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PubMed2005

Seasonal variations of selected cardiovascular risk factors.

This article reviews research on selected biomarkers of cardiovascular risk - cholesterol and other lipids, C-reactive protein (CRP), fibrinogen, homocysteine - in the attempt to determine the existence of a predictable seasonal chronobiological pattern of variation. Studies dating as far back as the 1930s have reported seasonal variations in cholesterol levels. Statistically significant seasonal changes in lipid levels have been found in individuals irrespective of the country where the research has been conducted, and irrespective of the age, sex, ethnicity, and baseline lipid levels of the study subjects. While not all studies have been in complete agreement on either the amplitude (degree of seasonal change) or month/s of highest lipid levels, a strong winter/summer difference has been found in most studies. Existing evidence for an independent effect of season in variation of CRP is weak. Studies have consistently reported significant seasonal variations in fibrinogen levels. While other biological factors clearly interact to affect fibrinogen variability, seasonality appears to be an independent source of variability. Evidence from several studies points to a lack of seasonal variability in homocysteine levels. Although seasonal variability is just one source of periodicity influencing biological function and assessments in clinical practice, for some biomarkers, including lipids and fibrinogen, it is a source of variability that warrants consideration prior to a decision to treat and in assessing response to interventions.

Biomarkers↗
PubMed2002

Biomarkers of frailty in older persons.

Trajectories of health and functioning with age show extreme variability among different individuals. Normal aging implies a progressive decline of physiological reserve and ability to compensate, but it is compatible with autonomy over the entire life span. In frail, older persons the decline in functional reserve is accelerated and compensatory mechanisms start failing, with high risk of homeostasis disruption and consequent negative health outcomes. Frailty is currently conceptualized as an age-related alteration in physiology and pathology that results into a typical constellation of signs and symptoms. Although current attempts to identify frail, older individuals for clinical purposes are based on measures of mobility and motor performance, candidate biological markers that may characterize the frailty syndrome start to emerge in the literature. These potential markers include, but are not limited to, soluble mediators of the inflammatory response, hormones, free radicals, antioxidants and macro- and micro-nutrients. This is a research area undergoing a rapid, dynamic development that may profit from new ways of defining disability outcomes in epidemiological studies of the elderly.

Aged↗
PubMed2001

Surrogate endpoint biomarkers and their modulation in cervical chemoprevention trials.

BACKGROUND: Surrogate endpoint biomarkers (SEBs) are used as intermediate indicators of a reduction in cancer incidence in chemoprevention studies. SEBs should be expressed differentially in normal and high risk tissue; appear at a well defined stage of carcinogenesis; be studied with reasonable sensitivity, specificity, and accuracy; and be modulated in chemoprevention trials. The concept of SEBs may be useful in the trials of many new therapies. METHODS: The current review includes a comprehensive review of the literature. Many SEBs have been the subject of intense study and include quantitative histopathology and cytology, proliferation markers, regulation markers, differentiation markers, general genomic instability markers, and tissue maintenance markers. Because of the critical biologic and epidemiologic role of the human papillomavirus (HPV) in cervical carcinogenesis, the relation between these markers and HPV should be considered. In addition, biomarkers of HPV infection and its regression should be sought. RESULTS: Several chemoprevention trials have been published that have included the use of SEBs. The biomarkers that appear most promising in these clinical trials can be measured quantitatively and reproducibly: quantitative histology and cytology, proliferating cell nuclear antigen (PCNA), MIB-1, MPM-2, HPV viral load, epidermal growth factor receptor, polyamines, and ploidy. The markers that have been demonstrated to be modulated in chemoprevention trials in the literature are quantitative histology and cytology, PCNA, MPM-2, HPV viral load, and polyamines. CONCLUSIONS: The surrogate endpoint biomarkers of most interest in future research should correlate well with HPV infection, be modulated by several therapeutic agents, and have limited variability and ease in measurement.

Antigens, Nuclear↗
PubMedDate not supplied

Biomarkers in fish from dioxin-contaminated fjords.

The Grenland fjords, southern Norway, have been heavily contaminated by dibenzo-p-dioxins and dibenzofurans (dioxins) over decades through inputs from a magnesium smelter. Despite radically decreased inputs since 1990, there are still high levels of dioxins in both biotic and abiotic components of the fjords. The aim of the study was to establish whether biomarkers' responses in three fish species, Atlantic cod (Gadus morhua L.), sea-trout (anadromous brown trout, Salmo trutta L.) and flounder (Platichthys flesus L.), could be used to discern the effects in the most contaminated ecosystem, Frierfjord, from the effects in the adjacent, less-contaminated ecosystem, Eidangerfjord. Biomarker responses clearly indicated that the three fish species were affected by dioxin exposure. Phase I responses in cod and trout could be used to differentiate exposure in the two fjord ecosystems. Phase II responses (glutathione S-transferase) in cod and trout similarly indicated a higher dioxin exposure in Frierfjord compared with Eidangerfjord. Results for glutathione S-transferase and glutathione reductase indicated different exposure levels in the two fjords, but also showed seasonal variability, and the results highlighted the need for baseline data for these biomarkers.

Animals↗
PubMed2002

Estimation of health effects of prenatal methylmercury exposure using structural equation models.

BACKGROUND: Observational studies in epidemiology always involve concerns regarding validity, especially measurement error, confounding, missing data, and other problems that may affect the study outcomes. Widely used standard statistical techniques, such as multiple regression analysis, may to some extent adjust for these shortcomings. However, structural equations may incorporate most of these considerations, thereby providing overall adjusted estimations of associations. This approach was used in a large epidemiological data set from a prospective study of developmental methyl-mercury toxicity. RESULTS: Structural equation models were developed for assessment of the association between biomarkers of prenatal mercury exposure and neuropsychological test scores in 7 year old children. Eleven neurobehavioral outcomes were grouped into motor function and verbally mediated function. Adjustment for local dependence and item bias was necessary for a satisfactory fit of the model, but had little impact on the estimated mercury effects. The mercury effect on the two latent neurobehavioral functions was similar to the strongest effects seen for individual test scores of motor function and verbal skills. Adjustment for contaminant exposure to poly chlorinated biphenyls (PCBs) changed the estimates only marginally, but the mercury effect could be reduced to non-significance by assuming a large measurement error for the PCB biomarker. CONCLUSIONS: The structural equation analysis allows correction for measurement error in exposure variables, incorporation of multiple outcomes and incomplete cases. This approach therefore deserves to be applied more frequently in the analysis of complex epidemiological data sets.

Biomarkers↗
PubMed2002

Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at cardiovascular risk: analysis of underlying factors.

BACKGROUND: Antioxidant supplementation with vitamin E had no effect in the prevention of cardiovascular diseases (CVD) in three recent large, randomized clinical trials. In order to reassess critically the role of vitamin E in CVD prevention, it is important to establish whether these results are related to a lack of antioxidant action. METHODS: We examined the in vivo antioxidant effect of vitamin E (300 mg/day for about three years) in 144 participants in the Primary Prevention Project (females and males, aged >/= 50 y, with at least one major CV risk factor, but no history of CVD). Urinary 8-epi-PGF2alpha (isoprostane F2alpha-III or 15-F2t-isoP), a validated biomarker of lipid peroxidation, was measured by mass spectrometry. RESULTS: Urinary excretion of 8-epi-PGF2alpha [pg/mg creatinine, median (range)] was 141 (67-498) in treated and 148 (76-561) in untreated subjects (p = 0.10). Taking into account possible confounding variables, multiple regression analysis confirmed that vitamin E had no significant effect on this biomarker. Levels of 8-epi-PGF2alpha were in the normal range for most subjects, except smokers and those with uncontrolled blood pressure or hyperglycemia. CONCLUSIONS: Prolonged vitamin E supplementation did not reduce lipid peroxidation in subjects with major cardiovascular risk factors. The observation that the rate of lipid peroxidation was near normal in a large proportion of subjects may help explain why vitamin E was not effective as an antioxidant in the PPP study and was ineffective for CVD prevention in large scale trials.

Journal Article↗
PubMed2005

Measurement of kidney function.

Accurate estimation of kidney function is central to the detection, evaluation, and treatment of chronic kidney disease (CKD). Glomerular filtration rate (GFR) is widely accepted as the best overall measure of kidney function and as such it forms the basis of definition and classification system for CKD. GFR cannot be measured directly in clinical practice and multiple methods are used to estimate GFR, all of which have their strengths and limitations. The current recommended method is to use estimating equations based on serum creatinine and which incorporate demographic and clinical variables.

Biomarkers↗
PubMed2002

A measure of the proportion of treatment effect explained by a surrogate marker.

Randomized clinical trials with rare primary endpoints or long duration times are costly. Because of this, there has been increasing interest in replacing the true endpoint with an earlier measured marker. However, surrogate markers must be appropriately validated. A quantitative measure for the proportion of treatment effect explained by the marker in a specific trial is a useful concept. Freedman, Graubard, and Schatzkin (1992, Statistics in Medicine 11, 167-178) suggested such a measure of surrogacy by the ratio of regression coefficients for the treatment indicator from two separate models with or without adjusting for the surrogate marker. However, it has been shown that this measure is very variable and there is no guarantee that the two models both fit. In this article, we propose alternative measures of the proportion explained that adapts an idea in Tsiatis, DeGruttola, and Wulfsohn (1995, Journal of the American Statistical Association 90, 27-37). The new measures require fewer assumptions in estimation and allow more flexibility in modeling. The estimates of these different measures are compared using data from an ophthalmology clinical trial and a series of simulation studies. The results suggest that the new measures are less variable.

Biomarkers↗
PubMedDate not supplied

Specificity of haemostasis abnormalities for vascular phenotypes.

Atherothrombosis is a systemic disease, hence it is difficult to prove the specificity of haemostasis abnormality for any single vascular phenotype. Associations between haemostatic variables and any given phenotype, e.g. (vascular) dementia, should be interpreted with caution, given the overlaps of vascular disease phenotypes, risk factors, and haemostatic variables.

Arteriosclerosis↗
PubMed1997

Chromosome translocations: a biomarker for retrospective biodosimetry.

We discuss here the results from our studies demonstrating that simple translocations detected by chromosome painting can be used to reconstruct radiation doses for workers exposed within the dose limits and for individuals with past exposure. To be useful, a biomarker for exposure and risk assessment should employ an end point that is highly quantitative, stable over time, and relevant to human risk. Recent advances in chromosome staining using fluorescence in situ hybridization facilitate fast and reliable measurement of simple translocations, a type of DNA damage linked both to prior clastogenic exposure and to risk. In contrast to other biomarkers available, the frequency of simple translocations in individuals exposed to whole-body radiation is stable over time postexposure, has little interindividual variability, and can be measured accurately at low frequencies.

Animals↗
PubMed2006

Pollution biomarkers in estuarine animals: critical review and new perspectives.

In this review, recent developments in monitoring toxicological responses in estuarine animals are analyzed, considering the biomarker responses to different classes of pollutants. The estuarine environment imposes stressful conditions to the organisms that inhabit it, and this situation can alter their sensitivity to many pollutants. The specificity of some biomarkers like metallothionein tissue concentration is discussed in virtue of its dependence on salinity, which is highly variable in estuaries. Examples of cholinesterase activity measurements are also provided and criteria to select sensitive enzymes to detect pesticides and toxins are discussed. Regarding non-specific biomarkers, toxic responses in terms of antioxidant defenses and/or oxidative damage are also considered in this review, focusing on invertebrate species. In addition, the presence of an antioxidant gradient along the body of the estuarine polychaete Laeonereis acuta (Nereididae) and its relationship to different strategies, which deal with the generation of oxidative stress, is reviewed. Also, unusual antioxidant defenses against environmental pro-oxidants are discussed, including the mucus secreted by L. acuta. Disruption of osmoregulation by pollutants is of paramount importance in several estuarine species. In some cases such as in the estuarine crab Chasmagnathus granulatus, there is a trade off between bioavailability of toxicants (e.g. metals) and their interaction with key enzymes such as Na(+)-K(+)-ATPase and carbonic anhydrase. Thus, the metal effect on osmoregulation is also discussed in the present review. Finally, field case studies with fish species like the croaker Micropogonias furnieri (Scianidae) are used to illustrate the application of DNA damage and immunosuppressive responses as potential biomarkers of complex mixture of pollutants.

Animals↗
PubMedDate not supplied

Evaluating measures of hematology and blood chemistry in male rhesus monkeys as biomarkers of aging.

Reliable and valid biomarkers of aging can provide valuable tools for examining the effectiveness of interventions that may influence the rate of aging processes. However, a standardized method for identifying biomarkers of aging has yet to be developed. The current analysis focused on hematology and blood chemistry variables obtained from a 5-year longitudinal study of male rhesus monkeys (N = 29) on a diet restriction regime known to retard aging processes and extend lifespan in laboratory rodents (70% of the diet intake of controls). For the current analysis, the major screening criteria for identifying candidate biomarkers of aging were cross-sectional and longitudinal correlation with chronological age (CA) and stability of individual differences. Six potential variables from the battery of blood chemistry tests were identified: 1) serum glutamic oxalacetic transaminase; 2) alkaline phosphatase; 3) total protein; 4) globulin; 5) blood urea nitrogen to creatinine ratio; and 6) phosphates. When submitted to principle component analysis, these variables loaded onto a single component that accounted for over 50% of the total variance to indicate marked covariance among them. By applying the factor score coefficients from the first principle component, an equation was derived for estimating a biological age score (BAS) for each individual monkey. A comparison of BAS between control and diet-restricted monkeys revealed no statistically significant difference at present; however, the slope of the regression of BAS onto CA appeared steeper for the control group compared to the experimental group. Thus, while demonstration of the validity of the candidate biomarkers awaits further evidence, a strategy by which additional biomarkers of aging can be identified is proposed as an improvement over past approaches.

Aging↗
PubMedDate not supplied

Measuring human functional age: a review of empirical findings.

A review of empirical functional age studies published in English was conducted. Types of biomarkers used in functional age studies included sensorimotor, cognitive, psychosocial, behavioral, anthropometric, biomedical, physiological, and dental variables. Previous criticisms of the validity and utility of functional age research were evaluated with reference to empirical studies. While some of these criticisms remain valid, areas of research currently using established biomarkers to predict functional outcomes were identified, including driving, falls, and cognitive functioning. It was concluded that the success of functional age research is dependent on the relevance of biomarkers to specific functional outcomes.

Adult↗
PubMed2004

The interaction between vigabatrin and diazepam on the electroencephalogram during active behaviour in rats: an isobolic analysis.

To test whether polytherapy with two gamma-aminobutyric acid (GABA) -ergic drugs might be clinically relevant for epilepsy treatment, effects on spike and wave discharges, the fraction of time spent being behaviourally active, and the background electroencephalogram (EEG) during behavioural activity of vigabatrin (15-500 mg/kg i.p.) and diazepam (1.25-10 mg/kg i.p.) were compared with their combination (dose ratio 1:25) in rats. Isobolic analyses were performed to describe the interactions. Unfortunately, no conclusions can be drawn concerning the interaction of both drugs on the spike and wave discharge activity because the effect of diazepam was shown to be dominant. Only vigabatrin decreased the behavioural activity, whereas there was a trend towards a decrease after diazepam. All treatments dose dependently increased the power in the beta frequency band. Unfortunately, the dose ratio was not optimal to describe the interaction. The theta peak frequency was dose dependently decreased after all treatments. There was a synergistic interaction between the two drugs on this variable. These data support both the idea that an increase in power in the beta frequency band can serve as a biomarker for GABAergic inhibition and the suggestion that clinically effective anxiolytics decrease the theta peak frequency. Furthermore, we show that on different variables, there might be different optimal dosage combinations, which might complicate the clinical application of polytherapy.

Animals↗
PubMed2004

Regulated bradycardia in the pulmonate limpet Siphonaria (Gastropoda: Mollusca) during pollutant exposure: implication for biomarker studies.

Although the cardiac activity of invertebrates is now widely used as a biomarker of marine pollution, few studies consider the intrinsic factors causing the variability of heart rate (HR), including the physiological states associated with metabolic depression and behavioural isolation. We examined the cardiac responses to copper exposure of a pulmonate limpet (Siphonaria capensis Quoy and Gaimard), known to adaptively depress heart rate (and metabolic rate) under naturally stressful conditions (hyposalinity). Analysis of variance was used to assess the effects of copper concentration (0-1000 microg/L), exposure time (0-2 h), and individual difference (eight limpets per concentration) on heart rate parameters. Minute by minute heart rate (HR) and heart rate variability (HRV), and bradycardia (< or =10 beats/min) were determined from continuous recording traces. Most of the HR variance was attributable to the interaction of concentration and individuals (35.8%). Considerably lower mean HRs for the higher range of copper concentrations (250 to 1000 microg/L), compared to the lower range (0 to 50 microg/L), were attributable to the virtually exclusive induction of bradycardia in the higher concentration treatments. With increasing concentration, bradycardia was induced sooner and became less interspersed with near normal heart rates (i.e., less episodic). This regulated bradycardial response is apparently associated with isolation (avoidance) behaviour rather than with copper uptake. These findings have implications for biomarker exercises which use heart rate, in cases where invertebrates depress metabolism.

Animals↗
PubMed2005

Altered metabolic profile in the frontal cortex of PS2APP transgenic mice, monitored throughout their life span.

The transgenic mouse line PS2APP (PS2N141I x APP(swe)) develops an age-related cognitive decline associated with severe amyloidosis, mimicking the pathophysiologic processes in Alzheimer disease (AD). In the quest for biomarkers to monitor, noninvasively, the progression of the disease, we used magnetic resonance imaging and 1H-spectroscopy to characterize PS2APP mice throughout their life span. Morphometric measurements revealed only small size differences to controls. The metabolic profile, however, showed clear indicators of hypometabolism with age in the PS2APP mice: both N-acetyl-aspartate and glutamate were significantly reduced in the older animals. These spectroscopic measures in vivo correlated well with the plaque load in the frontal cortex. A diagnostic test, based on these measures, reached 92% sensitivity and 82% specificity at age 20 months. These noninvasive biomarkers can be exploited in preclinical pharmaceutical research to cope with the high variability in transgenic animal models and to enhance the power of drug efficacy studies.

Age Factors↗
PubMed2006

Inferring causal relationships among intermediate phenotypes and biomarkers: a case study of rheumatoid arthritis.

MOTIVATION: Genetic association analysis is based on statistical correlations which do not assign any cause-to-effect arrows between the two correlated variables. Normally, such assignment of cause and effect label is not necessary in genetic analysis since genes are always the cause and phenotypes are always the effect. However, among intermediate phenotypes and biomarkers, assigning cause and effect becomes meaningful, and causal inference can be useful. RESULTS: We show that causal inference is possible by an example in a study of rheumatoid arthritis. With the help of genotypic information, the shared epitope, the causal relationship between two biomarkers related to the disease, anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) has been established. We emphasize the fact that third variable must be a genotype to be able to resolve potential ambiguities in causal inference. Two non-trivial conclusions have been reached by the causal inference: (1) anti-CCP is a cause of RF and (2) it is unlikely that a third confounding factor contributes to both anti-CCP and RF.

Arthritis, Rheumatoid↗