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Nitric oxide as a clinical guide for asthma management.

Asthma is a pathologically heterogeneous disease, and the phenotype is characterized by different types of airway inflammation. Exhaled nitric oxide (F(E)NO) measurements are a surrogate marker specific for eosinophilic airway inflammation. The latter is usually associated with steroid responsiveness, and hence, F(E)NO may be used to guide steroid requirements in certain clinical situations. High F(E)NO levels may be used to predict likely benefits with inhaled corticosteroid (ICS) therapy. Both high and low F(E)NO levels are prognostically significant when withdrawal of ICS treatment is being considered. Studies have shown that, just as for induced sputum, repeated F(E)NO measurements improve the cost-effectiveness of ICS therapy when used to guide dose requirements. In practice, F(E)NO measurements are useful in the management of severe or difficult asthma. High and low F(E)NO levels in symptomatic patients provide the clinician with information that enables active eosinophilic airway inflammation to be included or excluded. Either outcome is helpful in decision making. F(E)NO measurements complement the use of other tests in asthma, but more work is required to determine reference values and cut-points for appropriate interpretation.

Administration, Inhalation↗

CD63 expression on basophils as a tool for the diagnosis of pollen-associated food allergy: sensitivity and specificity.

BACKGROUND: Basophil activation is associated with the expression of CD63. Because allergens can induce basophil activation by cross-linking specific IgE, increased CD63 expression has been proposed as a novel in vitro test for immediate type allergy. OBJECTIVE: We compared the CD63-based basophil activation test (BAT) in the diagnosis of allergy to carrot, celery and hazelnut with skin prick tests (SPT) and measurement of allergen-specific IgE. METHODS: Twenty-nine patients with a history of an oral allergy syndrome induced by carrot, celery or hazelnut (n = 20 for each allergen) and 20 controls were studied. SPT were performed with standardized and native carrot, celery and hazelnut extracts. Allergen-specific IgE was determined by the CAP FEIA method and basophil activation was determined by flow cytometry upon double staining with anti-IgE/anti-CD63 mAb. RESULTS: SPT with native carrot, celery and hazelnut showed sensitivities of 100%, 100% and 90%, and specificities of 80%, 80% and 90%. SPT with commercial extracts of the same allergens gave sensitivities of 85%, 80% and 85%, and specificities of 80%, 80% and 90%. Sensitivity of allergen-specific IgE and the BAT for carrot, celery and hazelnut was 80% vs. 85%, 70% vs. 85%, and 80% vs. 90%, with corresponding specificities of 80% vs. 85%, 80% vs. 80%, and 95% vs. 90%. The cut-off for a positive BAT was 10% CD63+ basophils. Moreover, there was a positive correlation between IgE reactivity and the number of CD63+ basophils for all food allergens (carrot: r = 0.69, celery: r = 0.67, hazelnut: r = 0.66). CONCLUSIONS: Quantification of basophil activation by CD63 expression is a valuable new in vitro method for diagnosis of immediate type food sensitization. Although double-blind placebo-controlled food challenges remain the gold standard, the CD63-based BAT may supplement routine diagnostic tests such as SPT or allergen-specific IgE in the future.

Antigens, CD↗

Clinical use and pathogenetic basis of laboratory tests for the evaluation of primary arterial hypertension.

This review focuses on the laboratory biochemical tests that are useful in the diagnostic approach to the hypertensive patient. A "minimal" diagnostic laboratory work-up, including a small number of tests that are simple and relatively inexpensive, is first described. Because these tests provide basic information on the presence of major cardiovascular (CV) risk factors and target organ damage, and might give some clues to the presence of a secondary form of hypertension (HT), they should be performed on all patients presenting with HT. Other tests that are aimed at assessing the overall CV risk, a major determinant of prognosis that dictates the therapeutic strategy in the individual HT patient, are then discussed. They allow identification of major CV risk factors and associated clinical conditions which, if present, lead to a substantial change of therapeutic strategy. The role of C-reactive protein as a marker of atherosclerosis and its predictive value for CV events are also discussed. Finally, a section is devoted to tests that are currently confined to research purposes, such as markers of endothelial function including endothelin-1, homocysteine and genetic analysis.

Animals↗

Methods for the measurement of nutrition impact and adaptation of laboratory methods into field settings to enhance and support community-based nutrition research.

International nutrition will become increasingly concerned with evaluation of nutritional status at the community level to diagnose situations of risk for nutrient deficits and excesses, and to monitor the impact of remedial interventions. Advances in biologic concepts and technology (particularly miniaturization of assays) are assisting the creation of noninvasive, robust, and acceptable diagnostic tests of nutritional status for field settings. As with more complex and formal assays, the principles of accuracy, reliability, and construct validity need to be applied.

Biomarkers↗

Potential use of pharmacological markers to quantitatively assess liver function during liver transplantation surgery.

Early functioning of the transplanted liver is of crucial importance to the recipient. This function may be assessed by measuring the disposition of substances that are mainly eliminated via the liver. None of the agents currently used is ideal for this purpose. Measurement of mono-ethyleneglycinexylidide (MEGX) formation from lignocaine is useful and has been widely used in liver transplantation to assess liver graft function. MEGX formation can be affected by the use of drugs that influence liver perfusion or interfere with the CYP450 enzyme system. Indocyanine green clearance is a convenient method but both blood flow and hepatocellular function affect the test results. Tests of caffeine clearance, galactose elimination capacity and antipyrine clearance all require time-consuming, technically cumbersome and expensive serial blood sampling. The aminopyrine breath test is non-invasive, but gastric emptying and the patient's physical state affect results. The potential hazard of exposure to radioactive compounds limits the wide clinical use of both aminopyrine and erythromycin breath tests. Monitoring the rate of recovery from neuromuscular blockade induced by vecuronium and rocuronium can provide valuable information on liver function.

Adult↗

[The role of measurement of exhaled nitric oxide in asthma patients].

The aim of the study was to evaluate exhaled nitric oxide levels (F(ENO)) in asthmatics and to establish the possible correlation of these measurements with clinical symptoms, disease severity, anti-inflammatory treatment and spirometric indices. The measurement of exhaled NO was performed using NO analyser model 280i, Sievers Instruments, Inc., USA. This measurement was based on the gas phase chemiluminescence reaction between NO and ozone. The investigations were performed on the group of 85 asthmatic patients (34 with chronic mild asthma, 31 with chronic moderate asthma, 20 with chronic severe asthma). F(ENO) level in healthy, non-smoking volunteers (46 persons--control group) was mean 12.9 +/- 4.6 ppB and it was statistically significant lower than in all groups of asthmatics. The highest F(ENO) levels were observed in patients with severe asthma (74 +/- 72 ppB). Statistically significant lower levels of ENO were obtained in patients with moderate (42 +/- 31 ppB) and mild asthma (49 +/- 43 ppB). In all groups of asthmatic patients higher levels of F(ENO) were observed in subjects with allergic asthma. In patients with mild and moderate asthma ENO levels were negatively correlated with the used dosage of inhaled steroids. Similar dependences were not noticed in patients with severe asthma. The measurement of exhaled nitric oxide levels provides a rapid, reproducible, non-invasive and reliable test, which is very useful in diagnosis and treatment monitoring in asthmatic patients.

Adult↗

Using routine laboratory tests to detect heavy drinking in the general population.

This article describes a new biomarker known as the Early Detection of Alcohol Consumption (EDAC) test, which has been steadily penetrating the U.S. market. The EDAC uses routine laboratory tests to make a prediction of heavy drinking in any given person. When tested in mainstream insurance populations, the EDAC has shown twice the specificity of the traditional liver enzyme tests and is significantly more sensitive than the CDT test, which is expected because the EDAC uses a combination of laboratory tests. Maximum diagnostic accuracy is achieved when the CDT test is used to confirm a positive EDAC test. Since brief interventions have proven successful, the early identification of alcohol problems becomes a vital role for physicians. Improved awareness of alcohol misuse can certainly be accomplished through an increased use of biomarkers, with and without concomitant self-report. The ultimate goal is to facilitate early intervention and the successful management of patients diagnosed with heavy drinking.

Adolescent↗

Can an index of aging be constructed for evaluating treatments to retard aging rates? A 2,462-person study.

Biomarkers of aging are needed to evaluate proposed treatments to retard aging rates. At present, the only validated biomarker of aging is maximum life span, which remains impractical for human use. Identification of other biomarkers awaits development of a method of biomarker validation. This paper outlines an approach for this purpose intended for selecting biomarkers usable in humans. Prospective biomarkers are validated and weighted according to their correlation with interventions that, in healthy individuals, influence life span, namely mortality risk factors. A general mathematical method is presented for combining biomarker scores into an index of aging rate. This method addresses problems encountered with the traditional (multiple regression) method of calculating biological age and develops an index termed standardized biological age, SBA. In applying the method to 2,462 office workers, SBA, based on 12 physiological tests under investigation as biomarkers of aging, was found to depend on most of 17 surveyed dietary, exercise, life style, and geographical risk factors for mortality or health, suggesting that many risk factors predict rates of common functional declines with age. The 12 candidate biomarkers of aging in this study differed widely in validity according to the criterion employed. The approach holds promise for assembling an experimentally useful battery of biomarkers of aging.

Adult↗

Effect of Simvastatin on markers of triglyceride-rich lipoproteins in familial hypercholesterolaemia.

BACKGROUND: We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B-48 and remnant-like particle-cholesterol (RLP-C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG-CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB-48 and RLP-C in FH patients after long- and short-term simvastatin therapy and after a wash-out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant-like emulsion labeled with cholesteryl (13)C-oleate. METHODS: Fifteen FH patients were studied after > 6 months 40 mg day(-1) simvastatin treatment (long-term), a wash-out period (4 weeks), and 4 weeks of simvastatin treatment (short-term). Apolipoprotein B-48 was determined by SDS-PAGE and Western blotting/enhanced chemiluminescence and RLP-C by an immunoseparation assay. The FCR of the chylomicron remnant-like emulsion was determined from the appearance of (13)CO(2) in the breath and by multicompartmental mathematical modelling. RESULTS: Both long- and short-term treatment with simvastatin were associated with decreases in the plasma concentration of apoB-48 (P < 0.05) and RLP-C (P < 0.001), but there was no significant change in the FCR of the emulsion. CONCLUSIONS: We suggest that long- and short-term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride-rich remnants in heterozygous FH, as measured by fasting apoB-48 and RLP-C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up-regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured kinetically by the (13)CO(2) breath test.

Apolipoprotein B-48↗

Diagnostic accuracy of serum B-type natriuretic peptide for myocardial ischemia detection during exercise testing with spect perfusion imaging.

OBJECTIVE: To determine whether serum B-type natriuretic peptide measured at rest and peak exercise and DeltaBNP contribute to the predictive value and diagnostic accuracy of exercise test in the diagnosis of myocardial ischemia. BACKGROUND: Ventricular myocytes release BNP in response to increased wall stress that occurs in acute ischemia. During exercise testing, transient myocardial ischemia could also cause acute myocardial stress and changes in circulating BNP. METHODS: BNP was measured before and immediately after exercise testing with radionuclide imaging in 203 consecutive subjects referred for chest pain evaluation. Tested subjects were classified as ischemic and non-ischemic based on exercise results, and no ischemia, mild-moderate, and severe ischemia according to perfusion scan results. A logistic regression model, constructed of an ROC and an AUC (area under the curve), was used. RESULTS: Ischemic ECG changes (> or =1 mm, horizontal S-T shift) were detected in the treadmill exercise test in 127 subjects (62.6%), and 76 (37.4%) had neither ST segment shift nor chest pain. Baseline BNP was higher in the ischemic group compared to the non-ischemic group (p=0.044); peak BNP was also higher in the ischemic group (p=0.025), as was DeltaBNP (p=0.0126). Of these 127 subjects, 106 (52% of all) had abnormal perfusion scan results. In the ischemic group, the median baseline, peak exercise BNP, and DeltaBNP values from baseline to peak were higher than in the non-ischemic group. In the severe ischemic group these variables were approximately three-fold higher than in the mild-moderate ischemic group (p<0.0001 for baseline; p<0.0001 for peak; and p<0.0001 for DeltaBNP). Rest, peak exercise, and DeltaBNP values were significantly higher in patients with previous myocardial infarction (p<0.001) and in patients treated with beta blockers; peak exercise BNP was higher in hypertensives and diabetics (p<0.05). The ROC convergence model showed that the AUC for peak-exercise BNP was best able to discriminate and predict severe ischemia and no ischemia, while DeltaBNP from rest to peak exercise discriminated best between mild-moderate and severe ischemia. CONCLUSIONS: Peak exercise BNP and DeltaBNP improved the sensitivity, specificity, positive likelihood ratio, predictive value, and diagnostic accuracy of severe ischemia detection during an exercise test. The contribution of BNP determination during exercise was, however, less impressive than previously reported by others.

Aged↗

Exhaled nitric oxide as a marker of lung injury in coronary artery bypass surgery.

BACKGROUND: Exhaled nitric oxide (NO) concentrations have been suggested as a marker of disease onset and severity in a number of inflammatory conditions such as acute asthma. Known markers of the onset of acute lung injury require invasive tests and laboratory based analysis and have limited clinical applicability. We performed a study of the use of exhaled NO as a marker of developing acute lung injury during and after coronary artery bypass grafting in patients requiring cardiopulmonary bypass. METHODS: Mixed expired air samples were taken from the patient breathing system and analysed for exhaled NO using chemiluminescence analysis. RESULTS: Exhaled nitric oxide concentrations in expired gas correlated with the PaO2/FlO2 ratio (r = 0.23, P < 0.01). There was a non-significant trend towards a reduction in exhaled NO levels from after induction of anaesthesia to post-bypass time points, with the lowest exhaled NO concentrations occurring at this time (P = 0.07). There was no correlation between mean arterial pressure (r = -0.1, P = 0.54) or mean pulmonary artery pressure (r = -0.1. P = 0.67) and expired NO levels. CONCLUSIONS: Further work is required to test whether exhaled NO concentration may be useful in diagnosing the onset of acute lung injury in patients undergoing coronary artery bypass grafting.

Biomarkers↗

Can haematological tests predict cardiovascular risk? The 2005 Kettle Lecture.

The risk of venous or arterial thrombosis is routinely assessed by clinical variables (risk factors) supplemented by measurement of blood lipids and glucose for arterial thrombotic events. Haematological tests that might play a role in risk prediction include haemostatic variables, haematocrit and inflammatory markers (erythrocyte sedimentation rate, plasma viscosity, white cell count). Recent epidemiological studies of these phenotypes and related genotypes are reviewed. For the risk prediction of first venous thrombosis, screening for thrombophilias in 'high-risk' situations does not appear clinically effective or cost-effective; with the possible exception of women considering oral hormone replacement therapy. General screening after a first venous event to predict recurrence (or risk in asymptomatic relatives) does not appear effective; with the possible exception of d-dimer, which requires further study. For risk prediction of first arterial thrombosis, screening adds little to prediction by current clinical risk scores. Screening of persons after a first arterial event, or with atrial fibrillation (e.g. with D-dimer for stroke prediction), requires further study. In conclusion, haematological tests have very limited roles in the prediction of cardiovascular risk, and should only be used according to evidence-based guidelines. The need for management studies is highlighted.

Biomarkers↗

Ultrasound verification of bladder damage is associated with known biomarkers of bladder cancer in adults chronically infected with Schistosoma haematobium in Ghana.

Long-term infection with urinary schistosomiasis has been associated with development of bladder cancer. However, bladder cancer is difficult to diagnose without invasive measures such as cystoscopy, thus there is little information on the epidemiological extent of the problem. Studies have been either case-control studies or case examinations in different geographical areas, estimating a schistosome-associated bladder cancer incidence of 3-4 cases per 100,000. We have used three indicators to examine the potential bladder cancer problem in an adult rural population in Ghana endemic for urinary schistosomiasis: (i) parasitological positivity; (ii) age prevalence of bladder damage from ultrasound scans; and (iii) detection of biomarkers associated with the presence of bladder cancer. Biomarkers were BLCA-4 test (urine) and nuclear morphometry or quantitative nuclear grading (QNG) of epithelial cells (urine sediment), which quantifies DNA ploidy status and nuclear morphometric descriptors, both of which can detect the presence of bladder cancer. Our data show an increasing association between age, severe bladder abnormalities and the occurrence of these biomarkers. Sixty-two of 73 cytopathology Papanicolaou-stained smears were seen to have squamous metaplasia. Although further investigations are needed, we suggest that schistosome-associated bladder cancer is an important public health concern in areas where Schistosoma haematobium is prevalent.

Adult↗