Biomedical subjects

J Burton

Publications and source records attributed to J Burton.

At least 19 recordsLinked to original sources

PubMed2006

The DNA sequence and biological annotation of human chromosome 1.

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.

Base Sequence↗

PubMed2006

Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial.

OBJECTIVES: To evaluate the effect of intensive lipid-lowering treatment on coronary artery calcification in a substudy of a trial recruiting patients with calcific aortic stenosis. METHODS: In a double blind randomised controlled trial, 102 patients with calcific aortic stenosis and coronary artery calcification were randomly assigned by the minimisation technique to atorvastatin 80 mg daily or matched placebo. Coronary artery calcification was assessed annually by helical computed tomography. RESULTS: 48 patients were randomly assigned to atorvastatin and 54 to placebo with a median follow up of 24 months (interquartile range 24-30). Baseline characteristics and coronary artery calcium scores were similar in both groups. Atorvastatin reduced serum low density lipoprotein cholesterol (-53%, p < 0.001) and C reactive protein (-49%, p < 0.001) concentrations whereas there was no change with placebo (-7% and 17%, p > 0.95 for both). The rate of change in coronary artery calcification was 26%/year (0.234 (SE 0.037) log arbitrary units (AU)/year; n = 39) in the atorvastatin group and 18%/year (0.167 (SE 0.034) log AU/year; n = 49) in the placebo group, with a geometric mean difference of 7%/year (95% confidence interval -3% to 18%, p = 0.18). Serum low density lipoprotein concentrations were not correlated with the rate of progression of coronary calcification (r = 0.05, p = 0.62). CONCLUSION: In contrast to previous observational studies, this randomised controlled trial has shown that, despite reducing systemic inflammation and halving serum low density lipoprotein cholesterol concentrations, statin treatment does not have a major effect on the rate of progression of coronary artery calcification.

Adult↗

PubMed2005

An exploration of the decision-making processes at the point of referral to an Admiral Nurse team.

The Admiral Nursing Service supports individuals caring for people with dementia. As a response to the high demand for one team's service, a temporary closure to referrals was agreed. This provided the impetus to explore the influence of nurses' decision making at the point of referral on demand for the service. The research questions addressed were: How do Admiral Nurses make decisions regarding referrals and What factors influence this decision-making process? Sixteen case studies were retrospectively reviewed through the auspices of a semi-structured interview aimed at identifying which factors influenced the nurses' acceptance or rejection of these referrals. Results indicated that the Admiral Nurses had a clearly identified focus in supporting the carers of people with dementia, but that the complexity of the carers situation which included the person with dementia was significant. However, the desire to fulfil a case-management role while attempting to provide a service that is of a specialist nature and of limited capacity generated tensions. The decision to offer a service to carers was consequently influenced not only by perceived need but also upon the nurses feeling professionally responsible for perceived gaps in service provision.

Aged↗

PubMed2004

The DNA sequence and comparative analysis of human chromosome 10.

The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.

Animals↗

PubMed2004

DNA sequence and analysis of human chromosome 9.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

Base Composition↗

PubMed2004

The DNA sequence and analysis of human chromosome 13.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

Chromosome Mapping↗

PubMed2003

The DNA sequence and analysis of human chromosome 6.

Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome.

Animals↗

PubMed2003

Collaborative Angiographic Patency Trial Of Recombinant Staphylokinase (CAPTORS II).

AIMS: A fibrinolytic agent more effective than streptokinase available for bolus injection with reasonable cost-effectiveness is a desirable goal. Pilot studies with bolus pegulated staphylokinase (PEG-Sak) have revealed excellent Thrombolysis In Myocardial Infarction (TIMI) 3 60-minute flow. METHODS AND RESULTS: We evaluated patients with acute ST-elevation myocardial infarction within 6 hours of chest pain onset to determine a dose of PEG-Sak that had at least equal efficacy to recombinant tissue plasminogen activator (rt-PA) while maintaining an acceptable safety profile. After the initial study of 38 patients, of whom 27 received PEG-Sak, enrollment was temporarily halted because 3 patients receiving PEG-Sak had intracranial hemorrhage: 1 at a dose of 0.15 mg/kg and 2 at a dose of 0.05 mg/kg. Overall, 378 patients were studied across a PEG-Sak dose range from 0.01 mg/kg to 0.015 mg/kg, and 122 patients received accelerated rt-PA. At the lowest dose of PEG-Sak studied, 0.01 mg/kg, there was suggestive evidence of attenuation of efficacy; the point estimate for TIMI 3 flow was 24% (95% CI 9%-38%). At doses of 0.01875 to 0.0375 mg/kg (n = 314), TIMI 3 flow rates were 33% (95% CI 27%-38%), whereas the TIMI 3 flow was 41% (95% CI 20%-61%) at the highest PEG-Sak dose studied, 0.05 mg/kg (n = 23), which was similar to that found with rt-PA, 41% (95% CI 32%-50%). CONCLUSION: The efficacy of PEG-Sak, coupled with its ease of administration, provide further impetus for further study in acute myocardial infarction.

Adult↗

PubMed2003

Aortic valve calcification on computed tomography predicts the severity of aortic stenosis.

AIM: Incidental aortic valve calcification is often detected during computed tomography. The aim was to compare the severity of valvular stenosis and calcification in patients with aortic stenosis. MATERIALS AND METHODS: One hundred and fifty-seven patients aged 68+/-11 years (range: 34-85) with aortic valve stenosis underwent multislice helical computed tomography and Doppler echocardiography performed by independent, blinded observers. The aortic valve calcium score was determined using automated computer software calibrated with a phantom. RESULTS: Doppler echocardiography demonstrated a post-valve velocity of 3.45+/-0.66 m/s and a peak gradient of 49+/-11 mmHg. Computed tomography showed excellent reproducibility and the median aortic valve calcium score was 5858 AU (interquartile range, 1555-14,596). The computed tomography aortic valve calcium score positively correlated with the Doppler post-valve velocity and peak gradient (r=0.54, p<0.0001 for both) of the aortic valve. All patients with severe aortic stenosis had a calcium score of >3700 AU. CONCLUSION: Calcification of the aortic valve is closely associated with the severity of aortic stenosis, and heavy calcification suggests the presence of severe aortic stenosis that requires urgent cardiological assessment. Patients with lesser degrees of aortic valve calcification should be screened for aortic stenosis and monitored for disease progression.

Adult↗

PubMed2003

Evidence for cause of death in patients dying in an accident and emergency department.

OBJECTIVE: This study assesses the evidence used for certification of the cause of death in an accident and emergency department. METHODS: The subjects were all patients for whom a certificate of the cause of death was issued in the A&E department of a Scottish district general hospital over a period of two years from September 1998 to August 2000. The case notes and details of necropsies were examined for evidence of the cause of death. Patients were allocated to one of three descending categories according to the strength of the evidence available; (1) Evidence of the cause of death was available at the time of death or from postmortem examination. (2) There was a history (hospital notes/from relatives/from GP) of morbidity supporting the cause. (3) There was no recorded history of morbidity supporting the stated cause of death. RESULTS: There were a total of 28 deaths in the A&E department over the study period. Two of the patients who died in A&E received postmortem examinations and had death certificates completed by pathologists. Death certificates were issued from A&E for a total of 24 cases. Of these 24, nine patients had strong evidence of the given cause of death and eight patients had a past history or other identifiable evidence that could support the cause of death. The cause of death in seven patients was not directly supported by available evidence. CONCLUSION: Death certificates issued in an A&E department were supported by strong evidence in one third of cases. Many certificates seem to be issued with slender evidence for the cause of death readily identifiable, and few patients are subjected to necropsy.

Aged↗

PubMed2001

Detection of analytes by immunoassay using up-converting phosphor technology.

Up-Converting Phosphor Technology (UPT) is based on lanthanide-containing, submicrometer-sized, ceramic particles that can absorb infrared light and emit visible light. Biological matrices do not up-convert; hence, there is no contribution to test background from sample autofluorescence. Up-converting phosphors do not photobleach and are inert to common assay interferants such as hemoglobin. A reader called UPlink has been developed to interrogate lateral flow test strips that utilize UPT labels. The reader contains a miniaturized, 1-W, infrared laser with peak emission at 980 nm. Preliminary assays that use up-converting phosphor labels, including tests for a drugs of abuse panel and Escherichia coli O157:H7, have been developed. In a "sandwich" assay format, 10(3) org/mL E. coli O157:H7 organisms were detectable in a negative control background of 10(9) other organisms per milliliter of culture medium. Coefficients of variation in concentrations tested from 0 to 10(7) org/mL were all < or =10%. In a competitive inhibition assay format, a multiplexed test simultaneously detected amphetamine, methamphetamine, phencyclidine, and opiates in saliva. For all assays, the percent displacement at 10 ng/mL was > or =40% demonstrating performance comparable with lab-based, commercially available EIAs. All assays were complete in 10 min. The development of rapid tests using UPT creates new applications for on-site testing with sensitivity not available using other label technologies.

Amphetamine-Related Disorders↗

PubMed2001

Initial sequencing and analysis of the human genome.

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Animals↗

PubMed2001

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Adult↗

PubMed2001

Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenografts.

PURPOSE: Inhibition of the enzyme cyclooxygenase with celecoxib is cytotoxic in a variety of solid tumor cell lines. Previous work has shown that by charting circadian rhythms, it has been possible to find optimal times to deliver a dose of drug, such that it is most efficacious in killing cancer cells and least harmful to normal tissues. Therefore, we examined the time dependence of toxicity (chronotoxicity) and of antitumor effects (chronotherapy) of celecoxib to determine optimal time of day for dosing with respect to light-dark cycles. EXPERIMENTAL DESIGN: Celecoxib was administered i.p. for 10 days (5 days on, 2 days off, 5 days on) to nude mice bearing s.c. breast xenografts. Body weight, peripheral blood cells, clinical chemistry, and tumor growth were monitored. RESULTS: The highest tolerance (100% survival) was found at 7 HALO and the least occurred at 17 h after light onset (HALO; 10% survival). Chronotherapy at a 20-mg/kg dose varied between the seven HALO evaluated and between the three breast tumors (MCF-7, ZR-75-30, and MDA-MB-468) studied. When the maximum tolerated dose (MTD) of celecoxib was optimized for each HALO, we found that at 7-10 HALO, the MTD was 25 mg/kg, whereas at 17-20 HALO; the MTD was only 10 mg/kg. Tumor regression was observed when dosing was done at 23 HALO to 7 HALO (5 a.m. to 1 p.m.), whereas no therapeutic response was observed when dosing was done at 10-13 HALO (4 p.m. to 7 p.m.), and rapid tumor growth was noted when dosing was done at 17 HALO (11 p.m.). CONCLUSIONS: Tumor growth response to the MTD at each HALO revealed that there was no clear relationship between dose administered and therapeutic response. COX-2 expression was not able to explain either the chronotherapy or the chronotoxicity results obtained.

Animals↗

PubMed2000

An SNP map of human chromosome 22.

The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain.

Cell Line↗

PubMed2000

Localization of an antibody to CD74 (MHC class II invariant chain) to human B cell lymphoma xenografts in nude mice.

The tumor-specific localization of an anti-CD74 Ab, LL1, was demonstrated in nude mice bearing xenografts of human B-cell lymphoma. This Ab, conjugated to radionuclides emitting Auger electrons, including 125I and 111In, was previously reported to kill tumor cells in vitro effectively and specifically. The cytotoxic potency of this Ab is due to its uptake and catabolism at a very high level, which also affected the Ab biodistribution experiments. Thus, Ab localization to the tumor was only detected if a "residualizing" radiolabel was used, meaning a label that is trapped within cells, usually within lysosomes, after catabolism of the Ab to which it was conjugated. Similar results were obtained with three different residualizing labels: 111In conjugated via the chelators benzyl diethylenetriaminepentaacetic acid (DTPA) or 1.4,7,10-tetra-azacyclododecane-N, N', N", N"'-tetraacetic acid (DOTA), or 131I-dilactitol-tyramine, a residualizing form of iodine. The Ab protein dose could be high, 0.5 mg/mouse, without causing a decrease in specific tumor uptake, probably reflecting the high capacity for uptake. Moreover, tumors of moderate size were found to cause rapid, specific removal of the Ab from the blood, also a result of catabolic processes. This induced blood clearance naturally affected the Ab localization experiments, but this factor could be circumvented by increasing the Ab protein dose. Using a different Ab, anti-(mature MHC class II), the ability of Ab to penetrate relatively large solid tumors was investigated. Complete saturation of antigenic sites was observed in tumors up to 0.3 g in size, but quite high Ab protein doses were required, 5.0 mg/ mouse. These results provide a rationale for attempting therapy with radiolabeled LL1.

Animals↗

PubMed2000

Oscillometric blood pressure monitors.

The mercury sphygmomanometer has been used to measure blood pressure for over a century (O'Brien 2000, Smith 2000), but due to the hazards associated with mercury spillage, there is increasing reliance on other methods, such as automatic oscillometric blood pressure monitors and aneroid sphygmomanometers. Within the theatre and recovery areas, the oscillometric method appears to be most common (Ramsey 1991).

Blood Pressure Determination↗

PubMed2000

Radionuclides linked to a CD74 antibody as therapeutic agents for B-cell lymphoma: comparison of Auger electron emitters with beta-particle emitters.

UNLABELLED: We demonstrated previously that human B-cell lymphomas were effectively and specifically killed in vitro by an antibody to CD74 (LL1) linked to (111)In or other Auger electron emitters. This study was intended to more accurately compare the potency and specificity of 3Auger electron emitters, (111)In, 67Ga, and 125I, and to evaluate beta-particle emitters, 131I and 90Y. The unique property of LL1 is its high level of intracellular uptake. METHODS: Raji B-lymphoma cells were incubated with serial dilutions of the radiolabeled Abs for 2 d and then monitored for cell growth by 2 assays: a cell counting assay and a clonogenic assay. The uptake of radioactivity per cell was monitored at various time points, and the radiation dose was calculated using published S values for radioactivity located in the cytoplasm. Both specific and nonspecific toxicity were evaluated. RESULTS: The beta-particle emitters had considerably higher levels of nonspecific toxicity than the Auger electron emitters, but both 131I and 90Y, and particularly 131I, still had high levels of specificity. Both of these results were consistent with dosimetry calculations. Relative to the delivered disintegrations per cell, 131I and 67Ga were the most potent of the radionuclides tested, with 125I and (111)In being significantly weaker and 90Y being intermediate. The high potency of 67Ga, together with its low nonspecific toxicity, caused this radionuclide to have the highest specificity index. CONCLUSION: When delivered by Ab LL1, both Auger electron and beta-particle emitters can produce specific and effective toxicity. The choice of the optimal radionuclide for therapy may depend on the ease and efficiency of labeling, the specific activity obtained, the nature of the tumor being targeted, and other factors, but the high specificity indices of the Auger electron emitters may be an advantage.

Antibodies↗