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PubMedDate not supplied

Development of a biomarker-based index for assessing the ecotoxic potential of aquatic sites.

The use of biochemical or physiological measurements as indicators of ecotoxicity is under constant development and has the advantage of delineating effects before the appearance of disease. However, these biomarkers are often part of a battery of tests, and it is difficult to integrate them together to gain an overall view of an organism's health. The aim of this study was to develop an index that could integrate the data derived from a battery of biomarkers for application to both spatial and temporal studies. Mya arenaria clams were collected at different sites along the Saguenay Fjord (Quebec, Canada). Six biomarkers were measured: metallothioneins, DNA strand breakage, lipid peroxidation, vitellin-like proteins, phagocytosis, and non-specific esterase activity in haemocytes. A biomarker index was obtained by summing the biomarker values expressed in term of classes. Classes were determined by a distribution-free approach derived from the theory of rough sets. The results of the spatial study show that the index values discriminated well between contaminated and uncontaminated sites. The highly polluted sites had the highest index values (18 compared with a reference value of 14). In the temporal study, the index was also able to highlight possible contamination-induced alterations, even though the interpretation of temporal variation is complicated by natural variations occurring throughout the year. A control chart approach is proposed for determining contaminated sites in both spatial and temporal surveys.

Animals↗
PubMedDate not supplied

[The role of biological monitoring in health and epidemiological surveillance: the epidemiological approach].

A fundamental pre-requisite for the realization of biological monitoring programs for health surveillance is the availability of sufficiently accurate tests and adequate knowledge of the relationship between biomarkers and health effects. In this respect, epidemiology plays an essential role: in conjunction with other disciplines (industrial hygiene, toxicology, occupational medicine), it provides a conceptual and methodological framework for many biological monitoring activities. Compared to biomarkers of dose and effect, susceptibility markers (for example, metabolic polymorphisms), for which we have seen an explosion of research in recent years, need a specific consideration in that they pose (or may pose in a non-remote future) special problems. For different reasons, the use of genetic tests for predictive aims at the individual level should now be avoided; their use should be restricted to the research field for a better understanding of etiopathogenetic mechanisms.

Biomarkers↗
PubMed2004

Missed acute cardiac ischemia in the ED: limitations of diagnostic testing.

Correctly identifying and appropriately triaging patients who present to the ED with the broad range of symptoms suggestive of acute cardiac ischemia (ACI: unstable angina pectoris [UAP] and acute myocardial infarction [AMI]) remains one of the greatest challenges in EM. Although a number of diagnostic technologies have been described to aid in this triage process, each of these tests or technologies has limitations. We report a case series in which either the use of adjuncts with unknown performance or tests with known but not considered limitations could have contributed to the failure to appropriately triage and treat patients with ACI. Each case illustrates different aspects of this clinical challenge. One case illustrates the hazards of reliance on a single set of negative cardiac biomarkers. The limitations of a negative exercise electrocardiographic stress test (ETT) are illustrated in the second case. Finally, the limitations of a negative coronary angiogram, the "gold standard" test for symptomatic coronary artery disease, are discussed. We review the literature on technologies to aid in the evaluation of patients who present to the ED with symptoms suggestive of ACI.

Acute Disease↗
PubMed1989

Improving the precision of biological age determinations. Part 2: Automatic human tests, age norms and variability.

In order to eliminate variability due to test operators, procedures for measuring 12 physiological functions that are candidate biomarkers of aging have been automated. Data was collected from a norm group of 2462 male and female office workers using an instrument which requires no test operators, administers all 12 tests in about 45 min. per subject, computes biological age, prints out results, and stores data on floppy disks for transfer to other computers for analysis. This report a) describes the instrumentation and test procedures, b) presents normal age/sex standards for each of the 12 biomarkers, c) reports the variance of the data for each biomarker by sex, d) lists sources of biomarker variance, e) discusses criteria for biomarker selection and f) examines implications for information loss when biomarker data is combined to calculate biological age. After eliminating chronological age as a variable, the standard deviations of the frequency distributions of predicted age for individual biomarkers were found to vary from .226 to 1.075, a range of more than 4 to 1. Procedures are discussed for improving the ratio of useful-to-useless variance in calculating biological age.

Accommodation, Ocular↗
PubMed2006

Future of toxicology--mechanisms of toxicity and drug safety: where do we go from here?

Recent high-profile drug withdrawals increase the pressure on regulators and the pharmaceutical industry to improve preclinical safety testing. Understanding mechanisms of drug toxicity is an essential step toward improving drug safety testing by providing the basis for mechanism-based risk assessments. Nonetheless, despite several decades of research on mechanisms of drug-induced toxicity and the application of various new technologies to preclinical safety assessment, the overall impact on preclinical safety testing has been modest. Assessing the risk of exposing humans to new drug candidates still depends on preclinical testing in animals, which in many, but not all cases, predicts outcomes in humans accurately. The following offers a perspective on the challenges and opportunities facing efforts to improve preclinical safety testing and outlines gaps and needs that must be addressed. A case is built for focusing solutions on defined problems within the current safety testing paradigm rather than imposing wholesale change. Targets for application of new technologies, including in silico screening, biomarkers, surrogate assays and 'omic technologies, are outlined. Improving drug safety testing will depend on improving the application of mechanism-based risk assessment but will also require improving public and private collaborations in order to focus research regarding the mechanism of drug-induced toxicity on the most important problems.

Drug Approval↗
PubMed2002

The feasibility of integrated STI prevalence and behaviour surveys in developing countries.

BACKGROUND: In countries where STI/HIV prevalence data and behavioural data are scarce UNAIDS second generation HIV surveillance guidelines recommend measuring STI/HIV prevalence and risk behaviours in vulnerable populations but do not recommend conducting these surveys concurrently because of concerns about participation rates, cost, and provision of services. OBJECTIVES: To assess the feasibility of conducting a national combined STD prevalence and behaviour survey in Mali among vulnerable populations with the intention of institutionalisation. METHODS: From March to June 2000 an integrated STI prevalence and behaviour survey was conducted using cluster sampling among five risk groups in four sites in Mali, west Africa. 2229 individuals in non-traditional settings such as taxi/bus stations, market areas, households, and brothels participated in any one or all components of the study: (1) behavioural questionnaire, (2) urine sample for Neisseria gonorrhoeae (GC)/Chlamydia trachomatis (CT) testing, (3) a fingerstick drop of blood for syphilis, and/or (4) HIV testing. RESULTS: High participation rates of 84%-100% were achieved despite specimen collection and HIV testing. Rates fell only slightly when participants were asked to provide biological samples and participants were more likely to provide urine than blood. Rates among the different groups for HIV and syphilis testing are similar and suggest that refusal was most probably because of a reluctance to give blood rather than because of HIV testing. The cost of the biological component added approximately $30 per participant. Included in the $30 are the costs of training, participant services, laboratory personnel and supplies, STI drugs, and STI testing costs. The total cost of the survey was $154,905. Biomarkers aided in validation of answers to behavioural questions. Consenting individuals received HIV pretest and post-test counselling and referral to a trained health provider for treatment of STI and the provision of services provided the framework for interventions in the groups following the survey. CONCLUSION: This represents an effective methodology for collecting risk behaviour and STI/HIV prevalence information concurrently and should be considered by countries expanding STI/HIV surveillance as part of UNAIDS second generation HIV surveillance.

Automobile Driving↗
PubMed2000

Diagnostic testing.

The results of cardiac tests must always be interpreted through the lens of pretest probabilities created by the history and the physical examination. Tests should be chosen with a clear diagnostic and prognostic purpose in mind. A clear understanding of the relationship between the history and physical examination and more technologic diagnostic testing improves the primary care physician's ability to evaluate potential cardiac disease in an efficient and cost-effective manner.

Adult↗
PubMed2006

Sub-speciating Campylobacter jejuni by proteomic analysis of its protein biomarkers and their post-translational modifications.

We have identified several protein biomarkers of three Campylobacter jejuni strains (RM1221, RM1859, and RM3782) by proteomic techniques. The protein biomarkers identified are prominently observed in the time-of-flight mass spectra (TOF MS) of bacterial cell lysate supernatants ionized by matrix-assisted laser desorption/ionization (MALDI). The protein biomarkers identified were: DNA-binding protein HU, translation initiation factor IF-1, cytochrome c553, a transthyretin-like periplasmic protein, chaperonin GroES, thioredoxin Trx, and ribosomal proteins: L7/L12 (50S), L24 (50S), S16 (30S), L29 (50S), and S15 (30S), and conserved proteins similar to strain NCTC 11168 proteins Cj1164 and Cj1225. The protein biomarkers identified appear to represent high copy, intact proteins. The significant findings are as follows: (1) Biomarker mass shifts between these strains were due to amino acid substitutions of the primary polypeptide sequence and not due to changes in post-translational modifications (PTMs). (2) If present, a PTM of a protein biomarker appeared consistently for all three strains, which supported that the biomarker mass shifts observed between strains were not due to PTM variability. (3) The PTMs observed included N-terminal methionine (N-Met) cleavage as well as a number of other PTMs. (4) It was discovered that protein biomarkers of C. jejuni (as well as other thermophilic Campylobacters) appear to violate the N-Met cleavage rule of bacterial proteins, which predicts N-Met cleavage if the penultimate residue is threonine. Two protein biomarkers (HU and 30S ribosomal protein S16) that have a penultimate threonine residue do not show N-Met cleavage. In all other cases, the rule correctly predicted N-Met cleavage among the biomarkers analyzed. This exception to the N-Met cleavage rule has implications for the development of bioinformatics algorithms for protein/pathogen identification. (5) There were fewer biomarker mass shifts between strains RM1221 and RM1859 compared to strain RM3782. As the mass shifts were due to the frequency of amino acid substitutions (and thus underlying genetic variations), this suggested that strains RM1221 and RM1859 were phylogenetically closer to one another than to strain RM3782 (in addition, a protein biomarker prominent in the spectra of RM1221 and RM1859 was absent from the RM3782 spectrum due to a nonsense mutation in the gene of the biomarker). These observations were confirmed by a nitrate reduction test, which showed that RM1221 and RM1859 were C. jejuni subsp. jejuni whereas RM3782 was C. jejuni subsp. doylei. This result suggests that detection/identification of protein biomarkers by pattern recognition and/or bioinformatics algorithms may easily subspeciate bacterial microorganisms. (6) Finally, the number and variation of PTMs detected in this relatively small number of protein biomarkers suggest that bioinformatics algorithms for pathogen identification may need to incorporate many more possible PTMs than suggested previously in the literature.

Amino Acid Sequence↗
PubMed2001

Validated biomarker responses influence medical surveillance of individuals exposed to genotoxic agents.

There is currently a vast armamentarium of biomarkers for evaluating human exposures to environmental carcinogens, the effects of such exposures and/or susceptibility to disease outcome. Before application, however, these biomarkers require validation in terms of truly reflecting what is claimed. Transitional epidemiological studies bridge the gap between laboratory and field. In a transitional study, a biomarker response is the dependent variable being evaluated, while the intended measure, i.e. exposure effect or susceptibility, is the independent variable. Once validated, biomarker responses provide valuable data for use in making human health risk assessments and as guides for individual medical surveillance programmes. An analysis of medical decision-making illustrates how biomarker responses that increase the relative risk of subsequent disease occurrence change the 'pre-test likelihood' of having the disease, thereby influencing interpretation of medical diagnostic tests and even the choice of tests to be performed. This argues that an individual's response using salidated biomarkers should be made part of the medical record.

Biomarkers↗
PubMed2001

Modulation of biomarkers by chemopreventive agents in smoke-exposed rats.

Chemoprevention opens new perspectives in the prevention of cancer and other chronic degenerative diseases associated with tobacco smoking, exploitable in current smokers and, even more, in exsmokers and passive smokers. Evaluation of biomarkers in animal models is an essential step for the preclinical assessment of efficacy and safety of potential chemopreventive agents. Groups of Sprague Dawley rats were exposed whole body to a mixture of mainstream and sidestream cigarette smoke for 28 consecutive days. Five chemopreventive agents were given either with drinking water (N-acetyl-L-cysteine, 1 g/kg body weight/day) or with the diet (1,2-dithiole-3-thione, 400 mg; Oltipraz, 400 mg; phenethyl isothiocyanate, 500 mg; and 5,6-benzoflavone, 500 mg/kg diet). The monitored biomarkers included: DNA adducts in bronchoalveolar lavage cells, tracheal epithelium, lung and heart; oxidative damage to pulmonary DNA; hemoglobin adducts of 4-aminobiphenyl and benzo(a)pyrene-7,8-diol-9,10-epoxide; micronucleated and polynucleated alveolar macrophages and micronucleated polychromatic erythrocytes in bone marrow. Exposure of rats to smoke resulted in dramatic alterations of all investigated parameters. N-Acetyl-L-cysteine, phenylethyl isothiocyanate, and 5,6-benzoflavone exerted a significant protective effect on all alterations. 1,2-Dithiole-3-thione was a less effective inhibitor and exhibited both a systemic toxicity and genotoxicity in alveolar macrophages, whereas its substituted analogue Oltipraz showed limited protective effects in this model. Interestingly, combination of N-acetyl-L-cysteine with Oltipraz was the most potent treatment, resulting in an additive or more than additive inhibition of smoke-related DNA adducts in the lung and hemoglobin adducts. These results provide evidence for the differential ability of test agents to modulate smoke-related biomarkers in the respiratory tract and other body compartments and highlight the potential advantages in combining chemopreventive agents working with distinctive mechanisms.

Acetylcysteine↗
PubMed2002

Urinary hydroxyproline as a biomarker of effect after exposure to nitrogen dioxide.

A cross-sectional study was carried out on two groups of subjects differently exposed to nitrogen dioxide in order to test the urinary hydroxyproline ratio (UHP/mg/24 h/m(2)) as a biomarker of effect after exposure to this pollutant. UHP was determined in samples of 58 subjects divided into two groups comparable to as lifestyle and training. The first group was composed of 29 subjects who used to do jogging in urban areas polluted by nitrogen dioxide. The second group was made up of 29 subjects who used to do jogging in non-polluted countryside areas. The mean concentration of UHP of urban joggers was 25.02+/-9.21 mg/24 h/m(2), whereas in those training in the countryside it was 13.78+/-6.68 mg/24 h/m(2). Thus, UHP was higher in subjects training in areas polluted by nitrogen dioxide than in the subjects training in non-polluted areas.

Adolescent↗
PubMed2004

Investigation of the reliability of 24 h urine excretion as a biomarker of isoflavone exposure over time and over a wide range of isoflavone intakes.

OBJECTIVE: To study the variation in genistein + daidzein intake over a 6-month period and test the reliability of 24 h urinary isoflavones as a biomarker of exposure over time. DESIGN: Dietary genistein + daidzein intake was assessed at various time points throughout six months in 15 healthy subjects. Group 1 (n=8) followed nonsupplemented diets and Group 2 (n=7) took a 35 mg/d isoflavone supplement for 3 months and each subject provided a 24 h urine collection, validated with para-aminobenzoic acid, during weeks 7, 15 and 19. Urine was analysed for genistein and daidzein using LC-MS. RESULTS: Isoflavone intake in Groups 1 and 2 ranged from 0.00 to 1.1 mg/d and 0.1 to 53.1 mg/d, respectively. Urine excretion for both groups ranged from 0.20 to 9.56 mg/d. The relationship between 24 h excretion and isoflavone intake is y=0.44 x +/- 0.03(standard deviation) + 1.57; r=0.89, P<0.001. CONCLUSION: The 24 h urinary isoflavones can be used as biomarkers of isoflavone exposure over time.

Adult↗
PubMed2003

Further evaluation of the basic nature of the human biological aging process based on a factor analysis of age-related physiological variables.

This study aimed to reexamine whether there exists a primary aging process that controls the rate of aging in a number of different functions. Eighty-six adult males who successively received a 2-day routine health checkup test for 7 years from 1992 to 1998 at the Kyoto Red Cross Hospital were selected as subjects. Nine candidate biomarkers of aging were selected from the 25 physiological variables based on the investigation of age-related changes. A principal factor analysis was applied to the partial correlation matrix for 9 selected biomarkers calculated by controlling for age. Furthermore, a confirmatory factor analysis in testing first- and second-order factor models was applied to the covariance matrix for 9 biomarkers. The results of these factor analyses revealed that there existed one general factor and three system-specific factors. Therefore, biological age changes can be viewed as a time-dependent complex integration of the primary and secondary aging processes.

Adult↗
PubMed2004

Pharmacogenomics.

The discovery of the human genome and subsequent expansion of proteomics research combined with emerging technologies such as functional imaging, biosensors and sophisticated computational biology are producing unprecedented changes in today's healthcare. The expanding knowledge of the molecular basis of cancer has shown that significant differences in gene expression patterns can guide therapy not only for neoplastic conditions, but also for a variety of diseases including inflammatory disorders, cardiovascular disease and neurodegenerative processes. As a result, the fields of pharmacogenetics and pharmacogenomics have emerged as potential new testing platforms for the individualized management of patients. An individual's response to a drug is the complex interaction of both genetic and non-genetic factors. Genetic variants in the drug target itself, disease pathway genes, or drug metabolizing enzymes may all be used as predictors of drug efficacy or toxicity. In oncology, the SNP technology has focused on detecting the predisposition for cancer, predicting of toxic responses to drugs and selecting the best individual and combinations of anti-cancer drugs. Pharmacogenomics involves the application of whole genome technologies (e.g., gene and protein expression data) for the prediction of the sensitivity or resistance of an individual's disease to a single or group of drugs. Genomic microarrays and transcriptional profiling have the ability to generate hundreds of thousands of data points requiring sophisticated and complex information systems necessary for accurate and useful data analysis. This technique has generated a wealth of new information in the fields of leukemia/lymphoma, and solid tumor classification and prediction of metastasis, drug and biomarker target discovery and pharmacogenomic drug efficacy testing.

Drug Resistance, Neoplasm↗
PubMed2006

Urotensin II and biomarkers of endothelial activation and atherosclerosis in end-stage renal disease.

BACKGROUND: Urotensin II (UTN), a cyclic undecapeptide widely distributed in various organs and tissues, is found in high concentration in atheromatous lesions. Because UTN accumulates in patients with chronic renal failure, the association between plasma UTN and biomarkers of atherosclerosis and endothelial activation needs to be better understood. METHODS: We tested by a robust statistical approach (Holm method) the association between plasma UTN and biomarkers of atherosclerosis and endothelial activation in a population of 191 patients undergoing chronic hemodialysis. RESULTS: Plasma UTN was significantly higher in patients with end-stage renal disease (median: 6.5 ng/mL) than in healthy subjects (median: 3.1 ng/mL) (P < .001), and in both patients and control subjects it was independent of age and sex. Interestingly, UTN was inversely related to fibrinogen (r = -0.50, P < .004), intracellular adhesion molecule-1 (r = -0.24, P < .004) and with NO synthesis inhibitor asymmetric dimethyl-arginine (r = -0.40, P < .004). These links were paralleled by direct correlations with albumin (r = 0.21, P < .006) and with transforming growth factor-beta1 (TGFbeta1) (r = 0.36, P < .004). Of note, on multiple regression analysis, these associations remained highly significant also after data adjustment for potential confounders. CONCLUSIONS: The inverse links between UTN with biomarkers of atherosclerosis and endothelial activation suggest that downregulation of UTN may be a counter-regulatory response aimed at mitigating cardiovascular damage or that UTN itself is a protective factor.

Arginine↗
PubMed2005

Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach.

Quantitative proteomics can be used as a screening tool for identification of differentially expressed proteins as potential biomarkers for cancers. Candidate biomarkers from such studies can subsequently be tested using other techniques for use in early detection of cancers. Here we demonstrate the use of stable isotope labeling with amino acids in cell culture (SILAC) method to compare the secreted proteins (secretome) from pancreatic cancer-derived cells with that from non-neoplastic pancreatic ductal cells. We identified 145 differentially secreted proteins (>1.5-fold change), several of which were previously reported as either up-regulated (e.g. cathepsin D, macrophage colony stimulation factor, and fibronectin receptor) or down-regulated (e.g. profilin 1 and IGFBP-7) proteins in pancreatic cancer, confirming the validity of our approach. In addition, we identified several proteins that have not been correlated previously with pancreatic cancer including perlecan (HSPG2), CD9 antigen, fibronectin receptor (integrin beta1), and a novel cytokine designated as predicted osteoblast protein (FAM3C). The differential expression of a subset of these novel proteins was validated by Western blot analysis. In addition, overexpression of several proteins not described previously to be elevated in human pancreatic cancer (CD9, perlecan, SDF4, apoE, and fibronectin receptor) was confirmed by immunohistochemical labeling using pancreatic cancer tissue microarrays suggesting that these could be further pursued as potential biomarkers. Lastly the protein expression data from SILAC were compared with mRNA expression data obtained using gene expression microarrays for the two cell lines (Panc1 and human pancreatic duct epithelial), and a correlation coefficient (r) of 0.28 was obtained, confirming previously reported poor associations between RNA and protein expression studies.

Biomarkers, Tumor↗
PubMed2005

The potential value of blood biomarkers of intervertebral disk metabolism in the follow-up of patients with sciatica.

STUDY DESIGN: This is a prospective study with a follow-up period of 4 years. OBJECTIVES: The study aimed to evaluate the possible clinical utility of three biomarkers [i.e., keratan sulfate (KS), hyaluronan, and cartilage oligomeric matrix protein] measured in peripheral blood in severe acute sciatica at intake and follow-up. SUMMARY OF BACKGROUND: Our previous study and others have pointed out the interest of different laboratory tests in the acute phase of sciatica. Several blood biomarkers have been reported useful in the long-term follow-up of patients with osteoarthritis. We have found no information about the potential interest of these tests in spinal disorders. METHODS: Patients were admitted to the hospital for intensive conservative management of acute sciatica (n=82). A subgroup of patients (n=33) was selected based on the duration of symptoms at visit 1, and included those with the shortest (n=24) as well as those with the longest (n=9) duration of sciatica. Blood samples were drawn, centrifuged, and the plasma frozen. Antigenic KS, hyaluronan, and cartilage oligomeric matrix protein were measured by ELISA. Patients were re-evaluated at an average of 4.3 years (range: 2.1-6.8 years). RESULTS: Thirty-three subjects with an average age of 49.2+/-10.2 years participated. At intake, levels of the three biomarkers evaluated were within the range of normal values. No significant differences were found between the results of patients with a short history of sciatica (< or =3 weeks) and those with a long duration of symptoms (>20 weeks). At follow-up, a significant increase (P<0.05) in all three biomarkers was found. CONCLUSIONS: A single measurement of these three biomarker molecules does not seem to have any diagnostic or therapeutic relevance in patients with acute radicular compression. The significance of the increase in all three biomarkers after a mean follow-up of 4.3 years is unclear; it might reflect metabolic processes involved in degenerative spinal disorders. Even though we found no correlation with clinical outcome, we believe that more research is needed.

Adult↗