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PubMed1998

Standardization activities of markers of cardiac damage: the need of a comprehensive approach.

The field of biochemical markers of cardiac damage is in a dynamic state, with new applications continually appearing and new assays and markers being developed, but also with several analytical and interpretative problems to resolve. In this situation it is essential that a uniform and rigorous outlook be maintained to ensure optimal test utilization. For these reasons, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) agreed to establish a Committee on 'Standardization of Markers of Cardiac Damage' (C-SMCD). The first task of the C-SMCD concerns coordination of the different activities from affiliated associations, with (1) a review of documents and recommendations and (2) supervision and, possibly, the take-over of the standardization activities. Second, the C-SMCD supports development of scientific programmes for forthcoming international meetings and congresses. The third task of the C-SMCD is development of specific additional projects to promote the rational use of cardiac markers and to identify new areas of research.

Biomarkers↗
PubMed1992

Des-gamma-carboxyprothrombin (PIVKA II) and plasma vitamin K1 in newborns and their mothers.

Assessments of the vitamin K status in newborns and their mothers by means of des-gamma-carboxy-prothrombin (PIVKA II) measurement have given equivocal results. Part of the variability could be attributed to differences in sensitivity (i.e. the ability to detect small concentrations) and validity (i.e. ability to detect vitamin K deficiency) of the methods applied. None of these methods have yet been validated with respect to plasma vitamin K1. In 22 healthy mother/infant pairs PIVKA II was determined using three different assays including ratio Xa/ecarin (Xa/ec), crossed immunoelectrophoresis (CIE), and an ELISA with a monoclonal antibody (MAB). The results were compared with conventional clotting tests and plasma vitamin K1. The following results were obtained: Cord blood: Clotting tests within age-related normal ranges; PIVKA II detection rates: 0/22 (Xa/ec), 1/22 (CIE), 4/22 (MAB); plasma vitamin K1: undetectable in 20/22. Mothers: Clotting tests all within normal range; PIVKA II detection rates: 1/22 (Xa/ec), 0/22 (CIE), 5/22 (MAB); plasma vitamin K1 (pg/ml) for all mothers (median; range): 186; 55-833; for PIVKA II positive mothers: 213; 59-699. PIVKA II detectability in newborns and mothers was not correlated. The results show an increase in sensitivity for PIVKA II detection in the order of MAB >> CIE > Xa/ec. Due to the very low plasma vitamin K1 at birth, no correlation was possible between cord PIVKA II detectability and plasma vitamin K1. However, in mothers at term PIVKA II MAB appears to be unrelated to the vitamin K status.

Adult↗
PubMed1991

[The comparative value of myoglobin determination in patients with different forms of ischemic heart disease].

The hemagglutination test was used to measure the content of myoglobin (MG) in the blood serum in 92 patients suffering from coronary heart disease (myocardial infarction, unstable and stable angina pectoris). The content of MG turned out a safe indicator attesting to acute myocardial infarction. In complications and spreading of necrosis, the MG level was returning to normal slowly. In patients with angina pectoris, the MG level did not on the average differ from control. However, in patients with unstable angina pectoris, there was an increase of the MG content after long-term attacks and in the development of small-focal necroses in the myocardium.

Adult↗
PubMed1988

The role of the ras oncogene in the formation of tumours.

A c-Ha-ras 1 oncogene, cloned from the EJ human bladder carcinoma cell line, was inserted into a shuttle vector carrying the selectable marker gene gpt that encodes the enzyme xanthine-guanine phosphoribosyl transferase. This construct, pSV2gptEJ, was transfected into NIH 3T3 cells by the calcium phosphate precipitation method and cells that had incorporated the plasmid were selected by growth in the presence of mycophenolic acid to which gpt confers resistance. A number of transfectant clones were tested for tumorigenicity by inoculation into nude mice. The take incidence was variable and the tumours arose only after a prolonged latent period. Many inocula produced no tumours. These results were consistent with the view that the tumours arose by selective overgrowth of minority cell populations. Cell lines were derived by explantation of these tumours and were back-selected in 2-thioxanthine, a cytotoxic analogue of the xanthine-guanine phosphoribosyl transferase substrate. Five clones were obtained that did not express detectable levels of the c-Ha-ras 1 oncogene product, p21ras. All of them showed a less-transformed morphology than the transfected NIH 3T3 cells from which they originated. Nonetheless three of these clones were found to be tumorigenic at all sites tested. This finding demonstrates that once tumorigenic variants have been selected from the ras-transformed cells, continued production of the p21ras protein is not necessary for the maintenance of tumorigenicity. Cytogenetic analysis revealed that the transfection procedure itself introduced major and stable perturbations of the genome of the transfected cells and confirmed that tumours were produced by selective overgrowth of variants with a chromosome constitution palpably different from that of the majority of the cells injected. In the light of the complex background of genomic changes produced in NIH 3T3 cells by transfection with the c-Ha-ras 1 oncogene, no conclusion can be drawn in genetic terms concerning its dominance.

Animals↗
PubMed2002

Combined use of oligonucleotide and tissue microarrays identifies cancer/testis antigens as biomarkers in lung carcinoma.

High density oligonucleotide microarrays (OMAs) have been used recently to profile gene expression in lung carcinoma tissue homogenates. The length of the lists of potentially interesting genes generated by these studies is daunting, and biological and clinical relevance of these lists remains to be validated. Moreover, specific identification of individual biomarkers that might be used for early detection and surveillance has not been the objective of these early studies. We have developed a schema for combining the data derived from the OMA analysis of a few lung cancer cell lines with immunohistochemical testing of tissue microarrays to rapidly identify biomarkers of potential clinical relevance. Initially, we profiled gene expression in lung tumor cell lines using the Affymetrix HG-U95Av2 OMA. RNA from 2 non-small cell lung cancer (NSCLC) cell lines (A549 and H647) and 2 small cell lung cancer (SCLC) cell lines (SHP-77 and UMC-19) were tested. Cells from 1 histologically and cytogenetically normal bronchial epithelial primary culture from a volunteer who had never smoked and 10 samples of histologically unremarkable lung tissue from resection specimens served as normalization controls. Array results were analyzed with Gene Spring software. Results were confirmed by reverse transcription-PCR in an expanded number of cell lines. We then validated the cell line data by immunohistochemical testing for protein using a tissue microarray containing 187 NSCLC clinical samples. Of the 20 most highly expressed genes in the tumor lines, 6 were members of the cancer/testis antigen (CTAG) gene group including 5 MAGE-A subfamily members and NY-ESO-1. SCLC lines strongly expressed all of the MAGE-A genes as well as NY-ESO-1, whereas NSCLC lines expressed a subset of MAGE-A genes at a lower level of intensity and failed to express NY-ESO-1. Reverse transcription-PCR of an extended series of 25 lung cancer cell lines including 13 SCLC, 9 NSCLC, and 3 mesothelioma lines indicated that MAGE-A10 and NY-ESO-1 were expressed only by SCLC, and that MAGE-A1, 3, 6, 12, and 4b were expressed by both SCLC and NSCLC. By immunohistochemistry using the monoclonal antibody 6C1 that recognizes several MAGE-A gene subfamily members, 44% of NSCLC clearly expressed MAGE-A proteins in cytoplasm and/or nucleus. Expression of MAGE-A genes did not correlate with survival but did correlate with histological classification with squamous carcinomas more frequently MAGE-A positive than other NSCLC types (P < 0.00002). We conclude that expression of CTAG gene products, whereas apparently not of prognostic importance, may be useful for early detection and surveillance because of a high level of specificity for central airway squamous and small cell carcinomas.

Antigens, Neoplasm↗
PubMed1993

Serum malondialdehyde and mitochondrial aspartate aminotransferase activity as markers of chronic alcohol intake and alcoholic liver disease.

Since lipid peroxidation is a well-know mechanism of alcohol-related liver damage, the aim of the present study was to assess the role of serum malondialdehyde (MDA), a secondary product of lipoperoxidation, in the detection of alcoholism and different stages of alcoholic liver disease and to correlate serum levels of malondialdehyde with other markers. Sixty-five patients with a mean alcohol intake of 151 gr/day, were divided into three groups: alcoholics with normal liver function (ANLF, 7 pts), non-cirrhotic alcoholic liver disease (NCALD, 26 pts) and alcoholic cirrhosis (ALC, 32 pts). The control group consisted of 15 healthy subjects. Serum MDA was measured by the thiobarbituric acid reaction test, and mitochondrial aspartate aminotransferase (mAST) with immunochemical assay. MDA had a higher sensitivity (70% vs 37.5%) and specificity (100% vs 93%) than mAST in detecting alcohol abuse, irrespective of the presence of liver disease. Serum MDA levels were significantly higher in all three groups than in controls (2.3 +/- 0.1 nmol/ml), the highest value being found in NCALD (4.6 +/- 0.4). Serum MDA levels were correlated with prothrombin time (p < 0.005) and blood alcohol levels (p < 0.05). mAST serum activity was also significantly higher in all three groups than in controls. A significant correlation was found between serum MDA and mAST only when the whole group was considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Reported alcohol consumption and the serum carbohydrate-deficient transferrin test in third-year medical students.

The serum carbohydrate-deficient transferrin (CDT) test was performed on 143 third-year medical students along with questionnaires for the self-reporting of alcohol consumption during the last 2 weeks, the last 6 months, and questions on any alcohol-related untoward events. We found that the CDT test has poor sensitivity for detecting binge drinking in our population of students, despite some likely under-reporting of drinking. Self-reporting of drinking is commonly unreliable, and we found no significant correlation between the CDT concentrations in serum and the magnitude of self-reported alcohol use during 2-week and 6-month periods. Hangover was by far the commonest self-reported untoward event, and there was a highly significant relationship (P < 0.001) between drinking and untoward events. From a small population of non-drinkers, we estimated the reference ranges for CDT to be <27 U/l for men and <35 U/l for women.

Accidents↗
PubMed2004

Chromosome intrachanges and interchanges detected by multicolor banding in lymphocytes: searching for clastogen signatures in the human genome.

Genomic fingerprints of mutagenic agents would have wide applications in the field of cancer biology, epidemiology and prevention. The differential spectra of chromosomal aberrations induced by different clastogens suggest that ratios of specific aberrations can be exploited as biomarkers of carcinogen exposure. We have tested this hypothesis using the novel technique of multicolor banding in situ hybridization (mBAND) in human peripheral blood lymphocytes exposed in vitro to X rays, neutrons, heavy ions, or the restriction endonuclease AluI. In the heavy-ion-irradiated cells, we further analyzed aberrations in chromosome 5 using multicolor FISH (mFISH). Contrary to the expectations of biophysical models, our results do not support the use of the ratios of inter-/intrachromosomal exchanges or intra-/interarm intrachanges as fingerprints of exposure to densely ionizing radiation. However, our data point to measurable differences in the ratio of complex/simple interchanges after exposure to different clastogens. These data should be considered in current biophysical models of radiation action in living cells.

Biomarkers↗
PubMed1999

Accelerated coronary reperfusion through the use of rapid bedside cardiac markers--case reports.

Each year, acute myocardial infarctions (AMI) account for more than half a million deaths in the United States. Complicating treatment of AMI is the difficulty in accurately diagnosing the event, for patients have nondiagnostic electrocardiograms (ECG) more than 50% of the time. In this population, cardiac markers are essential to confirm the diagnosis. The new bedside cardiac markers, which use eight drops of whole blood and require 15 minutes to be read negative, make it possible to shorten time needed to diagnose AMI. One hundred twenty-seven consecutive patients presented to the emergency department complaining of atypical chest pain. All had ECGs that were nondiagnostic for myocardial infarction. Serial cardiac markers were performed: myoglobin, troponin I, rapid myoglobin, and rapid troponin I. One hundred eighteen patients with negative serial cardiac markers had exercise treadmill tests in the emergency department. Nine patients with positive serial cardiac markers received emergent primary angioplasty. Six of the nine patients were treated based on the positive results of the rapid bedside cardiac markers. A 100% correlation existed between the quantitative serum results and the rapid bedside markers. With the availability of rapid bedside assays, dependency on the laboratory can be minimized, since quantitative cardiac markers require at least 1 hour of turnaround time. Rapidly and correctly diagnosing AMIs in patients with ECGs nondiagnostic for AMI has always been a dilemma. Rapid bedside assays enable the physician to accurately diagnose myocardial infarction and safely decrease the time in evaluating chest pain, thus maximizing the benefits of early reperfusion.

Adult↗
PubMed1991

Seasonal incidence of subclinical vitamin K deficiency during early newborn period.

Eleven-Sixty six healthy, non-vitamin K treated and exclusively breast-fed 5-day-old newborns were screened with PIVKA-II and Hepaplastin test for subclinical vitamin K deficiency for two years. PIVKA-II values in 96 babies (8.2%) ranged from 1 to 8 micrograms/ml. These babies were divided into two groups: 83 (86.5%) had relatively low values ranging from 1 to 2 micrograms/ml, and 13 (13.5%) had higher values ranging from 2 to 8 micrograms/ml. Eleven babies in the latter group (84.6%) had a seasonal deviation in incidence in the summer and early fall (p less than 0.05). This seasonal variation in severe subclinical vitamin K deficiency during the early newborn period corresponds with the results of an epidemical survey of idiopathic late onset hemorrhagic disease in newborns in Japan, suggesting similar causative factors in both of these hemorrhagic diseases.

Biomarkers↗
PubMed2005

Biomarkers to assess potential developmental immunotoxicity in children.

Clinical tests are readily available for assessing severe loss of immune function in children with diseases such as AIDS or primary immunodeficiency. However tests that could reliably identify subtle immune changes, as might be expected to result from exposure to developmental immunotoxic agents, are not readily available. A number of tests are described which we believe have potential applicability for epidemiological studies involving developmental immunotoxicity. Several of the tests, such as T cell receptor rearrangement excision circles (TRECs) and cytokine measurements, while highly relevant from a biological standpoint, may be precluded from use at the current time, for either technical issues or insufficient validation. Immunophenotyping and measurement of serum immunoglobulin levels, on the other hand, are well validated. Yet they may require extraordinary care in experimental design and technical performance in order to obtain data that would consistently detect subtle changes, as these tests are not generally considered highly sensitive. Quantification of the immune response to childhood vaccine, while up to the present used sparingly, may represent an excellent indicator for developmental immunotoxicity when conducted under appropriate conditions.

Acquired Immunodeficiency Syndrome↗
PubMed2003

[Determination of peroxidase positive cells in semen: is it a secure parameter for the diagnosis of silent genital infections?].

BACKGROUND: The presence of leukocytes, detected by peroxidase test in semen, can be a good indicator of infections in the male genital tract. Peroxidase positive cells have been positively correlated with elevated values of elastase, one of the major proteases liberated by granulocytes at the inflammation place. However, seminal granulocytes may not be adequately detected by the peroxidase test in comparison with immunological methods. AIM: To correlate the determination of peroxidase positive cells with the elastase level in the seminal plasma. MATERIAL AND METHODS: Seminal plasma from 64 patients with a high number of round cells (> 106/ml) in semen, was studied. Correlation analysis was done using the Pearson correlation coefficient. RESULTS: No correlation between the level of granulocyte elastase and the number of peroxidase positive cells (r = 0.2237, p > 0.05), or even the number of round cells (r = 0.03934, p > 0.05) was observed. CONCLUSIONS: Our results suggest that the determination of peroxidase positive cells is not a reliable indicator of leukocytes in the seminal plasma and their absence do not discard a silent genital tract infection.

Biomarkers↗
PubMed2003

Correlation of exhaled nitric oxide levels and airway inflammation markers in stable asthmatic patients.

Monitoring of inflammation is an important factor in asthma management. The gold standard for measuring direct airway inflammation is bronchial biopsy specimens taken from proximal airways through a fiberoptic bronchoscope. As a noninvasive procedure, the use of exhaled nitric oxide (FENO) for monitoring airway inflammation has been reported in many studies. The aim of this study was to evaluate the correlation of FENO with direct measurements of airway inflammation in biopsy specimens and pulmonary function tests (PFT). Histopathologic features were observed on bronchial biopsy specimens obtained from nine stable mild-moderate asthmatics. Each subject had measurements of PFT, FENO levels, blood eosinophil count, and bronchoscopy with bronchial biopsies and bronchoalveolar lavage. Five subjects with forced expiratory volume in 1 second >80% had methacholine challenge test. None of the subjects had prior anti-inflammatory therapy for asthma. No correlation was found between PFT, blood eosinophil count, and FENO levels. There was a negative correlation between PC20 and FENO. Though there was no correlation between bronchial biopsy eosinophil, monocyte and lymphocyte counts, and FENO, we found a weak positive correlation between total inflammatory cell count in bronchial biopsies and FENO levels. A negative significant correlation was found between FENO levels and epithelial desquamation (p<0.05, r=-0.7). These results suggest that, FENO levels reflect the increased number of activated inflammatory cells in airways and the negative correlation with epithelial desquamation reflects the role of epithelium in NO syntheses. FENO should not be interpreted as a specific inflammation marker for asthma.

Adult↗
PubMed2005

Biological monitoring of carbon disulphide and phthalate exposure in the contemporary rubber industry.

OBJECTIVES: We studied the range in urinary levels of 2-thiothiazolidine-4-carboxyl acid (TTCA), a metabolite of CS2 and phthalic acid (PA), a common metabolite of phthalates, across factories and departments in the contemporary rubber manufacturing industry. METHODS: Spot urine samples from 101 rubber workers employed in nine different factories were collected on Sunday and during the workweek on Tuesday, Wednesday and Thursday at approximately 4 pm. In total, 386 urine samples were successfully analyzed. RESULTS: Levels of both biomarkers increased significantly by a factor 2 (paired t-test P-value <0.05) during the working week as compared to the Sunday biomarker levels with absolute increases of approximately 70 microg/l and 5 micromol/mol creatinine for PA and TTCA, respectively. Levels in both biomarkers did not differ markedly between working days. Increases seemed to be restricted to specific factories and/or departments (e.g. molding and curing). CONCLUSIONS: The results of this study demonstrate that rubber workers in the contemporary rubber industry are exposed to phthalates and low levels of CS2 ( approximately 0.05 ppm) as measured by PA and TTCA, respectively. Exposures to both compounds are largely driven by specific circumstances in factories. Therefore, when estimating exposures to phthalates and CS2 detailed information should be collected on the type and amount of phthalate containing ester plasticizers, dithiocarbamates and thiurams used. Preferably, personal exposure data should be collected. In this case, biological monitoring seems a reasonable approach. However, in the case of PA attention should be given to individual background levels as this could lead to a substantial overestimation of the occupational contribution to total phthalate exposure.

Air Pollutants, Occupational↗
PubMed2003

Quality assessment of seven types of fresh-frozen plasma leucoreduced by specific plasma filtration.

BACKGROUND AND OBJECTIVES: A study was undertaken to determine plasma quality after specific filtration. MATERIALS AND METHODS: Seven types of plasma were tested, after filtration of plasma from filtered or non-filtered whole blood. Leucocyte counting was carried out after a 30-fold concentration of the sample. Twenty-nine parameters (including coagulation testing, proteins, coagulation factors and activation markers) were measured before and after filtration, and after 6 months of storage. RESULTS: After specific plasma filtration, the average residual leucocyte counts were less than 2250/l. In spite of small statistically significant changes in proteins, coagulation factors and complement activation, this study showed that plasma filtration did not alter plasma quality. After 6 months of storage at -30 degrees C, factor VIII recovery varied between 91 and 109%. Haemostasis parameters and activation markers remained within the normal range. CONCLUSIONS: Specific plasma filtration reduced the leucocyte number to < 104 leucocytes/l. The quality of plasma was not altered by the additional step of specific plasma filtration.

Biomarkers↗
PubMed2005

Airway inflammation and cough sensitivity in cough-variant asthma.

BACKGROUND: Mechanisms underlying cough and bronchoconstriction in patients with cough-variant asthma (CVA) are not well established. Differences in location or degree of activation of eosinophils and allergic cytokines have been suggested as the likely causes. To address this issue, we have carried out a comparative study of airway inflammatory markers between patients with CVA and classic asthma (CA). The relationship between these markers with airway hyperresponsiveness (AHR) and cough sensitivity has also been studied. METHODS: Twenty-seven non-smokers and steroid-naive patients with CVA (12) and CA (15) were examined. Capsaicin challenge, histamine bronchoprovocation test, nitric oxide levels in exhaled air and sputum induction were performed in all of them. Differential cell sputum recount and supernatant concentrations of eosinophil granule-derived cationic proteins (ECP), interleukin (IL)5, IL8 and tumour necrosis factor (TNF)-alpha were also measured. RESULTS: There were no significant differences in either the inflammatory pattern of soluble markers or differential cell counts between CA and CVA. Histamine PC20 was correlated with IL-5 in CVA, whereas it was associated with sputum eosinophilia in CA. Cough sensitivity (log C5) and histamine PC20 were inversely related in CA. CONCLUSIONS: Although the pattern of inflammatory sputum markers in patients with asthma and cough-variant asthma is similar, its relation with bronchial hyperreactivity and cough sensitivity is different in each group.

Adult↗
PubMed2004

Identification of in vitro protein biomarkers of idiosyncratic liver toxicity.

Drug-induced idiosyncratic hepatotoxicity continues to be an important safety issue for the pharmaceutical industry. This toxicity is due, in part, to the limited predictive nature of current pre-clinical study systems. A hypothesis was formed that treatment of existing in vitro hepatocyte cultures with drugs clinically linked to idiosyncratic hepatotoxicity would result in the release of extracellular protein biomarkers indicative of liver toxicity. To test this hypothesis, a combination of proteomic and immunological techniques were used to first identify, and subsequently verify, components of the protein-laden conditioned culture media from immortalized human hepatocytes which overexpressed cytochrome p450 3A4. These cells were treated separately with seven individual compounds made up of a combination of thiazolidinedione and l-tyrosine PPARgamma agonists and HIV protease inhibitors, plus a vehicle control (dimethyl sulfoxide). For each drug class, clinically determined hepatotoxic and non-hepatotoxic compounds were compared. Two proteins, BMS-PTX-265 and BMS-PTX-837, were reproducibly and significantly increased in the conditioned media from cells treated with each of the toxic compounds as compared to media from cells treated with the non-toxic compounds (and vehicle). This result supported the hypothesis, and so a series of successive assays (western blots and enzyme linked immunosorbent assays) were used to measure the response of these two proteins as a function of an expanded set of 20 compounds. For all 20 drugs, elevations of BMS-PTX-265 correlated exactly with the known safety profile; whereas changes in BMS-PTX-837 correctly predicted the safety profile in 19 of 20 drugs (one false negative). In summary, the data supports both the pre-clinical in vitro method as a means to identify new biomarkers of liver toxicity, as well as the validity of the biomarkers themselves.

Biomarkers↗
PubMed2006

Increased cytogenetic damage in a zone in transition from agricultural to industrial use: Comprehensive analysis of the micronucleus test in peripheral blood lymphocytes.

A complex situation of chemical exposure has been described in México in a zone that is in transition from rural activities towards intensive industrialization, which has brought environmental pollution: chloroform, methylene chloride, indigo and toluene are some of the pollutants found in the Atoyac and Xochiac rivers. A biomonitoring study was planned in order to establish whether there was a biological effect due to the environmental situation. Communities where leukaemia and thrombocytopenic purpura cases have been reported were included in the study, as well as other communities where such cases have not been described. Three occupations were distinguished, according to chemical exposure: industrial workers, agricultural workers and workers in households, education and commerce. A comprehensive analysis in the micronucleus (MN) test was used to study genotoxicity biomarkers. Two metabolic polymorphisms were determined, namely, glutathione transferase mu1 (GSTM1) and theta1 (GSTT1), which are relevant when oxidative responses are involved. Increased genotoxic damage was found, including cells with >1 MN, >1 chromatin bud, and nucleoplasmic bridges. The genotoxic damage was differentially distributed in the regions studied, being more affected those that are closer to the Atoyac and Xochiac rivers, indicating an effect due to environmental exposure to the contaminants present in the rivers. Further characterization of the exposure regimes in these communities will be done in order to contribute to the alleviation of the health risks that environmental pollution is posing on the inhabitants of this area.

Adult↗