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Abstract
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARα, the first identified PPAR family member, is principally expressed in tissues exhibiting high rates of β-oxidation such as liver, kidney, heart and muscle. PPARγ, on the other hand, is expressed at high levels in adipose tissue. PPARs are activated by dietary fatty acids and eicosanoids, as well as by pharmacological drugs, such as fibrates for PPARα and glitazones for PPARγ. PPARα mediates the hypolipidemic action of fibrates in the treatment of hypertriglyceridemia and hypoalphalipoproteinemia. PPARα is considered a major regulator of intra- and extracellular lipid metabolism. Upon fibrate activation, PPARα down-regulates hepatic apolipoprotein C-III and increases lipoprotein lipase gene expression, key players in triglyceride metabolism. In addition, PPARα activation increases plasma HDL cholesterol via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II expression in humans. Glitazones exert a hypotriglyceridemic action via PPARγ-mediated induction of lipoprotein lipase expression in adipose tissue. PPARs play also a role in intracellular lipid metabolism by up-regulating the expression of enzymes involved in conversion of fatty acids in acyl-coenzyme A esters, fatty acid entry into mitochondria and peroxisomal and mitochondrial fatty acid catabolism. These observations have provided the molecular basis leading to a better understanding of the mechanism of action of fibrates and glitazones on lipid and lipoprotein metabolism and identify PPARs as attractive targets for the rational design of more potent lipid-lowering drugs.
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June 1, 2005
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The growing diffusion of banned practice to improve the athletic performances is forcing clinical laboratories to identify and standardize reliable assays to detect potential unfairness. Among the doping practices, the use of recombinant human erythropoietin is becoming fairly popular, due to simplicity and safeties of administration and troublesome detection. The heterogeneous response rate, the presence of a little but significant amount of naturally occurring hormone, the short half-life exhibited by recombinant human erythropoietin and the lack of standardization of commercial assays appear the main problems to overcome. Aim of the present article is to provide a critical review of some of the more widespread laboratory techniques currently available for the screening for erythropoietin abuse in sport.
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There is a large body of literature describing the causative role of oxidative stress mediated by increased levels of reactive oxygen species in the pathogenesis of cardiovascular disease such as atherosclerosis, hypertension, and restenosis after angioplasty. The positioning of a soft silicone collar around the rabbit carotid artery elicits intimal thickening. The findings from recent studies demonstrated that both intimal thickening and atherosclerosis lead to synthesis of inducible nitric oxide synthase, resulting in abundant amounts of nitric oxide. We investigated the effects of collaring and nicardipine treatment on the activities of antioxidant enzymes, superoxide dismutase and catalase, and total nitrite/nitrate levels, stable products of nitric oxide. Placing the collar increased the total nitrite/nitrate levels and decreased superoxide dismutase activity in collared arteries. Treatment with nicardipine (20 mg/kg/day, s.c.) prevented enhanced nitric oxide degradation without affecting superoxide dismutase and catalase activities. Our results suggest that enhanced nitric oxide production and superoxide anion are generated in response to the collaring, resulting in oxidative stress within the segment in this model.
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June 1, 2005
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Several peptides derived from the N-terminal sequence of pro-atrial natriuretic peptide (proANP) have been tested successfully as markers of heart disease. We have developed specific and sensitive competitive enzyme immunoassays for fragments [1–30] and [31–67] of proANP. Antisera were raised in sheep against synthetic peptides predicted to be highly immunogenic. Binding specificity was determined by epitope mapping. Microtiter plates were coated with antibody specific for the Fc region of sheep IgG to capture the affinity-purified specific anti-proANP antibodies in an oriented and reproducible form. Synthetic proANP calibrators or diluted samples were incubated simultaneously with biotinylated peptide and binding was quantitated using streptavidin-peroxidase and TMB. Immunoreactive proANP could be measured in diluted plasma, serum and urine. The detection limits of the proANP[1–30] and proANP[31–67] assays were 2.5 and 10 pmol/l respectively. The linearity of samples diluted beyond the recommended assay conditions was good. Recoveries of added standard peptides ranged from 102 to 112%. Circulating concentrations of immunoreactive proANP in 115 healthy subjects ranged from 0.11 to 0.47 nmol/l proANP[1–30] and 0.18 to 0.79 nmol/l proANP[31–67]. In patients with cardiac disease, proANP levels were increased significantly. The reference interval of proANP[31–67] in urine was 0.09 to 1.7 nmol/l, several-fold higher than proANP[1–30] (<0.03 to 1.1 nmol/l). After storage for 6 months at −20°C there was no detectable decrease in immunoreactivity.
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Two-site immunoassay methods have become the standard technique for measurement of a wide variety of drugs, hormones, and cell proteins. One limitation of these methods is their susceptibility to interference from heterophilic antibodies present in the sera of some patients. Human anti-murine antibodies represent a common heterophile antibody that can bind to mouse immunoglobulin and as well as to immunoglobulin from other species. While the mechanism of human anti-murine antibody interference has been well characterized, the time course over which this interference occurs and the susceptibility of different immunoassay procedures to human anti-murine antibody interference from patients with human anti-murine antibody have not been as well described. We report on the time course of interference in assays for cardiac markers for two patients with human anti-murine antibodies. We measured creatine kinase MB isoenzyme (CKMB) and troponins I and T using three different vendors' immunoassay procedures. Our results demonstrate that assay interference due to human anti-murine antibody interference is a transient phenomenon. In one of our patients, human anti-murine antibody interference appeared suddenly, peaked approximately 9 days following its appearance, and gradually resolved over the next 3 weeks. In addition, we found that immunoassay methods from different vendors can show highly variable interference effects when human anti-murine antibody-containing specimens are analyzed.
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June 1, 2005
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The aim of the study was to investigate whether procalcitonin, soluble CD14 and interleukin-6 show advantages in predicting the outcome and specificity for bacterial infection in patients with sepsis in comparison to common C-reactive protein measurement. Laboratory parameters were measured in plasma of patients during 14 days following the diagnosis of sepsis. Patients fulfilling the ACCP/SCCM criteria for sepsis were admitted to an intensive care unit (n=35). Procalcitonin was measured with an immunoluminometric assay, and soluble CD14 and interleukin-6 were analysed by ELISA. C-reactive protein was determined nephelometrically. Measurements were performed on days 0, 1, 2, 3, 4, 7 and 14. Separating the patients into survivors (n=22) and non-survivors (n=13), it was demonstrated that non-survivors mostly exhibited, after the day of admission, increasing procalcitonin concentrations which peaked around days three and four. In contrast, the procalcitonin concentrations of survivors fell continuously to the value of 2.1 ng/ml which was reported to be important for patients prognosis. The difference between procalcitonin median values of survivors (n=22) and non-survivors (n=13) attained the level of statistical significance on day 7 and on day 14 (p=0.05). When comparing the median values of C-reactive protein, soluble CD14 and interleukin-6 between survivors and non-survivors, no significant differences were detectable. In this study, plasma concentrations of soluble CD14 and interleukin-6 showed no predictive value for patients' outcome as compared with established laboratory parameters such as C-reactive protein or leukocyte count. Monitoring of procalcitonin seemed to detect severe episodes of sepsis and may improve the laboratory monitoring of septic patients.
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June 1, 2005
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In this study, we evaluated bone turnover in 52 epileptic patients receiving chronic anticonvulsant therapy and in 39 healthy volunteers whose ages matched those of the patients. We determined serum osteocalcin and total and bone alkaline phosphatase levels as markers of bone formation, and urinary deoxypyridinoline and urinary calcium levels as markers of bone resorption. Statistical comparison of the levels of these markers between sexes in epileptic patients and their control groups revealed that total alkaline phosphatase levels were significantly increased in patients from both sexes compared with those of their controls. Urinary deoxypyridinoline levels of male epileptic patients were significantly increased compared with those of their controls. On the other hand, 25-hydroxyvitamin D levels of the male patients were significantly reduced compared with those of their controls. Serum osteocalcin, bone alkaline phosphatase, and urinary calcium levels of epileptic patients were not statistically different from those of the controls. We found that urinary deoxypyridinoline levels of male epileptic patients were increased, however, we observed no difference in serum osteocalcin and bone alkaline phosphatase levels. The lack of difference may be attributed to the fact that only the resorption phase of bone turnover is affected during chronic anticonvulsant therapy.
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June 1, 2005
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The test performance of the fully automated AxSYM ® Estradiol available on the immunoassay analyser Abbott AxSYM ® was evaluated. Imprecision, sensitivity and linearity of dilution were examined. For assessment of accuracy, the assay results measured in 12 control pools and 9 patient samples were compared with the values obtained with isotope dilution—mass spectrometry (reference method). The correlation with the manual radioimmunoassay Estradiol MAIA ® was evaluated using 140 serum samples with estradiol concentrations ranging from 0 to 10 nmol/l. Imprecision studies revealed for the AxSYM ® Estradiol within-run coefficients of variation of 2.8–8.4% and day-to-day coefficients of variation of 3.4–9.5% (concentration range 0.3–2.8 nmol/l). The lower limit of quantification (lowest estradiol concentration with a day-to-day coefficient of variation <20%) was <0.11 nmol/l; the lower limit of detection was <0.05 nmol/l. The estradiol concentration recovered in patient samples after dilution did not differ by more than 10% from the expected values. The estradiol concentration measured with the AxSYM ® Estradiol in 12 commercial control pools in some cases grossly deviated from the reference method values; however, for 9 individual patient samples the AxSYM results deviated by not more than 22% (−11%−+22%). There was a good overall correlation (coefficient of correlation = 0.989) between the results measured with the AxSYM ® Estradiol and the Estradiol MAIA ® in patient samples. The AxSYM ® Estradiol assay exhibits a good precision and a sufficient degree of sensitivity for measurement of estradiol in serum of menstruating women. Although the AxSYM results measured in the control pools, in some cases did not meet the target values, the good correlation with the Estradiol MAIA ® indicates that the reliability of the AxSYM ® Estradiol for clinical practice is comparable with well established radioimmunoassays. Thus, the AxSYM ® Estradiol offers an alternative which is comparable with respect to clinical reliability but has great advantages in view of rapidity, flexibility and convenience of analysis.
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During the 19th century the first laboratories at hospitals and clinics in Central Europe were established. These ‘clinical laboratories’ were devoted to chemical analyses in practical medicine and clinical research. A characteristic feature of these laboratories was the use of measuring instruments, e.g. volumetric apparatus, polarimeters, spectroscopes, colorimeters, photometers. Using these techniques new phenomena were introduced into clinical medicine which could serve as signs in the diagnosis of diseases. Many of the new diagnostic signs were quantitative data as results of measurements. Their main advantage was the greater differentiation in the description of phenomena compared with the qualitative data used before. Another important characteristic of the new diagnostic signs was the discovery of causal relations to physiological and pathological processes in the organism. The physicians and chemists in the clinical laboratory were eager not only to collect empirical data but also to find causal relationships by research work similar to that carried out in physics and chemistry. Once causal chains were been identified more general relationships became clear. One example is the concept of metabolism which comprised a dynamic view on chemical processes in the body and the variation of "Stoff" (material) in time, including a quantitative input-output analysis of the body in health and disease. In the second half of the 19th century, scientifically based diagnostic signs began to replace the traditional symptoms and signs used since antiquity.
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