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At least 1,441 records · Page 80Linked to original sources
PubMed1998

[Diagnostic difficulties of myocardial infarct in an admissions and emergency service: influence of age].

OBJECTIVE: To analyze the clinical signs and electrocardiographic and enzyme data in patients admitted to an emergency ward for myocardial infarction in order to highlight diagnostic pitfalls. PATIENTS AND METHODS: All patients admitted to our emergency ward between October 1995 and October 1996 with elevated myoglobulin or creatinine phosphokinase (CPK) levels (n = 457 patients) were included in the study series. Patient files were randomly selected (n = 257 files) for review by an emergency ward specialist and a cardiologist to identify cases of myocardial infarction (n = 88 patients, mean age 73.4 +/- 15.2 years). Clinical, electrical and enzyme data (including CPK-MB) were analyzed. RESULTS: The patients had been referred for chest pain (69%), dyspnea (24%) or another disorder (7%). Pain was located in the retrosternal area in 51%, in the lower chest in 19% and elsewhere in 30%. Delay between onset of pain and transfer to the emergency ward was 5 h 20 min +/- 6 h. Signs of left heart failure were observed in 50% of the patients. The admission electrocardiogram showed complete criteria for myocardial infarction in 43% of the cases, incomplete criteria in 21% and was non-contributive in 36%. Enzyme results were elevated in 78% of the cases at the first assay and in 98.2% at the second assay. Both typical chest pain and ECG were observed in only 30% of the cases. Chest pain was present in 55% of the patients over 75 years of age and in 81% of those under 75 years (p = 0.007). CONCLUSION: A typical syndrome is observed in less than one-third of all patients with myocardial infarction admitted to emergency wards. The frequency of atypical presentations increases with age.

Age Factors↗
PubMed2002

Tyrosinemia I, a model for human diseases mediated by 2-oxoacid-utilizing dioxygenases: hepatotoxin suppression by NTBC does not normalize hepatic collagen metabolism.

OBJECTIVES: Medical treatment of tyrosinemia I relies on the herbicide NTBC [Orfadin 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione], an inhibitor of plant and mammalian 2-oxoacid-utilizing dioxygenases with a collective catalytic cycle ('HAG' mechanism). We hypothesize that NTBC-treated tyrosinemia I is a human model for the pathogenic role of two major enzymes in this class, 4-hydroxyphenylpyruvate dioxygenase (4-HPPD; EC 1.13.11.27) and prolyl 4-hydroxylase (P4-H; E.C. 1.14.11.2), essential for tyrosine and collagen metabolism, respectively. METHODS: In a patient with established tyrosinemia I, we monitored the in vivo activities of 4-HPPD and P4-H via five biomarkers before and during NTBC medication. Hypothesis testing at the molecular level was performed by computational modeling of NTBC binding to the crystal structure-derived active site of 4-HPPD, and then relating these findings to our experimental results and to known P4-H data. RESULTS: NTBC rapidly normalized the biomarkers for 4-HPPD activity. However, those for P4-H activity remained uniformly elevated after one hundred days on NTBC, the PIIINP biomarker even increasing above its grossly abnormal, initial level. This selective enzyme inhibition despite a collective catalytic cycle is attributed to the conformation of NTBC, which only fits the active site of 4-HPPD, as confirmed by its crystal structure. CONCLUSIONS: Normalization of hepatic collagen formation, highly desirable in all fibrotic liver diseases, is not achieved by NTBC in tyrosinemia I. By establishing the molecular cause for this failure, our results also establish a rational approach to identify inhibitors that achieve that goal, either by joint 4-HPPD / P-4H inhibition, or by inhibition of only P-4H.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2005

Multigene methylation analysis for detection and staging of prostate cancer.

PURPOSE: Aberrant gene promoter methylation profiles have been well-studied in human prostate cancer. Therefore, we rationalize that multigene methylation analysis could be useful as a diagnostic biomarker. We hypothesize that a new method of multigene methylation analysis could be a good diagnostic and staging biomarker for prostate cancer. EXPERIMENTAL DESIGN: To test our hypothesis, prostate cancer samples (170) and benign prostatic hyperplasia samples (69) were examined by methylation-specific PCR for three genes: adenomatous polyposis coli (APC), glutathione S-transferase pi (GSTP1), and multidrug resistance 1 (MDR1). The methylation status of representative samples was confirmed by bisulfite DNA sequencing analysis. We further investigated whether methylation score (M score) can be used as a diagnostic and staging biomarker for prostate cancer. The M score of each sample was calculated as the sum of the corresponding log hazard ratio coefficients derived from multivariate logistic regression analysis of methylation status of various genes for benign prostatic hyperplasia and prostate cancer. The optimal sensitivity and specificity of the M score for diagnosis and for staging of prostate cancer was determined by receiver-operator characteristic (ROC) curve analysis. A pairwise comparison was employed to test for significance using the area under the ROC curve analysis. For each clinicopathologic finding, the association with prostate-specific antigen (PSA) failure-free probability was determined using Kaplan-Meier curves and a log-rank test was used to determine significance. The relationship between M score and clinicopathologic findings was analyzed by either the Mann-Whitney U test, Kruskal-Wallis test, or the Spearman rank correlation test. RESULTS: The frequency of positive methylation-specific PCR bands for APC, GSTP1, and MDR1 genes in prostate cancer samples was 64.1%, 54.0%, and 55.3%, respectively. In benign prostatic hyperplasia samples, it was 8.7%, 5.8%, and 11.6%, respectively. There was a significant correlation of M score with high pT category (P < 0.001), high Gleason sum (P < 0.001), high preoperative PSA (P = 0.027), and advanced pathologic features. For all patients, the M score had a sensitivity of 75.9% and a specificity of 84.1% as a diagnostic biomarker using a cutoff value of 1.0. In patients with low or borderline PSA levels (<10.0 ng/mL), the M score was significantly higher in prostate cancers than in benign prostatic hyperplasias (2.635 +/- 0.200 and 0.357 +/- 0.121, respectively). ROC curve analysis revealed that the M score had a sensitivity of 65.4% and a specificity of 94.2% when 1.0 was used as a cutoff value. For all patients, M score can distinguish organ-confined (< or =pT(2)) from locally advanced cancer (> or =pT(3)) with a sensitivity of 72.1% and a specificity of 67.8%. Moreover, considering patients with PSA levels of <10 ng/mL, the M score has a sensitivity of 67.1% and a specificity of 85.7%. The ROC curve analysis showed a significant difference between M score and PSA (P = 0.010). CONCLUSIONS: This is the first report demonstrating that M score is a new method for multigene methylation analysis that can serve as a good diagnostic and staging biomarker for prostate cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Immunodiscrimination of colorectal neoplasia using MUC1 antibodies: discrepant findings in tissue versus stool.

Colorectal tumor-associated antigens are attractive targets for novel stool-screening assays. MUC1, a glycoprotein antigen, is aberrantly expressed in transformed colorectal mucosa and represents a candidate fecal biomarker. In this study, tissue staining and stool testing were performed to further clarify the discriminant potential of MUC1 in markedly different biologic media. One anti-MUC1 monoclonal antibody (MA5) was used for immunohistochemistry and two commercially available MUC1 assay kits (ELSA-CA 15-3 and Truquant BR) were used for stool detection. On tissue staining, MUC1 expression was strong in 40/40 (100%) adenocarcinomas, moderate in 42/55 (76%) adenomas, faint in 8/28 (29%) juxtatumoral mucosa specimens, and absent in 15/15 (0%) nonadjacent mucosa specimens. Conversely MUC1 levels in stool testing did not differ between colorectal cancer cases (N = 14) and controls (N = 14). Based on these results, MUC1 appears to be a functional tumor biomarker in colorectal tissue but not in stool. Bacterial metabolism within stool may unmask the core antigen of MUC1 and account for this discordance in immunoreactivity.

Adenocarcinoma↗
PubMed2005

Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers.

BACKGROUND: Age-related macular degeneration (AMD) and cardiovascular disease share common risk factors. Inflammatory biomarkers, including C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor alpha receptor 2, soluble intercellular and vascular adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), and lipid biomarkers, including lipoprotein(a) and apolipoprotein B, have all been associated with cardiovascular disease. We previously found an association between AMD and CRP in a cross-sectional analysis, but the prospective relationships between AMD, CRP, and the other cardiovascular disease markers are unknown. OBJECTIVE: To test the hypothesis that baseline cardiovascular disease biomarkers are associated with subsequent increased risk for progression of AMD. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study involved 251 participants aged 60 years and older who had some sign of nonexudative AMD and visual acuity of 20/200 or better in at least one eye at baseline. The AMD status was assessed by standardized grading of fundus photographs, and stored fasting blood specimens obtained at baseline were analyzed for levels of the various biomarkers. The average follow-up time was 4.6 years. MAIN OUTCOME MEASURES: Relationship between biomarkers and incidence rates of progression of AMD. RESULTS: Comparing the highest quartile with the lowest quartile, CRP was associated with progression of AMD, with a multivariate adjusted relative risk (RR) of 2.10 (95% confidence interval [CI], 1.06-4.18; P for trend, .046) controlling for body mass index, smoking, and other cardiovascular variables and a multivariate adjusted RR of 2.02 (95% CI, 1.00-4.04; P for trend, .06) controlling additionally for antioxidant nutrients. Interleukin 6 was also related to progression of AMD, with a multivariate adjusted RR of 1.81 (95% CI, 0.97-3.36; P for trend, .03). Comparing the highest quartile with the lowest quartile, the effect estimates for vascular cell adhesion molecule 1 (multivariate adjusted RR, 1.94) and apolipoprotein B (adjusted RR, 1.39) were in the positive direction but were not statistically significant (P for trend, .08 and .24, respectively). The CRP and IL-6 levels were both significantly related to higher body mass index and current smoking. CONCLUSIONS: Higher levels of the systemic inflammatory markers CRP and IL-6 are independently associated with progression of AMD.

Aged↗
PubMed2006

Determination of carbohydrate-deficient transferrin in human serum using the Bio-Rad %CDT by HPLC test.

BACKGROUND: Carbohydrate-deficient transferrin (CDT) in serum is a biomarker used to identify individuals with sustained, heavy alcohol consumption. This study evaluated the performance of a new commercial method for CDT, the Bio-Rad %CDT by HPLC test, that measures relative amounts of separate transferrin glycoforms in proportion to total transferrin. METHOD: The samples used were two human serum pools (low/high disialotransferrin), 150 clinical sera with low to highly elevated disialotransferrin values, and 18 genetic transferrin variants. Glycoforms are separated on a gradient HPLC system, followed by specific measurement of the iron-transferrin complex at 460 nm. Comparison was made with an HPLC candidate reference method on an Agilent 1100 LC system. RESULTS: The Bio-Rad %CDT by HPLC test allowed for reproducible separation and quantification of the transferrin glycoforms within approximately 6 min. Genetic variants were readily identified. For the low and high serum pool, the total CV was 8.5% and 4.3%, respectively. The relative amounts of disialotransferrin, the main CDT glycoform, were in good agreement with the results of the HPLC candidate reference method (r(2)=0.998, p<0.0001). CONCLUSIONS: The present results demonstrated that the Bio-Rad %CDT by HPLC test is appropriate for confirmatory and routine %CDT testing in human serum, with the added advantage over previously published HPLC methods of an improved serum sample pretreatment and a shorter total analysis time.

Alcoholism↗
PubMed2001

Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure?

Chelation challenge testing has been used to assess the body burden of various metals. The best-known example is EDTA challenge in lead-exposed individuals. This study assessed diagnostic chelation challenge with dimercaptosuccinic acid (DMSA) as a measure of mercury body burden among mercury-exposed workers. Former employees at a chloralkali plant, for whom detailed exposure histories were available (n = 119), and unexposed controls (n = 101) completed 24-hr urine collections before and after the administration of two doses of DMSA, 10 mg/kg. The urinary response to DMSA was measured as both the absolute change and the relative change in mercury excretion. The average 24-hr mercury excretion was 4.3 microg/24 hr before chelation, and 7.8 microg/24 hr after chelation. There was no association between past occupational mercury exposure and the urinary excretion of mercury either before or after DMSA administration. There was also no association between urinary mercury excretion and the number of dental amalgam surfaces, in contrast to recent published results. We believe the most likely reason that DMSA chelation challenge failed to reflect past mercury exposure was the elapsed time (several years) since the exposure had ended. These results provide normative values for urinary mercury excretion both before and after DMSA challenge, and suggest that DMSA chelation challenge is not useful as a biomarker of past mercury exposure.

Biomarkers↗
PubMed2000

Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast.

We tested the long-term effects of sublethal oxidative stresses on replicative senescence. WI-38 human diploid fibroblasts (HDFs) at early cumulative population doublings (CPDs) were exposed to five stresses with 30 microM tert-butylhydroperoxide (t-BHP). After at least 2 d of recovery, the cells developed biomarkers of replicative senescence: loss of replicative potential, increase in senescence-associated beta-galactosidase activity, overexpression of p21(Waf-1/SDI-1/Cip1), and inability to hyperphosphorylate pRb. The level of mRNAs overexpressed in senescent WI-38 or IMR-90 HDFs increased after five stresses with 30 microM t-BHP or a single stress under 450 microM H(2)O(2). These corresponding genes include fibronectin, osteonectin, alpha1(I)-procollagen, apolipoprotein J, SM22, SS9, and GTP-alpha binding protein. The common 4977 bp mitochondrial DNA deletion was detected in WI-38 HDFs at late CPDs and at early CPDs after t-BHP stresses. In conclusion, sublethal oxidative stresses lead HDFs to a state close to replicative senescence.

Biomarkers↗
PubMed2004

Albumin, a new biomarker of organophosphorus toxicant exposure, identified by mass spectrometry.

The classical laboratory tests for exposure to organophosphorus toxicants (OP) are inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in blood. In a search for new biomarkers of OP exposure, we treated mice with a biotinylated organophosphorus agent, FP-biotin. The biotinylated proteins in muscle were purified by binding to avidin-Sepharose, separated by gel electrophoresis, digested with trypsin, and identified from their fragmentation patterns on a quadrupole time-of-flight mass spectrometer. Albumin and ES1 carboxylesterase (EC 3.1.1.1) were found to be major targets of FP-biotin. These FP-biotinylated proteins were also identified in mouse plasma by comparing band patterns on nondenaturing gels stained for albumin and carboxylesterase activity, with band patterns on blots hybridized with Streptavidin Alexa-680. Two additional FP-biotin targets, AChE (EC 3.1.1.7) and BChE (EC 3.1.1.8), were identified in mouse plasma by finding that enzyme activity was inhibited 50-80%. Mouse plasma contained eight additional FP-biotinylated bands whose identity has not yet been determined. In vitro experiments with human plasma showed that chlorpyrifos oxon, echothiophate, malaoxon, paraoxon, methyl paraoxon, diazoxon, diisopropylfluorophosphate, and dichlorvos competed with FP-biotin for binding to human albumin. Though experiments with purified albumin have previously shown that albumin covalently binds OP, this is the first report of OP binding to albumin in a living animal. Carboxylesterase is not a biomarker in man because humans have no carboxylesterase in blood. It is concluded that OP bound to albumin could serve as a new biomarker of OP exposure in man.

Acetylcholinesterase↗