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Biomedical subjects

David Barker

Publications and source records attributed to David Barker.

11 recordsLinked to original sources
PubMed2005

Methyllycaconitine analogues have mixed antagonist effects at nicotinic acetylcholine receptors.

Bicyclic analogues of methyllycaconitine (MLA), such as 12, have been synthesised that incorporate the C1-OMe substituent present in the natural product. Electrophysiology experiments using Xenopus oocytes expressing nicotinic acetylcholine receptors (nAChRs) were conducted on these analogues and a related tricyclic analogue 2. The most potent compound, 2, was an antagonist at all receptors studied but displayed different antagonist effects at each receptor subtype. This study more clearly defines the biological effects of MLA analogues at nAChRs and demonstrates that these analogues are not selective ligands for the alpha7 nAChR subtype.

Aconitine↗
PubMed2005

The effects of driver training on simulated driving performance.

Given that the beneficial effects of driver training on accident risk may not be an appropriate criterion measure, this study investigates whether professionally trained and experienced drivers exhibit safer driving behaviour in a simulated driving task compared with drivers without professional driver training. A sample of 54 police trained drivers and a sample of 56 non-police trained drivers were required to complete two tasks. Firstly to overtake a slow-moving bus on a hazardous stretch of single-lane road with bends and hills and secondly to follow a lead vehicle travelling at 55mph in a built-up section with a speed limit of 30mph. Results showed that in comparison with non-police trained drivers, police drivers were significantly less likely to cross the central division of the road at unsafe locations during the overtaking task and reduced their speed on approach to pedestrians at the roadside in the following task to a greater extent. Police drivers also adopted a more central lane position compared with non-police trained drivers on urban roads and at traffic lights during the following task. Driver group differences in simulated driving performance are discussed with reference to the implications for driver training assessment and skill development.

Adult↗
PubMed2004

Developmental plasticity and human health.

Many plants and animals are capable of developing in a variety of ways, forming characteristics that are well adapted to the environments in which they are likely to live. In adverse circumstances, for example, small size and slow metabolism can facilitate survival, whereas larger size and more rapid metabolism have advantages for reproductive success when resources are more abundant. Often these characteristics are induced in early life or are even set by cues to which their parents or grandparents were exposed. Individuals developmentally adapted to one environment may, however, be at risk when exposed to another when they are older. The biological evidence may be relevant to the understanding of human development and susceptibility to disease. As the nutritional state of many human mothers has improved around the world, the characteristics of their offspring--such as body size and metabolism--have also changed. Responsiveness to their mothers' condition before birth may generally prepare individuals so that they are best suited to the environment forecast by cues available in early life. Paradoxically, however, rapid improvements in nutrition and other environmental conditions may have damaging effects on the health of those people whose parents and grandparents lived in impoverished conditions. A fuller understanding of patterns of human plasticity in response to early nutrition and other environmental factors will have implications for the administration of public health.

Adaptation, Physiological↗
PubMed2004

Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment.

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.

Aconitine↗
PubMed2004

Strategies for covalent attachment of DNA to beads.

Several covalent attachment chemistries were tested for the immobilization of DNA onto glass beads. The comparison was based on the ability of these chemistries to produce derivatized beads that give good hybridization signals. Cyanuric chloride, isothiocyanate, nitrophenyl chloroformate, and hydrazone chemistries gave us the best (yet comparable) hybridization signals. We further characterized the cyanuric chloride method for the number of attachment sites, number of hybridizable sites, hybridization kinetics, effect of linker length on hybridization intensity and stability of the derivatized beads.

Cross-Linking Reagents↗
PubMed2004

Quantitative gene expression profiling in formalin-fixed, paraffin-embedded tissues using universal bead arrays.

We recently developed a sensitive and flexible gene expression profiling system that is not dependent on an intact poly-A tail and showed that it could be used to analyze degraded RNA samples. We hypothesized that the DASL (cDNA-mediated annealing, selection, extension and ligation) assay might be suitable for the analysis of formalin-fixed, paraffin-embedded tissues, an important source of archival tissue material. We now show that, using the DASL assay system, highly reproducible tissue- and cancer-specific gene expression profiles can be obtained with as little as 50 ng of total RNA isolated from formalin-fixed tissues that had been stored from 1 to over 10 years. Further, tissue- and cancer-specific markers derived from previous genome-wide expression profiling studies of fresh-frozen samples were validated in the formalin-fixed samples. The DASL assay system should prove useful for high-throughput expression profiling of archived clinical samples.

Algorithms↗
PubMed2004

A novel, high-performance random array platform for quantitative gene expression profiling.

We have developed a new microarray technology for quantitative gene-expression profiling on the basis of randomly assembled arrays of beads. Each bead carries a gene-specific probe sequence. There are multiple copies of each sequence-specific bead in an array, which contributes to measurement precision and reliability. We optimized the system for specific and sensitive analysis of mammalian RNA, and using RNA controls of defined concentration, obtained the following estimates of system performance: specificity of 1:250,000 in mammalian poly(A(+)) mRNA; limit of detection 0.13 pM; dynamic range 3.2 logs; and sufficient precision to detect 1.3-fold differences with 95% confidence within the dynamic range. Measurements of expression differences between human brain and liver were validated by concordance with quantitative real-time PCR (R(2) = 0.98 for log-transformed ratios, and slope of the best-fit line = 1.04, for 20 genes). Quantitative performance was further verified using a mouse B- and T-cell model system. We found published reports of B- or T-cell-specific expression for 42 of 59 genes that showed the greatest differential expression between B- and T-cells in our system. All of the literature observations were concordant with our results. Our experiments were carried out on a 96-array matrix system that requires only 100 ng of input RNA and uses standard microtiter plates to process samples in parallel. Our technology has advantages for analyzing multiple samples, is scalable to all known genes in a genome, and is flexible, allowing the use of standard or custom probes in an array.

Animals↗
PubMed2004

Metabolic response after intraarterial 90Y-glass microsphere treatment for colorectal liver metastases: comparison of quantitative and visual analyses by 18F-FDG PET.

UNLABELLED: Our aim was to assess the feasibility of using PET for quantifying metabolic response after intraarterial (90)Y-glass microspheres for metastatic colorectal cancer to the liver by comparing visual estimates with hepatic standardized uptake values (SUVs). METHODS: Twenty-seven patients (15 men, 12 women; age, 68 +/- 12 y [+/-SD]) with metastatic colorectal cancer to the liver, and tumor progression despite polychemotherapy, were included. All patients had baseline CT or MRI, (18)F-FDG PET, hepatic angiography, and intraarterial (99m)Tc-labeled macroaggregated albumin scanning. Patients were treated with (90)Y-glass microspheres and were monitored for 3 mo using PET and serum carcinoembryonic antigen. The average absorbed dose was 139 +/- 22 Gy. All treatments were performed on a lobar basis. For each case analyzed, regions of interest were drawn along the liver edge to measure SUVs on maximum-intensity-projection (MIP) and resliced axial images. Concomitantly, the visual estimate was graded as +1, 0, -1, -2, or -3 for progression, no change, and mild, moderate, and dramatic improvement at posttreatment PET. RESULTS: Visual estimates placed 20 patients in the response category (-3 to -1) and 7 patients in the nonresponse category (0 to +1). There was a significant drop in the median SUV on the resliced axial images from 10,455 at baseline to 9,075 after treatment (P = 0.011) for the entire group. The percentage of metabolic response was significantly greater in the response group compared with that of the nonresponse group (-26% +/- 25% vs. +6% +/- 15%, P = 0.004). This correlated significantly with the respective visual estimates (r = 0.75, P < 0.0001). Furthermore, the direction of change agreed in 85% of patients using both methods. There was no significant correlation when the SUV from the simplified MIP images were used in the coronal or sagittal manner. CONCLUSION: It is feasible to quantify reduction of hepatic tumor metabolism objectively after (90)Y treatment for unresectable metastatic disease to the liver. SUVs of the entire axial slices of liver agree well with subjective visual evaluations. Quantitative PET is a useful technique in the treatment response evaluation of patients after (90)Y-glass microspheres.

Aged↗