Intraindividual Variability Research Articles

Hepatitis C, but Not Hepatitis B, Virus Infection Is Associated With Lower Concentration and Higher Intraindividual Variability of Circulating Total Cholesterol

Hepatitis C, but Not Hepatitis B, Virus Infection Is Associated With Lower Concentration and Higher Intraindividual Variability of Circulating Total Cholesterol

Accuracy and reliability for estimating jaw functional range of motion

BackgroundThree dimensional (3D) kinematic analysis based on motion capture can study synchronized data from the integrated jaw and neck motor system. Jaw function is commonly estimated on linear outcome variables of motion range. By combining jaw border movements in three planes the functional range of motion could be described by movement area and volume measures. Research questionCan we ensure the accuracy, test-retest reliability, and intra-individual variability with 3D kinematic analysis for estimating jaw functional range of motion (ROM), including jaw movement area and volume and jaw and head linear measures? MethodsAccuracy was estimated by applying the method to a set of beakers with known volume, based on the percentage deviation and Pearson correlation coefficient between target and estimated values. Test-retest reliability was then analysed on maximum jaw movements performed in a pre-determined movement sequence by 17 pain-free participants (25.4 years ± 2.4) to estimate jaw functional ROM. Intraclass correlation coefficients (ICC) were calculated, and Bland-Altman plots were constructed. Coefficient of variation (CV) tested the within session reliability. ResultsThe accuracy in volume and area measurements were high with a percentage deviation (0.03±0.59) and (1.2±0.45), respectively, with a strong linear relationship (R2=0.99) between target and estimated values. The test-retest reliability showed moderate to excellent reliability, and Bland-Altman plots showed good agreement. Overall, CVs showed high repeatability, but jaw movements in horizontal directions were less reliable and presented higher variability. SignificanceThe study with 3D kinematic analysis of jaw functional ROM, provides a methodological basis for accurate and reliable measurements. The study presents a new way to estimate jaw functional ROM measures, useful for evaluation in clinical intervention, for instance in pain and jaw dysfunction. Moreover, the natural biological movement variability and the complexity of the interplay of jaw-head movement will be emphasised.

Cardiovascular and cardiorespiratory effects of high-intensity interval training in body fat responders and non-responders

This study aimed to investigate cardiovascular and cardiorespiratory adaptations to exercise intervention among participants who showed higher (responders–RsBFP) and lower (non-responders–NRsBFP) levels of body fat percentage (BFP) responsiveness. Adolescents (42.5% males) participated in a ten-week school-based high-intensity interval training (HIIT), followed by a comparison of BFP, blood pressure (BP), and cardiorespiratory fitness (CRF). RsBFP age of 16.15 ± 0.36 years, body height 170.82 ± 8.16 cm, weight 61.23 ± 12.80 kg, and BMI 20.86 ± 3.29 kg/m2. Meanwhile, NRsBFP age of 16.04 ± 0.36 years, body height 168.17 ± 8.64 cm, weight 57.94 ± 8.62 kg, and BMI 20.47 ± 2.24 kg/m2. HIIT intervention impacted BFP, with a higher decrease in the RsBFP than the NRsBFP (ΔBFPRs = − 2.30 ± 3.51(10.34%) vs. ΔBFPNRs = 1.51 ± 1.54(6.96%) p < 0.001). The primary comparison showed a statistically significant interaction effect in relation to CRF (F(1,71) = 14.12; p < 0.001). Detailed comparisons showed large and significant CRF changes in RsBFP (7.52%; d = 0.86; p < 0.001) but not in NRsBFP (2.01%; d = 0.11; p = 0.576). In addition, RsBFP and NRsBFP benefited equally in SBP (5.49%, d = 0.75; p < 0.001; 4.95%, d = 0.74; p < 0.001, respectively). These findings highlight that exercise benefits on body fat may be mainly related to gains in CRF. Due to substantial intra-individual variability in adaptation, there is a need for personalized intervention tailored for those with different reaction thresholds in body mass components.

Assessment of the influence of demographic and anthropometric indicators on the variability of pharmacokinetic parameters

Relevance. Planning the design of bioequivalence clinical studies of generic highly variable drugs requires non-standard approaches – the use of replicative (repeated) or adaptive design. However, both approaches entail an increase in organizational, time, and financial costs. Therefore, it becomes relevant to search for ways to pre-select volunteers with a lower initial level of variability in pharmacokinetic parameters to reduce the number of subjects.Objective. The aim of this study was to determine the potential subjects in clinical trials with a low initial level of variability in pharmacokinetic parameters using methods for assessing initial gender – age and anthropometric and clinical laboratory parameters.Material and methods. Data from clinical studies of the bioequivalence of drugs (valganciclovir, carebastine and raltegravir) with different levels of variability conducted in the period 2020–2022 in Russia were used for analysis. To achieve this goal, a model for grouping pharmacokinetic parameters (PhK) with known demographic and clinical laboratory parameters was developed using discriminant analysis. Discrimination was performed between optimal pharmacokinetics (OPhK) and variable pharmacokinetics (VPhK). Mathematical and statistical analyses of the results were performed using Microsoft Excel 2013 and Statistica 10.0.Results. During the study, the variability of the maximum concentration of the drug in plasma (Cmax), including its logarithmic values, was used as a basis. The levels of intra-individual variability (CVintra), which is the main characteristic of drug variability, in the OPhK group were several times lower than those in the VPhK group for all studied drugs, but for the highly variable drug raltegravir, they differed by almost 10 times.Conclusion. Therefore, the obtained results indicated that using traditional gender – age and anthropometric indicators alone is impossible to separate the OPhK and VPhK groups for the analyzed drugs with high PhK variability.

Introducing the Intra-Individual Variability Hypothesis in Explaining Individual Differences in Language Development.

Response times (RTs) are commonly used in studying language acquisition. However, previous research utilizing RT in the context of language has largely overlooked the intra-individual variability (IIV) of RTs, which could hold significant information about the processes underlying language acquisition. We explored the association between language abilities and RT variability in visuomotor tasks using two data sets from previously published studies. The participants were 7- to 10-year-old children (n = 77). Our results suggest that increased variability in RTs is associated with weaker language abilities. Specifically, this within-participant variability in visuomotor RTs, especially the proportion of unusually slow responses, predicted language abilities better than mean RTs, a factor often linked to language skills in past research. Based on our findings, we introduce the IIV hypothesis in explaining individual differences in language development. According to our hypothesis, inconsistency in the timing of cognitive processes, reflected by increased IIV in RTs, degrades learning different aspects of language, and results in individual differences in language abilities. Future studies should further examine the relationship between IIV and language abilities, and test the extent to which the possible relationship is causal.

Harsh Discipline and the Development of Children’s Externalizing Problems: Longitudinal Mediation of Intraindividual Reaction Time Variability

ABSTRACT Research Findings: The present study aimed to investigate whether the trial-to-trial intraindividual reaction time variability (IIV), which reflects prefrontal cortex activity related to attentional and cognitive control, mediated the longitudinal effects of earlier harsh discipline on children’s later externalizing problems. The study involved 235 elementary school children (M age = 7.25, 46% female) who underwent up to three repeated assessments. Specifically, the Chinese version of the Parent-Child Conflict Tactics Scale and the Child Behavior Checklist were completed by the children’s mothers to assess harsh discipline (including corporal punishment and psychological aggression) and the children’s externalizing problems at three assessment waves. In addition, the children’s IIV was measured using the Go/No-Go task at three assessment waves. The results from structural equation modeling revealed that the longitudinal path between corporal punishment at T1 and externalizing problems at T3 was partially mediated by IIV at T2. This suggested that more corporal punishment children experienced, the greater IIV and the more externalizing problems they will develop at a later stage. Practice or Policy: The findings highlight the proposed process model, which shows that corporal punishment impairs the development of children’s prefrontal function as indexed by IIV, ultimately increasing the risk of externalizing problems.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study

BackgroundThe relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function.MethodsThis study recruited 1111 participants aged 25–83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function.ResultsCompared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = − 0.25, 95% confidence interval [CI] − 0.39 to − 0.11 and beta = − 0.15, 95% CI − 0.29 to − 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = − 0.24, 95% CI − 0.38 to − 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = − 0.18, 95% CI − 0.32 to − 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline.ConclusionsIt is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

Next-generation risk assessment read-across case study: application of a 10-step framework to derive a safe concentration of daidzein in a body lotion.

Introduction: We performed an exposure-based Next Generation Risk Assessment case read-across study using New Approach Methodologies (NAMs) to determine the highest safe concentration of daidzein in a body lotion, based on its similarities with its structural analogue, genistein. Two assumptions were: (1) daidzein is a new chemical and its dietary intake omitted; (2) only in vitro data were used for daidzein, while in vitro and legacy in vivo data for genistein were considered. Methods: The 10-step tiered approach evaluating systemic toxicity included toxicokinetics NAMs: PBPK models and in vitro biokinetics measurements in cells used for toxicogenomics and toxicodynamic NAMs: pharmacology profiling (i.e., interaction with molecular targets), toxicogenomics and EATS assays (endocrine disruption endpoints). Whole body rat and human PBPK models were used to convert external doses of genistein to plasma concentrations and in vitro Points of Departure (PoD) to external doses. The PBPK human dermal module was refined using in vitro human skin metabolism and penetration data. Results: The most relevant endpoint for daidzein was from the ERα assay (Lowest Observed Effective Concentration was 100 ± 0.0nM), which was converted to an in vitro PoD of 33nM. After application of a safety factor of 3.3 for intra-individual variability, the safe concentration of daidzein was estimated to be 10nM. This was extrapolated to an external dose of 0.5μg/cm2 for a body lotion and face cream, equating to a concentration of 0.1%. Discussion: When in vitro PoD of 33nM for daidzein was converted to an external oral dose in rats, the value correlated with the in vivo NOAEL. This increased confidence that the rat oral PBPK model provided accurate estimates of internal and external exposure and that the in vitro PoD was relevant in the safety assessment of both chemicals. When plasma concentrations estimated from applications of 0.1% and 0.02% daidzein were used to calculate bioactivity exposure ratios, values were >1, indicating a good margin between exposure and concentrations causing adverse effects. In conclusion, this case study highlights the use of NAMs in a 10-step tiered workflow to conclude that the highest safe concentration of daidzein in a body lotion is 0.1%.

Intraindividual Variability in Attention-Deficit/Hyperactivity Disorder: An Ex-Gaussian Approach.

Higher intraindividual variability (IIV) of response times is consistently noted in children with attention-deficit/hyperactivity disorder (ADHD). The current study investigated whether an ex-Gaussian estimate of IIV in children ages 6-13 years-old could differentiate between children with and without ADHD. Children completed a computerized go/no-go task to estimate trial-by-trial IIV and a continuous performance test (CPT) to estimate inattention and hyperactivity/impulsivity. Parents completed questionnaires assessing inattention and hyperactive/impulsive behaviors. IIV, commission errors, and attention problems as rated by parents were significantly greater in the ADHD group. Groups did not differ on errors of omission, but IIV was predictive of omission errors and parent ratings of inattention and hyperactivity/impulsivity. IIV predicted group membership (ADHD vs Control) whereas errors of omission did not. However, IIV did not improve diagnostic accuracy when parent ratings were used, such that parent ratings were superior at determining diagnosis. Current results support the use of IIV, based on the ex-Gaussian approach, as an objective measure of attention problems over omission errors on sustained attention CPT-type tasks. Additionally, while parent ratings of attention impairment remain the best predictor of ADHD diagnostic status, IIV may be helpful in determining when further assessment is required in the absence of those ratings.

Cytochrome P450 and UDP-Glucuronosyltransferase Expressions, Activities, and Induction Abilities in 3D-Cultured Human Renal Proximal Tubule Epithelial Cells.

The role of the kidney as an excretory organ for exogenous and endogenous compounds is well recognized, but there is a wealth of data demonstrating that the kidney has significant metabolizing capacity for a variety of exogenous and endogenous compounds that in some cases surpass the liver. The induction of drug-metabolizing enzymes by some chemicals can cause drug-drug interactions and intraindividual variability in drug clearance. In this study, we evaluated the expression and induction of cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) isoforms in 3D-cultured primary human renal proximal tubule epithelial cells (RPTEC) to elucidate their utility as models of renal drug metabolism. CYP2B6, CYP2E1, CYP3A4, CYP3A5, and all detected UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) mRNA levels in 3D-RPTEC were significantly higher than those in 2D-RPTEC and HK-2 cells and were close to the levels in the human kidney cortex. CYP1B1 and CYP2J2 mRNA levels in 3D-RPTEC were comparable to those in 2D-RPTEC, HK-2 cells, and the human kidney cortex. Midazolam 1'-hydroxylation, trifluoperazine N-glucuronidation, serotonin O-glucuronidation, propofol O-glucuronidation, and morphine 3-glucuronidation in the 3D-RPTEC were significantly higher than the 2D-RPTEC and comparable to those in the HepaRG cells, although bupropion, ebastine, and calcitriol hydroxylations were not different between the 2D- and 3D-RPTEC. Treatment with ligands of the aryl hydrocarbon receptor and farnesoid X receptor induced CYP1A1 and UGT2B4 expression, respectively, in 3D-RPTEC compared with 2D-RPTEC. We provided information on the expression, activity, and induction abilities of P450s and UGTs in 3D-RPTEC as an in vitro human renal metabolism model. SIGNIFICANCE STATEMENT: This study demonstrated that the expression of cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) in 3D-cultured primary human renal proximal tubule epithelial cells (3D-RPTEC) was higher than those in 2D-cultured primary human renal proximal tubule epithelial cells and HK-2 cells. The results were comparable to that in the human kidney cortex. 3D-RPTEC are useful for evaluating the induction of kidney P450s, UDP-glucuronosyltransferases, and human renal drug metabolism in cellulo.

Just-in-Time Adaptive Intervention for Stabilizing Sleep Hours of Japanese Workers: Microrandomized Trial.

Sleep disturbance is a major contributor to future health and occupational issues. Mobile health can provide interventions that address adverse health behaviors for individuals in a vulnerable health state in real-world settings (just-in-time adaptive intervention). This study aims to identify a subpopulation with vulnerable sleep state in daily life (study 1) and, immediately afterward, to test whether providing mobile health intervention improved habitual sleep behaviors and psychological wellness in real-world settings by conducting a microrandomized trial (study 2). Japanese workers (n=182) were instructed to collect data on their habitual sleep behaviors and momentary symptoms (including depressive mood, anxiety, and subjective sleep quality) using digital devices in a real-world setting. In study 1, we calculated intraindividual mean and variability of sleep hours, midpoint of sleep, and sleep efficiency to characterize their habitual sleep behaviors. In study 2, we designed and conducted a sleep just-in-time adaptive intervention, which delivered objective push-type sleep feedback messages to improve their sleep hours for a subset of participants in study 1 (n=81). The feedback messages were generated based on their sleep data measured on previous nights and were randomly sent to participants with a 50% chance for each day (microrandomization). In study 1, we applied hierarchical clustering to dichotomize the population into 2 clusters (group A and group B) and found that group B was characterized by unstable habitual sleep behaviors (large intraindividual variabilities). In addition, linear mixed-effect models showed that the interindividual variability of sleep hours was significantly associated with depressive mood (β=3.83; P=.004), anxiety (β=5.70; P=.03), and subjective sleep quality (β=-3.37; P=.03). In study 2, we found that providing sleep feedback prolonged subsequent sleep hours (increasing up to 40 min; P=.01), and this effect lasted for up to 7 days. Overall, the stability of sleep hours in study 2 was significantly improved among participants in group B compared with the participants in study 1 (P=.001). This is the first study to demonstrate that providing sleep feedback can benefit the modification of habitual sleep behaviors in a microrandomized trial. The findings of this study encourage the use of digitalized health intervention that uses real-time health monitoring and personalized feedback.

Bis-(2-Chloroisopropyl) ether.

Bis-(2-Chloroisopropyl) ether (BCIPE) was used as a solvent for fats, greases, paint, varnish removers, and in spotting and cleaning solutions. However, BCIPE has not been commercially manufactured or used for numerous years. In experimental animal studies, BCIPE is moderately toxic following acute oral, dermal, and inhalation routes of exposure. BCIPE is a severe eye irritant but not a dermal irritant or dermal sensitizer. BCIPE was not genotoxic or mutagenic in in vitro and in vivo assays; it was not toxic in a 3-generation reproductive dietary study in rats. Short-term, repeated inhalation and oral exposure in rats produced increased liver and kidney weights and congestion; dermal exposure in rabbits did not produce any observable adverse effects. BCIPE did not produce a statistically significant increase in tumors in two different 2-year dietary studies in mice and rats. In mice, technical grade BCIPE produced increased incidences of alveolar/bronchiolar adenomas in females, hepatocellular carcinomas in males, and a low incidence of forestomach hyperplasia (in both sexes at the high-dose). Further investigation with technical grade BCIPE concluded that these effects were species- and dose-specific with limited, if any, relevance to humans. The NOAEL of 400 ppm (15 mg/kg/day) from the 2-year dietary study in female rats was considered the point of departure for the health-based WEEL derivation. After adjustment for duration of exposure, interindividual variability, and intraindividual variability, an 8-h time-weighted average (TWA) WEEL value of 3 ppm (21 mg/m3) was derived. This exposure limit is expected to provide a significant margin of safety against any potential adverse health effects in workers.

Loneliness in daily life: A comparison between youths with autism spectrum disorders and 22q11.2 deletion syndrome (22q11DS).

Loneliness is a negative emotional experience that can stem from a gap between desires and the reality of social relationships. It is also a predictor of mental health. Loneliness is therefore important to investigate in neurodevelopmental populations known for having difficulties in the social sphere. This co-registered study involved 48 youths with autism spectrum disorders (ASD), 54 youths with 22q11.2 deletion syndrome (22q11DS) and 65 typically developing youths (TD) aged 12-30. State loneliness was assessed with an ecological momentary assessment. Paper-pencil questionnaires assessing attitude toward aloneness, trait loneliness, and mental health, were completed by the youths and their caregivers. A comparable level of state loneliness between clinical groups and TD were found, with greater loneliness when alone than in a social context. Clinical groups showed a greater intra-individual variability. Both individuals with ASD and 22q11DS revealed a greater affinity toward being alone than TD, but only individuals with ASD reported greater trait loneliness. However, no significant association was found between attitude toward aloneness, trait and state loneliness. Emotional reactivity to loneliness was different between the clinical groups. Self-reported mental health only was associated with loneliness in the clinical groups. These results provide new insights into the understanding of loneliness in these clinical populations and have an impact on clinical care by highlighting the need to remain vigilant when encountering youths who report feeling lonely, and that these youths need to be supported in developing their social network, which appears to be a protective factor against loneliness.

Modeling intra-individual inter-trial EEG response variability in autism.

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism. Traditional analysis of EEG data largely focuses on mean trends of the trial-averaged data, where trial-level analysis is rarely performed due to low neural signal to noise ratio. We propose to use nonlinear (shape-invariant) mixed effects (NLME) models to study intra-individual inter-trial EEG response variability using trial-level EEG data. By providing more precise metrics of response variability, this approach could enrich our understanding of neural disparities in autism and potentially aid the identification of objective markers. The proposed multilevel NLME models quantify variability in the signal's interpretable and widely recognized features (e.g., latency and amplitude) while also regularizing estimation based on noisy trial-level data. Even though NLME models have been studied for more than three decades, existing methods cannot scale up to large data sets. We propose computationally feasible estimation and inference methods via the use of a novel minorization-maximization (MM) algorithm. Extensive simulations are conducted to show the efficacy of the proposed procedures. Applications to data from a large national consortium find that children with autism have larger intra-individual inter-trial variability in P1 latency in a visual evoked potential (VEP) task, compared to their neurotypical peers.

Relationship between foliar polycyclic aromatic hydrocarbons (PAHs) concentrations and plant traits: Intracanopy variability for a broadleaf species in an urban environment

The emission of potentially harmful compounds, including polycyclic aromatic hydrocarbons (PAHs), and the resulting air pollution is a serious problem in modern cities. It is therefore important to develop mitigation strategies, such as “smart” planting of trees that act as sinks for PAHs. However, the intra-individual (within-tree) variability in leaf PAH concentrations remains unknown. In this paper, we studied 15 ornamental apple trees (Malus × moerlandsii ‘Profusion’) growing on a main street in a medium-sized city in Galicia (NW Spain). We determined the PAH concentrations at 12 canopy positions in each tree (2 orientations and 2 distances from the trunk at 3 heights), measured various ecological traits (specific leaf area [SLA], δ13C, stomatal density, fatty acid contents and leaf hairiness) and analyzed the variability in traits within the canopy in relation to PAH concentrations. We observed high intra-individual variability in the PAH concentrations and the leaf traits. Statistical analyses revealed that leaf height was the main source of variability both in the PAH concentrations and in the traits, mainly due to the leaf morphology, particularly to the SLA. Therefore, the ideal vegetation to remove PAHs would be high leaf biomass trees, not too tall and with a high proportion of shade leaves.

Improvement in gait velocity variability after cerebrospinal fluid elimination and its relationship to clinical symptoms in patients with idiopathic normal pressure hydrocephalus.

This study aimed to investigate the improvement in gait velocity variability after cerebrospinal fluid (CSF) elimination, and the association between gait velocity variability and gait and cognitive impairment in patients with idiopathic normal pressure hydrocephalus. The gait velocity of 44 patients with idiopathic normal pressure hydrocephalus was measured using the Timed Up and Go Test (TUG) for a total of 10 times over 3 days each before and after CSF elimination. The coefficient of variation (CV) in the time required for the sequence of actions in TUG (TUG-CV) was calculated using 10 TUG data, and used for measuring intraindividual gait velocity variability. Gait quality was evaluated with the Gait Status Scale Revised (GSSR), and cognitive function was evaluated with the Mini-Mental State Examination and the Frontal Assessment Battery. The TUG, TUG-CV, GSSR and Frontal Assessment Battery results improved significantly after CSF elimination. The analyses using pre-CSF elimination results showed that the TUG-CV significantly and positively correlated with the TUG and GSSR results, and negatively with Mini-Mental State Examination results, but not with age and the Frontal Assessment Battery results. The stepwise multiple regression analysis indicates that the TUG, GSSR and Mini-Mental State Examination results were significant predictors of the TUG-CV. The analysis using data of change after CSF elimination showed that ΔTUG and ΔGSSR were significant predictors of ΔTUG-CV. Gait velocity variability improved after CSF elimination, and gait velocity variability was associated with gait disturbances and cognitive impairment in patients with idiopathic normal pressure hydrocephalus. Geriatr Gerontol Int 2024; 24: 693-699.

Association between intra-individual variability and prefrontal cortex activity measured by functional Near Infrared Spectroscopy (fNIRS) in children with ADHD

ABSTRACT This study uses fNIRS to determine whether there is a difference in the relationship between intra-individual variability and frontal lobe activity between ADHD patients and typically developing children. A total of 28 subjects (14 in ADHD patient group and 14 in control group) participated in this study. The subjects were tested for K-SADS and intelligence, and then the frontal lobe activity of the subjects was measured by continuous performance test, using functional near-infrared spectroscopy (NIRSIT). Processing speed index was significantly lower in the ADHD patient group than in the control group (p = .04). The CPT test results showed a positive correlation in the activity of the right dorsolateral prefrontal region in the patient group, but not at a statistically significant level. In the control group, activity showed a significant level of negative correlation with commission and hit reaction time standard deviation (p = .023; p = .063 respectively). In contrary to ADHD patient group, activation of the right dorsolateral prefrontal area was significantly correlated with reduction of intra-individual variability. This result showing that the relationship between activation of the right dorsolateral prefrontal area of the ADHD patient group and intra-individual variability shows a different pattern from typically developing children.

Oral Drug Dosing After Gastric Bypass and Diet-Induced Weight Loss: Simpler Than We Think? Lessons Learned From the COCKTAIL Study.

This article summarizes the lessons learned from the COCKTAIL study: an open, three-armed, single-center study including patients with obesity scheduled for treatment with Roux-en-Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal- to overweight control group. The clinical implications of the results from multiple peer-reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug-metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion-transporting polypeptide (OATP) 1B1 and P-glycoprotein (P-gp)) are discussed in the perspective of three clinically relevant questions: (1) How should clinicians get the dose right in patients after RYGB? (2) Will drug disposition in patients with obesity be normalized after successful weight loss? (3) Are dose adjustments needed according to obesity and diabetes status? Overall, RYGB seems to have a lower impact on drug disposition than previously assumed, but clinicians should pay close attention to drugs with a narrow therapeutic range or where a high maximum drug concentration may be problematic. Whether obesity-related alterations of DMETs normalize with substantial weight loss depends on the DMET in question. Obesity and diabetes downregulate the in vivo activity of CYP2C19 and CYP3A (only obesity) but whether substrate drugs should be dose adjusted is also dependent on other factors that influence clearance, that is, liver blood flow and protein binding. Finally, we recommend frequent and individualized follow-up due to high inter- and intraindividual variability in these patients, particularly following RYGB.

Chromosomal damage, gene expression and alternative transcription in human lymphocytes exposed to mixed ionizing radiation as encountered in space

Astronauts travelling in space will be exposed to mixed beams of particle radiation and photons. Exposure limits that correspond to defined cancer risk are calculated by multiplying absorbed doses by a radiation-type specific quality factor that reflects the biological effectiveness of the particle without considering possible interaction with photons. We have shown previously that alpha radiation and X-rays may interact resulting in synergistic DNA damage responses in human peripheral blood lymphocytes but the level of intra-individual variability was high. In order to assess the variability and validate the synergism, blood from two male donors was drawn at 9 time points during 3 seasons of the year and exposed to 0–2 Gy of X-rays, alpha particles or 1:1 mixture of both (half the dose each). DNA damage response was quantified by chromosomal aberrations and by mRNA levels of 3 radiation-responsive genes FDXR, CDKN1A and MDM2 measured 24 h post exposure. The quality of response in terms of differential expression of alternative transcripts was assessed by using two primer pairs per gene. A consistently higher than expected effect of mixed beams was found in both donors for chromosomal aberrations and gene expression with some seasonal variability for the latter. No synergy was detected for alternative transcription.

Mast cell degranulation and bradykinin-induced angioedema - searching for the missing link.

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.