Measurement of internal body time by blood metabolomics.
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ABSTRACT:
SUBMITTER: Minami Y
PROVIDER: S-EPMC2689311 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, molecular-timetable method with human blood enables highly optimized and personalized medicine.
| S-EPMC3443163 | biostudies-literature
Project description:PurposeA 2-m axial field-of-view, total-body PET/CT scanner (uEXPLORER) has been recently developed to provide total-body coverage and ultra-high sensitivity, which together, enables opportunities for in vivo time-activity curve (TAC) measurement of all investigated organs simultaneously with high temporal resolution. This study aims at quantifying the cumulated activity and patient dose of 2-[F-18]fluoro-2-deoxy-D-glucose (F-18 FDG ) imaging by using delayed time-activity curves (TACs), measured out to 8-h post-injection, for different organs so that the comparison between quantifying approaches using short-time method (up to 75 min post-injection) or long-time method (up to 8 h post-injection) could be performed.MethodsOrgan TACs of 10 healthy volunteers were collected using total-body PET/CT in 4 periods after the intravenous injection of F-18 FDG. The 8-h post-injection TACs of 6 source organs were fitted using a spline method (based on Origin (version 8.1)). To compare with cumulated activity estimated from spline-fitted curves, the cumulated activity estimated from multi-exponential curve was also calculated. Exponential curve was fitted with shorter series of data consistent with clinical procedure and previous dosimetry works. An 8-h dynamic bladder wall dose model considering 2 voiding were employed to illustrate the differences in bladder wall dose caused by the different measurement durations. Organ absorbed doses were further estimated using Medical Internal Radiation Dose (MIRD) method and voxel phantoms.ResultsA short-time measurement could lead to significant bias in estimated cumulated activity for liver compared with long-time-measured spline fitted method, and the differences of cumulated activity were 18.38% on average. For the myocardium, the estimated cumulated activity difference was not statistically significant due to large variation in metabolism among individuals. The average residence time differences of brain, heart, kidney, liver, and lungs were 8.38%, 15.13%, 25.02%, 23.94%, and 16.50% between short-time and long-time methods. Regarding effective dose, the maximum differences of residence time between long-time-measured spline fitted curve and short-time-measured multi-exponential fitted curve was 9.93%. When using spline method, the bladder revealed the most difference in the effective dose among all the investigated organs with a bias up to 21.18%. The bladder wall dose calculated using a long-time dynamic model was 13.79% larger than the two-voiding dynamic model, and at least 50.17% lower than previous studies based on fixed bladder content volume.ConclusionsLong-time measurement of multi-organ TACs with high temporal resolution enabled by a total-body PET/CT demonstrated that the clinical procedure with 20 min PET scan at 1 h after injection could be used for retrospective dosimetry analysis in most organs. As the bladder content contributed the most to the effective dose, a long-time dynamic model was recommended for the bladder wall dose estimation.
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Project description:IntroductionInternal standards correct for measurement variation due to sample loss. Isotope labeled analytes are ideal internal standards for the measurement of fatty acids in human plasma but are not always readily available. For this reason, quantification of multiple analytes at once is most often done using only a single or few internal standards. The magnitude of the impact this has on method accuracy and precision is not well studied for gas chromatography-mass spectrometry systems.ObjectiveThis study aims to estimate bias and changes in uncertainty associated with using alternative fatty acid isotopologue internal standards for the estimation of similar or dissimilar long chain fatty acids.MethodUsing a previously reported method for the quantification of 27 fatty acids in human plasma using 18 internal standards we obtained estimates of bias and uncertainty at up to three levels of fatty acid concentration.ResultsWith some notable exceptions, method accuracy remained relatively stable when using an alternative internal standard (Median Relative Absolute Percent Bias: 1.76%, Median Spike-Recovery Absolute Percent Bias: 8.82%), with larger changes in method precision (Median Increase in Variance: 141%). Additionally, the degree of difference between analyte and internal standard structure was related to the magnitude of bias and uncertainty of the measurement.ConclusionThe data presented here show that the choice of internal standard used to estimate fatty acid concentration can affect the accuracy and reliability of measurement results and, therefore, needs to be assessed carefully when developing analytical methods for the measurement of fatty acid profiles.Disclaimer: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention, the Public Health Service, and the US Department of Health and Human Services.
| S-EPMC11365363 | biostudies-literature
Project description:BackgroundThe circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing.MethodsTo establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes.ResultsWe developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost.ConclusionThe BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient's circadian clock.FundingThis study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.
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Project description:Unattended automated office blood pressure (BP) measurement (u-AOBP) improves office BP measurement accuracy and reduces white-coat BP elevation, but there are reservations about its time efficiency in primary care. We used time-stamp methodology to measure u-AOBP procedure times performed without a rest period in 130 patients during routine clinic visits to three primary care clinics with 2.5-4.9 years u-AOBP experience. We documented the clinical activities of 30 medical assistants during the u-AOBP procedures. We also assessed MA and clinician satisfaction and knowledge about u-AOBP performance and interpretation. Median u-AOBP procedure time was <5 minutes, and MAs engaged in productive clinical activities during 83% of the procedures. Ninety-three percent of MAs and 100% of clinicians in the clinics agreed that u-AOBP is an efficient method to improve hypertension management. Barriers to effective u-AOBP implementation and ongoing utilization included initial difficulty incorporating u-AOBP into clinic workflow and medical staff knowledge deficiencies concerning correct u-AOBP performance and interpretation despite prior training and experience with the procedure. Intensive u-AOBP education and training programs are needed to facilitate effective u-AOBP implementation into primary care. The time required to perform u-AOBP can be utilized productively by staff.
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Project description:Metabolomics is the newest addition to the "omics" disciplines and has shown rapid growth in its application to human health research because of fundamental advancements in measurement and analysis techniques. Metabolomics has unique and proven advantages in systems biology and biomarker discovery. The next generation of analysis techniques promises even richer and more complete analysis capabilities that will enable earlier clinical diagnosis, drug refinement, and personalized medicine. A review of current advancements in methodologies and statistical analysis that are enhancing and improving the performance of metabolomics is presented along with highlights of some recent successful applications.
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Project description:Hearing aid equivalent input noise (EIN) measures assume the primary source of internal noise to be located prior to amplification and to be constant regardless of input level. EIN will underestimate internal noise in the case that noise is generated following amplification. The present study investigated the internal noise levels of six hearing aids (HAs). Concurrent with HA processing of a speech-like stimulus with both adaptive features (acoustic feedback cancellation, digital noise reduction, microphone directionality) enabled and disabled, internal noise was quantified for various stimulus levels as the variance across repeated trials. Changes in noise level as a function of stimulus level demonstrated that (1) generation of internal noise is not isolated to the microphone, (2) noise may be dependent on input level, and (3) certain adaptive features may contribute to internal noise. Quantifying internal noise as the variance of the output measures allows for noise to be measured under real-world processing conditions, accounts for all sources of noise, and is predictive of internal noise audibility.
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Project description:Combining different metabolomics platforms can contribute significantly to the discovery of complementary processes expressed under different conditions. However, analysing the fused data might be hampered by the difference in their quality. In metabolomics data, one often observes that measurement errors increase with increasing measurement level and that different platforms have different measurement error variance. In this paper we compare three different approaches to correct for the measurement error heterogeneity, by transformation of the raw data, by weighted filtering before modelling and by a modelling approach using a weighted sum of residuals. For an illustration of these different approaches we analyse data from healthy obese and diabetic obese individuals, obtained from two metabolomics platforms. Concluding, the filtering and modelling approaches that both estimate a model of the measurement error did not outperform the data transformation approaches for this application. This is probably due to the limited difference in measurement error and the fact that estimation of measurement error models is unstable due to the small number of repeats available. A transformation of the data improves the classification of the two groups.
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Project description:Pulse transit time (PTT), which refers to the travel time between two arterial sites within the same cardiac cycle, has been developed as a novel cuffless form of continuous blood pressure (BP) monitoring. The aim of this study was to investigate differences in BP parameters, including BP variability, between those assessed by beat-to-beat PTT-estimated BP (eBPBTB) and those assessed by intermittent PTT-estimated BP at fixed time intervals (eBPINT) in patients suspected of having sleep disordered breathing (SDB). In 330 patients with SDB (average age, 66.8 ± 11.9 years; 3% oxygen desaturation index [ODI], 21.0 ± 15.0/h) from 8 institutes, PTT-estimated BP was continuously recorded during the nighttime. The average systolic eBPBTB, maximum systolic and diastolic eBPBTB, standard deviation (SD) of systolic and diastolic eBPBTB, and coefficient variation (CV) of systolic and diastolic eBPBTB were higher than the respective values of eBPINT (all P < 0.05). Bland-Altman analysis showed a close agreement between eBPBTB and eBPINT in average systolic BP and SD and CV of systolic BP, while there were disagreements in both minimum and maximum values of eBPBTB and eBPINT in patients with high systolic BP (P < 0.05). Although systolic BP variability incrementally increased according to the tertiles of 3%ODI in both eBPBTB and eBPINT (all P < 0.05), there was no difference in this tendency between eBPBTB and eBPINT. In patients with suspected SDB, the difference between eBPBTB and eBPINT was minimal, and there were disagreements regarding both the minimum and maximum BP. However, there were agreements in regard to the index of BP variability between eBPBTB and eBPINT.
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Project description:The use of reference genes is commonly accepted as the most reliable approach to normalize qRT-PCR and to reduce possible errors in the quantification of gene expression. The most suitable reference genes in sheep have been identified for a restricted range of tissues, but no specific data on whole blood are available. The aim of this study was to identify a set of reference genes for normalizing qRT-PCR from ovine whole blood. We designed 11 PCR assays for commonly employed reference genes belonging to various functional classes and then determined their expression stability in whole blood samples from control and disease-stressed sheep. SDHA and YWHAZ were considered the most suitable internal controls as they were stably expressed regardless of disease status according to both geNorm and NormFinder software; furthermore, geNorm indicated SDHA/HPRT, YWHAZ/GAPDH and SDHA/YWHAZ as the best reference gene combinations in control, disease-stressed and combined sheep groups, respectively. Our study provides a validated panel of optimal control genes which may be useful for the identification of genes differentially expressed by qRT-PCR in a readily accessible tissue, with potential for discovering new physiological and disease markers and as a tool to improve production traits (e.g., by identifying expression Quantitative Trait Loci). An additional outcome of the study is a set of intron-spanning primer sequences suitable for gene expression experiments employing SYBR Green chemistry on other ovine tissues and cells.
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