Academic Research in 1998 Academic Research in 1998Work on the second volume on the International Incidence of Childhood Cancer was completed in 1998: two of the six editors are from the Childhood Cancer Research Group. These volumes are the main reference work for information on world-wide variations in childhood cancer rates. Two Department of Health reports to which the group made substantial contributions were also published during the course of the year: the report of the Expert Group on Cot Death Theories and the Fifth Report of the Committee on Medical Aspects of Radiation in the Environment on cancer and leukaemia around the former Greenham Common Airbase. The group continues its participation in a number of European epidemiological studies including leukaemia clustering (Alexander et al, 1998), the epidemiology of neuroblastoma (Satge et al, 1998) and childhood cancer survival rates.
The paediatric diabetes and endocrine research group continued their work exploring the use of IGF-I and insulin analogues in the treatment of diabetes during puberty. The Oxford Regional Prospective Study of Diabetes, which has been running in the region for almost 12 years, is now beginning to bear fruit as the longitudinal data are analysed. The UK study of cerebral oedema complicating diabetic ketoacidosis is well advanced through the BPSU and new studies have begun looking at antecedents and predictors of poor glycaemic control and behavioural problems in young adults with diabetes (also funded by the British Diabetic Association). In studies funded by the Wellcome Trust, we have been looking at the relationship between size at birth, early rates of growth and allelic variation at the insulin gene mini-satellite (INS VNTR). Preliminary data has been published in Nature Genetics and a number of other studies are now underway, looking at both hormonal and genetic determinants of early growth and weight gain. These studies are complementary to existing research programmes looking at endocrine changes and the response to growth hormone therapy in small for gestational age infants.
Dr Edge has clinical involvement in Diabetes, Endocrine and General Paediatrics. Her main research interest is a 3 year Case-Control Study of Cerebral Oedema during Diabetic Ketoacidosis. She is also involved in projects examining the transition of adolescents to adult diabetes clinics, new insulin regimen trials, studies in the use of IGF-1 in diabetes.
1998 was a productive year in which a long term investment to identify the major tissue specific control elements for the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been completed. We have identified a series of key regulatory elements and have now embarked on experiments to elucidate how these elements function in vivo. This will be of major importance in achieving gene therapy for CF that is targeted to specific cells in the airway. Our work on mucin glycoproteins, the other major interest in the group, has progressed substantially. Last year we identified the mucins that were important in the early pathology of CF. We have now generated the necessary molecular reagents to evaluate if and how CF affects the O-glycosylation of these mucins.
Dominic Kwiatkowski's group continued their research work on childhood diseases of the developing world. Their primary focus remains the pathogenesis of severe malaria, and particularly the role of cytokines and other inflammatory mediators, as this represents a potential target for vaccine-based approaches towards reducing malaria mortality. The group is using new tools in human molecular genetics to dissect causal mechanisms of pathogenesis at the molecular level. Automated sequencing technology has allowed the identification of over 40 novel polymorphisms in promoter regions of genes encoding inflammatory mediators. Functional studies at the cellular level have identified a number of common polymorphisms that may affect the binding of specific transcription factors and thereby alter the regulation of the corresponding gene. The clinical significance of these functional polymorphisms is being investigated by disease association studies, utilising a library of over 500 families of African children with severe malaria that the group has collected in collaboration with the MRC laboratories in The Gambia and the Wellcome Research Unit in Malawi.
Much of this work is a long term investment, aimed at the screening of multiple genetic markers at a wide range of different candidate gene loci, and this will be greatly facilitated by ongoing advances in the technology of high-throughput genotyping. One of this year's achievements has been the identification of a functional polymorphism within a novel regulatory element of the TNF promoter region, which confers a four-fold increase in susceptibility to cerebral malaria. Apart from malaria, the group are working on other aspects of the pathogenesis of infectious disease, including a new project on susceptibility to bronchiolitis being undertaken by Jeremy Hull in collaboration with Anne Thomson. In collaboration with other laboratories, this year the group published novel work on louse borne relapsing fever, dengue haemorrhagic fever and tuberculosis. He was involved in clinical trials, with Dr Thomson, on the treatment of empyema thoracis and the use of new mucolytic agents in cystic fibrosis.
Dr Mitchell and his group carried out a study on "Biologically generated primer to simplify clone specific PCR for antigen receptor gene rearrangement" (with Dr Carol Bindon). Work continues on this project and collaborations with Dr Colin Steward (Bristol) and Dr Chris Hatton (Oxford) are planned. These interactions will help establish the role of biologically generated primers as clinically useful tools in the assessment of remission in lymphoid malignancies.
The Molecular Infectious Diseases Group has continued its research focusing on the development of lipopolysaccharide based bacterial vaccines against N. meningitidis and non-typeable H. influenzae. This work is supported by a Medical Research Council Programme. A further major interest of the group lies in understanding the molecular mechanisms of antigenic variation of microbes and, in September, the Wellcome Trust awarded a Programme Grant (£763,413 over five years) to study the role of DNA antigenic variation and virulence of the pathogenic bacteria Haemophilus influenzae and Neisseria meningitidis.
Chris Tang has continued to develop his programme of research following his return from the USA in September 1997 and has built up an impressive team focusing on the applications of a novel mutagenesis technique for identifying virulence factors in N. meningitidis and Escherichia coli. David Stroud has been working on the genetic analysis of gastro-intestinal colonisation by Escherichia coli. The work has identified a number of factors required for this early step in pathogenesis. Sharmila Bakshi has been working in collaboration with Dr Chalmers (Department of Biochemistry) to develop genetic methods for working with Neisseria meningitidis.
The Oxford Vaccine Group has continued its programme of research focusing especially on conjugate vaccines against N. meningitidis. There is also a major interest in the epidemiology of invasive pneumococcal infections, carriage and transmission. The national surveillance of Hib conjugate vaccines continues and a new project on rotavirus epidemiology has been started. A new clinic for children with HIV infection was established by Paul Heath and Jim Buttery. We are delighted to have Dr Gareth Tudor-Williams, lecturer in the Department of Paediatrics at St Mary’s Hospital, London, as an honorary consultant and advisor who attends these joint clinics. In the latter part of the year, a major effort was invested in preparing an application for a Centre of Vaccinology and Tropical-based Medicine through the Joint Infrastructure Fund. This bid has been coordinated by Richard Moxon in conjunction with Adrian Hill, Tim Peto, Andrew McMichael and David Warrell. The plans are for an exciting new build on the Churchill Site which will be funded by the Wellcome Trust with the Office of Science and Technology during 1999.
Dr Jo Poulton (Royal Society University Research Fellow) and her group are investigating molecular mechanisms in mitochondrial DNA (mtDNA) diseases, including Mitochondrial Encephalomyopathy, Lactic Acidosis with Stroke-like episodes (MELAS). Progression of disease severity in MELAS patients is probably due to the accumulation of very high levels of mutant mtDNA in muscle and in brain in vivo. We have developed a new technique for measuring the rate of mtDNA replication in patient-derived cell lines which we we will use to investigate the variable tissue distribution of mutant and wild-type mtDNAs seen in MELAS. Transmission of mtDNA mutants is complicated by a genetic bottleneck. Dr DR Marchington has demonstrated that the major component of the bottleneck had occurred by the time oocytes were mature in a patient and a control. This work advances the prospects for prenatal diagnosis of mtDNA diseases. We have demonstrated an association of a mtDNA variant with type 2 diabetes. This is the first example of a common mitochondrial variant contributing towards the phenotype in a multifactorial disorder.
A programme of clinically-based research arising from the Paediatric Gastroenterology service focuses on two areas: namely the nutritional needs of disabled children with oral-motor dysfunction and investigation into the structural and functional relationships in the ano-rectum of children with intractable constipation. In addition to the locally-based clinical research, our Group is involved in a study of the Molecular Epidemiology of Helicobacter pylori infection at the MRC unit in The Gambia, West Africa.
Dr Thomson's group have been working in 4 main areas:
My group continued its research on Pneumocystis carinii, a fungal pathogen which causes severe pneumonia in AIDS patients and other immunocompromised individuals. During this year, my group has conducted a study on archival isolates of P. carinii from patients who died before the AIDS pandemic, to compare the nature and extent of diversity in these samples from a period when P. carinii pneumonia was a rare disease, with organisms isolated from HIV infected individuals. DNA sequence variation was analysed at four genetic loci. No major sequence variation was observed, suggesting that isolates of P. carinii from before the AIDS pandemic are genetically very similar to those currently isolated from HIV infected individuals. The reservoir of infectious P. carinii organisms and the mode of acquisition in the human infection are still unknown. There have been several reports of possible transmission between patients, observed as clusters of cases of P. carinii pneumonia.
My group has developed molecular methods of typing which are capable of distinguishing between different isolates of human-derived P. carinii. In a recent study, we have applied these methods to three clusters of P. carinii pneumonia among eight patients with haematological malignancies and six patients with HIV infection. Our data suggest that although person-to-person transmission of P.carinii sp. f. hominis may occur, direct transmission between patients did not account for the majority of cases within the clusters, and may not constitute the major route of transmission in man.
still to be written
1998 has seen the start of a number of clinically based projects from our departments: Pyloric Stenosis: Investigation of the efficacy of urine testing to establish metabolic equilibrium in children with pyloric stenosis. Prospective study of results of Thal v Nissen laparoscopic fundoplication Prospective study of alternative types of hernia repairs in babies Use of endo-anal ultrasound in ano-rectal malformations Comparison of anal ultrasound in ano-rectal malformations Comparison of ano-rectal ultrasound v MRI scans in demonstrating anatomy of ano-rectal malformation Endo and ultrasound and constipation
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Childhood Cancer Research Group