Within- and between-subject variation in commonly measured anthropometric and biochemical variables.
BACKGROUND: The biological variation of some commonly assessed metabolic variables in healthy subjects has not been studied extensively. The aim of the study was to assess, in 12 healthy subjects (6 male and 6 female; mean (SD) age; 22.7 (1.5) years) following an overnight fast, the day-to-day variation of body fat (impedance method), triglycerides, nonesterified fatty acid (NEFAs), glycerol, 3-hydroxybutyrate (3-OHB), lactate, glucose, insulin (RIA), C-peptide, and glucagon on 12 consecutive days. METHODS: Between- and within-subject coefficients of variation (CVG and CVW) were estimated using a random effects analysis of variance, and assay variation was subtracted to give the coefficient of within-subject biological variation (CVI). Individuality indices were calculated as CVW/CVG. RESULTS: The overall means, CVI, and individuality indices were as follows: for body fat, 24.2%, 10%, and 0.3; for triglycerides, 0.61 mmol/L, 21%, and 1.1; for NEFAs, 376 micromol/L, 45%, and 1.4; for glycerol, 48 micromol/L, 36%, and 0.8; for 3-OHB, 43 micromol/L, 61%, and 1.5; for lactate, 0.88 mmol/L, 31%, and 1.1; for glucose, 4.9 mmol/L, 4.8%, and 0.7; for insulin, 52 pmol/L, 26%, and 1.0; for C-peptide, 0.39 nmol/L, 24%, and 0.9; and for glucagon, 53 ng/L, 19%, and 0.8. CONCLUSIONS: The data presented here are necessary for the evaluation of several important metabolic variables in individual and group studies. The biological variation of some metabolites makes it difficult to characterize the status of healthy subjects with a single measurement. (+info)
Retigabine N-glucuronidation and its potential role in enterohepatic circulation.
The metabolism of retigabine in humans and dogs is dominated by N-glucuronidation (), whereas in rats, a multitude of metabolites of this new anticonvulsant is observed (). The comparison of the in vivo and in vitro kinetics of retigabine N-glucuronidation in these species identified a constant ratio between retigabine and retigabine N-glucuronide in vivo in humans and dog. An enterohepatic circulation of retigabine in these species is likely to be the result of reversible glucuronidation-deglucuronidation reactions. Rats did not show such a phenomenon, indicating that enterohepatic circulation of retigabine via retigabine N-glucuronide does not occur in this species. In the rat, 90% of retigabine N-glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A2, whereas family 2 UGT enzymes contribute also. Of ten recombinant human UGTs, only UGTs 1A1, 1A3, 1A4, and 1A9 catalyzed the N-glucuronidation of retigabine. From the known substrate specificities of UGT1A4 toward lamotrigine and bilirubin and our activity and inhibition data, we conclude that UGT1A4 is a major retigabine N-glucuronosyl transferase in vivo and significantly contributes to the enterohepatic cycling of the drug. (+info)
Effects of repeated hypoglycemia on cognitive function: a psychometrically validated reanalysis of the Diabetes Control and Complications Trial data.
OBJECTIVE: To test the conclusion that there is no association between multiple episodes of severe hypoglycemia and cognitive decrements by reanalyzing the data from the Diabetes Control and Complications Trial (DCCT) with psychometrically validated cognitive factors and to conduct a novel analysis of the association between individual differences in baseline cognitive ability and episodes of severe hypoglycemia documented after baseline. RESEARCH DESIGN AND METHODS: The factor structure of cognitive ability in the neuropsychological data from the DCCT study was derived. Four cognitive factors (spatial ability, processing speed, memory, and verbal ability) were extracted. Changes in patients' cognitive scores for each year of follow-up were obtained, and paired comparisons of these change scores were performed between groups experiencing zero and five or more hypoglycemic episodes. The association between cognitive ability at baseline and number of subsequent episodes of severe hypoglycemia was also examined. RESULTS: Repeated episodes of hypoglycemia were found not to be associated with cognitive decline in any of the validated cognitive factors. No significant association was found between prospectively documented numbers of severe hypoglycemic episodes and baseline cognitive ability level. CONCLUSIONS: Repeated episodes of hypoglycemia were not related to cognitive decrement, and initial mental ability level was not associated with eventual numbers of hypoglycemic episodes in this group of patients. (+info)
Physiologically based toxicokinetic modeling of inhaled ethyl tertiary-butyl ether in humans.
A physiologically based toxicokinetic (PBTK) model was developed for evaluation of inhalation exposure in humans to the gasoline additive, ethyl tertiary-butyl ether (ETBE). PBTK models are useful tools to relate external exposure to internal doses and biological markers of exposure in humans. To describe the kinetics of ETBE, the following compartments were used: lungs (including arterial blood), liver, fat, rapidly perfused tissues, resting muscles, and working muscles. The same set of compartments and, in addition, a urinary excretion compartment were used for the metabolite tertiary-butyl alcohol (TBA). First order metabolism was assumed in the model, since linear kinetics has been shown experimentally in humans after inhalation exposure up to 50 ppm ETBE. Organ volumes and blood flows were calculated from individual body composition based on published equations, and tissue/blood partition coefficients were calculated from liquid/air partition coefficients and tissue composition. Estimates of individual metabolite parameters of 8 subjects were obtained by fitting the PBTK model to experimental data from humans (5, 25, 50 ppm ETBE, 2-h exposure; Nihlen et al., Toxicol. Sci., 1998; 46, 1-10). The PBTK model was then used to predict levels of the biomarkers ETBE and TBA in blood, urine, and exhaled air after various scenarios, such as prolonged exposure, fluctuating exposure, and exposure during physical activity. In addition, the interindividual variability in biomarker levels was predicted, in the eight experimentally exposed subjects after a working week. According to the model, raising the work load from rest to heavy exercise increases all biomarker levels by approximately 2-fold at the end of the work shift, and by 3-fold the next morning. A small accumulation of all biomarkers was seen during one week of simulated exposure. Further predictions suggested that the interindividual variability in biomarker levels would be higher the next morning than at the end of the work shift, and higher for TBA than for ETBE. Monte Carlo simulations were used to describe fluctuating exposure scenarios. These simulations suggest that ETBE levels in blood and exhaled air at the end of the working day are highly sensitive to exposure fluctuations, whereas ETBE levels the next morning and TBA in urine and blood are less sensitive. Considering these simulations, data from the previous toxicokinetic study and practical issues, we suggest that TBA in urine is a suitable biomarker for exposure to ETBE and gasoline vapor. (+info)
Autonomy, liberalism and advance care planning.
The justification for advance directives is grounded in the notion that they extend patient autonomy into future states of incompetency through patient participation in decision making about end-of-life care. Four objections challenge the necessity and sufficiency of individual autonomy, perceived to be a defining feature of liberal philosophical theory, as a basis of advance care planning. These objections are that the liberal concept of autonomy (i) implies a misconception of the individual self, (ii) entails the denial of values of social justice, (iii) does not account for justifiable acts of paternalism, and (iv) does not account for the importance of personal relationships in the advance care planning process. The last objection is especially pertinent in light of recent empirical research highlighting the importance of personal relationships in advance care planning. This article examines these four objections to autonomy, and the liberal theoretical framework with which it is associated, in order to re-evaluate the philosophical basis of advance care planning. We argue that liberal autonomy (i) is not a misconceived concept as critics assume, (ii) does not entail the denial of values of social justice, (iii) can account for justifiable acts of paternalism, though it (iv) is not the best account of the value of personal relationships that arise in advance care planning. In conclusion, we suggest that liberalism is a necessary component of a theoretical framework for advance care planning but that it needs to be supplemented with theories that focus explicitly on the significance of personal relationships. (+info)
A systematic evaluation of preferences identified through person-centered planning for people with profound multiple disabilities.
Person-centered planning is becoming a popular means of designing supports for people with disabilities. However, very little research evaluating person-centered planning exists. We evaluated the degree to which items and activities reported to be preferred in person-centered plans represented accurate preferences based on how individuals responded when presented with the items and activities. Person-centered planning meetings were conducted with 4 individuals with profound multiple disabilities to develop preference maps and to identify leisure-related preferences. A sample of the reported preferences in the plans was then systematically assessed by observing each participant's approach and avoidance responses to the items and activities. Of the sampled items and activities reported to be preferred in the plans, 42% represented moderate preferences based on the latter assessment process and 33% represented strong preferences. With 2 participants, several preferences identified in the plans were nonpreferred items and activities based on the preference assessments, and some were frequently avoided. These results suggested that although person-centered plans may identify some accurate preferences for people with profound multiple disabilities, this approach should be used cautiously. Results also suggested that such plans should be supplemented with systematic preference assessments to ensure the accuracy of identified preferences. Future research areas focus on evaluating other aspects of person-centered planning. (+info)
Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction.
The role of individual differences in the etiology of addiction is a very controversial issue. Neuroendocrine phenotypes that are able to predispose an individual to the development of drug intake have been identified previously. However, such information has been gathered by comparing individuals who differ in their sensitivity to low doses of the drug. Consequently, it remains unclear whether a phenotype predicting a higher sensitivity to low drug doses would be relevant in environmental conditions, such as the ones encountered by humans in which high drug doses are available. In this report, we studied dose-response, dose-intake, and ratio-intake functions for intravenous cocaine self-administration in the laboratory rat. We show that individual differences in drug self-administration originate from vertical shift in the dose-response function. Thus, no matter the dose, drug intake is very high in some "vulnerable" subjects and very low in other "resistant" ones. Vulnerable subjects, the upward shifted ones, would then have a higher chance to develop drug abuse also when high drug doses are available. In conclusion, these results provide a solid foundation for the existence of a drug-vulnerable phenotype relevant for the etiology of addiction. (+info)
Task-related modulation of visual cortex.
We performed a series of experiments to quantify the effects of task performance on cortical activity in early visual areas. Functional magnetic resonance imaging (fMRI) was used to measure cortical activity in several cortical visual areas including primary visual cortex (V1) and the MT complex (MT+) as subjects performed a variety of threshold-level visual psychophysical tasks. Performing speed, direction, and contrast discrimination tasks produced strong modulations of cortical activity. For example, one experiment tested for selective modulations of MT+ activity as subjects alternated between performing contrast and speed discrimination tasks. MT+ responses modulated in phase with the periods of time during which subjects performed the speed discrimination task; that is, MT+ activity was higher during speed discrimination than during contrast discrimination. Task-related modulations were consistent across repeated measurements in each subject; however, significant individual differences were observed between subjects. Together, the results suggest 1) that specific changes in the cognitive/behavioral state of a subject can exert selective and reliable modulations of cortical activity in early visual cortex, even in V1; 2) that there are significant individual differences in these modulations; and 3) that visual areas and pathways that are highly sensitive to small changes in a given stimulus feature (such as contrast or speed) are selectively modulated during discrimination judgments on that feature. Increasing the gain of the relevant neuronal signals in this way may improve their signal-to-noise to help optimize task performance. (+info)