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PubMed1991

Histochemical and stereological analysis of putative preneoplastic hepatic lesions.

Histochemistry is a valuable tool in the analysis of altered hepatic foci. These lesions contain alterations in the activities of certain enzymes, including gamma-glutamyl transpeptidase (GGT), placental glutathione-S-transferase (PGST), glucose-6-phosphatase (G6Pase), and ATPase, or in certain cellular functions, such as the ability to store iron. The appearance of altered hepatic foci has been found to correlate with the later appearance of hepatocellular carcinomas in rodents. The markers PGST and GGT are the most sensitive at detecting altered hepatic foci induced by most chemicals, but are unable to detect altered hepatic foci induced by some agents, such as peroxisome proliferators. Other markers, such as ATPase or G6Pase, should therefore be used in combination with PGST or GGT in identifying altered hepatic foci. The strain of rat used and the type of diet fed also influence the number of altered hepatic foci induced and the enzyme markers seen. The number of foci per cm2 and the diameters of altered hepatic foci in histochemically-stained tissue sections can easily be quantified. The number of foci per cm2, however, does not give a reliable estimate of the number of altered hepatic foci induced because larger altered hepatic foci are more likely to be transected. The equations of quantitative stereology therefore should be used to transform the data to obtain the number of foci induced per cm3 or per liver, the average volume of individual foci, and the percent of the liver volume occupied by altered hepatic foci. In conclusion, the use of histochemistry to identify preneoplastic lesions and the use of quantitative stereology to estimate their number and volume allow accurate and sensitive quantitation of altered hepatic foci.

Animals↗
PubMed1999

Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study.

BACKGROUND: Many volatile organic compounds (VOCs), principally alkanes and benzene derivatives, have been identified in breath from patients with lung cancer. We investigated whether a combination of VOCs could identify such patients. METHODS: We collected breath samples from 108 patients with an abnormal chest radiograph who were scheduled for bronchoscopy. The samples were collected with a portable apparatus, then assayed by gas chromatography and mass spectroscopy. The alveolar gradient of each breath VOC, the difference between the amount in breath and in air, was calculated. Forward stepwise discriminant analysis was used to identify VOCs that discriminated between patients with and without lung cancer. FINDINGS: Lung cancer was confirmed histologically in 60 patients. A combination of 22 breath VOCs, predominantly alkanes, alkane derivatives, and benzene derivatives, discriminated between patients with and without lung cancer, regardless of stage (all p<0.0003). For stage 1 lung cancer, the 22 VOCs had 100% sensitivity and 81.3% specificity. Cross-validation of the combination correctly predicted the diagnosis in 71.7% patients with lung cancer and 66.7% of those without lung cancer. INTERPRETATION: In patients with an abnormal chest radiograph, a combination of 22 VOCs in breath samples distinguished between patients with and without lung cancer. Prospective studies are needed to confirm the usefulness of breath VOCs for detecting lung cancer in the general population.

Aged↗
PubMed2003

The use of non-tumor data in cancer risk assessment: reflections on butadiene, vinyl chloride, and benzene.

The estimation and characterization of a cancer risk is grounded in the observation of tumors in humans and/or experimental animals. Increasingly, however, other kinds of data (non-tumor data) are finding application in cancer risk assessment. Metabolism and kinetics, adduct formation, genetic damage, mode of action, and biomarkers of exposure, susceptibility, and effects are examples. While these and other parameters have been studied for many important chemicals over the past 30-40 years, their use in risk assessments is more recent, and new insights and opportunities are continuing to unfold. To provide some perspective on this field, the ILSI Risk Science Institute asked a select working group to characterize the pertinent non-tumor data available for 1,3-butadiene, benzene, and vinyl chloride and to comment on the utility of these data in characterizing cancer risks. This paper presents the findings of that working group and concludes with 15 simple principles for the use of non-tumor data in cancer risk assessment.

Animals↗
PubMed1998

Effect of DC shock on serum levels of total creatine kinase, MB-creatine kinase mass and troponin T.

After successful resuscitation from cardiac arrest, it is important to identify whether the event has been triggered by a myocardial infarction, since this determines subsequent investigations and management. Previous studies have shown that biochemical indices of infarction become elevated after resuscitation in patients without myocardial infarction. This can lead to overdiagnosis of myocardial infarction in the post-arrest setting. The cause of the elevated enzyme levels is not known, but may involve electrical or mechanical injury to the heart during resuscitation. In this study we aimed to identify the effects of isolated direct current shock on serum levels of creatine kinase (CK), MB creatine kinase mass (MB-CK), and troponin T, and examined the relationships between enzyme levels and the dose of electrical energy used. Thirteen patients were studied who underwent DC cardioversion for atrial fibrillation. Serum was obtained for CK, MB-CK and troponin T estimation before and 10 min after cardioversion, at hourly intervals for 8 h, and 18 h after cardioversion. Total serum CK became significantly elevated after only 3 h and rose to a peak of 1294.4 IU l(-1) (P < 0.02) at 18 h. Post-shock CK levels were strongly correlated with total shock energy (r = 0.8, P < 0.01). Serum MB-CK was significantly elevated at 18 h among patients receiving total shock energies greater than 1000 J than in those receiving lower doses, reflecting a positive correlation (r = 0.64, P < 0.05) between shock energy and peak MB-CK level. Troponin T levels were not significantly elevated after cardioversion. In conclusion, total serum CK levels become significantly elevated early after cardioversion, suggesting rapid wash-out from injured skeletal muscle. MB-CK levels become significantly elevated in individuals receiving high energy shocks, probably due to release of small quantities of the CK-MB isoform from skeletal muscle. The negligible troponin T levels seen after high energy cardioversion indicate that significant myocardial injury does not occur. Electrical injury is not likely to account for the elevated troponin T levels seen after out-of-hospital resuscitation in patients without myocardial infarction.

Aged↗
PubMed2004

Free cortisol awakening responses are influenced by awakening time.

Psychobiological investigations on the hypothalamus-pituitary-adrenal (HPA) axis depend on markers that adequately describe the activity of this system. There is evidence that the free cortisol response to awakening, proposed as a marker for the HPA axis, can be influenced by time of awakening. To further investigate this possible confounder, 24 shift working nurses and 31 female students on a regular sleep-wake cycle collected saliva samples 0, 30, 45 and 60 minutes after awakening. Nurses were investigated on the first and second day of their early (awakening: 04:00-05:30 h), late (awakening: 06:00-09:00 h), and night shift (awakening: 11:00-14:00 h), respectively. Students were studied after taking a short nap on two consecutive weekdays (awakening: 18:45-20:30 h). Mean cortisol levels after awakening increased significantly under all three shift conditions (p<0.01), but decreased in the student sample (p<.05). Within the three shift conditions, cortisol responses following waking in the early shift were more pronounced than in late (p<.01) and night shift (p<.05). The present study shows that in a sample with a large range of awakening times, an impact of this variable on the cortisol awakening response can be observed. The data furthermore strongly suggest that waking up per se is insufficient for adrenocortical stimulation.

Adrenal Cortex Function Tests↗
PubMed1998

Early laboratory indicators of acute myocardial infarction.

Biochemical markers of myocardial injury have evolved so that the diagnosis or exclusion of acute myocardial infarction can be determined within a short time with a high degree of sensitivity and specificity. The use of these markers in patients complaining of chest pain allows for medically appropriate and cost-effective triage decision making in the emergency department.

Biomarkers↗
PubMed1999

Myoglobin, creatine-kinase-MB and cardiac troponin-I 60-minute ratios predict infarct-related artery patency after thrombolysis for acute myocardial infarction: results from the Thrombolysis in Myocardial Infarction study (TIMI) 10B.

OBJECTIVES: We examined the diagnostic performance of serum myoglobin, creatine-kinase-MB (CK-MB) and cardiac troponin-I (cTnI) for predicting the infarct-related artery (IRA) patency in patients receiving TNK-tissue plasminogen activator (TNK-tPA) therapy for acute myocardial infarction (AMI) in the Thrombolysis in Myocardial Infarction (TIMI) 10B trial. BACKGROUND: A reliable noninvasive serum marker of IRA patency is desired to permit early identification of patients with a patent IRA after thrombolysis. METHODS: We measured myoglobin, CK-MB and cTnI concentrations in sera obtained just before thrombolysis (T0) and 60 min later (T60) in 442 patients given TNK-tPA and who underwent coronary angiography at 60 min. RESULTS: Angiography at 60 min showed a patent IRA (TIMI flow grade 2, 3) in 344 and occluded IRA (TIMI flow grade 0, 1) in 98 patients. The median serum T60 concentration, the ratio of the T60 and T0 serum concentration (60-min ratio) and the slope of increase over 60 min for each serum marker were significantly higher in patients with patent arteries compared with patients with occluded arteries. The area under the receiver-operating characteristic (ROC) curve for diagnosis of occlusion was 0.71, 0.70 and 0.71 for the 60-min ratio of myoglobin, cTnI and CKMB, respectively. The 60-min ratios of > or =4.0 for myoglobin, > or =3.3 for CK-MB and > or =2.0 for cTnI yielded a probability of patency of 90%, 88% and 87%, respectively. CONCLUSIONS: The diagnostic performance of serum myoglobin, CK-MB and cardiac troponin-I (cTnI) 60-min ratios was similar. The probability of a patent IRA was very high (90%) in patients with 60-min myoglobin ratio > or =4.0, and early invasive interventions to establish IRA patency may not be necessary in this group. Serum marker determinations at baseline and 60-min after thrombolysis may permit rapid triage of patients receiving thrombolytic therapy by ruling out IRA occlusion.

Aged↗
PubMed2002

Flow cytometry of platelets for clinical analysis.

Platelets are small, non-homogenous cells with distinctive surface features important to their essential role in hemostasis. The surface membrane is dynamic, and changes remarkably in lipid asymmetry and receptor expression on triggering of the activation process. There are also extensive and rapid intracellular changes in platelets as a result of biochemical activation through calcium fluxes, phospholipase activity, kinase activity, and phosphorylation mechanisms that lead to release of storage granule contents and generation of fast-acting prostaglandins, all in a matter of seconds after stimulation with a strong agonist. These characteristics make the platelet an interesting but difficult cell to study, and the explosion of knowledge over the last two decades has been fueled in large part by the application of flow cytometry techniques. Clinical applications of flow cytometry analysis of platelets have been pursued in individual specialized medical centers, but have not found widespread practice in clinical laboratories, mostly because of difficulties in standardization of techniques and the inherent biovariability in comparing normal to abnormal platelets. Despite these hurdles, it seems certain that flow cytometry analysis of platelets in pathological states will continue to evolve into more practical and robust procedures that will eventually become standard hematologic assays rather than specialized research tools.

Antigens, Human Platelet↗
PubMed1999

ADA1/ADAp ratio in pleural tuberculosis: an excellent diagnostic parameter in pleural fluid.

We analysed the efficacy of pleural adenosine deaminase (ADAp) and the ADA1/ADAp ratio in the diagnosis of pleural tuberculosis in 103 pleural effusions, 27 of which were tuberculosis (TB) and 76 other diagnoses (non-TB). Smears, cultures and pleural biopsies were carried out in all cases, and were used for final diagnosis. The diagnostic yield of the parameters under study were as follows: smears/cultures of mycobacteria in fluid 11.1%/33.3%; biopsy 33.3%/51.8% and tuberculosis granulomas 85.1%. The levels of ADAp and ADA1/ADAp ratio in TB and non-TB groups showed very significant differences (P < 0.00001); in the TB group: ADAp 54.7 +/- 23.5 IU and ADA1/ADAp 0.27 +/- 0.08; in the non-TB group: ADAp 18.3 +/- 43.2 IU and ADA1/ADAp 0.64 +/- 0.14. The assay established ADA levels in pleural fluid > or = 40 IU and an ADA1/ADAp ratio < or = 0.42 as cut-off levels to identify individuals in the TB group, with a sensitivity of 88.8%/100%, a specificity of 92%/98.6%, a positive predictive value (PPV) of 80%/96.4%, a negative predictive value (NPV) of 95.8%/100% and an accuracy of 91.2%/99.02%. The ADAp levels in 27 patients with TB, showed close correlation with the number of monocyte macrophages (P = 0.001), but not with the number of lymphocytes (P = n.s.). The ADA1/ADAp ratio overcomes the limitations of ADAp (false positives and negatives), and is the most useful parameter for diagnosis on account of a high diagnostic yield, low cost and speed of the assay for identifying a pleural tuberculosis diagnosis, when compared with traditional methods.

Adenosine Deaminase↗
PubMed2005

Addition of fexofenadine to inhaled corticosteroid therapy to reduce inflammatory biomarkers in atopic asthma.

BACKGROUND: We previously showed that H1-antihistamines may shift the PC20 (provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20%) threshold to adenosine monophosphate (AMP) challenge but may paradoxically prolong recovery. OBJECTIVES: To measure AMP recovery using a constant predetermined AMP PC20 and to evaluate whether fexofenadine use confers add-on effects to treatment with either fluticasone propionate alone or combined fluticasone propionate-salmeterol. METHODS: Fourteen atopic patients with mild-to-moderate asthma (forced expiratory volume in 1 second of 76%) completed a double-blind, randomized, crossover study consisting of 3-week treatment blocks of either fluticasone propionate-salmeterol, 250 microg twice daily, or fluticasone propionate alone, 250 microg twice daily, in conjunction with either fexofenadine, 180 mg once daily, or matched placebo. Recovery after a predetermined AMP PC20 challenge was measured (primary outcome), along with exhaled nitric oxide levels, plasma eosinophil cationic protein levels, peripheral eosinophil counts, pulmonary function, diary card outcomes, and quality of life (all secondary outcomes). RESULTS: There were no differences in any of the primary or secondary outcomes when fexofenadine was added to treatment with either fluticasone propionate-salmeterol or fluticasone propionate alone. The mean AMP recovery time was 25.0 vs 23.4 minutes for fexofenadine and placebo, respectively, as add-on to fluticasone-salmeterol and 22.5 vs 23.9 minutes, respectively, as add-on to fluticasone alone. CONCLUSION: Fexofenadine did not affect recovery to a fixed dose of AMP challenge or any other surrogate inflammatory markers when given as add-on therapy to corticosteroid-treatedatopic asthmatic patients.

Adenosine Monophosphate↗
PubMed2002

Vitellogenin induction by 17beta-estradiol and 17alpha-ethinylestradiol in male zebrafish (Danio rerio).

Adult male zebrafish (Danio rerio) were exposed to 17beta-estradiol (E2) or 17alpha-ethinylestradiol (EE2) in flow-through systems for 8 days. This was done to compare the sensitivity of the estrogen inducible vitellogenin (Vtg) biomarker system of this proposed OECD test guideline species to other relevant test species. Vtg was quantified in whole body homogenate by a species-specific ELISA. Actual water concentrations of E2 and EE2 were quantified by LC-MS, with detection limits of 1.0 and 0.6 ng/l, respectively. Vtg induction (LOEC) occurred in whole body homogenate at actual water concentrations of 21 ng E2/l and 3.0 ng EE2/l, respectively. As an alternative to the ANOVA approach, the relationship between the percentage of responding fish (Vtg) and the external E2 or EE2 concentration was determined by logistic regression analysis. Based on the regression analysis, EC-values could be determined: EC10, EC50 and EC90 were 15.4, 41.2 and 67.1 ng E2/l, respectively and 0.92, 2.51 and 4.09 ng EE2/l, respectively. Comparisons of these response limits to corresponding values for rainbow trout (Oncorhynchus mykiss), fathead minnow (Pimephales promelas) and Japanese medaka (Oryzias latipes) revealed the zebrafish as a sensitive test species.

Animals↗
PubMed2002

Chemoprevention of colon cancer: current status and future prospects.

Colorectal cancer is an important public health problem in the western world. Although some progress has been made in the prevention and management of this disease, colon cancer still remains one of the most common types of epithelial malignancies in both genders and is essentially incurable when it reaches the most advanced stages. Given the substantial morbidity and mortality associated with colorectal malignancies and their treatment, cancer prevention in its many forms emerges as a very attractive approach. Colorectal cancer chemoprevention refers to the administration of natural or synthetic compounds to block, reverse, delay or prevent the development of invasive large bowel neoplasms. The ultimate goal of implementing a chemopreventive intervention in the general, or alternatively, in an at-risk population is to decrease the incidence rate of the specific cancer being targeted. This article reviews the present status of colorectal cancer chemoprevention. Current insights into the molecular and genetic models of human colorectal carcinogenesis, preclinical models for efficacy testing as well as into promising biomarkers for colorectal chemoprevention are provided. The developmental status of many promising agents is also discussed emphasizing the epidemiological evidence, preclinical information substantiating an anticarcinogenic effect, their postulated mechanism of action and the status of human clinical development. Our perspective of the future prospects in this scientific area is also provided and has been predicated primarily on the firm belief that the proper integration of advances in the biology of colon carcinogenesis, experimental therapeutics and clinical trial methodology will be critical for the success of this promising field.

Animals↗
PubMed2003

Allergen-induced cytokine secretion in atopic and non-atopic asthmatic children.

Atopic asthma is characterized by excessive T helper 2 (Th2)-like immunity to allergens in the bronchial mucosa. The Th2-cytokine interleukin (IL)-4 induces IgE production, while the Th2-cytokine IL-5 promotes eosinophilic inflammation in the airways of asthmatics. Most asthmatics are atopic, but a subgroup is non-atopic. We hypothesize that allergen-induced Th2, particularly IL-5, responses can be observed in peripheral blood in both atopic and non-atopic asthmatic children but not in healthy control children. The aim of the present study was to determine IL-4, IL-5, IL-9, IL-10, IL-13 and IFN-gamma secretion induced from peripheral blood mononuclear cells (PBMC) by a broad panel of inhalant allergens (timothy, cat, birch, dog and house dust mite) in asthmatic children with and without sensitization. The study included 13 atopic asthmatic, 5 non-atopic asthmatic, and 12 non-atopic non-asthmatic children. PBMC were stimulated with allergens and cytokine production was measured with enzyme-linked immunosorbent assay (ELISA). Higher levels of cat and dog antigen-induced IL-5 release were more commonly observed in both atopic and non-atopic asthmatics than in controls. Children with atopic, but not non-atopic, asthma produced higher levels of allergen-induced IL-4 and IL-9 than controls. Non-atopic asthmatics produced more IL-10 than atopic asthmatics after cat stimulation. High levels of eosinophilia-associated IL-5 responses are induced by cat and dog allergen in both atopic and non-atopic asthmatic children. The Th2 cytokines IL-4 and IL-9 were associated only with atopic asthma, probably due to their IgE-inducing properties.

Adolescent↗
PubMed2003

Evidence for a bimodal relation between serum lysozyme and prognosis in 232 patients with acute myeloid leukaemia.

Lysozyme values are sometimes used as an aid for diagnostic subtyping of acute myeloid leukaemia (AML), since monocytic forms often show high levels. We wanted to study if pretreatment serum lysozyme has any relation to prognosis in AML. For this purpose, 232 adult AML patients who had received remission induction therapy at two hospitals were reviewed retrospectively. Their median age was 65.5 yr. Sixty-three patients were FAB classified as "monocytic" AML (M4, M5) and 169 as "non-monocytic" AML (M0, M1, M2, M3, M6). A linear relation was rejected, and a bimodal relation was found between lysozyme and prognosis where values below 20 or above 80 mg L-1 were indicative of better outcome than values in the range 20-80 mg L-1. Analysed in three categories with cut-off levels at 20 and 80 mg L-1, lysozyme showed an independent effect on complete remission (CR) frequency (P = 0.0003), overall survival (P < 0.0001), and CR duration (P = 0.0005) in multivariate analysis. The hazard ratios (HR) for lysozyme <20, 20-80, and >80 mg L-1 regarding overall survival were 1.0, 3.3, and 0.7. Influence of lysozyme on survival was bimodal both in "non-monocytic" AML (HR 1.0, 3.0, and 0.1) and M4-M5 (HR 1.0, 10.1, and 1.2). Our finding of a bimodal relation between serum lysozyme and prognosis in AML should be regarded as a new hypothesis and controlled in other studies.

Acute Disease↗
PubMed1999

Interrelationships among biological markers of aging, health, activity, acculturation, and cognitive performance in late adulthood.

In this study a structural equation model of predictors of age differences in cognitive performance in late adulthood was developed. Biological markers of aging (vision, hearing, vibration sense, forced expiratory volume, and grip strength) were used as indicators of a latent variable called BioAge. A sample of 180 community-dwelling women aged 60 to 90 years was assessed. Results showed that BioAge explained all of the age-related variance in cognitive test performance. Physical health and physical activity had direct effects on BioAge. Measures of acculturation explained non-age-related variance in cognitive test performance. Some variables used as biomarkers also explained individual differences in measures of crystallized intelligence and perceptual speed. It is concluded that the association between biomarkers and cognition in old age is due to more than a common statistical association with age.

Acculturation↗