Homeostatic Set Point Research Articles

Homeostasis in large networks of neurons through the Ising model - do higher order interactions matter?

Homeostatic activity in large networks of neurons is a relatively scantly explored area of neuroscience, both on experimental and computational level [1]. With recent advance in recording techniques, the lack of experimental data is gradually ceasing to be the limitation. New multielectrode arrays (MEA) allow for monitoring cultures of thousands of neurons over many days with high spatial resolution [2]. However, the interpretation of multi-neuron recordings is not straightforward and requires methods going beyond the simplest descriptive statistics. Here we explore a novel approach to analyzing multi-unit neuronal activity recorded over a five day homeostatic experiment by employing the Ising model [3,4]. This statistical model explains the probability of multi-neuron spike patterns solely on the basis of firing rates and correlations, assuming an otherwise minimally structured distribution. Its application to a variety of recordings has helped re-evaluate the importance of neural interactions in shaping the global activity [3,4]. In addition, due to the models minimal structure, the quality of the fits can be treated as an indicator of higher-order interactions in the activity [4]. We compare the Ising model fits in the same preparation over several recordings: before, during and after CNQX application. We find that, in addition to the changes in firing rates and correlations, also the quality of the fits changes significantly across recordings (Figure ​(Figure1).1). However, while firing rates and correlations to not appear to stabilize to a baseline level, the quality of the model fit does (Figure ​(Figure1).1). Altogether this indicates that changes to first and second order statistics cannot explain the homeostatic changes in activity; and that higher order interactions might be a significant component of homeostatic compensation. Whether homeostatic maintenance of a complex higher-order dynamics is an effect of interplay of simple mechanisms or a global homeostatic set-point remains to be investigated. Figure 1 Boxplot comparisons of different measures across seven recordings from the experimental culture. A Firing rates; B Pearson correlation coefficient; C Kullback-Leibler divergence between the distributions of patterns predicted by the Ising model and the ...

Changes in Well-Being: Complementing a Psychosocial Approach with Neurobiological Insights

The sustainability of changes in well-being achieved via positive interventions is challenged by findings that happiness levels are constrained by a homeostatic set-point. In this paper, we propose that while generally stable, the neurological and psychophysiological bases of well-being demonstrate plasticity. The neurobiological underpinnings of the hedonic component of well-being are first reviewed, demonstrating the value of both central (such as frontal asymmetry) and peripheral (such as heart rate variability) indices. Convergent evidence that certain well-being interventions are capable of modifying subjective, central and peripheral indices of positive affect or regulation of negative affect is then reported, although there is a clear need for longitudinal research to demonstrate the longevity of changes. It is recommended that a multi-level approach to evaluating positive interventions incorporating subjective psychosocial and neurobiological indices of affective change is adopted by researchers in an attempt to identify interventions most likely to achieve sustained positive outcome. Accumulating evidence through rigorous research that positive interventions can enhance psychosocial and neurophysiological factors can provide a compelling case for more widespread dissemination through public health policy.

Clonally Diverse T Cell Homeostasis Is Maintained by a Common Program of Cell-Cycle Control

Lymphopenia induces T cells to undergo cell divisions as part of a homeostatic response mechanism. The clonal response to lymphopenia is extremely diverse, and it is unknown whether this heterogeneity represents distinct mechanisms of cell-cycle control or whether a common mechanism can account for the diversity. We addressed this question by combining in vivo and mathematical modeling of lymphopenia-induced proliferation (LIP) of two distinct T cell clonotypes. OT-I T cells undergo rapid LIP accompanied by differentiation that superficially resembles Ag-induced proliferation, whereas F5 T cells divide slowly and remain naive. Both F5 and OT-I LIP responses were most accurately described by a single stochastic division model where the rate of cell division was exponentially decreased with increasing cell numbers. The model successfully identified key biological parameters of the response and accurately predicted the homeostatic set point of each clone. Significantly, the model was successful in predicting interclonal competition between OT-I and F5 T cells, consistent with competition for the same resource(s) required for homeostatic proliferation. Our results show that diverse and heterogeneous clonal T cell responses can be accounted for by a single common model of homeostasis.

Mineral nutrition and elevated [CO2] interact to modify 13C, an index of gas exchange, in Norway spruce

The effects of the past century's increase in atmospheric CO2 concentration ([CO2]) have been recorded in the stable carbon isotope composition (δ(13)C) of the annual growth rings of trees. The isotope record frequently shows increases in photosynthetic CO2 uptake relative to stomatal conductance, which estimates the CO2 concentration gradient across the stomata (ca - ci). This variable, which is one control over the net photosynthetic rate, has been suggested as a homeostatic gas-exchange set point that is easy to estimate from δ(13)C and [CO2]. However, in high-latitude conifer forests, the literature is mixed; some studies show increases in (ca - ci) and others show homeostasis. Here we present leaf and tree-ring δ(13)C data from a controlled experiment that tested factorial combinations of elevated [CO2] (365 and 700 ∝mol mol(-1)) and fertilization on mature Norway spruce (Picea abies (L.) Karst.) trees in northern Sweden. We found first that the leaf carbon pool was contaminated by the current photosynthate in the older leaf cohorts. This is the reverse of the common observation that older photosynthate reserves can be used to produce new tissue; here the older tissue contains recent photosynthate. We found that the tree-ring data lack such contamination and in any case they better integrate over the canopy and the growing season than do leaves. In the second and third years of treatment, elevated [CO2] alone increased (ca - ci) by 38%; when combined with fertilization, it increased (ca - ci) by 60%. The results of this study support the idea that annual rings provide a clearer isotopic signal than do foliage age-classes. The tree-ring data show that inferred (ca - ci) depends not only on [CO2], but also on mineral-nutrient status. The differences in (ca - ci) are sufficiently large to account for the treatment-induced increase in wood-volume production in these stands.

General Error Analysis in the Relationship between Free Thyroxine and Thyrotropin and Its Clinical Relevance

Background. This treatise investigates error sources in measurements applicable to the hypothalamus-pituitary-thyroid (HPT) system of analysis for homeostatic set point computation. The hypothalamus-pituitary transfer characteristic (HP curve) describes the relationship between plasma free thyroxine [FT4] and thyrotropin [TSH]. Objective. We define the origin, types, causes, and effects of errors that are commonly encountered in TFT measurements and examine how we can interpret these to construct a reliable HP function for set point establishment. Design and Methods. The error sources in the clinical measurement procedures are identified and analyzed in relation to the constructed HP model. Results. The main sources of measurement and interpretation uncertainties are (1) diurnal variations in [TSH], (2) TFT measurement variations influenced by timing of thyroid medications, (3) error sensitivity in ranges of [TSH] and [FT4] (laboratory assay dependent), (4) rounding/truncation of decimals in [FT4] which in turn amplify curve fitting errors in the [TSH] domain in the lower [FT4] range, (5) memory effects (rate-independent hysteresis effect). Conclusions. When the main uncertainties in thyroid function tests (TFT) are identified and analyzed, we can find the most acceptable model space with which we can construct the best HP function and the related set point area.

A Mechanistic Model for Naive CD4 T Cell Homeostasis in Healthy Adults and Children

The size and composition of the T lymphocyte compartment is subject to strict homeostatic regulation and is remarkably stable throughout life in spite of variable dynamics in cell production and death during T cell development and immune responses. Homeostasis is achieved by careful orchestration of lymphocyte survival and cell division. New T cells are generated from the thymus and the number of peripheral T cells is regulated by controlling survival and proliferation. How these processes combine is however very complex. Thymic output increases in the first year of life and then decreases but is crucial for establishing repertoire diversity. Proliferation of new naive T cells plays a crucial role for maintaining numbers but at a potential cost to TCR repertoire diversity. A mechanistic two-compartment model of T cell homeostasis is described here that includes specific terms for thymic output, cell proliferation, and cell death of both resting and dividing cells. The model successfully predicts the homeostatic set point for T cells in adults and identifies variables that determine the total number of T cells. It also accurately predicts T cell numbers in children in early life despite rapid changes in thymic output and growth over this period.

Biological Variations of Leukocyte Numerical and Morphologic Parameters Determined by UniCel DxH 800 Hematology Analyzer

The Coulter DxH 800 hematology analyzer can determine leukocyte numerical parameters (total leukocyte counts and differentials). It also measures intrinsic biophysical properties of these cells in their near-native state. These morphologic measurements are known as cell population data (CPD). To study, for the first time, the biological variations of morphologic parameters or CPD and reinvestigate numerical parameters using the newest Coulter hematology analyzer. Design.-Forty adult volunteers (21 women, 19 men) were included. All participants maintained their normal lifestyles. Blood samples were drawn in duplicate by a single experienced phlebotomist and analyzed within 2 hours using a single analyzer. Before each batch analysis, the instrument quality controls were performed using the same lots of reagents. Within-subject (CV(I)) and between-subjects (CV(G)) biological variations for numerical parameters are smaller than previously reported. Cell population data have much smaller overall CV(I) and CV(G) compared to numerical parameters, suggesting that these parameters are less variable around the homeostatic set point intraindividually and interindividually. Index of individuality (ratio of CV(I)/CV(G)) for CPD was low. In addition, intraday and interday biological variations of all parameters are fairly constant. These observations are clinically valuable. Data on CV(I) and analytical precision may be used to generate objective delta-check values for use in quality management. Comparing CV(I) and CV(G) on CPD may allow us to decide the utility of traditional population-based reference ranges. Documentation of CPD on biological variations is an essential prerequisite in the development of any new application clinically.

Bone-specific alkaline phosphatase concentrations are less variable than those of parathyroid hormone in stable hemodialysis patients

Abnormalities of bone mineral metabolism and vascular calcification are prevalent in patients with kidney failure. Clinical management is based on biochemical targets, in particular parathyroid hormone (PTH) concentrations, but this has many limitations including high biological variation. A possible alternative is bone-specific alkaline phosphatase (ALP); therefore, we evaluated the biological variation of this marker in patients undergoing hemodialysis. Bone ALP was measured in non-fasting serum samples taken twice a week over a 6-week period in 22 stable hemodialysis patients and 12 healthy volunteers. The within-individual coefficients of variance were calculated and used to derive the critical difference required to be certain that an observed change was significant. The coefficient of variance for bone ALP was significantly higher in hemodialysis patients compared to healthy individuals. Seven samples were required to estimate the homeostatic set point of bone ALP, within 10%, in a hemodialysis patient. The concentration of serial bone ALP measurements would need to change by 36% between any two measurements before it can be considered a significant change. Since the biological variation of bone ALP is less than half that reported for PTH, our study provides further support for the use of bone ALP as an alternative marker of bone mineral metabolism in the setting of chronic kidney disease–mineral and bone disorder.

Biological Variability of Plasma Intact and C-Terminal FGF23 Measurements

FGF23 measurement may have a role in the management of patients with chronic kidney disease (CKD). Our objective was to study the biological variability of plasma intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) concentrations. Plasma samples were taken from 12 healthy adults at multiple time points on 2 consecutive days to assess diurnal variability of FGF23 concentrations. Early-morning fasting and nonfasting samples were also taken over a 6-wk period to estimate components of biological variation. Samples from 170 volunteers were used to define reference intervals. FGF23 concentrations were measured by commercial ELISA. Western blotting was used to analyze FGF23 species from the plasma of healthy adults and patients with predialysis CKD and those undergoing dialysis. A total of 180 healthy adults and 18 adults with stage 3-5D CKD participated in this study at a hospital research unit. Estimates were made of the biological variability of plasma FGF23 concentrations. iFGF23, but not cFGF23, showed significant diurnal variation. cFGF23 had a significantly lower intra-individual variation than iFGF23 (8.3 vs. 18.3%) but higher inter-individual variation than iFGF23 (28.9 vs. 19.2%). Fourteen samples would be needed to estimate an individual's homeostatic set point (within 10%) for iFGF23 compared with only three samples for cFGF23. Using Western blotting, C-terminal FGF23 fragments were detected in the plasma of individuals with normal renal function and at all stages of renal disease. The percent cFGF23 was significantly higher in those without renal impairment (P < 0.001) and was positively correlated with plasma phosphate concentration in those with normal renal function. The high intra-individual biological variability of iFGF23 may limit its clinical use as a diagnostic or management tool. Risk-related thresholds may be more appropriate for clinical decision making based on cFGF23 measurements than conventional reference intervals. FGF23 cleavage pathways may be an important natural regulatory mechanism for phosphate control.

Mody in pregnancy – a case report and literature review

Case ReportA 26 year old primigravida, was diagnosed with Maturity Onset Diabetes of the Young (MODY) type 2 at the age of 15 after having previous history of impaired glucose...

Subject‐based reference values: biological variation, individuality, and reference change values

Subject-based reference values have been largely overlooked in veterinary medicine. These values represent longitudinal data rather than the cross-sectional data represented by standard population-based reference values. As such they provide information about biological and analytical variation. Inherent random variation of analytes around a homeostatic set point is referred to as biological variation; data on biological variation are underutilized in veterinary medicine and have multiple applications that include setting analytical goals, predicting the utility of population-based reference intervals (RIs), assessing the value of partitioning reference values, and evaluating the significance of changes in serial results. To generate these data, relatively few individuals are sampled for a short period of time. Given the difficulty of obtaining specimens from large number of healthy individuals to establish a cross-sectional RI for many veterinary species, especially exotic species, use of subject-based RIs is a practical alternative approach for the veterinary diagnostician. Furthermore, for the majority of biochemical analytes and even many hemostatic variables, population-based reference values are less sensitive than subject-based reference values for detecting pathologic changes in an individual. The focus of this review is the clinical usefulness of subject-based reference values and diagnostic implications for their use. Implementation of the concepts of biological variation, individuality, and reference change value (RCV) may allow large diagnostic laboratories to offer more sensitive reference values to assess health and detect disease.

Interleukin‐2, Interleukin‐7, T cell‐mediated autoimmunity, and N‐glycosylation

T cell activation and self-tolerance are tightly regulated to provide effective host defense against foreign pathogens while deflecting inappropriate autoimmune responses. Golgi Asn (N)-linked protein glycosylation coregulates homeostatic set points for T cell growth, differentiation, and self-tolerance to influence risk of autoimmune disorders such as multiple sclerosis (MS). Human autoimmunity is a complex trait that develops from intricate and poorly understood interactions between an individual's genetics and their environmental exposures. Recent evidence from our group suggests that in MS, additive and/or epistatic interactions between multiple genetic and environmental risk factors combine to dysregulate a common biochemical pathway, namely Golgi N-glycosylation. Here, we review the multiple regulatory mechanisms controlling N-glycan branching in T cells and autoimmunity, focusing on recent data implicating a critical role for interleukin-2 (IL-2) and IL-7 signaling.

Tumeurs endocrines de l’appendice diagnostiquées fortuitement sur pièces d’appendicectomie : étude de 143 cas

Complex local crosstalk amongst endocrine cells within the islet ensures tight coordination of their endocrine output. This is illustrated by the recent demonstration that the negative feedback control by delta cells within pancreatic islets determines the homeostatic set-point for plasma glucose during mouse postnatal development. However, the close association of islet endocrine cells that facilitates paracrine crosstalk also complicates the distinction between effects mediated directly on beta cells from indirect effects mediated via local intermediates, such as somatostatin from delta cells.To resolve this problem, we generated reporter mice that allow collection of pure pancreatic delta cells along with alpha and beta cells from the same islets and generated comprehensive transcriptomes for each islet endocrine cell type. These transcriptomes afford an unparalleled view of the receptors expressed by delta, alpha and beta cells, and allow the prediction of which signal targets which endocrine cell type with great accuracy.From these transcriptomes, we discovered that the ghrelin receptor is expressed exclusively by delta cells within the islet, which was confirmed by fluorescent in situ hybridization and qPCR. Indeed, ghrelin increases intracellular calcium in delta cells in intact mouse islets, measured by GCaMP6 and robustly potentiates glucose-stimulated somatostatin secretion on mouse and human islets in both static and perfusion assays. In contrast, des-acyl-ghrelin at the same dose had no effect on somatostatin secretion and did not block the actions of ghrelin.These results offer a straightforward explanation for the well-known insulinostatic actions of ghrelin. Rather than engaging beta cells directly, ghrelin engages delta cells to promote local inhibitory feedback that attenuates insulin release. These findings illustrate the power of our approach to resolve some of the long-standing conundrums with regard to the rich feedback that occurs within the islet that is integral to islet physiology and therefore highly relevant to diabetes.

Sources of Variability in Measurements of Cardiac Troponin T in a Community-Based Sample: The Atherosclerosis Risk in Communities Study

Application of cardiac troponin T (cTnT) as a marker of myocyte damage requires knowledge of its measurement variability. Using a highly sensitive assay for measurement, we evaluated the long-term storage stability of plasma cTnT at -70 °C and the sources of cTnT variability. Samples from the Atherosclerosis Risk in Communities study collected in 1996-1998 and 2005-2006 were assayed centrally to quantify variability in cTnT attributable to processing (replicates from same blood draw, n = 87), laboratory (replicates after freeze thaw, n = 29), short-term (n = 40) and long-term biological variation (repeat visit, n = 38), and degradation in frozen storage (n = 7677). Approximately 30% of this population-based cohort had cTnT concentrations below the detection limit (3 ng/L). Reliability coefficients for all paired comparisons exceeded 0.93 except for samples drawn 8 years apart (r = 0.36). Sources of cTnT variation (as CVs) were: laboratory, 2.1% and 11.2% in those with and without heart failure, respectively; processing, 18.3%; biological, 16.6% at 6 weeks and 48.4% at 8 years. The reference change value at 6 weeks (68.5%) indicated that 4 samples are needed to determine a homeostatic set point within ±25%. The estimated cTnT degradation rate over the first year in long-term frozen storage was 0.36 ng/L per year. cTnT was detectable in approximately 70% of community-dwelling middle-aged study participants and stable in -70 °C storage. The variability in cTnT attributable to 1 freeze-thaw cycle is of small magnitude. The observed high laboratory and intraindividual (biological) reliability of cTnT support its use for population-based research, and in clinical settings that rely on classification and serial measurements.

Increase in water-use efficiency and underlying processes in pine forests across a precipitation gradient in the dry Mediterranean region over the past 30 years

Motivated by persistent predictions of warming and drying in the entire Mediterranean and other regions, we have examined the interactions of intrinsic water-use efficiency (W(i)) with environmental conditions in Pinus halepensis. We used 30-year (1974-2003) tree-ring records of basal area increment (BAI) and cellulose (13)C and (18)O composition, complemented by short-term physiological measurements, from three sites across a precipitation (P) gradient (280-700 mm) in Israel. The results show a clear trend of increasing W(i) in both the earlywood (EW) and latewood (LW) that varied in magnitude depending on site and season, with the increase ranging from ca. 5 to 20% over the study period. These W(i) trends were better correlated with the increase in atmospheric CO(2) concentration, C(a), than with the local increase in temperature (~0.04°C year(-1)), whereas age, height and density variations had minor effects on the long-term isotope record. There were no trends in P over time, but W(i) from EW and BAI were dependent on the interannual variations in P. From reconstructed C(i) values, we demonstrate that contrasting gas-exchange responses at opposing ends of the hydrologic gradient underlie the variation in W(i) sensitivity to C(a) between sites and seasons. Under the mild water limitations typical of the main seasonal growth period, regulation was directed at increasing C(i)/C(a) towards a homeostatic set-point observed at the most mesic site, with a decrease in the W(i) response to C(i) with increasing aridity. With more extreme drought stress, as seen in the late season at the drier sites, the response was W(i) driven, and there was an increase in the W(i) sensitivity to C(a) with aridity and a decreasing sensitivity of C(i) to C(a). The apparent C(a)-driven increases in W(i) can help to identify the adjustments to drying conditions that forest ecosystems can make in the face of predicted atmospheric change.

Reboxetine Ineffective for Depression

The science of intrauterine development of sex differences, also known as “fetal programming” is concerned with the impacts of exogenous stimuli on the developing fetus. It is now largely acknowledged that during intrauterine life epigenetic processes in the fetus modulate homeostatic set-points and the stage is set for the future development of health and disease. Whatever affects the pregnant mother may affect her growing fetus and this includes nutrition, habits, medications, and stress. Understanding the concept of fetal programming means to understand the care of the pregnant women and must include the care of the fetus as a patient for the benefit its future well-being.

MGluR7 Genetics and Alcohol: Intersection Yields Clues for Addiction

Development of addiction to alcohol or other substances can be attributed in part to exposure-dependent modifications at synaptic efficacy leading to an organism which functions at an altered homeostatic setpoint. Genetic factors may also influence setpoints and the stability of the homeostatic system of an organism. Quantitative genetic analysis of voluntary alcohol drinking, and mapping of the involved genes in the quasi-congenic Recombinant QTL Introgression strain system, identified Eac2 as a Quantitative Trait Locus (QTL) on mouse chromosome 6 which explained 18% of the variance with an effect size of 2.09g/kg/day alcohol consumption, and Grm7 as a quantitative trait gene underlying Eac2 [Vadasz et al. in Neurochem Res 32:1099-1112, 100, Genomics 90:690-702, 102]. In earlier studies, the product of Grm7 mGluR7, a G protein-coupled receptor, has been implicated in stress systems [Mitsukawa et al. in Proc Natl Acad Sci USA 102:18712-18717, 63], anxiety-like behaviors [Cryan et al. in Eur J Neurosci 17:2409-2417, 14], memory [Holscher et al. in Learn Mem 12:450-455, 26], and psychiatric disorders (e.g., [Mick et al. in Am J Med Genet B Neuropsychiatr Genet 147B:1412-1418, 61; Ohtsuki et al. in Schizophr Res 101:9-16, 72; Pergadia et al. in Paper presented at the 38th Annual Meeting of the Behavior Genetics Association, Louisville, Kentucky, USA, 76]. Here, in experiments with mice, we show that (1) Grm7 knockout mice express increased alcohol consumption, (2) sub-congenic, and congenic mice carrying a Grm7 variant characterized by higher Grm7 mRNA drink less alcohol, and show a tendency for higher circadian dark phase motor activity in a wheel running paradigm, respectively, and (3) there are significant genetic differences in Grm7 mRNA abundance in the mouse brain between congenic and background mice identifying brain areas whose function is implicated in addiction related processes. We hypothesize that metabotropic glutamate receptors may function as regulators of homeostasis, and Grm7 (mGluR7) is involved in multiple processes (including stress, circadian activity, reward control, memory, etc.) which interact with substance use and the development of addiction. In conclusion, we suggest that mGluR7 is a significant new therapeutic target in addiction and related neurobehavioral disorders.

Role of Integrative Signaling Through Gap Junctions in Toxicology

Gap junctional intercellular communication (GJIC) plays a central role in coordinating signal-transduction pathways that control gene expression inside of cells with those of neighboring cells in maintaining the homeostasis of a tissue. The normal homeostatic set point of gap junctions within tissues is in an open state, and although transient closure of gap junctions in response to mitogenic effectors is normal, chronic closure of channels by continuous exposure to environmental and food-borne contaminants can result in adverse health effects such as cancer, teratogenesis, reproductive dysfunction, neuropathies, and cardiac arrhythmias. GJIC is the primary means of integrating signal transduction pathways controlling gene expression between contiguous cells. Thus, bioassay systems that can measure GJIC offer a central, more biosystems approach to assessing the potential for toxicants to epigenetically alter gene expression.

Biological variation and diagnostic accuracy of dehydration assessment markers

Well-recognized markers for static (one time) or dynamic (monitoring over time) dehydration assessment have not been rigorously tested for their usefulness in clinical, military, and sports medicine communities. This study evaluated the components of biological variation and the accuracy of potential markers in plasma, urine, saliva, and body mass (B(m)) for static and dynamic dehydration assessment. We studied 18 healthy volunteers (13 men and 5 women) while carefully controlling hydration and numerous preanalytic factors. Biological variation was determined over 3 consecutive days by using published methods. Atypical values based on statistical deviations from a homeostatic set point were examined. Measured deviations in body fluid were produced by using a separate, prospective dehydration experiment and evaluated by receiver operating characteristic (ROC) analysis to quantify diagnostic accuracy. All dehydration markers displayed substantial individuality and one-half of the dehydration markers displayed marked heterogeneity of intraindividual variation. Decision levels for all dehydration markers were within one SD of the ROC criterion values, and most levels were nearly identical to the prospective group means after volunteers were dehydrated by 1.8-7.0% of B(m). However, only plasma osmolality (P(osm)) showed statistical promise for use in the static dehydration assessment. A diagnostic decision level of 301 plusmn 5 mmol/kg was proposed. Reference change values of 9 mmol/kg (P(osm)), 0.010 [urine specific gravity (U(sg))], and 2.5% change in B(m) were also statistically valid for dynamic dehydration assessment at the 95% probability level. P(osm) is the only useful marker for static dehydration assessment. P(osm), U(sg), and B(m) are valid markers in the setting of dynamic dehydration assessment.

Can Changes in Troponin Results Be Useful in Diagnosing Myocardial Infarction?

In 1979, the WHO defined 3 specific criteria for use in the diagnosis of myocardial infarction (MI)1 : (a) clinical symptoms typical for ischemic heart disease, (b) specific electrocardiogram changes, and (c) a typical change in serial measurements of cardiac enzymes (1). Later definitions have continued in the mold of listing specific criteria, and in the current definition of MI, a characteristic increase and/or decrease in a cardiac biomarker with at least 1 result >99 percentile of a healthy population and evidence of myocardial ischemia (either specific symptoms or electrocardiographic or ultrasound findings) are mandatory (2). During the last decade, troponin T or I molecules, which are found only in myocardial cells and released after cell necrosis, have been the preferred cardiac biomarkers because of their high sensitivity and specificity (3), although myocardial cell necrosis can be seen in conditions other than myocardial ischemia (renal failure, sepsis, treatment with cardiotoxic drugs, myocarditis, and so on). A common problem in clinical practice is how to diagnose an acute MI in a patient who already has increased troponin concentrations. The National Academy of Clinical Biochemistry has suggested that a 20% increase in troponin results can be used to diagnose an ischemic event. This recommendation is based on analytical variation for troponin analysis alone, without taking biological variation into account (4). Recently, troponin assays with better analytical sensitivity have become commercially available. These assays not only have opened up new diagnostic opportunities but also have challenged our understanding of ischemic heart disease, because the assays can detect low troponin concentrations, even in the healthy population (5)(6). The natural fluctuations of troponin concentrations around a homeostatic set point (i.e., within-person biological variation) as well as the between-person biological variation can be established, as is reported by Vasile et al. in …