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A Davison

Publications and source records attributed to A Davison.

At least 55 records · Page 3Linked to original sources
PubMed1994

In vivo metabolism of the technetium isonitrile complex [Tc(2-ethoxy-2-methyl-1-isocyanopropane)6]+.

Technetium(2-ethoxy-2-methyl-1-isocyanopropane)6+, [Tc-EIBT] is a complex of technetium(I) structurally similar but slightly more lipophilic than the commercial myocardial perfusion agent Cardiolite [Tc-MIBI]. Tc-EIBI exhibits rapid extraction from the blood into heart, liver, kidney and striated muscle and rapid hepatobiliary clearance. In the guinea pig, unlike Tc-MIBI, this compound is almost completely enzymatically metabolized to numerous cationic complexes containing a mixture of ethyl other and hydroxy isonitrile ligands. Substitution of the ethyl other group for a methyl ether produces an agent that shows selective in vivo metabolism and more rapid clearance from the liver.

Animals↗
PubMed1994

The effects of nucleotide sequence changes on DNA secondary structure formation in Escherichia coli are consistent with cruciform extrusion in vivo.

The construction in bacteriophage lambda of a set of long DNA palindromes with paired changes in the central sequence is described. Identical palindrome centers were previously used by others to test the S-type model for cruciform extrusion in vitro. Long DNA palindromes prevent the propagation of carrier phage lambda on a wild-type host, and the sbcC mutation is sufficient to almost fully alleviate this inviability. The plaque areas produced by the palindrome containing phages were compared on an Escherichia coli sbcC lawn. Central sequence changes had a greater effect upon the plaque area than peripheral changes, implying that the residual palindrome-mediated inviability in E. coli sbcC is center-dependent and could be due to the formation of a cruciform structure. The results argue strongly that intrastrand pairing within palindromes is critical in determining their effects in vivo. In addition, the same data suggests that DNA loops in vivo may sometimes contain two bases only.

Bacteriophage lambda↗
PubMed1994

Squamous cell carcinoma in situ involving mesonephric remnants. A potential diagnostic pitfall.

A case of uterine cervical squamous cell carcinoma in situ (CIS) in which there was extensive endocervical glandular involvement was found to have, in addition, a deep-seated squamous epithelial lesion within the cervical stroma. Because of the deep location of this lesion, which was composed of nests of pleomorphic squamous epithelial cells, found at a site not usually occupied by endocervical glands, it was initially thought to be an invasive squamous cell carcinoma (SCC). However, on review it was found that there was CIS in the deep cervical stroma that appeared to involve small tubular structures and dilated ducts that were lined by mucin-free cuboidal epithelial cells. There was no stromal reaction to this lesion. Tubules had a poorly defined lobular arrangement and had intraluminal bright eosinophilic hyaline material. Tubular epithelial cells demonstrated immunohistochemical staining for low-molecular-weight keratin (LMWK) and vimentin but showed no staining for carcinoembryonic antigen (CEA) and high-molecular-weight keratin (HMWK). It was apparent that these tubular structures and ducts were mesonephric remnants and that this lesion represented involvement of mesonephric remnants by CIS. Although involvement of endocervical glands by CIS is well recognized, a similar lesion involving mesonephric remnants has not been previously described. Familiarity with the histological features of these lesions is essential to avoid a misdiagnosis and potential mismanagement.

Carcinoma in Situ↗
PubMed1993

The effects of central asymmetry on the propagation of palindromic DNA in bacteriophage lambda are consistent with cruciform extrusion in vivo.

The propagation of lambda phages carrying long perfect palindromes has been compared with that of phages carrying imperfect palindromes with small regions of central asymmetry. The perfect palindromes confer a more deleterious phenotype than those with central asymmetry and the severity of the phenotype declines with the length of asymmetry in the range from O to 27 base pairs. These results argue that a center-dependent reaction is involved in the phenotypic effects of palindromic DNA sequences, consistent with the idea that cruciform extrusion occurs in vivo.

Bacteriophage lambda↗
PubMed1993

Putative anticarcinogenic actions of carotenoids: nutritional implications.

This review provides an update on nutritional aspects of carotenoids (as distinct from retinoids), with specific relevance to anticarcinogenesis. Critical gaps remain in our knowledge of the nutritional functions of carotenoids despite an overwhelming accumulation of research data in areas tangential to human nutrition. In addition to their roles as precursors of retinol and retinoids, carotenoids have distinct functions of their own in animals and humans. In vitro they are antioxidants with a broad range of potencies. In vivo, they protect porphyrics against sunlight. The evidence for anticarcinogenic actions of beta-carotene in certain specified test situations is persuasive. Nevertheless, despite a large number of studies demonstrating protection by carotenoids, the characteristics that render a given carotenoid effective and the relative efficacy of the individual carotenoids are not known. Moreover, dose-response and pharmacokinetic relationships remain virtually unexplored. Research to uncover mechanisms of protection by carotenoids is, for technical reasons, painfully slow. Epidemiological studies reveal associations but not cause and effect. To explore cause and effect, intervention trials are underway, hampered by the paucity of data regarding optimal choice of carotenoid, dosage, and regimen. The in vitro test systems that would provide this information are not available because the molecular sites relevant to the chemopreventive action of carotenoids are obscure. Each of these problems has a solution, but not a simple one. Until these are resolved, blanket recommendations regarding supplementation will remain problematic. To this point, health authorities have not recommended dietary supplementation with carotenoids. Instead, they recommend increased consumption of yellow and dark green carotenoid-rich vegetables. In the future, an individual at risk for a particular carcinogenic process may be recommended a supplement of the most appropriate anticarcinogen, specific to their individual endowment of genetic and environmental risk factors. This review emphasizes not only what is known but also what is not known. Consequently we identify priorities for research that, if undertaken, will allow such recommendations to be made or discounted with more confidence.

Animal Nutritional Physiological Phenomena↗
PubMed1992

Comparison of neutral and cationic myocardial perfusion agents: characteristics of accumulation in cultured cells.

Uptake and washout kinetics of two new neutral lipophilic technetium-99m-labeled boronic acid adducts of technetium tris(dioxime) (BATO complexes) were studied in monolayers of contractile chick heart cells and compared to the cationic myocardial perfusion agents, 99mTc(CNCH2C(CH3)2OCH3)6+ (Tc-MIBI) and 201Tl+. 99mTcCl(CDOH)2(CDO)(BCH3), where CDO = cyclohexanedione dioxime (CDO-MeB), had a 7-fold greater net accumulation than Tc-MIBI and the most rapid unidirectional washout with a fast initial phase and a slower secondary component. Incubation with cationic membrane transport inhibitors or metabolic inhibitors had little or modest influence, respectively, on uptake of these BATO complexes. Studies with NIH 3T3 fibroblasts indicated that the neutral complexes did not show myocyte specific accumulation.

3T3 Cells↗
PubMed1992

Human pharmacokinetics and radiopharmacological studies of the myocardial perfusion agent: technetium (2-carbomethoxy-2-isocyano-propane)6+.

The myocardial perfusion agent technetium (2-carbomethoxy-2-isocyano-propane)6+ (99mTc-CPI) is unique from other cationic technetium isonitrile complexes in that it exhibits moderate washout from the heart and rapid hepatobiliary clearance in animal models and human volunteers. Dynamic imaging and HPLC analysis were performed in humans and guinea pigs to outline the pharmacological basis of its pharmacokinetics. Enzymatic hydrolysis of the terminal ester groups in blood was found to occur at a moderate rate producing new species that have been shown not to accumulate in heart tissue. However, after extraction by the heart, liver or kidneys, the 99mTc-CPI complex undergoes metabolism at a much slower rate than observed in the blood. Differences in hydrolysis rate and products obtained indicate separate mechanisms of hydrolysis occurring in blood and other organs. It is proposed that the heart washout occurring after hydrolysis produces a neutral compound which is no longer retained by the negative cytosolic and mitochondrial membrane potentials in myocardial tissue.

Adult↗
PubMed1992

Technetium- and rhenium-labeled progestins: synthesis, receptor binding and in vivo distribution of an 11 beta-substituted progestin labeled with technetium-99 and rhenium-186.

In an effort to develop radiopharmaceuticals useful for the diagnostic imaging of steroid receptor-positive breast tumors, we have radiolabeled an analog of the antiprogestin RU486 (mifepristone), modified to incorporate an N2S2 chelate system in the 11 beta-position, with 99Tc, 99mTc, and 186Re. For the 99Tc-labeled analogs (3), a syn pair and two individual antidiastereomers (linker methylene versus metal-oxo, relative to the N2S2 plane) were isolated. In competitive radiometric binding assays, the syn pair (3syn1,2) had affinity for the progesterone receptor that was 25% that of (promegestone) R5020 (or 161% that of progesterone), and the individual anti-diastereomers had affinities of 47% (3anti1) and 7% (3anti2) that of R5020 (or 303% and 45% that of progesterone). The specific-to-nonspecific binding ratio of the 99mTc (4) and 186Re (5) 11 beta-linked syn systems are 75/25 and 54/46, respectively. In vivo, conjugates 4 and 5 showed progesterone receptor-mediated uptake in rat uterus, but also high uptake in non-target tissues, presumably because of the high lipophilicity of the metal complexes. Modified systems may be useful in vivo as receptor-directed agents for diagnostic imaging or treatment of steroid receptor-positive tumors.

Animals↗
PubMed1992

Interspecies variation in biodistribution of technetium (2-carbomethoxy-2-isocyanopropane)6+.

The cationic complex technetium (2-carbomethoxy-2-isocyanopropane)6+ (99mTc-CPI) contains terminal ester groups that were included to provide a pathway for in-vivo metabolism of this compound, thereby enhancing its performance as a myocardial perfusion agent. Biodistribution studies of the compound demonstrated myocardial accumulation in rabbit, guinea pig, and chick, but not in rat and mouse. Radiochemical analysis by HPLC after in-vitro incubation of 99mTc-CPI in blood plasma from the various species confirmed enzymatic hydrolysis to numerous new compounds. Rat and mouse serum produced complete hydrolysis of this agent after incubation for less than 5 sec at 25 degrees C or rates greater than 500 times those observed in human, rabbit, guinea pig and chick serum. Chemical synthesis and isolation of the monohydrolyzed species with subsequent biodistribution studies in guinea pig and rabbit confirmed that this neutral lipophilic complex did not accumulate in heart tissue. It is concluded that varying rates of enzymatic in-vivo hydrolysis produce the interspecies biodistribution differences and may account for the moderate myocardial clearance relative to other isonitrile complexes.

Animals↗
PubMed1990

Uptake of the cation hexakis(2-methoxyisobutylisonitrile)-technetium-99m by human carcinoma cell lines in vitro.

Uptake of the cationic compound hexakis(2-methoxyisobutylisonitrile)-technetium-99m ([99mTc]MIBI) was examined in nine human tumor cell lines. The concentration of [99mTc]MIBI after a 1-h incubation with the compound varies from 5 to 28% of the activity in the external medium. In contrast, normal V79 cells (Chinese hamster lung fibroblasts) and human peripheral blood mononuclear cells exhibit a minimal uptake of less than 2% of the activity in the medium. Kinetic experiments with SW-13 cells indicate a rapid uptake over time (t1/2 of 10 min) until a steady state is approached whose concentration appears directly correlated with the extracellular concentration of [99mTc]MIBI with no evidence of saturation over the range tested (10(-12)-10(-9) M). [99mTc]MIBI is taken up by a temperature dependent process that is restricted to living cells. Microautoradiography demonstrates that [99mTc]MIBI is clustered in the cytoplasm around the nucleus. Given that depolarizing the plasma membrane potential in high K+ buffer results in lowering the uptake of [99mTc]-MIBI and that alteration of the mitochondrial membrane potential with valinomycin or nigericin induces, respectively, a significant decrease or increase of [99mTc]MIBI uptake, we propose that the plasma and mitochondrial membrane potentials play a major role in the uptake. These data suggest that the gamma emitter [99mTc]MIBI exhibits interesting tumor cell interaction characteristics with promise for in vivo tumor imaging.

Autoradiography↗
PubMed1990

Distribution of inhaled 99mtechnetium labelled ultrafine carbon particle aerosol (Technegas) in human lungs.

Using a gamma camera, we quantified the topographical intrapulmonary distribution of inhaled 100 ml boluses of Technegas (TG), an ultrafine dispersion of carbon aggregates labelled with 99mTc, and 133Xenon (Xe) in six seated, normal subjects, inhaling from residual volume (RV) and from within a 1 l volume range above functional residual capacity (FRC) at a flow less than 0.5 l.s-1. Following inspiration of air to total lung capacity (TLC) counts were recorded during a 20 s breathhold. Twenty min after administration of the final TG bolus (TGF) counts were again recorded (TG20). Upper (U), middle (M) and lower (L) zones, as well as central (C) and peripheral (P) regions were identified in each lung. The relative fractional concentration (Fr) of TG and Xe was calculated for all zones after RV and FRC boluses, using counts obtained during Xe equilibration. The U/M or U/L ratios for XeFr did not differ significantly from those for TGFr (paired t-test; p greater than 0.1). The P/C count ratio constitutes a penetration index, which for TG was 1.07 +/- 0.13 (mean +/- SD) that of Xe. After correction for radioactive decay, TG20 counts were no different from TGF counts. The results suggest that the intrapulmonary distribution and penetration of TG in normal lungs is no different from Xe and that stable deposition in the lung periphery makes TG suitable for multiple-view imaging of ventilation distribution.

Adult↗
PubMed1990

Intrapulmonary distribution of 99mtechnetium labelled ultrafine carbon aerosol (Technegas) in severe airflow obstruction.

Technegas (TG), an ultrafine dispersion of carbon aggregates labelled with 99mTechnetium (99mTc), has been recently introduced for clinical imaging of lung ventilation. In 12 selected subjects with severe chronic airflow limitation (FEV1 = 0.89 +/- 0.22; mean +/- SD, l) we have studied the regional intrapulmonary distribution of TG and compared it quantitatively with that of 133Xenon (133Xe). A 133Xe equilibration image was acquired for 10-15 s during a breathhold at total lung capacity (TLC). Six subjects (Group 1) inspired 100 ml boli of TG or 133Xe from functional residual capacity (FRC) and another 6 subjects (Group 2) inspired 1.0 l of labelled gas from FRC followed by air to TLC at a constant flow rate less than 0.5 l.s-1. Lung images were then acquired with the chest position rigorously controlled. From the equilibration image, upper, middle, lower, central and peripheral regions were defined. Relative regional fractional concentrations (RFC) were then calculated using the equilibration image to correct for ventilated lung volume. In addition, in four of the Group 2 subjects, each lung image was divided into multiple regions (12-17 per lung). The RFC were then calculated as above (RFCM). The highest and lowest RFC were not significantly different between 133Xe and TG in either Group 1 or Group 2 subjects. Similarly the RFCM analysis showed no systematic difference between 133Xe and TG. The ratio of peripheral to central RFC constitutes a penetration index which for TG was 0.99 +/- 0.23 that of 133Xe. Our results indicate that even in the presence of severe airflow limitation the radiolabelled tracer TG mimics the regional distribution of a real gas.

Aged↗
PubMed1989

MS: a localized immune disease of the central nervous system.

The precise role of T cells in multiple sclerosis (MS) remains to be defined. No MS-specific antigen has been found. The autoimmune hypothesis for MS rests on immune changes seen in the spinal fluid and brain and on the demonstration, in an experimental animal model, that T cells raised to myelin basic protein transfer demyelination. In this review, Virginia Calder and colleagues focus on recent studies suggesting that in MS, the initial T-cell response occurs within the central nervous system and that the blood poorly reflects this immune activity. This contrasts with the animal model, experimental allergic encephalomyelitis, where the initial immune response is peripheral.

Central Nervous System↗
PubMed1989

Comparative myocardial uptake characteristics of hexakis (alkylisonitrile) technetium(I) complexes. Effect of lipophilicity.

Hexakis (alkylisonitrile) technetium(I) complexes are a new class of cationic, lipophilic myocardial perfusion imaging agents. To further evaluate the effect of lipophilicity on myocardial uptake characteristics, the authors systematically synthesized and tested Tc-isonitrile complexes of varying lipophilicity in both cellular and whole animal systems. In chick heart cells in monolayer culture, cellular plateau level uptake in general correlated with lipophilicity of the complexes (determined by reverse phase high performance liquid chromatography) (r = .71) as well as with scintigraphic intensity of imaged rabbit hearts (r = .91). Exceptions to this trend indicated that additional factors such as size of the complex and form of the terminal alkyl chain branching also may have influenced uptake. The data indicated that neither the lipophilic properties nor the cation charge alone were sufficient to predict myocardial uptake. In addition, intravenous injection of complexes into rabbits showed optimal myocardial images with agents of intermediate lipophilicity. Results indicated that, following intravenous administration, complexes of low lipophilicity yielded suboptimal myocardial images because of low heart cell uptake, whereas complexes of high lipophilicity yielded poor relative myocardial visualization because of excessive binding to additional organs and compartments.

Animals↗