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A case-cohort study of an early biomarker of lung cancer in a screening cohort of Yunnan tin miners in China.

We initiated the present study to evaluate the accuracy of a new epithelial biomarker of early lung cancer. We tested the hypothesis that expression of a tumor-associated antigen by exfoliated sputum epithelial cells has greater accuracy (sensitivity and specificity) for the detection of preclinical, localized lung cancer than do routine clinical detection methods. Monoclonal antibody (MAb) 703D4 recognizes heterogeneous nuclear ribonuclear protein (hnRNP) A2/B1. We compared the accuracy of hnRNP up-regulation with cytology and radiographic screening for lung cancer detection in miners who were highly exposed to tobacco smoke, radon, and arsenic in southwestern China. The results showed that MAb 703D4 detection of hnRNP expression by sputum epithelial cells had greater accuracy for the detection of lung cancer than did routine screening methods, particularly for early (localized) disease. Among 57 cases and 76 noncases at the first screening, overall MAb detection of hnRNP was more sensitive (74 versus 21% for cytology and 42% for chest x-ray) but had lower specificity (70 versus 100% for cytology and 90% for chest x-ray) than standard methods. Recognizing hnRNP up-regulation resulted in detection of approximately one-third more early cases than did the combination of X-ray and cytology. Detection of hnRNP A2/B1 expression appears to be a good initial screening test for lung carcinogenesis, as it identified 74% of those who developed subsequent clinical lung cancer. Future studies might separate individuals with high lung cancer risk by MAb detection, confirming the positives with markers having greater specificity (e.g., clinical studies that become positive later in the morphological progression).

Adult↗

Preclinical diagnosis of Parkinson's disease: are we there yet?

Preclinical Parkinson's disease (PD) can be defined as a state that precedes the diagnosis of PD but without the presence of the characteristic motor features of the disorder. In such a situation, subtle non-motor features may be present or subclinical abnormalities may exist that can be detected only by physiologic testing. Alternatively, lifelong traits such as genetic mutations may predict the onset of PD in the absence of any clinical or physiologic abnormalities. A number of diagnostic technologies are currently available that can detect both preclinical states and traits that will lead to PD in the future. The current challenges are to refine these technologies and to determine how they should be employed so that their use is ethical, practical, and meaningful to at-risk individuals.

3-Iodobenzylguanidine↗

Helicobacter pylori "test-and-scope" strategy for dyspeptic patients. Is it useful and safe?

AIM: To evaluate outcome of test-and-scope strategy using 13C-urea breath test, Helicobacter pylori IgG serology, and CagA serology. PATIENTS AND METHODS: A series of 100 dyspeptic patients were studied. Biopsies were obtained for histology and rapid urease test (gold standard). Serum samples were obtained for Helicobacter pylori IgG and CagA serology, and 13C-urea breath test was carried out. RESULTS: If endoscopy had not been performed in Helicobacter pylori patients based on 13C-urea breath test, <45 years, without alarm symptoms, and without non-steroidal anti-inflammatory drug use, 15% of endoscopies would have been saved, and one gastric ulcer and two oesophagitis would have been missed. Based on Helicobacter pylori IgG serology, 21% of endoscopies would have been saved. Finally, if endoscopy had been performed only in CagA+ patients, 31% of endoscopies would have been saved, missing one gastric ulcer and two cases of oesophagitis. CONCLUSIONS: In our geographical area, the test-and-scope strategy based on 13C-urea breath test or Helicobacter pylori IgG serology would have saved only 15-20% of endoscopies. Although some relevant pathology would have been missed, it is not of a malignant type. 13C-urea breath test is the preferred non-invasive method to be used in this strategy, while Helicobacter pylori IgG serology is of limited value due to its low accuracy. With the use of CagA serology a larger number of unnecessary endoscopic examinations can be avoided.

Adult↗

The usefulness of serum adenosine deaminase 2 (ADA2) activity in adults for the diagnosis of pulmonary tuberculosis.

Rapid diagnosis of Mycobacterium tuberculosis remains an obstacle for therapy of tuberculosis (TB). Adenosine deaminase isoform 2 (ADA2) is produced by activated macrophages and has been used for diagnosis of TB from extra-pulmonary sites. However, few studies adequately address whether serum ADA2 activity is useful for diagnosis of active pulmonary tuberculosis (PTB). We prospectively measured serum ADA2 activity in 110 patients with pulmonary disease (65 cases with active PTB and 45 cases with other respiratory diseases) and 78 healthy volunteers (eight with tuberculin skin test positive). The serum ADA2 for the diagnosis of PTB had the sensitivity of 36.9%, the specificity of 84.5%, the positive predictive value of 10.9% and the negative predictive value of 96.2%. We concluded that serum ADA2 activity is neither useful to diagnosis of active PTB nor to differentiate from other respiratory diseases.

Adenosine Deaminase↗

Effect of gas cooking on lung function in adolescents: modifying role of sex and immunoglobulin E.

BACKGROUND: A study was undertaken to investigate the effect of gas cooking on the lung function of adolescents while considering serum IgE level as a possible effect modifier. METHOD: The cross sectional study was performed in 702 subjects aged 11-13 years from primary and secondary schools in Civitavecchia and Viterbo ( Latium region in Central Italy), categorised according to how often they were in the kitchen while the mother cooked (never, sometimes, often). Data were collected by questionnaire and lung function was measured by spirometric tests. Bronchial hyperresponsiveness was evaluated by the methacholine test, atopic status by a skin prick test, and a blood sample was collected to determine serum IgE levels. The results were analysed separately for boys and girls. Multiple regression analysis was performed, taking functional parameters (FEV(1), FEV(1)/FVC, FEF(25-75), FEF(50), FEF(75)) as the dependent variables and age, height, parental smoking, and father's education as independent variables. RESULTS: There was no association between time spent in the kitchen and lung function level in boys, but a reduction in lung function was detected in girls which was statistically significant for FEF(75) (sometimes -10.3%, often -11.1%). After stratifying boys and girls into four groups on the basis of the IgE serum level (below and above the median value of IgE), the reduction in lung function was significant in girls with a high IgE value whereas no significant deleterious effects were evident in girls with a low IgE value or in boys with either a low or high IgE. The results remained substantially unchanged after excluding girls with a response to methacholine below the concentration of 4 mg/ml, asthmatic patients, and those with positive skin prick tests. CONCLUSION: Gas cooking has a harmful effect on the lung function of girls with a high serum level of IgE. We do not know whether serum IgE, a marker of allergic susceptibility, is a simple indicator that an inflammatory process is in progress or whether it is involved in the pathogenesis of injury leading to bronchial obstruction.

Adolescent↗

An assessment of a urinary biomarker for total human environmental exposure to benzo[a]pyrene.

Urinary banzo[a]pyrene (BaP) metabolite levels were compared to human environmental exposure to BaP through inhalation and dietary ingestion to assess the predictive validity of the exposure biomarker. These measurements were made for 14 adult volunteers over 14 consecutive days, once during summer/fall, again during winter periods. Based on personal air monitoring, median potential inhalation doses of 11.0 and 2.3 ng/day were estimated for the winter and summer/fall studies, respectively. A median potential ingested dose of 176 ng/day, estimated from "duplicate plate" sampling, exceeded inhalation by 6- and 122-fold for the winter and summer/fall studies, respectively. "Total" urinary BaP metabolites were measured using a published "reverse metabolism" (BaP) method of analysis. Median rates of urinary BaP metabolite elimination for the winter and summer/fall studies were 121 and 129 ng/day, respectively. The changes in inhaled and ingested potential doses were regressed on the change in urinary metabolite elimination from week 1 to week 2 to test the predictive validity of the biomarker measurement. The regression was statistically significant (r = 0.620, p = 0.015, n = 25) when body weight was included and two extreme values were removed. Consistent with the exposure measurements showing diet as the dominant route of exposure, most of the variation in urinary metabolite elimination was explained by the ingested dose. It is concluded that the measurement of urinary BaP by "reverse metabolism" is qualitative and of marginal predictive validity as an exposure biomarker due to the method's low recoveries and the large unexplained variance.

Adult↗

Risk markers for the graded severity of auditory processing abnormality in an older Australian population: the Blue Mountains Hearing Study.

A recent report from a population-based survey of hearing loss in 2015 older adults showed that the overall prevalence of central auditory processing (CAP) abnormality was high at 76.4% using abnormality on one or more of seven speech-based test outcomes as the criteria. The present study grouped these test outcomes to reflect increasing severity of CAP abnormality and examined the relationship between this graded dependent variable and 16 independent variables. Logistic regression modeling suggested that moderate and severe CAP abnormality increased with age and was associated with increased hearing handicap, and men were more likely than women to show severe abnormality. While 98.5% of the population passed a cognitive screening assessment, declining cognitive function was still associated with the increased likelihood of CAP abnormality.

Aged↗

Plasma intestinal alkaline phosphatase isoenzymes in neonates with bowel necrosis.

AIM: To determine if the intestinal isoenzymes of alkaline phosphatase (ALP) are biochemical markers of bowel necrosis in neonates. METHODS: Plasma ALP isoenzymes were measured in 22 babies with bowel necrosis, histologically confirmed, and in 22 matched controls. The isoenzymes were also measured in 16 infants with signs of necrotising enterocolitis, who recovered without histological confirmation of bowel necrosis. The isoenzymes were separated by polyacrylamide gel electrophoresis. Auxiliary tests for identification included neuraminidase digestion and treatment with monoclonal and polyclonal antiplacental antibodies. RESULTS: Intestinal ALP was detected in 16 infants with bowel necrosis--13 had fetal intestinal ALP (FI-ALP) and three had adult intestinal ALP (AI-ALP). FI-ALP was detected in nine of the controls. In the babies with bowel necrosis intestinal ALP was found over all gestations, but in the controls only in those less than 34 weeks. The percentages of total ALP activity due to intestinal ALP were significantly higher in those with bowel necrosis compared with matched controls (p = 0.028). In babies of all gestations diagnostic sensitivity for the presence of intestinal ALP as a marker of bowel necrosis was 73% and diagnostic specificity 59%. In babies greater than 34 weeks' gestation, diagnostic sensitivity fell to 60% but the test became completely specific. In two babies FI-ALP increased from zero/trace to high activity coincident with the episode of bowel necrosis. In 16 babies with signs of necrotising enterocolitis but unconfirmed bowel necrosis FI-ALP was detected in four. CONCLUSION: Intestinal ALP seems to be released into the circulation in some babies with bowel necrosis, but its detection does not have the diagnostic sensitivity and specificity to be a reliable biochemical marker of the condition.

Alkaline Phosphatase↗

Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIC) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human model of endotoxemia: toward a better definition of DIC.

OBJECTIVE: Work toward a better definition of disseminated intravascular coagulation (DIC) by characterizing the difference between compensated and uncompensated responses of the hemostatic system to inflammatory stress in baboons and human subjects using global coagulation and molecular marker assays of hemostatic, inflammatory, and endothelial perturbation. DESIGN: We conducted prospective evaluation of the response of baboons to increasing concentrations of intravenous Escherichia coli, human subjects to intravenous endotoxin, and baboons to intraperitoneal E. coli. SETTING: Animal laboratory and medical intensive care facilities, University of Oklahoma Medical School laboratories. SUBJECTS: Cynocephalus baboons; normal healthy male human subjects (age, 24-37 yrs). MEASUREMENTS AND MAIN RESULTS: Global coagulation assays, white blood cell counts, and molecular marker assays (ELISA) of components of the inflammatory and hemostatic systems, neutrophil release products, and endothelial injury. A fall in both fibrinogen concentration and platelet counts indicated a decompensated hemostatic response to inflammatory stress (ie, overt DIC). These responses were observed 2-6 hrs after intravenous infusion of 10(9) and 10(10) colony-forming units (CFU)/g of E. coli and after implantation of 10(11) CFU/g of E. coli into the peritoneal cavity. However, 6 hrs after E. coli challenge, these tests were much less reliable as markers of overt DIC because the fibrinogen underwent an acute phase response and the platelet count fell and remained depressed for 48 hrs in the face of a coagulopathic response that was already beginning to resolve, as reflected by a rising fibrinogen concentration. This lack of reliability was particularly evident in the E. coli peritonitis studies, in which one third of the animals recovered, one third remained sick for up to 14 days, and one third died. In contrast, fibrin degradation products and the molecular markers thrombin/antithrombin, soluble fibrin monomer, protein C, and activated protein C/inhibitor complexes responded consistently in a dose-dependent manner regardless of the length of time after challenge. These variables exhibited this dose response to 106 and 108 CFU/g of E. coli in absence of a fall in fibrinogen concentration. This was defined as a compensated hemostatic response to inflammatory stress (ie, non-overt DIC). The values of these variables correlated closely with rising concentrations of markers of neutrophil activation (elastase/alpha 1 antitrypsin) and endothelial injury (soluble thrombomodulin). This was particularly evident in the human response to endotoxin, in which there was abundant evidence of hemostatic marker response in absence of a fall in platelet or fibrinogen concentration, both immediately after endotoxin infusion (first stage, 0-8 hrs after endotoxin) and later (second stage, 12-48 hrs after endotoxin). CONCLUSION: Global coagulation tests are most useful in detecting overt consumptive coagulopathy (overt DIC) near the time of challenge or injury (1 to 6 hrs). Molecular markers can detect and grade the degree of hemostatic stress of a non-overt consumptive coagulopathy (nonovert DIC). These markers correlate with degree of endothelial cell injury and reveal a reperfusion injury stage (second stage) in the human endotoxin model of compensated hemostatic stress after all clinical symptoms have subsided and the subjects have returned to work.

Animals↗

Use of a dual monoclonal solid phase and a polyclonal detector to create an immunoassay for the detection of human cardiac troponin I.

OBJECTIVES: We report the development of a fully automated, random access, chemiluminescent immunoassay, for the detection of human cardiac Troponin I (cTnI) in serum and plasma for use on the ACS:180(R) System. DESIGN AND METHODS: This assay format uses a combination of two monoclonal antibodies covalently coupled to paramagnetic (PMP) particles as a solid phase and an affinity purified polyclonal antibody, specific to the N-terminal domain of cTnI (peptide-3 region) labeled with a chemiluminescent compound as the detector antibody. The assay offers excellent low-end sensitivity and precision. RESULTS: No interferences are observed from by blood components such as HAMA and drugs used in cardiac therapy. Patient samples tested on the ACS:180 cTnI assay showed good correlation with the Stratus cTnI assay (ACS: cTnI = 1. 02*Stratus + 0.05 g/L, r = 0.96, n = 1170). CONCLUSION: Paired with the other ACS:180 cardiac assays, myoglobin and CKMBII, the ACS:180 system now offers an excellent panel of cardiac assay for use in rapid and accurate diagnosis of a myocardial event.

Antibodies, Monoclonal↗

Pseudoanaphylaxis.

Profound hypotension and cardiac arrest after commencement of combined spinal and general anaesthesia in a patient for knee replacement surgery raised the suspicion of anaphylaxis. This seemed to be confirmed when a mast cell tryptase test taken about 90 minutes after the onset of the hypotension was elevated. However, subsequent intradermal skin testing twelve weeks later did not identify a causal drug. Repeat mast cell tryptase at the time showed the same elevation, which led to the correct diagnosis of mastocytosis and a secondary diagnosis that the patient's hypotension and cardiac arrest were the result of her spinal anaesthesia. If the serum tryptase is elevated during the event but no allergic agent can be identified, a further serum tryptase should be taken several weeks later to exclude a persistent elevation due to mastocytosis.

Anaphylaxis↗

Performance of a new-generation chemiluminescent assay for hepatitis B surface antigen.

BACKGROUND: The usual criteria for analysis of hepatitis B surface antigen (HBsAg) are detection of HBsAg and result confirmation by antibody neutralization. We observed that with the Immulite 2000 HBsAg assay [Diagnostics Product Corporation (DPC)] a relatively high percentage of weakly reactive (WR) samples did not pass the neutralization step. METHODS: For each of 3 lots of Immulite 2000 HBsAg reagent (DPC), we collected and analyzed HBsAg data from approximately 3000 to 4000 patient blood samples and compared these data with HBsAg data from 3393 samples tested with the Abbott Auszyme assay. For 127 samples with initially WR detection signals (relative signal/cutoff index of 1.00-2.5) on the Immulite 2000 HBsAg assay, we then measured hepatitis B (HB) viral load and/or other HB serologic markers. RESULTS: The Immulite 2000 HBsAg assay produced more initially reactive results than the Abbott Auszyme method. Many of these reactive samples, however, were WR and did not meet the confirmation criteria in the neutralization test. Moreover, DNA PCR testing indicated that 22 of the 38 WR samples (58%) that did meet the confirmation criteria had no detectable HB viral DNA. CONCLUSIONS: Immulite 2000 HBsAg assay results include a unique group of WR samples that are associated with both false-positive and false-negative results, regardless of neutralization status, and require careful interpretation. WR HBsAg samples should be reported as confirmed HBsAg reactive only if the samples not only meet the neutralization criteria but also are positive for other HB serologic markers such as anti-HB core total and anti-HB core IgM.

Biomarkers↗

Assessment of micronuclei induction in peripheral erythrocytes of fish exposed to xenobiotics under controlled conditions.

The aim of the present study was to standardize and to assess the predictive value of the cytogenetic analysis by MN test in fish erythrocytes as a biomarker for marine environmental contamination. MN frequency baseline in erythrocytes was evaluated in a number of fish species from a reference area (S. Teresa, La Spezia Gulf) and genotoxic potential of a number of common chemical contaminants and mixtures was determined in fish experimentally exposed in aquarium under controlled conditions. Fish (Scophthalmus maximus) were exposed for 3 weeks to 50 ppb of single chemicals (dialkyl phthalate, bisphenol A, tetrabromodiphenyl ether), 30 ppb nonylphenol and mixtures (North Sea oil and North Sea oil with alkylated phenols). Chromosomal damage was determined as micronuclei (MN) frequency in fish erythrocytes. Nuclear anomalies such as blebbed, notched and lobed nuclei were also recorded. Significant increase in MN frequency was observed in erythrocytes of fish exposed to bisphenol A and tetrabromodiphenylether. Chemical mixture North Sea oil+alkylated phenols induced the highest MN frequency (2.95 micronucleated cells/1000 cells compared to 1 MNcell/1000 cells in control animals). The study results revealed that micronucleus test, as an index of cumulative exposure, appears to be a sensitive model to evaluate genotoxic compounds in fish under controlled conditions.

Animals↗

Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production.

Asthma may respond to dietary modification, thereby reducing the need for pharmacologic agents. This study determined the effectiveness of n-3 polyunsaturated fatty acid (PUFA) ingestion in ameliorating methacholine-induced respiratory distress in an asthmatic population. The ability of urinary leukotriene excretion to predict efficacy of n-3 PUFA ingestion was assessed. After n-3 PUFAs in ratios to n-6 PUFAs of 0.1:1 and 0.5:1 were ingested sequentially for 1 mo each; patient respiratory indexes were assessed after each treatment. Forced vital capacity (FVC), forced expiratory volume for 1 s (FEV1), peak expiratory flow (PEF), and forced expiratory flow 25-75% (FEF 25-75) were measured along with weekly 24-h urinary leukotriene concentrations. With low n-3 PUFA ingestion, methacholine-induced respiratory distress increased. With high n-3 PUFA ingestion, alterations in urinary 5-series leukotriene excretion predicted treatment efficacy. Elevated n-3 PUFA ingestion resulted in a positive methacholine bronchoprovocation dose change in > 40% of the test subjects (responders). The provocative dose to cause a 20% reduction (PD20) in FEV1, FVC, PEF, and FEF25-75 values could not be calculated because of a lack of significant respiratory reduction. Conversely, elevated n-3 PUFA ingestion caused some of the patients (nonresponders) to further lose respiratory capacity. Five-series leukotriene excretion with high n-3 PUFA ingestion was significantly greater for responders than for nonresponders. A urinary ratio of 4-series to 5-series leukotrienes < 1, induced by n-3 PUFA ingestion, may predict respiratory benefit.

Adult↗

Cardiac troponins I and T in patients with suspected acute coronary syndrome: a comparative study in a routine setting.

We compared cardiac troponin I (cTnI), using Access, Sanofi Pasteur, and cardiac troponin T (cTnT), using Elecsys, Boehringer Mannheim, in the first two routine blood samplings in a routine panel of cardiac markers for the biochemical diagnostic evaluation of patients with symptoms of acute myocardial infarction (AMI). No significant differences in the overall clinical performances of cTnI and cTnT were observed for the diagnosis of AMI (n = 68), but cTnI demonstrated lower initial sensitivity and higher specificity compared with cTnT. cTnT was increased to higher relative values than cTnI (P = 0.023). Discordances were found between cTnI and cTnT in sample I but not in sample II; positive cTnT/negative cTnI was more common than the opposite discordance (P = 0.027). cTnT was more frequently increased in patients with unstable angina pectoris (UAP) than cTnI (P = 0.038), with no significant differences between sample I and sample II; discordant results with respect to cTnI and cTnT appeared in 6 (33%) of these patients, all of which were positive for cTnT and negative for cTnI. Four patients with UAP (22%) developed AMI within 4 months; three were associated with increased cTnI and cTnT at the time of initial testing, and one was discordant (positive cTnT). In patients classified with no acute coronary syndrome (n = 84), five concordant positives for cTnI and cTnT were observed, indicating the existence of a myocardial injury of recent origin in these patients. AMI evolved in one of these patients 5 months later. We conclude that cTnT and cTnI detect acute myocardial injury with equal clinical performance in AMI patients classified by WHO criteria. cTnT was more frequently increased in patients with UAP than cTnI, but the clinical significance of this discordance could not be determined from this study.

Acute Disease↗

Comparison of the responses of global tests of coagulation with molecular markers of neutrophil, endothelial, and hemostatic system perturbation in the baboon model of E. colisepsis--toward a distinction between uncompensated overt DIC and compensated non-overt DIC.

This study correlates changes in neutrophilic activity and endothelial injury with markers of hemostatic activity following the infusion of increasing concentrations of E. coli organisms. It focuses on the hemostatic response as a marker of microvascular injury and uses the response to increasing concentrations of E. coli to refine our definition of disseminated intravascular coagulation (DIC) and distinguish between a compensated (non-overt DIC) and uncompensated (overt DIC) response. We observed that the global coagulation tests reflected activation of the hemostatic system in a dose dependent manner (overt DIC) in the early phases (T+2 to 6 h) of the response to increasing concentrations of E. coli, but that they failed to do so in the late phases (T+ 24 to 48 h). We observed that molecular markers, soluble thrombomodulin and elastase, unlike thrombin/antithrombin and plasmin/antiplasmin complexes, remained elevated out to T+24 to 48 h indicating endothelial injury that persists beyond the initial inflammatory insult in compensated as well as uncompensated DIC.

Animals↗