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Biomedical subjects

A Davison

Publications and source records attributed to A Davison.

At least 37 records · Page 2Linked to original sources
PubMed1999

Winter planning. Quantity surveying.

During Christmas and new year 1999-2000 there will be eight bank holiday or weekend days. Emergency admissions are likely to be high during this period. A mathematical model can be used to calculate how many beds will need to be empty on Christmas day in order to cope with an increase in emergency admissions afterwards. In this study of a 781-bed acute hospital, a minimum of 209 beds--equivalent to seven wards--will need to be empty on Christmas day. This model is derived from information on the patient administration system and could be used by all hospitals to plan care.

Bed Occupancy↗
PubMed1999

Perturbation of radiotherapy beams by radiographic film: measurements and Monte Carlo simulations.

Radiographic film is an established practical tool used in the measurement of the dose distribution for radiotherapy purposes. The accuracy and reproducibility of film optical density as an indicator of dose has been associated with several factors including photon energy, processing conditions and film plane orientation. Few studies have investigated the factors causing variability in film dosimetry, due to the difficulty of separating the individual contributions. The effect that a sheet of radiographic film in a water phantom has on its response to a 6 MV photon and a cobalt-60 teletherapy beam, when orientated perpendicular and parallel to the beam central axis, is reported. Monte Carlo generated spectra were used to calculate collision kerma (Kcoll) for water and film elements. Measured and calculated results indicate a potential over-response at 25 cm depth of the order of 14 +/- 2.4% and 18 +/- 6.0% respectively for 6 MV photons and 15 +/- 3.4% and 32 +/- 4.5% respectively for a cobalt beam. For film exposed parallel as compared to perpendicular to the central axis of the beam, the calculated results suggest an explanation in terms of the predominantly forward directed secondary electrons for the measured difference in film response at depth. It is proposed that the difference in response of the parallel as compared to perpendicular exposed film be due to the predominantly 'upstream' photon interactions giving rise to energy deposition in film. The simulations indicate that the variation with depth of relative energy imparted in film and water elements correlates with the observed variation in film response with depth.

Energy Transfer↗
PubMed1999

Identification of a spliced gene from Kaposi's sarcoma-associated herpesvirus encoding a protein with similarities to latent membrane proteins 1 and 2A of Epstein-Barr virus.

Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is a novel herpesvirus implicated as the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma, and some cases of multicentric Castleman's disease. KSHV persists in the majority of KS spindle (endothelial tumor) cells and lymphoid cells in a latent form, with only a limited set of viral genes expressed in a tissue-specific manner. Here, we report the identification of a family of alternatively-spliced transcripts of approximately 7.5 kb expressed in latently infected body cavity-based lymphoma (BCBL) cell lines which are predicted to encode membrane proteins with similarities to the LMP2A and LMP1 proteins of Epstein-Barr virus. In two highly divergent sequence variants of the right end of the KSHV genome, alternative splicing of eight exons located between KSHV ORF 75 and the terminal repeats yields transcripts appropriate for proteins with up to 12 transmembrane domains, followed by a hydrophilic C-terminal, presumably cytoplasmic, domain. This C-terminal domain contains several YxxI/L motifs reminiscent of LMP2A and a putative TRAF binding site as in LMP1. In latently (persistently) infected BCBL cells the predominant transcript utilizes all eight exons, whereas in phorbol-ester-induced cells, a shorter transcript, lacking exons 4 and 5, is also abundant. We also found evidence for an alternative use of exon 1. Transfection of an epitope-tagged cDNA construct containing all exons indicates that the encoded protein is localized on cell surface and intracellular membranes, and glutathione S-transferase pull-down experiments indicate that its cytoplasmic domain, like that of LMP1, interacts with TRAF1, -2, and -3. Two of 20 KS patients had antibodies to the hydrophilic C-terminal domain, suggesting that the protein is expressed in vivo.

Alternative Splicing↗
PubMed1999

Genetic medicine: an experiment in community-expert interaction.

This project tested a two-way model of communication between lay groups and experts about genetic medicine in Perth, Western Australia. Focus group discussion with community group participants was followed by a communication workshop between community group participants and experts. Four groups of concerns or themes emerged from discussion: clinical considerations; legislative concerns; research priorities, and ethical and wider considerations. Community group concerns are not always met by the actions of "experts". This is, in part, because of the differing life-worlds of each group. However, the communication workshop showed the potential of two-way communication for both lay and expert members in understanding the others' viewpoint. Further, the approach developed here offers one possible way for community groups to participate in a substantial way in policy formulation processes.

Attitude to Health↗
PubMed1998

Characterization of P-glycoprotein transport and inhibition in vivo.

The P-glycoprotein is an energy-dependent efflux pump capable of decreasing the intracellular concentration of a broad range of chemotherapeutic agents. [99mTc]Sestamibi, a P-glycoprotein transport substrate, is a sensitive probe of P-glycoprotein function both in vitro and in vivo. A human tumor model in nude mice was evaluated to determine whether [99mTc]Sestamibi could detect in vivo differences in P-glycoprotein expression and P-glycoprotein modulation by the reversal agent SDZ PSC 833. Differential [99mTc]Sestamibi accumulation based upon P-glycoprotein expression was demonstrated in xenografts in vivo. Dose-dependent inhibition of P-glycoprotein function was achieved with SDZ PSC 833. Administration of the reversal agent increased [99mTc]Sestamibi accumulation in the xenografts expressing P-glycoprotein. These observations show that [99mTc]Sestamibi as capable of detecting the modulation of P-glycoprotein in a solid tumor model by the reversal agent SDZ PSC 833.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Uptake of cationic technetium complexes in cultured human carcinoma cells and human xenografts.

We evaluated lipophilicity, in vitro cell accumulation, and biodistribution of a series of 99mTc-ether isonitrile complexes to determine whether increased lipophilicity promotes extraction by tumor or enhances imaging properties of the radiopharmaceutical. Nine 99mTc-sestamibi analogs were synthesized and their lipophilicity was determined. Net cellular accumulation and membrane-potential-independent uptake were quantitatively compared in cultured human colon, breast, and lung carcinoma cells. The biodistribution of [99mTc-(2-methoxy-2-ethyl-isocyanopropane)6]+ (99mTc-MMBI) and [99mTc-(2-ethoxy-2-methyl-1-isocyanopropane)6]+ (99mTc-EIBI) was studied in nude mice using subcutaneous, subrenal capsule, and hepatic tumor xenografts. Accumulation of these compounds in colon cells correlated with increasing lipophilicity. Compared with 99mTc-sestamibi, 99mTc-EIBI exhibited (i) in colon cells both higher net accumulation and a higher specific/nonspecific uptake ratio; (ii) in all three cell lines higher membrane-potential-dependent accumulation; and (iii) in all subcutaneous tumor xenografts and in colon subrenal capsule and hepatic tumor xenografts higher tumor/background ratios.

Animals↗
PubMed1997

A technetium-99m SPECT imaging agent which targets the dopamine transporter in primate brain.

The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for certain neurological diseases. In particular, the DAT is depleted in Parkinson's disease, and the extent of depletion correlates with the loss of dopamine. Herein we describe the design, synthesis, and biological evaluation of technepine, the first 99mTc-labeled SPECT imaging agent which targets the dopamine transporter in striatum. We have demonstrated that the DAT can accommodate a chelating unit attached to the 8-amine function of a tropane skeleton. Further, we have demonstrated for the first time that a molecule can be designed to carry the radionuclide 99mTc across the blood-brain barrier in sufficient quantity to obtain in vivo images of the striatum in monkeys. This advance will undoubtedly lead to the design of new receptor and transporter-mediated 99mTc agents which can label specific transporter and receptor targets in the central nervous system.

Animals↗
PubMed1997

The U(L)15 gene of herpes simplex virus type 1 contains within its second exon a novel open reading frame that is translated in frame with the U(L)15 gene product.

The U(L)15 gene of herpes simplex virus type 1 is composed of two exons. A mutation previously shown to preclude viral DNA cleavage and packaging at the nonpermissive temperature was identified as a change from a highly conserved serine to proline at codon 653. Separate viral mutants that contained stop codons inserted into exon I of U(L)15 (designated S648) or an insertion of the Escherichia coli lacZ gene into a truncated U(L)15 exon II [designated HSV-1(delta U(L)15ExII)] were constructed. Recombinant viruses derived from S648 and HSV-1(delta U(L)15ExII) and containing restored U(L)15 genes were constructed and designated S648R and HSV-1(delta U(L)15ExIIR), respectively. Unlike HSV-1(delta U(L)15ExIIR) and S648R, the viruses containing mutant U(L)15 genes failed to cleave and package viral DNA when propagated on noncomplementing cells. As revealed by electron microscopy, large numbers of enveloped capsids lacking viral DNA accumulated within the cytoplasm of cells infected with either S648 or HSV-1(delta U(L)15ExII) but not in cells infected with HSV-1(delta U(L)15ExIIR) or S648R. Thus, one function of the U(L)15 gene is to effectively prevent immature particles lacking DNA from exiting the nucleus by envelopment at the inner lamella of the nuclear membrane. Cells infected with HSV-1(delta U(L)15ExII) did not express the 75,000- or 35,000-apparent-Mr proteins previously shown to be products of the U(L)15 open reading frame, whereas the 35,000-apparent-Mr protein was readily detectable in cells infected with S648. We conclude that at least the 75,000-Mr protein is required for viral DNA cleavage and packaging and hypothesize that the 35,000-Mr protein is derived from translation of a novel mRNA located partially or completely within the second exon of U(L)15.

Animals↗
PubMed1997

The validity of using radiographic film for radiotherapy dosimetry.

Radiographic film is routinely used to obtain dosimetric information about therapy treatment beams. One source of inaccuracy is the variability of the chemical processing of the radiographic film. Several processors, film types and two sources (light and x-rays) were used to investigate the reproducibility of film processing for valid film dosimetry. Particular attention is paid to films commonly used in radiation therapy. The results suggest that for this series of film, given the same exposure, the variability in processing may result in an error of +/- 3.3% in optical density, which would lead to an error of +/- 4.4% in indicated dose. This level of inaccuracy is typical for both point and relative dose estimates. These results indicate that film should not be used as a point or relative dosimeter, unless the combination of film type, exposure, processing and reading have been specifically validated.

Equipment Design↗
PubMed1996

A new approach to labeling cells with technetium-99m, Part II. Evaluation of radiolabeled human-lymphocyte immune functions.

Technetium-99m-modified polylysine (MPL) is a mild and efficient method for cell labeling that is easily applicable to human lymphocytes. 99mTc-MPL uptake is maximal in 40 min at room temperature. Cell labeling efficiency (from 60 to 80%) increases with rising concentrations of cells and labeling agent. In vitro stability of 99mTc-MPL on lymphocytes incubated in serum at 37 degrees C is high. Microautoradiography indicates that 99mTc-MPL is equally distributed within the cells. The radiolabeling procedure does not alter expression of surface receptors involved in T lymphocyte effector functions, adhesion function, cytolytic activity or proliferative response to IL-2.

Antibodies, Monoclonal↗
PubMed1996

A new approach to labeling cells with technetium-99m, Part I. Preparation of modified polylysine and in vitro cell labeling.

A method for labeling cells with technetium-99m via hydrophilic, polycationic poly D-lysine modified by N-acetyl homocysteine has been developed. The modified polylysine (MPL) is labeled with 99mTc in > 95% yield and is stable for > 12 h. Maximum cell labeling is achieved by a 1-h incubation at room temperature with isolated leukocytes, granulocytes and peripheral blood mononuclear cells attaining 60-75% 99mTc incorporation, and red blood cells 35%. Ninety-two percent of the label is retained by leukocytes after a 1-h incubation at room temperature in 50% serum. The cell uptake of 99mTc-MPL is affected by the presence of negatively charged species in the medium; the inhibitory effects of 5% serum or serum albumin can be reversed by increasing the concentration of 99mTc-MPL, while those of heparin are not.

Adult↗
PubMed1996

Synthesis of oligonucleotides labelled with 2,4-dinitrophenyl groups at thymidine sites.

A phosphoramidite has been produced for labelling oligonucleotides with DNP groups at thymidine sites during solid-phase synthesis. The dinitrophenylamino group is attached via a caproamidopropargyl group to the 5-position of uracil. A related DNP-labelling phosphoramidite has been synthesised where the propargyl group is replaced by propyl. Both phosphoramidites have been used to synthesises DNP-labelled oligonucleotides. A related DNP-labelled deoxyuridine triphosphate has also been synthesised. DNP labelled oligonucleotide probes are valuable in diagnostic applications for the antibody-based detection of DNA and RNA.

Chromatography, High Pressure Liquid↗
PubMed1996

Antibody-mediated detection and physical properties of oligonucleotides labelled with multiple internal and terminal 2,4-dinitrophenyl groups.

DNP-labelled phosphoramidites have been used to synthesis oligonucleotides with multiple DNP reporter groups. The antibody-mediated detection and the stability of duplexes formed by these labelled oligonucleotides have been studied. A DNP-labelled deoxyuridine triphosphate has also been used to enzymatically incorporate DNP-labels into DNA via the polymerase chain reaction. The use of DNP-labelled primers in the PCR has also been investigated.

Antibodies↗
PubMed1994

Two-base DNA hairpin-loop structures in vivo.

In vitro studies have revealed that DNA hairpin-loops usually contain four unpaired bases. However, a small subset of sequences can form two-base loops. We have previously described an in vivo assay that is sensitive to tight loop formation and have set out to test whether DNA sequences known to form two-base loops in vitro also form tight loops in vivo. It is shown that the sequences 5'dCNNG and 5'dTNNA behave as predicted if they favour two-base loop formation in vivo, a result that is consistent with previously described in vitro studies. The ability of specific DNA sequences to form tight loops in vivo has implications for their potential to form transient structures involved in gene regulation, recombination and mutagenesis.

Bacteriophage lambda↗
PubMed1994

Mitochondrial localization and characterization of 99Tc-SESTAMIBI in heart cells by electron probe X-ray microanalysis and 99Tc-NMR spectroscopy.

As the development of targeted intracellular magnetic resonance contrast agents proceeds, techniques for the quantitative analysis of the subcellular compartmentation and characterization of metallopharmaceuticals must also advance. To this end, the subcellular distribution and chemical state of hexakis (2-methoxyisobutyl isonitrile) technetium-99 (99Tc-SESTAMIBI), the ground state of the organotechnetium radiopharmaceutical used for the noninvasive evaluation of myocardial perfusion and viability by scintigraphy, has been determined by a novel application of electron probe X-ray microanalysis (EPXMA) and 99Tc-NMR spectroscopy. In cryopreserved cultured chick heart cells equilibrated in 36 microM 99Tc-SESTAMIBI, EPXMA imaging of mitochondria yielded a respiratory uncoupler-sensitive characteristic 99Tc X-ray peak representing 32.0 +/- 2.9 nmoles Tc/mg dry weight, while EPXMA of cytoplasm or nucleus showed no peak significantly greater than the threshold detectability limit of approximately 1 nmole/mg dry weight. Technetium-99 NMR spectroscopy of heart cells equilibrated with 99Tc-SESTAMIBI showed a single peak at -45.5 ppm with no evidence of significant line broadening or chemical shift compared to aqueous chemical standards, indicating that the majority of the complex exists unbound within the mitochondrial matrix. These data quantitatively demonstrate the localization of this lipophilic cationic organometallic complex within mitochondria in situ, consistent with a sequestration mechanism dependent on membrane potentials. Furthermore, this study establishes the general feasibility of combined EPXMA and NMR spectroscopy for the direct subcellular localization and characterization of metallopharmaceuticals, techniques that are readily applicable to MR contrast agents.

Animals↗