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Can GOLD Stage 0 provide information of prognostic value in chronic obstructive pulmonary disease?

In the recently published guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) for chronic obstructive pulmonary disease (COPD), the staging system included a Stage 0 for subjects without airways obstruction but with respiratory symptoms, denoting these subjects "at risk" for COPD. Our aim was to validate this staging approach using data from three surveys in The Copenhagen City Heart Study, in which a sample of the general population was examined at baseline and in which, after 5 and 15 years, spirometry was performed at all surveys. Criteria for GOLD Stage 0 was fulfilled by 5.8% of the total adult population and 7.2% of smokers. After 5 and 15 years, 13.2 and 20.5%, respectively, of smokers with GOLD Stage 0 had developed COPD fulfilling criteria for GOLD Stage 1 or worse. This was the case for 11.6 and 18.5%, respectively, of smokers without respiratory symptoms. Further analyses using multivariate logistic regression analysis confirmed that GOLD Stage 0 was not identifying subsequent airways obstruction. When analyzing FEV(1) decline, Stage 0 carried a risk of excess decline. GOLD Stage 0 was not a stable feature, which may explain the lack of predictive value. In the Western world, smoking is still in itself the most important indicator of risk of COPD, and alternative markers of susceptibility in the population must be investigated.

Adult↗

Nondestructive analysis of silver in gold foil using synchrotron radiation X-ray fluorescence spectrometry.

Small particles of gold foil detached from an indoor decoration might be important evidence to associate a suspect with a crime scene. We have investigated the application of elemental analysis using synchrotron radiation X-ray fluorescence spectrometry to discriminate small particles of gold foil. Eight kinds of gold foil samples collected in Japan were used in the experiments. As a result of synchrotron radiation X-ray fluorescence spectrometry, only two elements, gold and silver, were detected from all gold foil samples. The intensity ratios of AgKalpha/AuLalpha showed good correlation with the content ratios of Ag/Au. The variation of intensity ratio within a same sample was sufficiently small compared with those of different samples. Therefore the comparison of this intensity ratio can be an effective method to discriminate small particles originating from different types of gold foil.

Journal Article↗

Double-staining methods at the ultrastructural level applying colloidal gold conjugates.

Several double gold-labeling methods have been reviewed, and our own results of applying some of these methods have been included. Of the six double-staining methods tested, four gave satisfactory results (indirect double immunogold staining method, two-face protein A-gold staining method, two-face amplified protein A-gold staining method, and formaldehyde blockade protein A-gold staining method). The other two techniques (sequential double protein A-gold staining method and formaldehyde blockade amplified protein A-gold staining method) showed cross-reaction between the first and second staining sequence.

Adenoma↗

Methotrexate, hydroxychloroquine, and intramuscular gold in rheumatoid arthritis: relative area under the curve effectiveness and sequence effects.

OBJECTIVE: The use of disease modifying antirheumatic drugs (DMARD) for rheumatoid arthritis (RA) is predicated on the expected value of the treatment course. Most clinical data are generalized from randomized controlled trials (RCT), which may result in estimates that are discordant with clinical experience and cannot address the effects of sequence of drugs. We computed estimates of relative DMARD effectiveness from a large observational database using area under the curve (AUC) data. METHODS: We examined data collected over a 20 year period on 1160 patients who were followed at the Wichita Arthritis Center. We utilized Health Assessment Questionnaire (HAQ) disability index data to quantify the effect of methotrexate (MTX), hydroxychloroquine (HCQ), and injectable gold (gold) on subsequent patient outcome. Using an AUC analysis, we compared length of treatment course, total disability averted, annual disability averted, and percentage of possible disability averted across drugs, and examined differences between first courses of therapy in DMARD naive patients and subsequent courses of the same and different DMARD in patients. RESULTS: Patients treated with MTX, HCQ, and gold improved at a rate of -0.33, -0.18 and -0.38 annualized HAQ area units, respectively. Since duration taking drug was greatest for MTX, then HCQ, then gold, the cumulative improvement was greatest with MTX (-1.07) versus gold (-0.74) versus HCQ (-0.47) in disability unit years. All 3 drugs were better cumulatively with earlier disease (MTX-1.74 for < 1 yr vs -0.95 for > 1 yr; HCQ -0.68 vs -0.43; gold -1.71 vs -0.49). A second trial of the same drug was far less effective than the first course. On a percentage of possible improvement basis, these drugs were nearly equal since HCQ is given to less severely affected patients. CONCLUSION: MTX is the most effective DMARD of these 3 because of the length the therapeutic segment. In terms of disability averted, none of the agents decrease disability by more than 25% of the theoretically possible improvement. We documented that effectiveness of RA treatment is a function of drug sequence, duration of disease, whether it is a first or second course, and severity of disease. None of these clinically relevant observations have emerged from clinical trials. These methodologic approaches provide important quantitative comparative data and will be useful in further assessment of the relative effectiveness of present and future DMARD.

Antirheumatic Agents↗

[Lichenoid eruption induced by gold salts. An autonomous eruption].

INTRODUCTION: We report a severe lichenoid drug eruption due to gold salts which relapsed 8 months after the cessation of chrysotherapy. CASE REPORT: A 56 year old man, 3 months after the beginning of a gold sodium propanol sulfonate therapy, developed a polymorphous eruption with violin papules on the trunk, eczematous lesions on the limbs and erosive stomatitis. Gold salts were definitively withdrawn. We saw the patient four months after gold therapy cessation: the eruption remained and diagnosis of severe drug cutaneo-mucous lichenoid eruption was done. We saw thereafter the patient again, 8 months after gold therapy cessation: the eruption had relapsed, more intense. DISCUSSION: We suggest that lichenoid eruption, first caused by gold salts, has become autonomous.

Antirheumatic Agents↗

Mucocutaneous reactions to gold: a prospective study of 74 patients with rheumatoid arthritis.

OBJECTIVE: To describe causality, morphology, course, and risk factors of mucocutaneous reactions to gold. METHODS: A prospective study of 74 patients with rheumatoid arthritis starting with gold thioglucose. RESULTS: Thirty-nine patients experienced an episode of gold dermatitis. Sixteen patients continued gold treatment. The estimated treatment withdrawal at 1 year was 26%. The clinical picture was variable and nonspecific. Gold dermatitis was associated with HLA-B35 and disease duration. CONCLUSION: Mucocutaneous reactions to gold are nonspecific, therefore a causality assessment is necessary. Incidence is high, but treatment can often be continued with dose reduction and local steroids. The predictive value of risk factors is low.

Adolescent↗

[Cutaneous reactions to gold salts].

Gold salts are used for rheumatoid arthritis, and also in resistant corticosteroid dermatoses such as pemphigus. Gold salts inhibit the expression of endothelial cell adhesion molecules, but activity varies from one molecule to another; thiomalate alone gives the same effect. Patients given gold salts have as high risk of cutaneous reactions, and a provisional diagnosis of "gold dermatisis" is insufficient. The mechanisms of cutaneous reactions are unknown and vary according to the molecules. Smokers, HLA Bw35 patients and perhaps atopic states are more prone to gold drug reaction. Inflammation at the site of injections is frequent but with no consequence. Accumulation (chrysiasis) may be observed with long-term treatment. The main problem is its diagnosis as it may mimic numerous dermatoses. Immunological adverse events are the most frequently encountered. Pruritus is frequently observed, more often with oral salts. Exanthemas are common and may disclose an associated visceral disease. Drug hypersensitivity is rare, but severe. All these types necessitate drug interruption although prescription has been continued after development of pityriasis rosea-like and eczematous eruptions in some series without worsening. Lichenoid eruptions require withdrawal, but the skin disease may continue. Oral presentation is frequent, either as a taste abnormality, or as stomatitis. Contact dermatitis may flare in patients sensitized to gold. Rare non-immunological skin diseases have been also observed. Careful dermatological assessment correlated with an imputability method and search of visceral side-effects could lead to a better choice for the patient. Skin tests are not reliable.

Animals↗

Auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. Cooperative systematic studies of rheumatic diseases.

Two hundred eight patients were studied in a prospective, controlled, double-blind multicenter trial comparing auranofin (AUR), gold sodium thiomalate (GST), and placebo. One hundred sixty-one patients completed at least 20 weeks of therapy. Response to a variety of measures of efficacy was generally modest for both gold treatment groups although improvement was continuing in both groups at the end of the study. There was statistically significant improvement with both gold preparations compared to placebo for the number of tender joints, the joint tenderness score, and physician assessment of disease severity. GST was also significantly better than placebo for the joint swelling score. GST demonstrated more improvement in patients with anemia and thrombocytosis compared to the other treatment groups and both gold preparations were superior to placebo in improvement of an elevated erythrocyte sedimentation rate. Twenty-seven percent of patients on GST were withdrawn from the study for adverse drug reaction with rash and stomatitis being the predominant cause. Only 6% of patients on AUR were withdrawn for untoward drug effect. The time of onset of the adverse reactions is discussed. The two gold preparations were similar in efficacy although AUR was better tolerated.

Anti-Inflammatory Agents↗

Transplacental transport of gold in rats exposed to sodium aurothiomalate.

The ultrastructural localization of gold in yolk sacs and fetuses from rats exposed to sodium aurothiomalate (Myocrisin, 25 mg/kg intraperitoneally) was examined by a photochemical technique. Gold was found in epithelial cells of the yolk sac and in hepatocytes of the fetuses. Ultrastructurally, gold was located in lysosome-like bodies. Gold was not detected in the kidney or the central nervous system of the fetuses. Maternal liver and kidney were included as controls for efficacy of gold treatment.

Animals↗

Localization of gold in the anterior pituitary gland of rats exposed to sodium aurothiomalate.

The ultrastructural localization of gold in the anterior pituitary of rats injected intraperitoneally with sodium aurothiomalate has been demonstrated using a histochemical technique that visualizes minute traces of gold. Gold was located intracellularly within lysosome-like bodies of marginal layer cells, follicular cells, and thyrotrophs. Gold was not seen within secretion granules. The possible mechanism by which gold is taken up into the cells is discussed.

Animals↗

Determination of gold-based antiarthritis drugs and their metabolites in urine by reversed-phase ion-pair chromatography with ICP-MS detection.

A sensitive method for the determination of gold-based drugs auranofin, myochrysine, and their metabolites has been developed. These gold-containing compounds were separated by reversed-phase ion-pair chromatography with tetrabutylammonium chloride as the ion-pairing agent. Gold-specific on-line detection utilized inductively coupled plasma mass spectrometry (ICP-MS). The separation conditions of pH, methanol content, concentration of the ion-pairing agent and ionic strength have been investigated. The detection limit for auranofin, the last peak in the chromatogram, was 0.3 ng. These methods were applied to the analysis of gold-containing species in urine from arthritis patients on auranofin, myochrysine or solganol therapy. The recovery of the total gold-containing species from urine was greater than 90%. Dicyanogold(I) anion, [Au(CN)2]-, was detected in the urine of several patients.

Auranofin↗

Water-dispersible tryptophan-protected gold nanoparticles prepared by the spontaneous reduction of aqueous chloroaurate ions by the amino acid.

The synthesis of water-dispersible amino-acid-protected gold nanoparticles by the spontaneous reduction of aqueous chloroaurate ions by tryptophan is described. Water-dispersible gold nanoparticles may also be obtained by the sequential synthesis of the gold nanoparticles by borohydride reduction of chloroauric acid followed by capping with tryptophan. Comparison of the proton NMR spectroscopic signatures from the tryptophan-protected gold nanoparticles obtained by the two processes indicated that the indole group in tryptophan is responsible for reduction of the aqueous chloroaurate ions. The reduction of the metal ions is accompanied by oxidative polymerization of the indole group of the tryptophan molecules and, consequently, some degree of cross-linking of the gold nanoparticles.

Amino Acids↗

THE EFFECT OF HYPERGLYCEMIA ON HYPOTHALAMIC GOLD UPTAKE AND HYPERPHAGIA IN GOLDTHIOGLUCOSE-TREATED MICE.

The accumulation of gold in the hypothalamus and the development of hyperphagia and obesity were studied in mice given a single intravenous injection of goldthioglucose at various levels of blood glucose concentration. It was found that the glucose concentration prevailing at the time of goldthioglucose injection was correlated directly with the level of free and bound goldthioglucose in the blood 3 minutes later, with the hypothalamic uptake of gold, with the extent of the hypothalamic lesion, and with the severity of the subsequent hyperphagia and obesity. Hyperglycemia was associated with an increased gold deposition throughout the brain. A gold content of 88 +/- 12 microg/mg wet tissue in the hypothalamus of fasted animals was associated with clearcut lesions in all animals studied, whereas a similar gold content in the control brain lobes of hyperglycemic animals was not associated with lesions in any animal. This finding indicates that some regions in the brain (e.g. the ventral hypothalamus) are more susceptible than others to damage by goldthioglucose.

Animals↗

Histochemical characteristics of fat-storing cells in alcoholic liver disease: a study by the gold chloride method using needle biopsy specimens of the liver.

To evaluate the relationship between fat-storing cells and fibrosis of the liver in alcoholic liver disease, the characteristics of fat-storing cells were studied by light microscopy with a modification of Kupffer's gold chloride method. Liver biopsy specimens were obtained at laparoscopy with a Trucut needle from 59 patients with alcoholic liver disease, 10 with no hepatic fibrosis, 18 with mild fibrosis, 18 with moderate fibrosis, and 13 with liver cirrhosis. These specimens were divided into three classes (weak, moderate, and strong) with respect to the response of fat-storing cells to the gold chloride reaction, which indicates the amount of vitamin A contained in fat-storing cells. It was found that in alcoholic liver disease the gold chloride reaction became weaker as hepatic fibrosis progressed (P less than 0.001). By contrast, no significant association was observed between the gold chloride reaction and the degree of hepatic fibrosis in 74 specimens from patients with nonalcoholic liver disease. These results show that in alcoholic liver disease hepatic fibrosis is characterized histochemically by the reduced response of fat-storing cells to the gold chloride reaction. The role of the change in fat-storing cells in alcoholic liver disease remains to be elucidated.

Biopsy, Needle↗

Gold sodium thiomalate (GTM) induces hypersensitivity to thiomalate, the thiol carrier of GTM.

A case of the gold sodium thiomalate (GTM)-induced eruptions with thiomalate (TM) hypersensitivity was reported. A 61-year-old Japanese woman developed lichenoid and seborrheic dermatitis (SD)-like eruptions with alopetia, when the total dosage of GTM administered for rheumatoid arthritis became 110 mg. The eruptions slowly disappeared with pigmentation after discontinuance of the GTM therapy, and the resumption resulted in the development of similar eruptions. She showed a positive reaction to GTM in an intradermal test. She also showed a positive response to TM, which is the thiol carrier of GTM, in the patch test, but a negative one to metallic gold. After administration of auranofin (AF), she also developed the SD-like eruptions with hypersensitivity to metallic gold as well as AF on patch testing, but did not develop the lichenoid ones. Our animal experiments revealed an almost complete cross reaction between GTM and TM, but only a partial one between GTM and aurothioglucose, which have dissmilar structures in the carrier part for gold. Probable roles of hypersensitivity to TM and metallic gold, which are metabolites of GTM, were discussed, respectively, in the genesis of the GTM-induced lichenoid eruptions and the AF-induced SD-like eruptions.

Animals↗

Problems in the production and use of 5 nm avidin-gold colloids.

Over the past 5 years we have encountered several problems in the production and use of 5 nm avidin-gold colloids for markers in electron microscopy. These problems include flocculation of colloids during reduction of chloroauric acid, insoluble gold pellets following ultracentrifugation, and non-specific binding of avidin-gold colloids to biological membranes. We are able to avoid these problems by: avoiding the use of crystalline chloroauric acid; succinoylating egg white avidin prior to adsorption on the gold sols; resuspending the pellets following ultracentrifugation in 5 mM phosphate buffer, pH 7.5; and using the avidin-gold colloids within 4 weeks of production.

Animals↗

In vitro lymphocyte reactivity to gold compounds in the diagnosis of contact hypersensitivity.

The use of the lymphocyte transformation test (LTT) in the diagnosis of contact hypersensitivity to gold was studied in 8 patients who had positive patch tests to gold salts, and in 8 control subjects who were negative to such patch tests. Gold sodium thiosulfate and gold chloride were added to cultures of lymphocytes, which were labeled by 3H-thymidine after 96 h. The lymphocyte stimulation index was calculated as the beta-counts in stimulated cultures divided by those in control cultures. The index was statistically significantly higher for the patient group (p=0.005-0.04) than for the control group. Levels of interferon-gamma (IFN-gamma) were determined for the supernatants of the lymphocyte cultures. An index IFN-gamma, which is defined as the level of IFN-gamma in stimulated cultures divided by that in control cultures, was statistically significantly higher for the patient group (p=0.01-0.006). The LTT stimulation index showed specificity and sensitivity between 67 and 80%, the respective values for Index IFN-gamma being between 73 and 100% when the patch test was used as a reference method. Evaluation of lymphocyte reactivity might be of future interest in the diagnosis of allergic reactions to gold if the sensitivity and specificity can be improved.

Adult↗

Localization of gold in synovial membrane of rheumatoid arthritis treated with sodium aurothiomalate. Studies by electron microscope and electron probe x-ray microanalysis.

The localization of gold in the synovial membrane of rheumatoid arthritis patients treated with sodium aurothiomalate was examined and quantitative analysis of epon-embedded sections was carried out with a wavelength dispersive x-ray microanalyser. Gold was only detected in the lysosomes of synovial lining type A cells and subsynovial mononuclear cells in the form of filamentous deposits and highly electron-dense granules, the latter being few in number. The concentration of gold within the lysosomes containing the characteristic deposits and granules was equivalent to that in epon-embedded standard specimens of freeze-dried albumin in which 2-0-87-4 mg/ml of gold was included. In addition, sulphur was detected in the lysosomes containing the filamentous deposits, but the S/Au x-ray signal ratio was not equal to that detected in sodium aurothiomalate. The significance of the coexistence of gold with sulphur in lysosomes is discussed.

Aged↗