelated individuals from five specific population groups in four continents: Africa, Europe, Asia, and the Caribbean. There were highly significant differences in allele frequencies between the ethnically diverse populations. The repeat variation may have implications for the selective pressure of malaria or other infectious diseases that may operate at the NOS2 locus.

DNA↗
PubMed1999

Epidemiology of Cryptosporidium parvum in symptomatic paediatric oncology patients.

BACKGROUND: Although Cryptosporidium parvum is known to cause significant morbidity in immunocompromised individuals, including adults with cancer, the epidemiology of this pathogen in paediatric oncology patients is not known. OBJECTIVE: We prospectively investigated the incidence of symptomatic C. parvum infection in children receiving treatment for malignancy. METHODOLOGY: Over a 9 month period, all oncology inpatients with diarrhoea had stool analysis for C. parvum oocysts. The incidence of cryptosporidiosis was also recorded in non-oncology patients who had a stool analysed for C. parvum during the 6 years of the study period. RESULTS: None of the 149 stool samples from 60 oncology patients analysed contained C. parvum oocysts. Thirteen per cent of 173 samples from non-oncology patients were positive for C. parvum oocysts. CONCLUSIONS: In contrast to studies of adult oncology patients, paediatric oncology patients in our institution appear at low risk of cryptosporidiosis.

Animals↗
PubMed1998

Disseminated invasive infection due to Metarrhizium anisopliae in an immunocompromised child.

The first reported human case of possible disseminated infection with the insect pathogen Metarrhizium anisopliae var. anisopliae, a fungus which has been used commercially for biocontrol of insects, is described. The patient, a 9-year-old boy, had a 5-year history of pre-B-cell acute lymphoblastic leukemia and had been on chemotherapy throughout this period. After 10 days of profound neutropenia, lesions consistent with ecthyma gangrenosum appeared on his arms and legs. M. anisopliae was grown from specimens from three separate sites, collected at different times over a period of 1 month: a skin biopsy, a swab from the base of a lesion, and the core of another skin lesion which spontaneously discharged. The initial skin biopsy also showed histological evidence of epidermal necrosis and dermal invasion with fungal hyphae. A computed-tomography (CT) scan of the chest demonstrated a lesion in the superior segment of the lower lobe of the left lung. A CT scan of the brain revealed a lesion in the left temporoparietal region of the brain, consistent with an abscess. Despite antifungal treatment including liposomal amphotericin and 5-flucytosine, the patient eventually died. The initial portal of entry is unknown, but hematogenous dissemination to the skin appears likely because of the multiple ecthymic lesions, and the appearances of the brain lesion on the CT scan are consistent with a hematogenous fungal abscess.

Child↗
PubMed1997

A prospective study of Clostridium difficile infection and colonization in pediatric oncology patients.

BACKGROUND: Patients with cancer often receive broad spectrum antibiotics in addition to antineoplastic chemotherapy. Both treatments predispose adult oncology patients to infection and colonization with Clostridium difficile, but the role of this pathogen in pediatric oncology patients is poorly defined. METHODS: A prospective study of 149 fecal samples from symptomatic pediatric oncology patients and 58 samples from asymptomatic patients was performed. Each sample was analyzed for the presence of C. difficile and its toxins A and B. RESULTS: In 8.7% of the symptomatic samples and 19% of the asymptomatic samples toxigenic C. difficile was found. No association was found between either the use of antibiotics and/or the administration of chemotherapy and the presence of toxigenic C. difficile. Younger children were more likely to be infected or colonized with C. difficile, and there was no evidence of nosocomial transmission of C. difficile within the study population. CONCLUSIONS: As toxigenic C. difficile may form part of the normal flora in young children, this study indicates that in the absence of a defined outbreak, C. difficile does not appear to be an important pathogen in pediatric oncology patients.

Adolescent↗