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PubMed1989

Clinical review 3: The clinical use of thyrotropin receptor antibody measurements.

There are relatively few circumstances wherein the assay of TRAb, as TSAb or TBIAb, is merited in the routine clinical management of patients with autoimmune thyroid disease. These include: 1. the prediction of neonatal hyperthyroidism; 2. the confirmation, by assay of maternal serum, and perhaps newborn blood, that neonatal hypothyroidism, identified on routine screening, may be transient and due to transplacental passage of TBIAb; 3. the prediction of relapse of hyperthyroidism at the end of a course of antithyroid drugs; this information should lead to more careful observation to identify relapse as early as possible; 4. the confirmation that adult agoitrous hypothyroidism reflects the effect of an antibody (TBIAb) blocking the action of TSH although, as discussed, there is little, if any, practical gain from this information. Additional applications of the routine use of TRAb assays will require the development of a procedure that combines the sensitivity, specificity, availability, and ease found variably in current TSAb and TBI procedures, and at much less cost than what is provided today.

Autoantibodies↗
PubMed2005

Estrogen supplementation failed to attenuate biochemical indices of neutrophil infiltration or damage in rat skeletal muscles following ischemia.

This study examined the effects of estrogen supplementation on markers of neutrophil infiltration and damage in skeletal muscle of rats following ischemia. Male and female gonad-intact rats, with or without 14 days of estrogen supplementation were subjected to two hours of hind-limb ischemia and sacrificed at 24, 48 or 72 hours post-ischemia. Control animals were sacrificed without ischemia. Plantaris and red and white gastrocneimus muscles were removed and assayed for myeloperoxidase (MPO), a marker of neutrophil infiltration, and glucose-6-phosphate dehydrogenase (G6PD) and beta-glucuronidase (betaGLU), as markers of muscle damage. Significant elevations of MPO, G6PD and betaGLU activities were observed at various time points post-ischemia. No systematic differences between genders were noted in any of the measures. Estrogen supplementation in both male and female animals failed to significantly attenuate post-ischemia increases in MPO, G6PD and betaGLU activities in any of the muscles studied and in some cases accentuated activities of some of these measures. Unlike previous findings following exercise in skeletal muscle, this study failed to demonstrate estrogen-induced attenuation of indices of neutrophil infiltration or damage in skeletal muscles of rats up to 72 hours following ischemia. This demonstrates that estrogen may not consistently attenuate neutrophil infiltration and that a number of variables including damage modality, tissue or estrogen level may influence this.

Animals↗
PubMed2003

Comparison of exhaled breath condensate from nasal and oral collection.

BACKGROUND: Analysis of exhaled breath condensate may provide new insights into pulmonary inflammatory processes. A new collection method via suction of nasally expired air especially suitable for younger children was presented recently. Here we compare this nasal suction method with the more widely used oral collection method regarding the amount of condensate collected as well as the concentrations of hydrogen peroxide (H2O2), nitrite and nitrate, respectively. MATERIALS AND METHODS: Exhaled breath condensate was collected from 11 healthy adults for the measurements of the amount of condensate and H2O2 concentration and from 17 children for the measurements of nitrite and nitrate. Condensate was collected via nasal suction and oral exhalation from each subject. RESULTS: Overall, no differences between both collection methods were found for all variables assessed except the concentration of H2O2, whereas the latter closely correlated (Spearman r = 0.88, p = 0.0007) between both collection methods. No correlation was found for the amount of condensate collected and the concentration of nitrite and nitrate. The Bland-Altman limits of agreement scattered over a wide range with clinical impact, proving significant differences between both collection methods for all variables measured. CONCLUSIONS: Although nasal and oral collection method proved again suitable for the collection of exhaled breath condensate, the variability of the results obtained precludes the interchangeable usage of the inflammatory markers assessed here.

Adult↗
PubMed1998

[Prostate-specific antigen in the follow-up of conservatively treated prostatic cancer].

The determination of serum prostate specific antigen (PSA) has made the diagnosis of prostate cancer easier. PSA is also used extensively in the follow-up of patients, both treated and untreated. On the basis of material from 308 patients who were mainly managed conservatively, we discuss the usefulness of this practice. It is important to monitor PSA after radical treatment because an increase may indicate local recurrence. In some patients this may lead to further treatment with cure as the aim. For patients under observation only, or those being treated by endocrine intervention, the value of regular PSA measurements is less certain. Where such patients were followed up for at least three years, we found considerable overlaping of PSA values among patients with different outlooks. Within the present therapeutic possibilities it may be better to base their management on clinical signs rather than on PSA. Regular measurements of PSA lead to focusing on this variable, causing unnecessary distress to patients months, or even years, before clinical progression of the disease.

Biomarkers, Tumor↗
PubMed2005

BNP in the diagnosis and risk stratification of heart failure.

Heart failure (HF) is a common disorder that is associated with significant mortality and morbidity. However, the diagnosis of HF may at times be difficult when using conventional tools. The cardiac natriuretic peptides, particularly brain (B-type) natriuretic peptide (BNP), have evolved to be useful biomarkers of cardiac function and prognosis in HF and other cardiovascular disorders. Multiple observational studies have established the close association between plasma BNP as well as the N-terminal fragment of the BNP prohormone (NT-proBNP) with the diagnosis of HF and an independent prediction of mortality and HF events. Although there are confounding variables to consider, when used in the correct clinical settings, BNP or NT-proBNP testing can be extremely useful. Furthermore, preliminary data from randomized controlled trials suggest that knowledge of BNP and/or NT-proBNP level may optimize the management of patients with HF. Large-scale randomized controlled trials that evaluate BNP/NT-proBNP-guided therapy are ongoing.

Biomarkers↗
PubMed2005

Prediction of complications following nonemergency percutaneous coronary interventions.

Previous models for prediction of complications after percutaneous coronary interventions (PCIs) have included in-hospital mortality and major in-hospital complications. In general, these models have excluded elevated cardiac biomarkers as a complication. We sought to determine whether a risk model could predict complications, including biomarker elevation, in patients undergoing nonemergency PCI. We examined the outcomes of nonemergency PCI performed on patients at Mayo Clinic from 2000 to 2003. The primary end point was in-hospital complications of death, myocardial infarction (MI) (Q-wave MI, or post-PCI creatine kinase-MB elevation >or=3 times the upper limit of normal), emergency coronary artery bypass grafting, or stroke. We used the Hosmer-Lemeshow test to demonstrate the adequacy of the model fit, and the c-index for discriminatory ability of the model. Of 2,894 nonemergency PCIs, the end point was noted in 232 (8%). The final prediction model included vein graft intervention (odds ratio [OR] 2.19), angiographic thrombus (OR 2.12), preprocedure stenosis of a minor (OR 1.98) or major (OR 1.62) side branch, and type C lesion (OR 1.48). The model had modest ability to discriminate between event and nonevent patients (c = 0.641). In the 500 bootstrap samples for internal validation, the c-index was 0.642 +/- 0.020, indicating only fair discriminatory ability. The average number of observed events was 232.0 +/- 14.7 compared with 232.1 +/- 2.5 expected events (average difference -0.06 +/- 14.5). In conclusion, the 5 risk variables associated with an increased risk of complications in patients undergoing elective PCI included vein graft intervention, presence of angiographic thrombus, stenosis of a major or minor side branch, and type C lesion; however, the discriminatory ability of the model derived from the variables was only modest.

Aged↗
PubMed2005

Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure.

BACKGROUND: Recent studies have suggested that higher body mass index (BMI) is associated with improved prognosis in chronic heart failure (CHF). The adipocytokine adiponectin is inversely associated with BMI, and in healthy subjects, low adiponectin is a predictor of mortality. In a prospective study, we therefore evaluated the association between plasma adiponectin levels and mortality among patients with CHF. METHODS AND RESULTS: In 195 CHF patients (age 69.3+/-10.2 years, BMI 27.3+/-5.2 kg/m2, left ventricular ejection fraction 30+/-8.9%, mean+/-SD), plasma adiponectin and N-terminal pro brain natriuretic peptide (NT-proBNP) were measured at baseline. Adiponectin was positively associated with NT-proBNP (beta=0.47, P<0.001), and both biomarkers were negatively associated with BMI (beta=-0.43, P<0.001 for adiponectin and beta=-0.38, P<0.001 for NT-proBNP, respectively) During a median follow-up of 2.6 years, 46 (23.5%) of the patients died. After adjustment for clinical variables associated with CHF severity (age, systolic blood pressure, left ventricular ejection fraction <25%, duration of CHF, and creatinine clearance) and for NT-proBNP, the hazard ratio of mortality for values in the 2 upper tertiles relative to the lowest tertile of adiponectin was 3.23 (P=0.032). BMI predicted mortality independently of clinical parameters of CHF severity (hazard ratio=0.63, P=0.012), but this association became insignificant after additional adjustment for NT-proBNP (hazard ratio=0.74, P=0.13). CONCLUSIONS: A high adiponectin level was a predictor of mortality, independent of risk markers of CHF severity, presumably because of its role as a marker for wasting. BMI was also associated with mortality, but a part of this relation may be mediated by adiponectin and NT-proBNP levels.

Adiponectin↗
PubMed2002

Tobacco smoking, harm reduction, and biomarkers.

The only known way to reduce cancer risk in smokers is complete cessation, but many smokers are unable or unwilling to quit. Consequently, tobacco companies are now marketing products that purport to reduce carcinogen exposure, with the implication that such products provide a safer way to smoke. Moreover, researchers are exploring ways to reduce the amount of cigarette smoke carcinogens to which the smokers are exposed. Although these methods are, in theory beneficial, it is possible that the perceived availability of "safe" ways to smoke will cause some former smokers to resume smoking and some current smokers to delay quitting. Thus, the extent of exposure reduction and the impact on public health of these methods need to be considered carefully. However, risk reduction and its relation to exposure are not simple to estimate. The way people smoke and the way they respond to carcinogen exposure are both highly variable, as evidenced by the previous history of smokers who switched to light, or low-tar cigarettes. This can actually increase risk in some smokers. The evaluation of exposure reduction will therefore need to be multidisciplinary and include in vitro cell culture studies, animal studies, human clinical studies, and epidemiologic studies. Biomarkers will be critical for rapidly evaluating the effects of new strategies or products to reduce exposure to tobacco smoke carcinogens. No single biomarker will likely satisfy our assessment needs, and so a panel of biomarkers should be used that includes biomarkers of exposure, biologically effective dose, and potential harm. In addition, usefulness of new products will need to be tested in people of different susceptibilities (i.e., who vary in behavior, sex, age, genetics, and prior tobacco use). Even if the new products are shown to be effective at reducing lung carcinogens, they should not be used alone but rather be incorporated into a comprehensive tobacco control program.

Biomarkers↗
PubMed2004

Creatinine normalization in biological monitoring revisited: the case of 1-hydroxypyrene.

OBJECTIVES: To compare the apparent urinary excretion rates of both creatinine and 1-hydroxypyrene (1-OHP) and to assess the value of creatinine normalization for both toxicokinetic analysis and the routine examination of workers. METHODS: All urine samples were collected from individuals who had been exposed to polycyclic aromatic hydrocarbons (PAHs), occupationally and non-occupationally, for at least 24 consecutive hours. Urinary creatinine and 1-OHP were determined. 1-OHP excretion rates were expressed either as a function of creatinine excretion rate or as unadjusted values. Theoretical relationships between creatinine-normalized excretion of metabolites and body weight-adjusted inhaled dose were drawn for men with a constant body mass index. RESULTS: Creatinine excretion rate paralleled 1-OHP excretion rate. The plot of creatinine excretion rate-adjusted excretion rate of 1-OHP vs time led to smooth curves for determination of toxicokinetic parameters. Creatinine normalization was adequate, even for samples with a urinary creatinine concentration below 0.5 g/l or above 3 g/l. A theoretical analysis revealed that men weighing between 50 kg and 100 kg, exposed to a constant dose of a pollutant producing a urinary metabolite excreted by the same mechanism as creatinine, would exhibit a body weight-adjusted dose span of 2 with an accompanying creatinine-normalized metabolite excretion span of 2.23-fold. CONCLUSION: The kinetics of creatinine excretion parallels that of 1-OHP, and a creatinine excretion rate-normalized excretion rate of 1-OHP appears to allow for a better determination of the toxicokinetic parameters of 1-OHP urinary excretion. At least in the case of 1-OHP, creatinine normalization seems valid, even for very dilute or very concentrated urine samples. Finally, because creatinine normalization not only compensates for variable diuresis but also correlates better with the body weight-adjusted dose of the parent compound, it should be used in biological monitoring of exposure to (PAHs) pyrene and to other substances whose urinary biomarker excretion kinetics parallel that of creatinine.

Creatinine↗
PubMed2004

Analysis of the low molecular weight fraction of serum by LC-dual ESI-FT-ICR mass spectrometry: precision of retention time, mass, and ion abundance.

This study quantifies the experimental uncertainty for LC retention time, mass measurement precision, and ion abundance obtained from replicate nLC-dual ESI-FT-ICR analyses of the low molecular weight fraction of serum. We used ultrafiltration to enrich the < 10-kDa fraction of components from the high-abundance proteins in a pooled serum sample derived from ovarian cancer patients. The THRASH algorithm for isotope cluster detection was applied to five replicate nLC-dual ESI-FT-ICR chromatograms. A simple two-level grouping algorithm was applied to the more than 7000 isotope clusters found in each replicate and identified 497 molecular species that appeared in at least four of the replicates. In addition, a representative set of 231 isotope clusters, corresponding to 188 unique molecular species, were manually interpreted to verify the automated algorithm and to set its tolerances. For nLC retention time reproducibility, 95% of the 497 species had a 95% confidence interval of the mean of +/- 0.9 min or less without the use of chromatographic alignment procedures. Furthermore, 95% of the 497 species had a mass measurement precision of < or = 3.2 and < or = 6.3 ppm for internally and externally calibrated spectra, respectively. Moreover, 95% of replicate ion abundance measurements, covering an ion abundance range of approximately 3 orders of magnitude, had a coefficient of variation of less than 62% without using any normalization functions. The variability of ion abundance was independent of LC retention time, mass, and ion abundance quartile. These measures of analytical reproducibility establish a statistical rationale for differentiating healthy and disease patient populations for the elucidation of biomarkers in the low molecular fraction of serum.

Algorithms↗
PubMed2006

Metabolic profiling of glucuronides in human urine by LC-MS/MS and partial least-squares discriminant analysis for classification and prediction of gender.

Mass spectrometry (MS) is increasingly being used for metabolic profiling, but detection modes such as constant neutral loss or multiple reaction monitoring have not often been reported. These modes allow focusing on structurally related compounds, which could be advantageous for situations in which the trait under investigation is associated with a particular class of metabolites. In this study, we analyzed endogenous glucuronides excreted in human urine by monitoring characteristic transitions of putative steroid glucuronides by LC-MS/MS for discrimination of females from males. Two methods for data extraction were used: (i) a manual procedure based on visual inspection of the chromatograms and selection of 23 peaks and (ii) a software-supported method (MarkerView) set to extract 100 peaks. Data from 10 female and 10 male students were analyzed by principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) using software SIMCA. With PCA, only the manual peak selection resulted in clustering males and females. With PLS-DA, the manual method provided full separation on the basis of one single discriminant; the software-supported approach required a two-component model for complete separation. Loading plots were analyzed for their ability to reveal peaks with high discriminating power, that is, potential biomarkers. The PLS-DA models were validated with urine samples collected from five new females and five new males. Gender was correctly assigned for all. Our results indicate that inclusion of biological criteria for variable selection coupled to class-specific MS analysis and data extraction by appropriate software may constitute a valuable addition to the methods available for metabolomics.

Adult↗
PubMed2004

Neuroendocrine testing in community patients with heart disease: plasma N-terminal proatrial natriuretic peptide predicts morbidity and mortality stronger than catecholamines and heart rate variability.

BACKGROUND: Patients with heart disease are at risk of developing congestive heart failure (CHF). Neurohormonal activation may make an important contribution. AIM: In stable heart patients from primary care, to examine neuroendocrine markers of cardiac performance for the association to cardiac dysfunction, morbidity and mortality. METHODS: Plasma N-terminal atrial natriuretic peptide (N-ANP), catecholamines, 24-h ECG and blood pressure, serum urea and creatinine, echocardiography, chest X-ray and physical examination were performed. Death was recorded during 5 to 7 years of follow-up. RESULTS: The study included 56 patients. Mean age was 71 years, 54% were men, 43% had clinical signs of CHF, 39 + 52 + 9% were in NYHA I + II + III, 34% had echocardiographic cardiac dysfunction, and 18 died during follow-up. N-ANP was related to all subtypes of cardiac dysfunction (p < 0.05). Catecholamines and premature ventricular captures (PVC) were related to valvular and systolic dysfunction, but heart rate variability and dipping blood pressure were not (p > 0.05). On multivariate analyses only, N-ANP and PVC were associated with clinical signs of CHF, echocardiographic cardiac dysfunction, and mortality (p < 0.05). CONCLUSIONS: Plasma N-ANP was stronger than catecholamines and variables of 24-h monitoring (blood pressure and electrocardiogram) in predicting morbidity and mortality, thereby supporting the use of cardiac natriuretic peptides (i.e. N-ANP, BNP, or N-BNP) as the most valuable biomarker in community patients at risk of CHF.

Adult↗
PubMedDate not supplied

Fingernail fluoride: a method for monitoring fluoride exposure.

This work was based on the hypothesis that fingernail clippings can be used as a biomarker for the subchronic exposure to fluoride. The results provide data on factors that may affect the concentration of fluoride in fingernail clippings as determined with the electrode following HMDS-facilitated diffusion. The following variables had only minor or no effects on the concentrations: (1) the surface area of the clippings (intact, minced or filed into powder) that were placed into the diffusion dishes; (2) soaking in deionized water for up to 6 h; (3) soaking in fluoridated water (1.0 ppm) for 2 h, and (4) removal of the organic material of nails by dry ashing. Fingernail fluoride concentrations were approximately 50% higher than those in toenails. A 1-month period of increased fluoride intake by one of the authors resulted in significant increases in fingernail fluoride concentrations after a lag time of approximately 3.5 months. The fluoride concentrations in fingernail clippings obtained from three groups of Brazilian children were directly related to the concentrations in the drinking water (0.1, 1.6 or 2.3 ppm). The results indicate that: (1) HMDS-facilitated diffusion completely separates fluoride from intact nail clippings, so the need for ashing or other preparative methods is obviated; (2) fingernail fluoride is derived mainly from the systemic circulation, and (3) fluoride intake is reflected by the concentrations in fingernails.

Analysis of Variance↗
PubMed1996

Methylation study of a population environmentally exposed to arsenic in drinking water.

Methylation is considered the detoxification pathway for inorganic arsenic (InAs), an established human carcinogen. Urinary speciation analysis is used to assess the distribution of metabolites [monomethylarsonate (MMA), dimethylarsinate (DMA), and unmethylated arsenic (InAs)], as indicators of methylation capacity. We conducted a large biomarker study in northern Chile of a population chronically exposed to high levels of arsenic in drinking water. We report the results of the methylation study, which focused on the effects of exposure and other variables on the percent InAs, MMA, DMA, and the ratio of MMA to DMA in urine. The study consisted of 122 people in a town with arsenic water levels around 600 micrograms/l and 98 participants in a neighboring town with arsenic levels in water of about 15 micrograms/l. The corresponding mean urinary arsenic levels were 580 micrograms/l and 60 micrograms/l, of which 18.4% and 14.9% were InAs, respectively. The main differences were found for MMA:DMA; exposure, smoking, and being male were associated with higher MMA:DMA, while longer residence, Atacameño ethnicity, and being female were associated with lower MMA:DMA. Together, these variables explained about 30% of the variability in MMA:DMA. Overall, there was no evidence of a threshold for methylation capacity, even at very high exposures, and the interindividual differences were within a much wider range than those attributed to the variables investigated. The differences in percent InAs were small and within the ranges of other studies of background exposure levels. The biological significance of MMA:DMA, which was more than 1.5 times greater in the exposed group, and its relationship to sex, length of exposure, and ethnicity need further investigation because its relevance to health risk is not clear.

Adolescent↗
PubMed2006

Human kallikrein 8 protein is a favorable prognostic marker in ovarian cancer.

Human kallikrein 8 (hK8/neuropsin/ovasin; encoded by KLK8) is a steroid hormone-regulated secreted serine protease differentially expressed in ovarian carcinoma. KLK8 mRNA levels are associated with a favorable patient prognosis and hK8 protein levels are elevated in the sera of 62% ovarian cancer patients, suggesting that KLK8/hK8 is a prospective biomarker. Given the above, the aim of the present study was to determine if tissue hK8 bears any prognostic significance in ovarian cancer. Using a newly developed ELISA, hK8 was quantified in 136 ovarian tumor extracts and correlated with clinicopathologic variables and outcome [progression-free survival (PFS); overall survival (OS)] over a median follow-up period of 42 months. hK8 levels in ovarian tumor cytosols ranged from 0 to 478 ng/mg total protein, with a median of 30 ng/mg. An optimal cutoff value of 25.8 ng/mg total protein (74th percentile) was selected based on the ability of hK8 values to predict the PFS of the study population and to categorize tumors as hK8 positive or negative. Women with hK8-positive tumors most often had lower-grade tumors (G1), no residual tumor after surgery, and optimal debulking success (P < 0.05). Univariate and multivariate analyses revealed that patients with hK8-positive tumors had a significantly longer PFS and OS than hK8-negative patients (P < 0.05). Kaplan-Meier survival curves further confirmed a reduced risk of relapse and death in women with hK8-positive tumors (P = 0.001 and P = 0.014, respectively). These results indicate that hK8 is an independent marker of favorable prognosis in ovarian cancer.

Adenocarcinoma, Clear Cell↗
PubMed2026

AI-Supported, Integrative Prediction of Postoperative Delirium: Protocol for the CONFUSED Study.

BACKGROUND: Postoperative delirium (POD) is a frequent and serious complication in older surgical patients, characterized by acute cognitive dysfunction and fluctuating levels of consciousness. POD is associated with prolonged hospitalization, long-term cognitive decline, reduced quality of life, and increased mortality. Despite its clinical relevance, the underlying pathophysiological mechanisms remain poorly understood, and reliable biomarkers for early prediction and prevention are lacking. OBJECTIVE: The CONFUSED study aims to identify molecular and clinical predictors of POD by integrating clinical data with proteomic, transcriptomic, and epigenetic analyses. The primary objective is to develop predictive models for POD using multimodal data. Secondary objectives include the identification of delirium-associated genes, proteins, and epigenetic signatures, as well as the exploration of patient subgroups at increased risk for POD. METHODS: CONFUSED is a prospective observational cohort study conducted at a German university hospital. Adult patients undergoing major surgery under general anesthesia will be enrolled until 100 cases of POD have been observed, which is expected to require a total sample size of approximately 200 to 300 patients. Blood samples are collected at 4 predefined time points: before premedication, immediately after surgery, and on postoperative days 2 and 5. Samples undergo comprehensive proteomic profiling, transcriptomic analysis using RNA microarrays, DNA methylation analysis, and genotyping of selected polymorphisms. Clinical data, including demographics, comorbidities, perioperative variables, medications, and delirium assessments using the Confusion Assessment Method (CAM) and CAM for the intensive care unit, are systematically recorded. Statistical analyses include univariate and multivariate methods, as well as machine learning approaches such as random forests and support vector machines, to identify relevant biomarkers and develop predictive models. The study protocol follows STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) guidelines and was approved by the responsible ethics committees. RESULTS: The study was registered in the German Clinical Trials Register (DRKS00033854) on March 18, 2024. Recruitment started in January 2024 and is ongoing at the time of manuscript submission. As of now, 135 patients have been enrolled. Sample collection and laboratory analyses are ongoing. Data analysis began in January 2026, with first results anticipated in July 2026. Final data lock is anticipated after the completion of recruitment. CONCLUSIONS: By integrating multimodal molecular data with clinical parameters and applying advanced machine learning techniques, the CONFUSED study aims to improve the prediction and understanding of POD. The results are expected to support the development of personalized preventive strategies and contribute to improved perioperative care for patients at risk of POD.

Humans↗