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October 7, 2005
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June 1, 2005
Abstract
Although prostate-specific antigen (PSA), or human kallikrein 3, is the most valuable tool available for the diagnosis and management of prostate cancer, as currently used it is insufficiently sensitive and specific for early detection or staging of the malignancy. Many new concepts have been introduced in order to optimize the clinical use of PSA measurements, but each one has its own drawbacks. The molecular forms of PSA, especially the free PSA, seem to be useful for the detection of prostate cancer in men with PSA concentrations falling in the 4–10 μg/l range. New molecular techniques, such as reverse transcriptase polymerase chain reaction for the detection of minimal amounts of PSA messenger RNA and prostate-specific membrane antigen, offer new promise for the prognosis and possibly staging of prostate cancer. On the other hand, human kallikrein 2, a serine protease closely related to PSA that is also expressed predominantly in the prostate, may be a new adjuvant marker for prostate cancer. As for its biological functions, PSA can no longer be regarded as a specific prostate molecule associated mainly with semen liquefaction when it has a possible role as a prognostic indicator in female breast cancer. The biological role of PSA in normal tissues and tumors may be much more complex than previously thought and requires further investigation.
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June 1, 2005
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Inconsistencies in the way physicians perceive and handle identical laboratory results have untoward effects on morbidity, mortality and cost of medical care. In this context, the selection of suitable tests to answer definite clinical questions, and the manner in which laboratory results are presented have great impact on the action taken by the clinician. This review addresses preferred methods to improve laboratory test selection, and examines methods that more effectively convey laboratory results to clinicians. It is anticipated that refined selection of tests, and presentation of the test results in a configuration that is easily perceived by the clinician, will facilitate interpretation of laboratory reports. Furthermore, any measures that promote the application of laboratory information in medical practice improve economics at the laboratory-clinical interface. The presently described methods to optimize test selection and interpretation are: likelihood ratios to provide estimates of the ability of a test to identify a clinical condition; consensus-and discriminant function-analysis to estimate the performance of tests in diagnosing a particular disease or condition; receiver operating characteristic (ROC) curves to assess discrimination capabilities. The methods which improve test result perception are expression of results as multiples of the upper normal limit, utilizing signal strength to provide prognostic probabilities, and presentation of results in graphic forms that display mutually interrelated functions, with a specific cluster of results being highly suggestive of a given condition. In addition, we discuss application of expert systems to provide rules based on knowledge and experience to analyze results of tests and suggest diagnosis and action, including additional tests when required. It is anticipated that judicious utilization of laboratory services by application of the reviewed methodologies will help to achieve medically justified responses at a lower cost and help to achieve a proper balance between cost of tests and their clinical usefulness.
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June 1, 2005
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The haptoglobin (Hp) 2–1 and 2–2 phenotypes have been shown to agglutinate Streptococcus pyogenes carrying the membrane antigen T4. In this study, the growth rate of two strains of Streptococcus pyogenes (T1 and T4) in human serum was compared among haptoglobin phenotypes in vitro . During incubation for 16 hours in serum of different haptoglobin types, only Hp 2–1 and Hp 2–2 sera showed an inhibitory effect on growth, Hp 2–2 being 1.85 times more potent than Hp 2–1. Growth of Streptococcus pyogenes T4 negatively correlated with the serum concentration of Hp 2–1 (r = −0.908) and Hp 2–2 (r = −0.953). Haptoglobin-depleted serum had no inhibitory effect on bacterial growth. Addition of haemoglobin and ferric citrate to the serum accelerated the growth of Streptococcus pyogenes T4 (P < 0.05) but not in Hp 2–2 serum. Haptoglobin types 2–1 and 2–2 can be regarded as inhibitors of Streptococcus pyogenes growth in vitro . These data point towards a potential protective role of Hp 2–2 in Streptococcus pyogenes infection in vivo , independently of iron uptake.
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June 1, 2005
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Membrane binding of urokinase type plasminogen activator (u-PA) is thought to play a pivotal role in connective tissue remodeling and invasive processes. We compare the ability of different matrix-metalloproteinases involved in connective tissue turnover to cleave pro-urokinase type plasminogen activator between the catalytic domain and the receptor binding part to investigate a potential role for matrix-metalloproteinases in the regulation of membrane-associated proteolytic activity. We employed several forms of human stromelysin-1 (full length, C-truncated, and recombinant catalytic domain), rabbit C-truncated stromelysin-1, the human gelatinases A and B and the human catalytic domain of neutrophil collagenase. The gelatinases and the collagenase did not separate the receptor binding domain of pro-urokinase type plasminogen activator from the catalytic domain, whereas all stromelysin-1 forms cleaved the glutamic acid 143-leucine 144 bond of pro-urokinase type plasminogen activator. This reaction could be inhibited by specific inhibitors of matrix metalloproteinases and was not affected by inhibitors of serine proteinases. The M r 31000 cleavage product with leucine 144 as N-terminus displayed no proteolytic activity towards the prourokinase type plasminogen activator substrate pyro-Glu-Gly-Arg-pNA-HCl (S2444), but it could be activated by an additional treatment with plasmin. Comparison between full length stromelysin-1 and its C-truncated forms, showed that both exhibited the same cleavage properties towards pro-urokinase type plasminogen activator. Thus, the cleavage of pro-urokinase type plasminogen activator by stromelysin-1 is not influenced by the presence or absence of the C-terminal domain. The recombinant catalytic domain of MMP-3 generated pro-urokinase type plasminogen activator, whereas incubation of pro-urokinase type plasminogen activator with the native forms of human or rabbit stromelysin-1 led to a moderate activation of pro-uPA due to an additional cleavage that is catalyzed by a serine proteinase.
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June 1, 2005
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We have applied a method using the fluorigenic substrate benzoloxycarbonyl-Arg-Arg-amido-4-methylcoumarin to measure cathepsin B, a thiol proteinase, in homogenates of human leukocytes. Data like pH optimum, stability, influence of thiol groups and effects of thiol proteinase inhibitors, lack of binding to Concanavalin A and lack of contribution to the fluorescence by other cathepsins indicate that cathepsin B is the enzyme masured. Although the activity of the enzyme was linear with respect to time at all protein concentrations measured, there was an acceptable 10% deviation of the enzyme activity from linearity as a function of protein concentration. The enzyme in the homogenate was stable at 0 °C but was rapidly inactivated at 50 °C and above pH 6.5–7. Very limited activation on the one hand and variable inhibition on the other was seen by reagents containing thiol groups and thiol proteinase inhibitors respectively. Latency (60% of the enzyme activity) indicates a probable subcellular lysosomal localization. There is no affinity towards the lectin Concanavalin A and the K m value was around 1 mmol/l. Normal enzyme activity values in leukocyte homogenates were determined.
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June 1, 2005
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To evaluate the pattern of plasma cyclic adenosine 3′,5‵-monophosphate, cyclic guanosine 3‵,5‵-monophosphate, atrial natriuretic factor and glucagon levels in different stages of chronic liver diseases, we measured these variables in 20 normal subjects, 25 patients with genetic hemochromatosis, associated with liver cirrhosis in 19 cases and not in six, eight patients with compensated and 15 with decompensated alcoholic or posthepatitic cirrhosis, and 12 with hepatocellular carcinoma. All variables were within the normal range in non-cirrhotic hemochromatotic patients. Cyclic adenosine 3‵,5‵-monophosphate levels were within the normal range (9.5–15.7 nmol/l) in hemochromatotic cirrhotics and elevated in other patients. Cyclic guanosine 3‵,5‵-monophosphate, atrial natriuretic factor and glucagon were above the normal ranges (1.92–5.91 nmol/l, 8.8–62.7 ng/l, and 39–165 ng/l, respectively) in most patients with cirrhosis both with and without hemochromatosis and in most individuals with hepatocellular carcinoma. Cyclic guanosine 3‵,5‵-monophosphate correlated with atrial natriuretic factor in the former groups but not in the latter. These findings indicate that glucagon and atrial natriuretic factor hypersecretion is an early event in cirrhosis, regardless of its etiology. In hepatocellular carcinoma, the underlying cirrhosis may account for most hormonal and metabolic changes although cyclic guanosine 3‵,5‵-monophosphate increases could also be due to the neoplastic process per se .
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June 1, 2005
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In serum, magnesium exists in three fractions: protein-bound, complex-bound and free ionized form. Only the free ionized fraction is biologically active. Until recently, only the measurement of serum total magnesium has been in clinical use. Now, commercially available instruments using new ion-selective electrodes for Mg ++ have made possible the reliable measurement of serum ionized magnesium in clinical practice. For the measurement of serum ionized magnesium we used a magnesium-selective electrode installed in a six-channel electrolyte analyzer. We compared the use of ionized versus total magnesium measurement in 52 patients with intestinal disease, 54 with liver disease, and in 75 healthy control subjects. In the patients with alcoholic liver disease both serum ionized and total magnesium were lower, and in those with inflammatory bowel disease slightly higher than in control subjects. The correlation coefficient between serum ionized and total magnesium was r=0.87 (p<0.001) in the patients, and r=0.75 (p<0.001) in the controls. In the patient group the fraction of ionized magnesium in the total was negatively related to the serum albumin level (r=−0.41, p<0.001). Serum total magnesium was below the reference range in 30 out of 150 measurements, serum ionized magnesium in only 9 out of 150 measurements, respectively. Thus, 21 cases with low total but normal ionized magnesium (two thirds of hypomagnesemia according to serum total magnesium) were false positive. Total magnesium measurement may overestimate the incidence of hypomagnesemia when significant hypoalbuminemia is present. Measurement of serum ionized magnesium instead of total magnesium may therefore be of advantage in evaluating patients with hypoalbuminemia and when hypomagnesemia is expected.
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June 1, 2005
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Several commercial methods have been proposed for lipoprotein(a) (Lp(a)) measurements over the past decades. However, only a few of them appear completely suitable in terms of analytical performance, costs and practicability. We evaluated the analytical performance of a new commercial fully automated immunonephelometric assay for Lp(a) measurements on the IMMAGE ® Immunochemistry System. Mean within- and between-run coefficients of variation were 2.7 % (range 1.2–4.7 %) and 3.8 % (range 1.8–7.9 %), respectively. The linearity of the assay was confirmed up to 102 mg/dl and the deviation from the expected values did not exceed 4% (mean deviation: 1.9%). Moreover, the relative non-linearity was acceptable, ranging from 1.4 % to 1.6 % and hence constantly lower than the 2.5 % upper limit. Since there is no reference method for Lp(a) measurements, 100 routine random serum samples measured by the IMMAGE ® Immunochemistry System immunonephelometric assay were further compared with two other commercial immunonephelometric assays (Array ® LPA immunonephelometric assay and BNA Latex-Enhanced Lp(a) nephelometric assay). Non-parametric regression and relative Spearman's correlation coefficients were satisfactory, ( y = 1.009x−1.38; r = 0.998 IMMAGE ® Immunochemistry System vs. Array LPA and y = 0.922x−0.40; r = 0.989 IMMAGE ® Immunochemistry System vs. Behring Nephelometer Analyzer (BNA) Latex Lp(a) assay). On the basis of the results of the present evaluation we conclude that the analytical performance and the main technical features of the IMMAGE ® Immunochemistry System immunonephelometric assay make it a suitable method for Lp(a) measurement in clinical laboratories.
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June 1, 2005
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As interference from thyroglobulin autoantibodies appears to have been overcome in new commercial thyroglobulin assays by the use of monoclonal antibodies, the need for thyroglobulin recovery tests became uncertain. Sera (n=45) from patients with differentiated thyroid carcinomas were selected on the basis of a thyroglobulin recovery value below 70 % in the Dynotest Tg immunoradiometric assay (Brahms) routinely used in our laboratory. Serum thyroglobulin levels were then measured using three other commercial immunoradiometric assays: thyroglobulin ERIA (Pasteur), HTGK (Sorin) and ELSA HTG (Cis Bio International). Thyroglobulin autoantibodies were measured using the Thyrak assay (Brahms). Although many patients were thyroglobulin antibodies-negative (< 200 U/ml, n=26), most immunoradiometric assays failed to detect thyroglobulin in patients with evidence of recurrence. Low thyroglobulin values associated with low thyroglobulin recovery in thyroglobulin antibodynegative patients appear to be more biologically relevant than a single low thyroglobulin value, which can lead to lack of medical intervention. We conclude that the thyroglobulin recovery test is a prerequisite for the correct interpretation of serum thyroglobulin levels determined with immunoradiometric assays in the follow-up of thyroglobulin autoantibody-negative patients treated for differentiated thyroid carcinomas.
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June 1, 2005
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The effect of thyroid hormones on lipoprotein(a) plasma concentrations and the other parameters of lipoprotein metabolism was studied in 158 patients with thyroid dysfunction and in 37 euthyroid controls (cross-sectional study). Multiple regression analysis revealed that 65.5 % of the variability in lipoprotein(a) levels were predicted by changes in lipoprotein(a) phenotypes (60.5 %), thyrotropin (3.5 %), and age (0.8 %). The lipid parameters, however, showed no significant effect on lipoprotein(a). A subgroup analysis on samples from patients with large lipoprotein(a) isoforms showed that 28% of the variability in lipoprotein(a) concentrations could be explained by changes in thyroid function (19.1 %), age (6.5 %) and triglycerides (3.5 %). Much stronger correlations were found between thyrotropin and total cholesterol, low density lipoprotein cholesterol or apolipoprotein B respectively (R 2 =0.951 for low density lipoprotein cholesterol, R 2 =0.801 for apolipoprotein B). Our data suggest that thyroid hormone is a significant modulator of lipoprotein(a) metabolism. However, different mechanisms are responsible for the change in lipoprotein(a) levels and for the decrease in total-and low density lipoprotein cholesterol levels.
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