Prospective randomized controlled trials: when the gold in the gold standard isn't pure.
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The term evidence-based practice is not new. For over twenty years the debate has been ongoing about how to make it happen. To practice within an evidence base, practitioners must determine if the evidence available is relevant for the particular patient (DiCenso et al 1998). This article aims to contextualise, clarify and explore the meaning of evidence-based practice for perioperative practitioners and, through introducing two models, identify and categorise sources of evidence to base practice on.
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The interactions of certain gold(I) and gold(III) complexes with isolated plasmid pBR322 DNA were defined and compared to those of cis-diamminedichloroplatinum(II), CDDP, using an agarose gel electrophoresis assay. Trichloro(pyridine)gold(III) appeared to bind to DNA as evidenced by its ability to produce dose-dependent changes in the electrophoretic mobilities of closed circular, supercoiled, closed circular, relaxed, and open circular plasmid DNAs. These effects suggest that the gold containing complex induces conformational changes in the plasmid as a result of the compound binding to the DNA and the subsequent unwinding of the double helix and shorting of the DNA. Auranofin [(2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S)-triethyl phosphine gold(I)] did not appear to interact with DNA under any conditions. However, its analog chloro(triethylphosphine) gold(I) interacted with DNA at pH 9.5 in borate buffer and produced electrophoretic mobility changes in pBR322 DNA which were different from those produced by the gold(III) complexes that were evaluated. Binding of chloro(triethylphosphine) gold(I) was inhibited by the co-addition of the thiosugar portion of auranofin suggesting preferential binding of the gold moiety to thiosugar, which results in the production of auranofin (or a sugar containing) gold complex and inhibition of gold binding to DNA. The interactions of a number of gold compounds with DNA were also evidenced by their abilities to inhibit the binding of ethidium bromide to DNA. The results from these studies indicate that: gold containing complexes can bind to, and produce conformational changes in, DNA; gold(I) and gold(III) complexes may interact with DNA via different chemical mechanisms to produce different conformational changes in DNA; and certain coordinating ligands in gold complexes (e.g. Cl, Br and SCN) can be exchanged for binding sites on DNA by gold.
The purpose of this study was to test whether a new retrograde tracer, the B subunit of cholera toxin conjugated to colloidal gold particles (CTB-gold), was taken up and transported by neurons in the central nervous system of the rat. Retrograde transport of CTB-gold was assessed from axon terminals, from damaged nerve fibers, and from axons of passage. For light microscopy, CTB-gold was visualized by silver intensification; for electron microscopy, sections were silver-intensified with or without subsequent gold toning. Retrogradely transported CTB-gold was detected in neurons after survival times of 12 hours to 42 days and appeared as black punctate deposits in perikarya and proximal dendrites at the light microscope level. Ultrastructurally, the deposits were usually associated with lysosomes. Injections of CTB-gold into the caudal ventrolateral medulla or into the lateral horn of the spinal cord gave small well-defined injection sites and resulted in retrograde labelling in medullary neurons in the same locations as similarly placed injections of wheat germ agglutinin-horseradish peroxidase. When injected into the superior cervical ganglion, CTB-gold was transported to nerve cell bodies in the spinal cord, but application of CTB-gold to the cut cervical sympathetic trunk did not label neurons in the spinal cord. Injection of CTB-gold into the nodose ganglion retrogradely labelled neurons in the dorsal motor nucleus of the vagus and the nucleus ambiguus. CTB-gold was not transported anterogradely from injections sites within the medulla. Nerve fibers and cell bodies containing neuropeptides, monoamines, or neurotransmitter-synthesizing enzymes were readily immunostained after silver intensification of retrogradely transported CTB-gold. Immunoreactivity for neuropeptides and enzymes was also demonstrated ultrastructurally after silver intensification and gold toning. These results show that CTB-gold is retrogradely transported from nerve terminals and fibers of passage but not from damaged axons. CTB-gold gives well-localized injection sites and persists in neurons for weeks. Transported CTB-gold is easily visualized and its detection is compatible with light and electron microscopic immunocytochemistry. These properties make CTB-gold a valuable tool for studying the connectivity and neurochemistry of pathways in the central nervous system.
PURPOSE: To determine the efficacy of applying adaptive and off-line setup correction models to bony anatomy and gold fiducial markers implanted in the prostate, relative to daily alignment to skin tattoos and daily on-line corrections of the implanted gold markers. METHODS AND MATERIALS: Ten prostate cancer patients with implanted gold fiducial markers were treated using a daily on-line setup correction protocol. The patients' positions were aligned to skin tattoos and two orthogonal diagnostic digital radiographs were obtained before treatment each day. These radiographs were compared with digitally reconstructed radiographs to obtain the translational setup errors of the bony anatomy and gold markers. The adaptive, no-action-level and shrinking-action-level off-line protocols were retrospectively applied to the bony anatomy to determine the change in the setup errors of the gold markers. The protocols were also applied to the gold markers directly to determine the residual setup errors. RESULTS: The percentage of remaining fractions that the gold markers fell within the adaptive margins constructed with 1.5sigma' (estimated random variation) after 5, 10, and 15 measurement fractions was 74%, 88%, and 93% for the prone patients and 55%, 77%, and 93% for the supine patients, respectively. Using 2sigma', the percentage after 5, 10, and 15 measurements was 85%, 95%, and 97% for the prone patients and 68%, 87%, and 99% for the supine patients, respectively. The average initial three-dimensional (3D) setup error of the gold markers was 0.92 cm for the prone patients and 0.70 cm for the supine patients. Application of the no-action-level protocol to bony anatomy with N(m) = 3 days resulted in significant benefit to 4 of 10 patients, but 3 were significantly worse. The residual average 3D setup error of the gold markers was 1.14 cm and 0.51 cm for the prone and supine patients, respectively. When applied directly to the gold markers with N(m) = 3 days, 5 patients benefited and 3 were significantly worse. The residual 3D error of the gold markers was 1.14 cm and 0.76 cm for the prone and supine patients, respectively. Application of the shrinking-action-level protocol to bony anatomy with an initial action level of 1.0 cm and N(max) = 5 days decreased the residual systematic offset of the gold markers in 2 of 10 patients. The residual average 3D setup error of the gold markers was 1.2 cm and 1.0 cm for the prone and supine patients, respectively. When applied directly to the gold markers with N(max) = 5 days, the residual systematic offset of the gold markers decreased in 6 of 10 patients (0.84 cm and 0.67 cm for the prone and supine patients, respectively). In general, between 3 and 5 of the 10 patients showed significant decreases in setup errors with the application of these off-line protocols, and the remaining patients showed no significant improvement or showed significantly larger setup errors, as determined by the residual error of the gold markers. CONCLUSION: Changes in a prostate cancer patient's systematic and random setup characteristics during the course of therapy often violate the gaussian assumptions of adaptive and off-line correction models. Thus, off-line setup correction procedures, especially those directed at prostate localization using markers, will result in limited benefit to a minority of patients. The relative benefit of on-line localization is still potentially significant if the intrafraction motion is relatively small.
The pharmacokinetics of intramuscular and oral gold compounds differ widely. Aurothioglucose and gold sodium thiomalate absorption is complete; 25% of auranofin (AF) is absorbed. Blood gold concentrations with conventional parenteral treatment generally peak between 600-800 microgram/dl the day of injection and decline gradually to about 300 micrograms/dl 7 days later. Levels range between 30 and 100 micrograms/dl, using 2-9 mg/d AF, and show little variation. A smaller percentage of gold is found in the cellular fraction of blood with I.M. than with oral gold. The blood half-life is approximately 6 days with gold sodium thiomalate, and 21 days with AF. Forty percent of the administered dose of injectable gold is excreted; depending upon dosage, 75-100% of oral gold is recovered in excreta, which is a combination of unabsorbed and excreted gold. Nearly 70% of parenteral gold is excreted in the urine and 30% in feces, while only 5% of AF is in urine and 95% in feces. The amount of gold retained following intravenous 195Au-labelled gold sodium thiomalate is 43% at 60 days and 25% at 250 days, but only 15% with oral radiolabeled AF 10 days after ingestion. Synovial fluid gold levels are much higher with parenteral than with oral gold but the blood-to-synovial fluid ratio is similar. Skin gold concentrations rise steadily with injectable but not oral treatment, but hair and nail accumulation is insignificant. Corneal, lens, and skin chrysiasis may develop with parenteral therapy, but has not been recognized with AF.
The production of hydrogen containing very low levels of carbon monoxide for use in polymer electrolyte fuel cells requires the development of catalysts that show very high activity at low temperatures where the equilibrium for the removal of carbon monoxide using the water-gas shift reaction is favourable. It has been claimed that oxide-supported gold catalysts have the required high activity but there is considerable uncertainty in the literature about the feasibility of using these catalysts under real conditions. By comparing the activity of gold catalysts with that of platinum catalysts it is shown that well-prepared gold catalysts are significantly more active than the corresponding platinum catalysts. However, the method of preparation and pre-treatment of the gold catalysts is critical and activity variations of several orders of magnitude can be observed depending on the methods chosen. It is shown that an intimate contact between gold and the oxide support is important and any preparative procedure that does not generate such an interaction, or any subsequent treatment that can destroy such an interaction, may result in catalysts with low activity. The oxidation state and structure of active gold catalysts for the water-gas shift reaction is shown to comprise gold primarily in a zerovalent metallic state but in intimate contact with the support. This close contact between small metallic gold particles and the support may result in the "atoms" at the point of contact having a net charge (most probably cationic) but the high activity is associated with the presence of metallic gold. Both in situ XPS and XANES appear unequivocal on this point and this conclusion is consistent with similar measurements on gold catalysts even when used for CO oxidation. In situ EXAFS measurements under water gas shift conditions show that the active form of gold is a small gold cluster in intimate contact with the oxide support. The importance of the gold/oxide interface is indicated but the possible role of special sites (e.g., edge sites) on the gold clusters cannot be excluded. These may be important for CO oxidation but the fact that water has to be activated in the water gas shift reaction may point towards a more dominant role for the interfacial sites. The mechanism of the water gas shift reaction on gold and other low temperature catalysts has been widely investigated but little agreement exists. However, it is shown that a single "universal" model is consistent with much of the experimental literature. In this, it is proposed that the dominant surface intermediate is a function of reaction conditions. For example, as the temperature is increased the dominant species changes from a carbonate or carboxylate species, to a formate species and eventually at high temperatures to a mechanism that is characteristic of a redox process. Similar changes in the dominant intermediate are observed with changes in the gas composition. Overall, it is shown that reported variations in the kinetics, structure and reaction mechanism for the water gas shift reaction on gold catalysts can now be understood and rationalised.