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Magnetic resonance cardiac perfusion imaging-a clinical perspective.

Coronary artery disease (CAD) with its clinical appearance of stable or unstable angina and acute myocardial infarction is the leading cause of death in developed countries. In view of increasing costs and the rising number of CAD patients, there has been a major interest in reliable non-invasive imaging techniques to identify CAD in an early (i.e. asymptomatic) stage. Since myocardial perfusion deficits appear very early in the "ischemic cascade", a major breakthrough would be the non-invasive quantification of myocardial perfusion before functional impairment might be detected. Therefore, there is growing interest in other, target-organ-specific parameters, such as relative and absolute myocardial perfusion imaging. Magnetic resonance (MR) imaging has been proven to offer attractive concepts in this respect. However, some important difficulties have not been resolved so far, which still causes uncertainty and prevents the broad application of MR perfusion imaging in a clinical setting. This review explores recent technical developments in MR hardware, software and contrast agents, as well as their impact on the current and future clinical status of MR imaging of first-pass myocardial perfusion imaging.

Contrast Media↗

GIS-based quantification of future nutrient loads into Lake Peipsi/Chudskoe using qualitative regional development scenarios.

This study aims at the quantification of possible future nutrient loads into Lake Peipsi/Chudskoe under different economic development scenarios. This drainage basin is on the borders of Russia, Estonia and Latvia. The sudden disintegration of the Soviet Union in 1991 caused a collapse of agricultural economy, and consequently, a substantial decrease of diffuse and point-source nutrient emissions. For the future, uncertainties about economic development and the priorities that will be set for this region make it difficult to assess the consequences for river water quality and nutrient loads into the lake. We applied five integrated scenarios of future development of this transboundary region for the next twelve to fifteen years. Each scenario consists of a qualitative story line, which was translated into quantitative changes in the input variables for a geographical information system based nutrient transport model. This model calculates nutrient emissions, as well as transport and retention and the resulting nutrient loads into the lake. The model results show that the effects of the different development scenarios on nutrient loads are relatively limited over a time span of about 15 years. In general, a further reduction of nutrient loads is expected, except for a fast economic development scenario.

Estonia↗

Methylmercury measurement in whole blood by isotope-dilution GC-ICPMS with 2 sample preparation methods.

BACKGROUND: Despite its known toxicity, methylmercury is rarely measured directly in clinical studies; instead, conclusions are based on total mercury measurements. We have developed isotope-dilution-based methods for methylmercury-specific analysis of whole blood by coupled gas chromatography-inductively coupled plasma mass spectrometry (GC-ICPMS). METHODS: We analyzed animal and human blood samples after alkaline digestion or extraction of methylmercury into dichloromethane and back extraction into water. Methylmercury was converted to the volatile ethyl derivative, purged, and trapped on a solid-phase collection medium, and then introduced into the GC-ICPMS system. RESULTS: Limits of quantification were 0.4 and 0.03 microg/L at a signal-to-noise ratio of 10 with the alkaline digestion and extraction methods, respectively. Extraction met our selected acceptable total error criterion, with an SD of 0.58 microg/L at the critical maternal blood concentration of 5.8 microg/L. Results obtained with alkaline digestion indicated the need for improved random analytical uncertainty, which was achieved by increasing the enrichment of the isotope dilution. For 37 blood samples, the mean (SD) proportion of total mercury present as methylmercury was 60 (27)%, range 6%-100%. CONCLUSIONS: The combination of extraction and isotope-dilution GC-ICPMS meets the requirements for use as a reference method for measuring methylmercury in whole blood.

Animals↗

Bayesian estimation of allele-specific expression in the presence of phasing uncertainty.

MOTIVATION: Allele-specific expression (ASE) analyses aim to detect imbalanced expression of maternal versus paternal copies of an autosomal gene. Such allelic imbalance can result from a variety of cis-acting causes, including disruptive mutations within one copy of a gene that impact the stability of transcripts, as well as regulatory variants outside the gene that impact transcription initiation. Current methods for ASE estimation suffer from a number of shortcomings, such as relying on only one variant within a gene, assuming perfect phasing information across multiple variants within a gene, or failing to account for alignment biases and possible genotyping errors. RESULTS: We developed BEASTIE, a Bayesian hierarchical model designed for precise ASE quantification at the gene level, based on given genotypes and RNA-Seq data. BEASTIE addresses the complexities of allelic mapping bias, genotyping error, and phasing errors by incorporating empirical phasing error rates derived from Genome-in-a-Bottle individual NA12878. BEASTIE surpasses existing methods in accuracy, especially in scenarios with high phasing errors. This improvement is critical for identifying rare genetic variants often obscured by such errors. Through rigorous validation on simulated data and application to real data from the 1000 Genomes Project, we establish the robustness of BEASTIE. These findings underscore the value of BEASTIE in revealing patterns of ASE across gene sets and pathways. AVAILABILITY AND IMPLEMENTATION: The software is freely available from Github (https://github.com/x811zou/BEASTIE); and Zendo (DOI: 10.5281/zenodo.15062124).

Bayes Theorem↗

Evolution of ochratoxin A content from must to wine in Port Wine microvinification.

To study the evolution of ochratoxin A (OTA) content from must to wine during the making of Port Wine, grapes from the five most common varieties of Port Wine were harvested and combined in equal percentages in order to perform microvinifications. Three sets of assays were studied: a blank (A), where the most common Port Wine-making process was used; in the second (B), a solution of OTA was added to the initial must; in the third (C), the grapes were aspersed with an inoculating solution of OTA-producing fungi. Samples were collected, in duplicate, on four different occasions throughout the process. The influence of the addition of SO2 to the must was also assessed in each set. The quantification of OTA was based on the standard reference method for wines (European Standard prEN 14133), which includes clean-up via immunoaffinity columns and HPLC with fluorescence detection. The limits of detection were 0.076 microg/l for wine and 0.114 microg/l for must. The method was validated by assessing the precision, accuracy and by obtaining an estimate of the global uncertainty. Overall, the levels of OTA observed during the vinifications dropped by up to 92%, and no grapes used in this work were contaminated naturally.

Chromatography, High Pressure Liquid↗

Risk management and the precautionary principle: a fuzzy logic model.

The aim of this article is to illustrate a procedure for applying the precautionary principle within a strategy for reducing the possibility of underestimating the effective risk caused by a phenomenon, product, or process, and of adopting insufficient risk reduction measures or overlooking their need. We start by simply defining risk as the product between the numerical expression of the adverse consequences of an event and the likelihood of its occurrence or the likelihood that such consequences will occur. Uncertainty in likelihood estimates and several key concepts inherent to the precautionary principle, such as sufficient certainty, prevention, and desired level of protection, are represented as fuzzy sets. The strategy described may be viewed as a simplified example of a precautionary decision process that has been chiefly conceived as a theoretical contribution to the debate concerning the precautionary principle, the quantification of its application, and the formal approach to such problems.

Journal Article↗

Ionic dialysance: principle and review of its clinical relevance for quantification of hemodialysis efficiency.

Ionic dialysance (D) is an online measured variable now available on several dialysis monitors to evaluate small-solute clearance. Based on conductivity measurements in the inlet and outlet dialysate, the principle of the measurement and the different measurement methods are described. Studies that have evaluated the reliability of ionic dialysance to assess dialysis efficiency are discussed. These studies are divided into two groups: the first comparing ionic dialysance to urea clearance and the second comparing Dt/V to Kt/V(urea), in which the uncertainties of the measurement of V(urea) could have misrepresented the relationship between Dt/V and Kt/V(urea). When Kt/V(urea) via the Daugirdas second-generation equation taking the rebound into account is considered, slight-even nonsignificant-differences are evidenced between Kt/V(urea) and Dt/V. Therefore, ionic dialysance should be considered as a valid measure in future guidelines for dialysis efficiency.

Autoanalysis↗

Analytical method for the quantitative determination of urinary ethylenethiourea by liquid chromatography/electrospray ionization tandem mass spectrometry.

A direct, rapid and selective method for the quantitative determination of the ethylenethiourea (ETU) in human urine has been validated and is reported in the present study. It allows the accurate quantification of ETU in this complex matrix without the use of any internal standard as the sample cleanup is effective enough for the removal of interferences that could lead to ion suppression in the electrospray ionization (ESI) source. This simple and rapid purification system, based on the use of a Fluorosil phase of a BondElut column followed by a liquid-liquid extraction procedure, achieves mean extracted recoveries, assessed at three different concentrations (2.5, 10.0, and 25.0 microg/L), always more than 85%. High-performance liquid chromatography (HPLC) with positive ion tandem mass spectrometry, operating in selected multiple reaction monitoring (MRM) mode, is used to quantify ETU in human urine. The assay is linear over the range 0-50 microg/L, with a lower limit of quantification (LOQ) of 1.5 microg/L and a coefficient of variation (CV) of 8.9%. The lower limit of detection (LOD) is assessed at 0.5 microg/L. The overall precision and accuracy were determined on three different days. The values for within- and between-day precision are < or = 8.3 and 10.1%, respectively, and the accuracy is in the range 97-118%. The relative uncertainties for the LOQ and QC concentrations have been estimated to be 18 and 8%, respectively. The assay was applied to quantify ETU in human urine from growers that regularly handle ethylenebisdithiocarbamate pesticides in large crop plantations. The biological samples were collected at the start and end of the working day, and the ETU urine levels were found to vary between 1.9 and 8.2 microg/L.

Chromatography, Liquid↗

Chromatographic multivariate quality control of pharmaceuticals giving strongly overlapped peaks based on the chromatogram profile.

In the present paper, the simultaneous quantification of two analytes showing strongly overlapped chromatographic peaks (alpha = 1.02), under the assumption that both available equipment and training of the laboratory staff are basic, is studied. A pharmaceutical preparation (Mutabase) containing two drugs of similar physicochemical properties (amitriptyline and perphenazine) is selected as case of study. The assays are carried out under realistic working conditions (i.e. routine testing laboratories). Uncertainty considerations are introduced in the study. A partial least squares model is directly applied to the chromatographic data (with no previous signal transformation) to perform quality control of the pharmaceutical formulation. Under the adequate protocol, the relative error in prediction of analytes is within the tolerances found in the pharmacopeia (10%). For spiked samples simulating formulation mistakes, the errors found have the same magnitude and sign to those provoked.

Multivariate Analysis↗

The public health relevance of air pollution abatement.

Assuming a causal relationship between current levels of air pollution and morbidity/mortality, it is crucial to estimate the public health relevance of the problem. The derivation of air pollution attributable cases faces inherent uncertainties and requires influential assumptions. Based on the results of the trinational impact assessment study of Austria, France, and Switzerland, where prudent estimates of the air pollution attributable cases (mortality, chronic bronchitis incidence, hospital admissions, acute bronchitis among children, restricted activity days, asthma attacks) have been made, influential uncertainties are quantified in this review. The public health impact of smoking, environmental tobacco smoke, and air pollution on the prevalence of chronic cough/phlegm are outlined. Despite all methodological caveats, impact assessment studies clearly suggest that public health largely benefits from better air quality. The studies are selective underestimates as they are strongly driven by mortality, but do not include full quantification of the impact on morbidity and their consequences on quality of life among the diseased and the caregivers. Air pollution abatement strategies are usually political in nature, targeting at polities, regulation and technology in mobile or stationary sources rather than at individuals. It is of note that key clean air strategies converge into abatement of climate change. In general, energy consumption is very closely related to both air pollution and greenhouse gases. The dominant causes of both problems are the excessive and inefficient combustion of fossil fuel. Thus, for many policy options, the benefit of air pollution abatement will go far beyond what prudent health-impact assessments may derive. From a climate change and air pollution perspective, improved energy efficiency and a strong and decisive departure from the "fossil fuel" combustion society is a science-based must. Health professionals must raise their voices in the political decision process to give strong support for clean air policies, both on a national and international level.

Air Pollution↗

Chronobiology of human blood pressure in the light of static (room-restricted) automatic monitoring.

Systematic 24-h automatic physiologic monitoring has obvious merits, even without rhythmometry. It can lead more readily to the recognition of odd-hour blood pressure elevation (e.g., of 'evening' or 'morning' hypertension). Such a condition can constitute an initial diagnosis or it may be found under treatment that may seem to be satisfactory if its effects are assessed only on the basis of a conventional check at a casual, possibly 'wrong' time. The mere inspection of a 24-h record, however, does not necessarily allow one to make objective quantitative global statements as to a change in pattern, e.g., after a given intervention. This paper illustrates how by rhythmometry, some of the uncertainties of a subjective interpretation of a record may be removed by practitioners of medicine, as well as basic scientists interested in mechanisms of blood pressure variability. This is possible since a large part of blood pressure variability can be accounted for by its circadian periodic behavior. We herein present a methodology for data collection and analysis that allows the objective quantification of blood pressure rhythm parameters in health and disease and the derivation of reference standards for such parameters. The chronobiologic approach thus makes it possible to define 'hypertension' objectively, and to distinguish between 'mesor-' and 'amplitude-hypertension', i.e., between an elevation in overall mean and one in the predictable extent of variability. Moreover, chronobiology has shown that mesor-hypertension may be preceded by an elevation in circadian amplitude only (amplitude-hypertension). Parameter tests readily allow the assessment, in relation to an objective reference standard, of these conditions, with a defined probability. Similarly, response to drug or non-drug therapy can be established and a given intervention optimized by timing treatment. Using chronobiologic tools in cardiovascular research provides new insights into possible mechanisms underlying mesor- and amplitude-hypertension. The teaching of the chronobiology of blood pressure and autorhythmometry in schools has been proven to be feasible and has been recommended as a step toward self-help for health care.

Adolescent↗

Quantification of single fluid inclusions by combining synchrotron radiation-induced micro-X-ray fluorescence and transmission.

Fluid inclusions represent the only direct samples of ancient fluids in many crustal rocks; precise knowledge of their chemical composition provides crucial information to model paleofluid-rock interactions and hydrothermal transport processes. Owing to its nondestructive character, micrometer-scale spatial resolution, and high sensitivity, synchrotron radiation-induced micro-X-ray fluorescence has received great interest for the in situ multielement analysis of individual fluid inclusions. Major uncertainties associated with the quantitative analysis of single fluid inclusions arise from the inclusion depth and the volume of fluid sampled by the incident beam. While the depth can be extracted directly from the fluorescence spectrum, its volume remains a major source of uncertainty. The present study performed on natural and synthetic inclusions shows that the inclusion thickness can be accurately evaluated from transmission line scans. Experimental data matched numerical simulations based on an elliptical inclusion geometry. However, for one nonelliptical inclusion, the experimental data were confirmed using a computed absorption tomography reconstruction. Good agreement between the imaging and scanning techniques implies that the latter provides reliable fluid thickness values independent of the shape of the inclusion. Taking into consideration the incident angle, the incident beam energy, the inclusion fluid salinity, and the transmission measurement stability resulted in errors of 0.3-2 microm on calculated fluid inclusion thicknesses.

Journal Article↗

Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women?

In the decade that has elapsed since the suggestion that exposure of the foetal/developing male to environmental oestrogens could be the cause of subsequent reproductive and developmental effects in men, there has been little definitive research to provide conclusions to the hypothesis. Issues of exposure and low potency of environmental oestrogens may have reduced concerns. However, the hypothesis that chemicals applied in body care cosmetics (including moisturizers, creams, sprays or lotions applied to axilla or chest or breast areas) may be affecting breast cancer incidence in women presents a different case scenario, not least in the consideration of the exposure issues. The specific cosmetic type is not relevant but the chemical ingredients in the formulations and the application to the skin is important. The most common group of body care cosmetic formulation excipients, namely p-hydroxybenzoic acid esters or parabens, have been shown recently to be oestrogenic in vitro and in vivo and now have been detected in human breast tumour tissue, indicating absorption (route and causal associations have yet to be confirmed). The hypothesis for a link between oestrogenic ingredients in underarm and body care cosmetics and breast cancer is forwarded and reviewed here in terms of: data on exposure to body care cosmetics and parabens, including dermal absorption; paraben oestrogenicity; the role of oestrogen in breast cancer; detection of parabens in breast tumours; recent epidemiology studies of underarm cosmetics use and breast cancer; the toxicology database; the current regulatory status of parabens and regulatory toxicology data uncertainties. Notwithstanding the major public health issue of the causes of the rising incidence of breast cancer in women, this call for further research may provide the first evidence that environmental factors may be adversely affecting human health by endocrine disruption, because exposure to oestrogenic chemicals through application of body care products (unlike diffuse environmental chemical exposures) should be amenable to evaluation, quantification and control. The exposure issues are clear and the exposed population is large, and these factors should provide the necessary impetus to investigate this potential issue of public health.

Breast Neoplasms↗

A photochemical model of the martian atmosphere.

The factors governing the amounts of CO, O2, and O3 in the martian atmosphere are investigated using a minimally constrained, one-dimensional photochemical model. We find that the incorporation of temperature-dependent CO2 absorption cross sections leads to an enhancement in the water photolysis rate, increasing the abundance of OH radicals to the point where the model CO abundance is smaller than observed. Good agreement between models and observations of CO, O2, O3, and the escape flux of atomic hydrogen can be achieved, using only gas-phase chemistry, by varying the recommended rate constants for the reactions CO + OH and OH + HO2 within their specified uncertainties. Similar revisions have been suggested to resolve discrepancies between models and observations of the terrestrial mesosphere. The oxygen escape flux plays a key role in the oxygen budget on Mars; as inferred from the observed atomic hydrogen escape, it is much larger than recent calculations of the exospheric escape rate for oxygen. Weathering of the surface may account for the imbalance. Quantification of the escape rates of oxygen and hydrogen from Mars is a worthwhile objective for an upcoming martian upper atmospheric mission. We also consider the possibility that HOx radicals may be catalytically destroyed on dust grains suspended in the atmosphere. Good agreement with the observed CO mixing ratio can be achieved via this mechanism, but the resulting ozone column is much higher than the observed quantity. We feel that there is no need at this time to invoke heterogeneous processes to reconcile models and observations.

Atmosphere↗

Procedure for quantification of platelet adhesion to biomaterials by radioscintigraphy.

Detection of adhered platelets on biomaterial surface that has blood-contacting application is an important test to assess its thrombogenicity. Usually, for measurement of platelet adhesion, after exposure to platelet-rich plasma (PRP) under standardized conditions the test surface is rinsed to remove non-adherent cells and is analyzed under scanning electron microscopy (SEM) to detect morphology of adhered cell and degree of aggregate formation. However, being a qualitative test it is unlikely to give an accurate estimate of platelets adhered to the surface. On the other hand, use of radiolabels enables quantification of platelets deposited on a material or device. Because of high gamma emission of (111)In, it can be used for radioscintigraphy, however, its short half life (2.5 days) is a major hurdle in using it for quantification of platelet adhesion. (125)I is a relatively strong radiolabel that is easily tagged to most of the proteins and has a relatively long half-life (60 days). The major objectives of this study are to standardize the labeling conditions to get good (125)I activity on platelets, while maintaining normal cell function after they are labeled. Considering all possible uncertainties, quantity of isotope and platelets to be used and the conditions of iodination reaction are established to get repeatable and reproducible labeling of platelets. Further, it is demonstrated that (125)I-platelets can be used to determine total number of cells adhered to titanium surface, which is known to be used as a blood-contacting biomaterial.

Biocompatible Materials↗

Temperature quantification using the proton frequency shift technique: In vitro and in vivo validation in an open 0.5 tesla interventional MR scanner during RF ablation.

Open magnetic resonance (MR) scanners allow MR-guided targeting of tumors, as well as temperature monitoring of radio frequency (RF) ablation. The proton frequency shift (PFS) technique, an accurate and fast imaging method for temperature quantification, was used to synthesize thermal maps after RF ablation in an open 0.5 T MR system under ex vivo and in vivo conditions. Calibration experiments with 1.5% agarose gel yielded a chemical shift factor of 0.011 +/- 0.001 ppm/ degrees C (r2 = 0.96). Three gradient echo (GRE) pulse sequences were tested for thermal mapping by comparison with fiberoptic thermometer (Luxtron Model 760) readings. Temperature uncertainty decreased from high to low bandwidths (BW): +/-5.9 degrees C at BW = 15.6 kHz, +/-1.4 degrees C at BW = 3.9 kHz, and +/-0.8 degrees C at BW = 2.5 kHz. In vitro experiments (N = 9) in the paraspinal muscle yielded a chemical shift factor of 0.008 +/- 0.001 ppm/ degrees C. Temperature uncertainty was determined as +/-2.7 degrees C (BW = 3.9 kHz, TE = 19.3 msec). The same experiments carried out in the paraspinal muscle (N = 9) of a fully anesthetized pig resulted in a temperature uncertainty of +/-4.3 degrees C (BW = 3.9 kHz, TE = 19.3 msec), which is higher than it is in vitro conditions (P < 0.15). Quantitative temperature monitoring of RF ablation is feasible in a 0.5 T open-configured MR scanner under ex vivo and in vivo conditions using the PFS technique.

Animals↗

Prokaryotic and eukaryotic unicellular chronomics.

An impeccable time series, published in 1930, consisting of hourly observations on colony advance in a fluid culture of E. coli, was analyzed by a periodogram and power spectrum in 1961. While the original senior author had emphasized specifically periodicity with no estimate of period length, he welcomed further analyses. After consulting his technician, he knew of no environmental periodicity related to human schedules other than an hourly photography. A periodogram analysis in 1961 showed a 20.75-h period. It was emphasized that "... the circadian period disclosed is not of exactly 24-h length." Confirmations notwithstanding, a committee ruled out microbial circadian rhythms based on grounds that could have led to a different conclusion, namely first, the inability of some committee members to see (presumably by eyeballing) the rhythms in their own data, and second, what hardly follows, that there were "too many analyses" in the published papers. Our point in dealing with microbes and humans is that analyses are indispensable for quantification and for discovering a biologically novel spectrum of cyclicities, matching physical ones. The scope of circadian organization estimated in 1961 has become broader, including about 7-day, about half-yearly, about-yearly and ex-yearly and decadal periodisms, among others. Microbial circadians have become a field of their own with eyeballing, yet time-microscopy can quantify characteristics with their uncertainties and can assess broad chronomes (time structures) with features beyond circadians. As yet only suggestive differences between eukaryotes and prokaryotes further broaden the perspective and may lead to life's sites of origin and to new temporal aspects of life's development as a chronomic tree by eventual rhythm dating in ontogeny and phylogeny.

Acetabularia↗

Critical illness myopathy and neuropathy.

PURPOSE OF REVIEW: To present the major pathophysiological and diagnostic features of critical illness myopathy (CIM) and polyneuropathy (CIP), and to discuss problems concerning the risk factors for CIM and CIP. RECENT FINDINGS: The pathophysiology of critical illness myopathy and critical illness polyneuropathy is complex, involving metabolic, inflammatory, and bioenergetic alterations. This review cites new evidence supporting several pathogenetic mechanisms. These include microvascular changes in peripheral nerves (with increased endothelial expression of E-selectin), the possible role for an altered lipid serum profile in promoting organ dysfunction (including nerve dysfunction), the damage or inhibition of complex I of the respiratory chain as a cause of muscle ATP depletion and bioenergetic failure, and the activation of specific intracellular proteolytic systems causing myofilament loss and apoptosis in CIM. The diagnostic role of direct muscle stimulation and the rapid quantification of myosin/actin ratio based on electrophoresis are also presented. SUMMARY: Basic and clinical research is unraveling the pathophysiological mechanisms of critical illness myopathy and polyneuropathy, and methods for rapid diagnosis are actively investigated. Future studies should better define the population at risk of developing CIM and CIP. In fact, although sepsis, multi-organ failure and steroids are often cited as risk factors, uncertainty remains due to the poor methodological quality of studies, or because of inferences that are exclusively based on animal studies. New simplified diagnostic techniques and machines for electrophysiological investigations of peripheral nerves and muscles in the intensive-care unit (ICU) patient would also be welcome.

Critical Illness↗