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Biomedical subjects

D Ogilvie

Publications and source records attributed to D Ogilvie.

At least 19 recordsLinked to original sources

Hospital based alternatives to acute paediatric admission: a systematic review.

AIMS: To synthesise published evidence of the impacts of introducing hospital based alternatives to acute paediatric admission. METHODS: Systematic review of studies of interventions for children with acute medical problems. Main outcome measures were: admission or discharge, unscheduled returns to hospital, satisfaction of parents and general practitioners, effects on health service activity, and costs. RESULTS: Twenty five studies were included: one randomised controlled trial, 23 observational or cross-sectional studies, and one qualitative study. Many studies were of uncertain quality or were open to significant potential bias. About 40% of children attending acute assessment units in paediatric departments, and over 60% of those attending acute assessment units in A&E departments, do not require inpatient admission. There is little evidence of serious clinical consequences in children discharged from these units, although up to 7% may subsequently return to hospital. There is some evidence that users are satisfied with these services and that they are associated with reductions in inpatient activity levels and certain hospital costs. Evidence about the impact of urgent outpatient clinics is very limited. CONCLUSIONS: Current evidence supports a view that acute paediatric assessment services are a safe, efficient, and acceptable alternative to inpatient admission, but this evidence is of limited quantity and quality. Further research is required to confirm that this type of service reorganisation does not disadvantage children and their families, particularly where inpatient services are withdrawn from a hospital.

Acute Disease↗

Reducing social inequalities in smoking: can evidence inform policy? A pilot study.

OBJECTIVE: To assess the potential contribution of evidence from existing systematic reviews of effectiveness to answering the question: what works in reducing social inequalities in smoking? DATA SOURCE: The Cochrane Library (2002/4). STUDY SELECTION: Systematic reviews of the effectiveness of community based tobacco control interventions, and all the primary studies included in one of these reviews. DATA EXTRACTION: Reviews and primary studies were assessed for intent to assess the social distribution of intervention effects, information about the social inclusiveness or targeting of interventions, baseline sociodemographic data collected on participants, and estimates of effect size stratified by sociodemographic variables. DATA SYNTHESIS: Only one review aimed to examine outcomes stratified by sex, age or socioeconomic status, and these aims were only achieved with respect to sex. Sociodemographic data about participants were frequently collected in primary studies, but not used to compare intervention effects between social groups. CONCLUSIONS: There may be scope for using existing research more effectively to contribute to evidence based policy to reduce social inequalities in smoking-by explicitly seeking stratified outcome data in new systematic reviews, by re-analysing original datasets, and/or by meta-analysis of individual participant data.

Age Factors↗

The angiogenic receptor KDR is widely distributed in human tissues and tumours and relocates intracellularly on phosphorylation. An immunohistochemical study.

AIMS: Angiogenesis is an important factor in tumour growth and metastasis. Vascular endothelial growth factor receptor 2 (VEGFR-2) or KDR plays a crucial role in angiogenesis. The aim of this study was to raise and characterize antibodies against phosphorylated KDR which could be used for studies on human tissues to assess KDR activation and novel inhibitors of KDR activation in clinical trials. METHODS AND RESULTS: Three monoclonal antibodies and one rabbit polyclonal antiserum were produced. The specificity of the antibodies was confirmed by ELISA. One of the mouse antibodies and the rabbit polyclonal antiserum reacted with a 200-kDa band on a Western blot of human umbilical vein endothelial cell (HUVEC) lysates, the molecular weight of KDR. Immunohistochemical staining showed that phosphorylated KDR is present in a wide variety of normal tissues including liver, colon and placenta, and is not restricted to endothelium. It was also present in a number of human tumours including breast carcinomas, colonic carcinomas and non-Hodgkin's lymphomas. The pattern of staining was membranous, cytoplasmic and nuclear. CONCLUSIONS: This study has shown that phosphorylated KDR is present in a wide variety of tumour and tissue types and is not confined to endothelium.

Animals↗

Early discharge of low-risk women from cervical screening.

BACKGROUND: The Scottish Cervical Screening Programme currently offers three-yearly screening to all women between the ages of 20 and 60. However, previous studies have indicated that well-screened women over the age of 50 are likely to be at low risk of cervical neoplasia. This study aimed to explore the implications of discharging these women from screening in a typical area of Scotland. METHODS: A case-control study of the screening histories of women with and without screen-detected cervical neoplasia between ages 50 and 59 in Lanarkshire was carried out, as well as a cross-sectional study of the prevalence of adequate screening histories among women currently aged 50 in Lanarkshire. Routine screening programme statistics were used to estimate the effects of introducing an early discharge policy. RESULTS: Women reaching the age of 50 with two recent, consecutive, negative smears had reduced odds of screen-detected neoplasia in the subsequent decade. The estimated odds ratio for all screen-detected neoplasia (CIN 1-3, adenocarcinoma in situ and invasive carcinoma) was 4.4 [95 per cent confidence interval (CI) 1.6-13.2, p = 0.002]. The estimated odds ratio for screen-detected high-grade CIN and invasive squamous carcinoma was 17.0 (95 per cent CI 2.4-243.0, p = 0.0004). A total of 54.0 per cent (95 per cent CI 47.9-59.9 per cent) of screening participants currently aged 50 fulfilled the definition of adequate screening. Discharging these women might be expected to reduce screening workload by approximately 10 per cent, but those discharged would be at increased risk of neoplasia. CONCLUSION: Now that full screening histories are available in all health board areas since 1990, the identification of a low-risk group within the screened population could be the first step towards a screening programme targeted more closely on those with the greatest capacity to benefit.

Case-Control Studies↗

Elucidation of the mechanism of homozygous deletion of 3p12-13 in the U2020 cell line reveals the unexpected involvement of other chromosomes.

Homozygous deletions in tumor cells have been useful in the localization and validation of tumor suppressor genes. We have described a homozygous deletion in a lung cancer cell line (U2020) which is located within the most proximal of the three regions on the short arm of chromosome 3 believed to be lost in lung cancer development. Construction of a YAC contig map indicates that the deletion spans around 8 Mb, but no large deletion was apparent on conventional cytogenetic analysis of the cell line. To investigate this paradox, whole chromosome, arm-specific, and regional paints have been used. This analysis has revealed that genetic loss has occurred by complex rearrangements of chromosomes 3, rather than simple interstitial deletion. These studies emphasize the power of molecular cytogenetics to disclose unsuspected tumor-specific translocations within the extremely complex karyotypes characteristic of solid tumors.

Carcinoma, Small Cell↗

Homozygous deletions at 3p12 in breast and lung cancer.

We have constructed a physical map of the region homozygously deleted in the U2020 cell line at 3p12, including the location of putative CpG islands. Adjacent to one of these islands, we have identified and cloned a new gene (DUTT1) and used probes from this gene to detect two other homozygous deletions occurring in lung and breast carcinomas: the smallest deletion is within the gene itself and would result in a truncated protein. The DUTT1 gene is a member of the neural cell adhesion molecule family, although its widespread expression suggests it plays a less specialized role compared to other members of the family.

Breast Neoplasms↗

Mapping of the gene encoding the B56 beta subunit of protein phosphatase 2A (PPP2R5B) to a 0.5-Mb region of chromosome 11q13 and its exclusion as a candidate gene for multiple endocrine neoplasia type 1 (MEN1).

The multiple endocrine neoplasia type 1 (MEN1) locus has been previously localised to 11q13 by combined tumour deletion mapping and recombination studies, and a 0.5-Mb region, flanked by PYGM and D11S449, has been defined. In the course of constructing a conting, we have identified the location of the gene encoding the B56 beta subunit of protein phosphatase 2A (PP2A), which is involved in cell signal transduction pathways and thus represents a candidate gene for MEN1. We have searched for mutations in the PP2A-B56 beta coding region, together with the 5' and 3' untranslated regions in six MEN1 patients. DNA sequence abnormalities were not identified and thus the PP2A-B56 beta gene is excluded as the candidate gene for MEN1. However, our precise localisation of PP2A-B56 beta to this region of 11q13 may help in elucidating the basis for other disease genes mapping to this generich region.

Chromosome Mapping↗

Amplification and sequencing of genomic breakpoints located within the M-bcr region by Vectorette-mediated polymerase chain reaction.

The polymerase chain reaction (PCR) cannot be used to amplify the breakpoint in the chimaeric BCR-ABL gene in CML and acute leukaemias due to the large variation in the sites of breakpoint in the BCR gene (within a 5.8 kb region) and in the ABL gene (within a 150 kb region). The disease state is usually monitored using RNA-PCR to monitor abnormal transcripts. We have used a new modification of the PCR to amplify breakpoints within zone 3 of the M-bcr. A synthetic oligonucleotide linker, the Vectorette, is ligated to restriction digested DNA, and amplification is carried out between primers for a known target sequence and the Vectorette linker. Three Philadelphia chromosome Ph1-positive CML patients with breakpoints within the ALU region of zone 3 have been amplified and the sequence immediately around the breakpoint determined. The breaks occurred within 70 bp and two were only 14 bp apart. The Vectorette-PCR technique has the potential to rapidly identify and sequence breakpoints, and will enable the design of patient-specific primers to monitor disease progression, particularly following bone marrow transplantation.

Base Sequence↗

A limited association of generalized osteoarthritis with alleles at the type II collagen locus: COL2A1.

A significant genetic influence in osteoarthritis has been observed in the combination of Heberden's nodes and generalized osteoarthritis. We examined whether mutation in the gene encoding the major cartilage matrix protein type II collagen was responsible by comparing allele frequencies at the locus (COL2A1) in a group of 61 patients with nodal GOA with a control population and by analysing the COL2A1 genotypes of 21 affected sibling pairs. There were no significant allele differences but a slightly increased tendency over chance alone for affected siblings to have inherited the same COL2A1 alleles from their parents.

Alleles↗

Prenatal diagnosis of osteogenesis imperfecta by identification of the concordant collagen 1 allele.

Dominantly inherited osteogenesis imperfecta is consistently linked to the two loci encoding the alpha 1 and alpha 2 subunits of collagen 1, the predominant bone collagen. We have performed several prenatal diagnoses based on identification of the segregating allele at the concordant locus in chorionic villus samples both in families where the linkage can be independently shown and in those where it cannot. Especially in the latter category, calculation of the final risk must incorporate an estimate of genetic heterogeneity within the OI population to give a prior probability of linkage. This figure can then be modified for each family by additional information from concordant meioses.

Alleles↗

Genetic analysis in cystic fibrosis using the amplification refractory mutation system (ARMS): the J3.11 MspI polymorphism.

A new method of genetic analysis has been devised. The method, amplification refractory mutation system (ARMS), has been used to genotype the J3.11 MspI restriction fragment length polymorphism (RFLP) closely linked to cystic fibrosis (CF). The DNA sequence for both alleles of this dimorphism has been used to design ARMS primers. These allow genotyping of DNA isolated from blood, Guthrie cards, and buccal cells.

Alleles↗

A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones.

The recent development of yeast artificial chromosome (YAC) vectors has provided a system for cloning fragments that are over ten times larger than those that can be cloned in more established systems. We have developed a method for the rapid isolation of terminal sequences from YAC clones. The YAC clone is digested with a range of restriction enzymes, a common linker is ligated to the DNA fragments and terminal sequences are amplified using a vector specific primer and a linker specific primer. Sequence data derived from these terminal specific products can be used to design primers for a further round of screening to isolate overlapping clones. The method also provides a convenient method of generating Sequence Tagged Sites for the mapping of complex genomes.

Base Sequence↗

Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.

The segregation of COL1A1 and COL1A2, the two genes which encode the chains of type I collagen, was analyzed in 38 dominant osteogenesis imperfecta (OI) pedigrees by using polymorphic markers within or close to the genes. This was done in order to estimate the consistency of linkage of OI genes to these two loci. None of the 38 pedigrees showed evidence of recombination between the OI gene and both collagen loci, suggesting that the frequency of unlinked loci in the population must be low. From these results, approximate 95% confidence limits for the proportion of families linked to the type I collagen genes can be set between .91 and 1.00. This is high enough to base prenatal diagnosis of dominantly inherited OI on linkage to these genes even in families which are too small for the linkage to be independently confirmed to high levels of significance. When phenotypic features were compared with the concordant collagen locus, all eight pedigrees with Sillence OI type IV segregated with COL1A2. On the other hand, Sillence OI type I segregated with both COL1A1 (17 pedigrees) and COL1A2 (7 pedigrees). The concordant locus was uncertain in the remaining six OI type I pedigrees. Of several other features, the presence or absence of presenile hearing loss was the best predictor of the mutant locus in OI type I families, with 13 of the 17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this feature.

Chromosomes, Human, Pair 17↗

Genetic segregation analysis of familial mitral valve prolapse shows no linkage to fibrillar collagen genes.

Three pedigrees were identified in which mitral valve prolapse seemed to be inherited as a mendelian autosomal dominant trait. The segregation of the genes encoding the major fibrillar collagens present in valve tissue, collagens I and III, was analysed by use of restriction enzyme site variants as genetic markers. In one pedigree there was discordance between the segregation of the disease and markers for all three collagen genes. In another, there was discordance between the disease and markers for both collagen I loci. This is evidence against the disease being generally the result of mutations of the genes encoding the major fibrillar collagens.

Collagen↗

Homozygous osteogenesis imperfecta unlinked to collagen I genes.

In a consanguineous pedigree in which a severe type of osteogenesis imperfecta was segregating as an autosomal recessive trait, analysis of genetic markers for both collagen I structural loci COL1A1 and COL1A2 showed that the phenotype was unlinked to either locus.

Collagen↗