Age-related, interindividual, and right/left differences in anterior-posterior foot pressure ratio in preschool children

PubMed Central

2013-01-01

Background This study aimed to examine age-related, interindividual, and right/left differences in anterior-posterior foot pressure ratio in 764 preschool children (364 boys and 400 girls) aged 3.5-6.5 years. Methods Subjects maintained an upright standing posture for 10 seconds on the Footview Clinic, an instrument designed to calculate the anterior-posterior foot pressure ratio. The ratio of anterior foot pressure in each subject’s right and left feet was selected as a variable, and the mean of a 10 s measurement was used for analysis. Results The ratio of anterior foot pressure was significantly larger in the right foot than in the left foot. With regard to age, the ratio of anterior foot pressure was significantly larger in children aged over 4.5 years than in children aged 3.5 years. It was also larger in children aged 6 and 6.5 years than in children aged 4 years. Interindividual differences in variables were large, and coefficients of variance were highest in children aged 3.5 years and lowest in children aged 6.5 years. Conclusions In conclusion, anterior foot pressure increases with age in preschool children. Interindividual differences in anterior foot pressure are large and tend to decrease with age. Furthermore, the anterior foot pressure is slightly higher in the right foot than in the left foot. These results will be useful for various studies, such as examining relationships between the anterior-posterior foot pressure ratio and factors, such as untouched toes, physical fitness, and level of exercise. PMID:23601375

Human Occipital and Parietal GABA Selectively Influence Visual Perception of Orientation and Size.

PubMed

Song, Chen; Sandberg, Kristian; Andersen, Lau Møller; Blicher, Jakob Udby; Rees, Geraint

2017-09-13

GABA is the primary inhibitory neurotransmitter in human brain. The level of GABA varies substantially across individuals, and this variability is associated with interindividual differences in visual perception. However, it remains unclear whether the association between GABA level and visual perception reflects a general influence of visual inhibition or whether the GABA levels of different cortical regions selectively influence perception of different visual features. To address this, we studied how the GABA levels of parietal and occipital cortices related to interindividual differences in size, orientation, and brightness perception. We used visual contextual illusion as a perceptual assay since the illusion dissociates perceptual content from stimulus content and the magnitude of the illusion reflects the effect of visual inhibition. Across individuals, we observed selective correlations between the level of GABA and the magnitude of contextual illusion. Specifically, parietal GABA level correlated with size illusion magnitude but not with orientation or brightness illusion magnitude; in contrast, occipital GABA level correlated with orientation illusion magnitude but not with size or brightness illusion magnitude. Our findings reveal a region- and feature-dependent influence of GABA level on human visual perception. Parietal and occipital cortices contain, respectively, topographic maps of size and orientation preference in which neural responses to stimulus sizes and stimulus orientations are modulated by intraregional lateral connections. We propose that these lateral connections may underlie the selective influence of GABA on visual perception. SIGNIFICANCE STATEMENT GABA, the primary inhibitory neurotransmitter in human visual system, varies substantially across individuals. This interindividual variability in GABA level is linked to interindividual differences in many aspects of visual perception. However, the widespread influence of GABA raises the question of whether interindividual variability in GABA reflects an overall variability in visual inhibition and has a general influence on visual perception or whether the GABA levels of different cortical regions have selective influence on perception of different visual features. Here we report a region- and feature-dependent influence of GABA level on human visual perception. Our findings suggest that GABA level of a cortical region selectively influences perception of visual features that are topographically mapped in this region through intraregional lateral connections. Copyright © 2017 Song, Sandberg et al.

Inter- and Intra-individual Variability in Response to Transcranial Direct Current Stimulation (tDCS) at Varying Current Intensities.

PubMed

Chew, Taariq; Ho, Kerrie-Anne; Loo, Colleen K

2015-01-01

Translation of transcranial direct current stimulation (tDCS) from research to clinical practice is hindered by a lack of consensus on optimal stimulation parameters, significant inter-individual variability in response, and in sufficient intra-individual reliability data. Inter-individual differences in response to anodal tDCS at a range of current intensities were explored. Intra-individual reliability in response to anodal tDCS across two identical sessions was also investigated. Twenty-nine subjects participated in a crossover study. Anodal-tDCS using four different current intensities (0.2, 0.5, 1 and 2 mA), with an anode size of 16 cm2, was tested. The 0.5 mA condition was repeated to assess intra-individual variability. TMS was used to elicit 40 motor-evoked potentials (MEPs) before 10 min of tDCS, and 20 MEPs at four time-points over 30 min following tDCS. ANOVA revealed no main effect of TIME for all conditions except the first 0.5 mA condition, and no differences in response between the four current intensities. Cluster analysis identified two clusters for the 0.2 and 2 mA conditions only. Frequency distributions based on individual subject responses (excitatory, inhibitory or no response) to each condition indicate possible differential responses between individuals to different current intensities. Test-retest reliability was negligible (ICC(2,1) = -0.50). Significant inter-individual variability in response to tDCS across a range of current intensities was found. 2 mA and 0.2 mA tDCS were most effective at inducing a distinct response. Significant intra-individual variability in response to tDCS was also found. This has implications for interpreting results of single-session tDCS experiments. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Inter-individual variability and pattern recognition of surface electromyography in front crawl swimming.

PubMed

Martens, Jonas; Daly, Daniel; Deschamps, Kevin; Staes, Filip; Fernandes, Ricardo J

2016-12-01

Variability of electromyographic (EMG) recordings is a complex phenomenon rarely examined in swimming. Our purposes were to investigate inter-individual variability in muscle activation patterns during front crawl swimming and assess if there were clusters of sub patterns present. Bilateral muscle activity of rectus abdominis (RA) and deltoideus medialis (DM) was recorded using wireless surface EMG in 15 adult male competitive swimmers. The amplitude of the median EMG trial of six upper arm movement cycles was used for the inter-individual variability assessment, quantified with the coefficient of variation, coefficient of quartile variation, the variance ratio and mean deviation. Key features were selected based on qualitative and quantitative classification strategies to enter in a k-means cluster analysis to examine the presence of strong sub patterns. Such strong sub patterns were found when clustering in two, three and four clusters. Inter-individual variability in a group of highly skilled swimmers was higher compared to other cyclic movements which is in contrast to what has been reported in the previous 50years of EMG research in swimming. This leads to the conclusion that coaches should be careful in using overall reference EMG information to enhance the individual swimming technique of their athletes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Polymorphisms in the Wilms Tumor Gene Are Associated With Interindividual Variations in Rubella Virus-Specific Cellular Immunity After Measles-Mumps-Rubella II Vaccination.

PubMed

Voigt, Emily A; Haralambieva, Iana H; Larrabee, Beth L; Kennedy, Richard B; Ovsyannikova, Inna G; Schaid, Daniel J; Poland, Gregory A

2018-01-30

Rubella vaccination induces widely variable immune responses in vaccine recipients. While rubella vaccination is effective at inducing immunity to rubella infection in most subjects, up to 5% of individuals do not achieve or maintain long-term protective immunity. To expand upon our previous work identifying genetic polymorphisms that are associated with these interindividual differences in humoral immunity to rubella virus, we performed a genome-wide association study in a large cohort of 1843 subjects to discover single-nucleotide polymorphisms (SNPs) associated with rubella virus-specific cellular immune responses. We identified SNPs in the Wilms tumor protein gene (WT1) that were significantly associated (P < 5 × 10-8) with interindividual variations in rubella-specific interleukin 6 secretion from subjects' peripheral blood mononuclear cells postvaccination. No SNPs were found to be significantly associated with variations in rubella-specific interferon-γ secretion. Our findings demonstrate that genetic polymorphisms in the WT1 gene in subjects of European ancestry are associated with interindividual differences in rubella virus-specific cellular immunity after measles-mumps-rubella II vaccination. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Costs and Benefits of Orthographic Inconsistency in Reading: Evidence from a Cross-Linguistic Comparison

PubMed Central

Marinelli, Chiara Valeria; Romani, Cristina; Burani, Cristina; McGowan, Victoria A.; Zoccolotti, Pierluigi

2016-01-01

We compared reading acquisition in English and Italian children up to late primary school analyzing RTs and errors as a function of various psycholinguistic variables and changes due to experience. Our results show that reading becomes progressively more reliant on larger processing units with age, but that this is modulated by consistency of the language. In English, an inconsistent orthography, reliance on larger units occurs earlier on and it is demonstrated by faster RTs, a stronger effect of lexical variables and lack of length effect (by fifth grade). However, not all English children are able to master this mode of processing yielding larger inter-individual variability. In Italian, a consistent orthography, reliance on larger units occurs later and it is less pronounced. This is demonstrated by larger length effects which remain significant even in older children and by larger effects of a global factor (related to speed of orthographic decoding) explaining changes of performance across ages. Our results show the importance of considering not only overall performance, but inter-individual variability and variability between conditions when interpreting cross-linguistic differences. PMID:27355364

Costs and Benefits of Orthographic Inconsistency in Reading: Evidence from a Cross-Linguistic Comparison.

PubMed

Marinelli, Chiara Valeria; Romani, Cristina; Burani, Cristina; McGowan, Victoria A; Zoccolotti, Pierluigi

2016-01-01

We compared reading acquisition in English and Italian children up to late primary school analyzing RTs and errors as a function of various psycholinguistic variables and changes due to experience. Our results show that reading becomes progressively more reliant on larger processing units with age, but that this is modulated by consistency of the language. In English, an inconsistent orthography, reliance on larger units occurs earlier on and it is demonstrated by faster RTs, a stronger effect of lexical variables and lack of length effect (by fifth grade). However, not all English children are able to master this mode of processing yielding larger inter-individual variability. In Italian, a consistent orthography, reliance on larger units occurs later and it is less pronounced. This is demonstrated by larger length effects which remain significant even in older children and by larger effects of a global factor (related to speed of orthographic decoding) explaining changes of performance across ages. Our results show the importance of considering not only overall performance, but inter-individual variability and variability between conditions when interpreting cross-linguistic differences.

The contribution of interindividual factors to variability of response in transcranial direct current stimulation studies

PubMed Central

Li, Lucia M.; Uehara, Kazumasa; Hanakawa, Takashi

2015-01-01

There has been an explosion of research using transcranial direct current stimulation (tDCS) for investigating and modulating human cognitive and motor function in healthy populations. It has also been used in many studies seeking to improve deficits in disease populations. With the slew of studies reporting “promising results” for everything from motor recovery after stroke to boosting memory function, one could be easily seduced by the idea of tDCS being the next panacea for all neurological ills. However, huge variability exists in the reported effects of tDCS, with great variability in the effect sizes and even contradictory results reported. In this review, we consider the interindividual factors that may contribute to this variability. In particular, we discuss the importance of baseline neuronal state and features, anatomy, age and the inherent variability in the injured brain. We additionally consider how interindividual variability affects the results of motor-evoked potential (MEP) testing with transcranial magnetic stimulation (TMS), which, in turn, can lead to apparent variability in response to tDCS in motor studies. PMID:26029052

Longitudinal Growth Curves of Brain Function Underlying Inhibitory Control through Adolescence

PubMed Central

Foran, William; Velanova, Katerina; Luna, Beatriz

2013-01-01

Neuroimaging studies suggest that developmental improvements in inhibitory control are primarily supported by changes in prefrontal executive function. However, studies are contradictory with respect to how activation in prefrontal regions changes with age, and they have yet to analyze longitudinal data using growth curve modeling, which allows characterization of dynamic processes of developmental change, individual differences in growth trajectories, and variables that predict any interindividual variability in trajectories. In this study, we present growth curves modeled from longitudinal fMRI data collected over 302 visits (across ages 9 to 26 years) from 123 human participants. Brain regions within circuits known to support motor response control, executive control, and error processing (i.e., aspects of inhibitory control) were investigated. Findings revealed distinct developmental trajectories for regions within each circuit and indicated that a hierarchical pattern of maturation of brain activation supports the gradual emergence of adult-like inhibitory control. Mean growth curves of activation in motor response control regions revealed no changes with age, although interindividual variability decreased with development, indicating equifinality with maturity. Activation in certain executive control regions decreased with age until adolescence, and variability was stable across development. Error-processing activation in the dorsal anterior cingulate cortex showed continued increases into adulthood and no significant interindividual variability across development, and was uniquely associated with task performance. These findings provide evidence that continued maturation of error-processing abilities supports the protracted development of inhibitory control over adolescence, while motor response control regions provide early-maturing foundational capacities and suggest that some executive control regions may buttress immature networks as error processing continues to mature. PMID:24227721

Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine.

PubMed

Néant, Nadège; Gattacceca, Florence; Lê, Minh Patrick; Yazdanpanah, Yazdan; Dhiver, Catherine; Bregigeon, Sylvie; Mokhtari, Saadia; Peytavin, Gilles; Tamalet, Catherine; Descamps, Diane; Lacarelle, Bruno; Solas, Caroline

2018-04-01

Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50 ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9 L/h and 321 L, respectively, resulting in a half-life of 25.2 h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from "real-life" conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.

Genetic Influence on Slope Variability in a Childhood Reflexive Attention Task.

PubMed

Lundwall, Rebecca A; Watkins, Jeffrey K

2015-01-01

Individuals are not perfectly consistent, and interindividual variability is a common feature in all varieties of human behavior. Some individuals respond more variably than others, however, and this difference may be important to understanding how the brain works. In this paper, we explore genetic contributions to response time (RT) slope variability on a reflexive attention task. We are interested in such variability because we believe it is an important part of the overall picture of attention that, if understood, has the potential to improve intervention for those with attentional deficits. Genetic association studies are valuable in discovering biological pathways of variability and several studies have found such associations with a sustained attention task. Here, we expand our knowledge to include a reflexive attention task. We ask whether specific candidate genes are associated with interindividual variability on a childhood reflexive attention task in 9-16 year olds. The genetic makers considered are on 11 genes: APOE, BDNF, CHRNA4, COMT, DRD4, HTR4, IGF2, MAOA, SLC5A7, SLC6A3, and SNAP25. We find significant associations with variability with markers on nine and we discuss the results in terms of neurotransmitters associated with each gene and the characteristics of the associated measures from the reflexive attention task.

Age and CD161 Expression Contribute to Inter-Individual Variation in Interleukin-23 Response in CD8+ Memory Human T Cells

PubMed Central

Abraham, Clara; Cho, Judy H.

2013-01-01

The interleukin-23 (IL-23) pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation) in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant (Pearson’s correlation coefficient, r = −0.37, p = 0.001) source of variability observed in CD8+CD45RO+ memory T cells, with IL-23 responsiveness gradually decreasing with increasing age. Relative to cells from individuals demonstrating low responsiveness to IL-23 stimulation, CD8+CD45RO+ memory T cells from individuals demonstrating high responsiveness to IL-23 stimulation showed increased gene expression for IL-23 receptor (IL-23R), RORC (RORγt) and CD161 (KLRB1), whereas RORA (RORα) and STAT3 expression were equivalent. Similar to CD4+ memory T cells, IL-23 responsiveness is confined to the CD161+ subset in CD8+CD45RO+ memory T cells, suggesting a similar CD161+ precursor as has been reported for CD4+ Th17 cells. We observed a very strong positive correlation between IL-23 responsiveness and the fraction of CD161+, CD8+CD45RO+ memory T cells (r = 0.80, p<0.001). Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = −0.34, p = 0.05). Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population. Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes. PMID:23469228

Spontaneous individual differences in cognitive performances of young adult rats predict locomotor response to amphetamine.

PubMed

Dellu-Hagedorn, F

2005-01-01

Inter-individual differences in cognitive capacities of young adult rats have largely been ignored. To explore this variability and its neurobiological bases, the relationships between individual differences in working memory and locomotor responses to novelty and to amphetamine were investigated in SD rats. Groups of good and poor learners were isolated, the latter demonstrating a markedly slower learning of the task compared to performant rats, with more perseverations independently to motivational state. They also presented a much higher increase in amphetamine-induced locomotion that remained significant for more than 1h after the injection. These results provide evidence that variability in cognitive capacities can be used to reveal their neurobiological substrates. They open new perspectives to study a possible cognitive origin of addictive behaviors and to investigate the involvement of these inter-individual differences on those observed later in life.

Use of Physiologically Based Pharmacokinetic (PBPK) Models ...

EPA Pesticide Factsheets

EPA announced the availability of the final report, Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk Final Report for Cooperative Agreement. This report describes and demonstrates techniques necessary to extrapolate and incorporate in vitro derived metabolic rate constants in PBPK models. It also includes two case study examples designed to demonstrate the applicability of such data for health risk assessment and addresses the quantification, extrapolation and interpretation of advanced biochemical information on human interindividual variability of chemical metabolism for risk assessment application. It comprises five chapters; topics and results covered in the first four chapters have been published in the peer reviewed scientific literature. Topics covered include: Data Quality ObjectivesExperimental FrameworkRequired DataTwo example case studies that develop and incorporate in vitro metabolic rate constants in PBPK models designed to quantify human interindividual variability to better direct the choice of uncertainty factors for health risk assessment. This report is intended to serve as a reference document for risk assors to use when quantifying, extrapolating, and interpretating advanced biochemical information about human interindividual variability of chemical metabolism.

Reduced variability and execution time to reach a target with a needle GPS system: Comparison between physicians, residents and nurse anaesthetists.

PubMed

Fevre, Marie-Cécile; Vincent, Caroline; Picard, Julien; Vighetti, Arnaud; Chapuis, Claire; Detavernier, Maxime; Allenet, Benoît; Payen, Jean-François; Bosson, Jean-Luc; Albaladejo, Pierre

2018-02-01

Ultrasound (US) guided needle positioning is safer than anatomical landmark techniques for central venous access. Hand-eye coordination and execution time depend on the professional's ability, previous training and personal skills. Needle guidance positioning systems (GPS) may theoretically reduce execution time and facilitate needle positioning in specific targets, thus improving patient comfort and safety. Three groups of healthcare professionals (41 anaesthesiologists and intensivists, 41 residents in anaesthesiology and intensive care, 39 nurse anaesthetists) were included and required to perform 3 tasks (positioning the tip of a needle in three different targets in a silicon phantom) by using successively a conventional US-guided needle positioning and a needle GPS. We measured execution times to perform the tasks, hand-eye coordination and the number of repositioning occurrences or errors in handling the needle or the probe. Without the GPS system, we observed a significant inter-individual difference for execution time (P<0.05), hand-eye coordination and the number of errors/needle repositioning between physicians, residents and nurse anaesthetists. US training and video gaming were found to be independent factors associated with a shorter execution time. Use of GPS attenuated the inter-individual and group variability. We observed a reduced execution time and improved hand-eye coordination in all groups as compared to US without GPS. Neither US training, video gaming nor demographic personal or professional factors were found to be significantly associated with reduced execution time when GPS was used. US associated with GPS systems may improve safety and decrease execution time by reducing inter-individual variability between professionals for needle-handling procedures. Copyright © 2016 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

N1 Magnitude of Auditory Evoked Potentials and Spontaneous Functional Connectivity Between Bilateral Heschl's Gyrus Are Coupled at Interindividual Level.

PubMed

Tan, Ao; Hu, Li; Tu, Yiheng; Chen, Rui; Hung, Yeung Sam; Zhang, Zhiguo

2016-07-01

N1 component of auditory evoked potentials is extensively used to investigate the propagation and processing of auditory inputs. However, the substantial interindividual variability of N1 could be a possible confounding factor when comparing different individuals or groups. Therefore, identifying the neuronal mechanism and origin of the interindividual variability of N1 is crucial in basic research and clinical applications. This study is aimed to use simultaneously recorded electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data to investigate the coupling between N1 and spontaneous functional connectivity (FC). EEG and fMRI data were simultaneously collected from a group of healthy individuals during a pure-tone listening task. Spontaneous FC was estimated from spontaneous blood oxygenation level-dependent (BOLD) signals that were isolated by regressing out task evoked BOLD signals from raw BOLD signals and then was correlated to N1 magnitude across individuals. It was observed that spontaneous FC between bilateral Heschl's gyrus was significantly and positively correlated with N1 magnitude across individuals (Spearman's R = 0.829, p < 0.001). The specificity of this observation was further confirmed by two whole-brain voxelwise analyses (voxel-mirrored homotopic connectivity analysis and seed-based connectivity analysis). These results enriched our understanding of the functional significance of the coupling between event-related brain responses and spontaneous brain connectivity, and hold the potential to increase the applicability of brain responses as a probe to the mechanism underlying pathophysiological conditions.

The gravity of pollination: integrating at-site features into spatial analysis of contemporary pollen movement.

PubMed

DiLeo, Michelle F; Siu, Jenna C; Rhodes, Matthew K; López-Villalobos, Adriana; Redwine, Angela; Ksiazek, Kelly; Dyer, Rodney J

2014-08-01

Pollen-mediated gene flow is a major driver of spatial genetic structure in plant populations. Both individual plant characteristics and site-specific features of the landscape can modify the perceived attractiveness of plants to their pollinators and thus play an important role in shaping spatial genetic variation. Most studies of landscape-level genetic connectivity in plants have focused on the effects of interindividual distance using spatial and increasingly ecological separation, yet have not incorporated individual plant characteristics or other at-site ecological variables. Using spatially explicit simulations, we first tested the extent to which the inclusion of at-site variables influencing local pollination success improved the statistical characterization of genetic connectivity based upon examination of pollen pool genetic structure. The addition of at-site characteristics provided better models than those that only considered interindividual spatial distance (e.g. IBD). Models parameterized using conditional genetic covariance (e.g. population graphs) also outperformed those assuming panmixia. In a natural population of Cornus florida L. (Cornaceae), we showed that the addition of at-site characteristics (clumping of primary canopy opening above each maternal tree and maternal tree floral output) provided significantly better models describing gene flow than models including only between-site spatial (IBD) and ecological (isolation by resistance) variables. Overall, our results show that including interindividual and local ecological variation greatly aids in characterizing landscape-level measures of contemporary gene flow. © 2014 John Wiley & Sons Ltd.

Interindividual differences in motor network connectivity and behavioral response to iTBS in stroke patients.

PubMed

Diekhoff-Krebs, Svenja; Pool, Eva-Maria; Sarfeld, Anna-Sophia; Rehme, Anne K; Eickhoff, Simon B; Fink, Gereon R; Grefkes, Christian

2017-01-01

Cerebral plasticity-inducing approaches like repetitive transcranial magnetic stimulation (rTMS) are of high interest in situations where reorganization of neural networks can be observed, e.g., after stroke. However, an increasing number of studies suggest that improvements in motor performance of the stroke-affected hand following modulation of primary motor cortex (M1) excitability by rTMS shows a high interindividual variability. We here tested the hypothesis that in stroke patients the interindividual variability of behavioral response to excitatory rTMS is related to interindividual differences in network connectivity of the stimulated region. Chronic stroke patients ( n  = 14) and healthy controls ( n  = 12) were scanned with functional magnetic resonance imaging (fMRI) while performing a simple hand motor task. Dynamic causal modeling (DCM) was used to investigate effective connectivity of key motor regions. On two different days after the fMRI experiment, patients received either intermittent theta-burst stimulation (iTBS) over ipsilesional M1 or control stimulation over the parieto-occipital cortex. Motor performance and TMS parameters of cortical excitability were measured before and after iTBS. Our results revealed that patients with better motor performance of the affected hand showed stronger endogenous coupling between supplemental motor area (SMA) and M1 before starting the iTBS intervention. Applying iTBS to ipsilesional M1 significantly increased ipsilesional M1 excitability and decreased contralesional M1 excitability as compared to control stimulation. Individual behavioral improvements following iTBS specifically correlated with neural coupling strengths in the stimulated hemisphere prior to stimulation, especially for connections targeting the stimulated M1. Combining endogenous connectivity and behavioral parameters explained 82% of the variance in hand motor performance observed after iTBS. In conclusion, the data suggest that the individual susceptibility to iTBS after stroke is influenced by interindividual differences in motor network connectivity of the lesioned hemisphere.

Evaluation of inter-day and inter-individual variability of tear peptide/protein profiles by MALDI-TOF MS analyses

PubMed Central

González, Nerea; Iloro, Ibon; Durán, Juan A.; Elortza, Félix

2012-01-01

Purpose To characterize the tear film peptidome and low molecular weight protein profiles of healthy control individuals, and to evaluate changes due to day-to-day and individual variation and tear collection methods, by using solid phase extraction coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling. Methods The tear protein profiles of six healthy volunteers were analyzed over seven days and inter-day and inter-individual variability was evaluated. The bilaterality of tear film and the effect of tear collection methods on protein profiles were also analyzed in some of these patients. MALDI-TOF MS analyses were performed on tear samples purified by using a solid phase extraction (SPE) method based on C18 functionalized magnetic beads for peptide and low molecular weight protein enrichment, focusing spectra acquisition on the 1 to 20 kDa range. Spectra were analyzed using principal component analysis (PCA) with MultiExperiment Viewer (TMeV) software. Volunteers were examined in terms of tear production status (Schirmer I test), clinical assessment of palpebral lids and meibomian glands, and a subjective OSD questionnaire before tear collection by a glass micro-capillary. Results Analysis of peptides and proteins in the 1–20 kDa range showed no significant inter-day differences in tear samples collected from six healthy individuals during seven days of monitoring, but revealed subtle intrinsic inter-individual differences. Profile analyses of tears collected from the right and left eyes confirmed tear bilaterality in four healthy patients. The addition of physiologic serum for tear sample collection did not affect the peptide and small protein profiles with respect to the number of resolved peaks, but it did reduce the signal intensity of the peaks, and increased variability. Magnetic beads were found to be a suitable method for tear film purification for the profiling study. Conclusions No significant variability in tear peptide and protein profiles below 20 kDa was found in healthy controls over a seven day period, nor in right versus left eye profiles from the same individual. Subtle inter-individual differences can be observed upon tear profiling analysis and confirm intrinsic variability between control subjects. Addition of physiologic serum for tear collection affects the proteome and peptidome in terms of peak intensities, but not in the composition of the profiles themselves. This work shows that MALDI-TOF MS coupled with C18 magnetic beads is an effective and reproducible methodology for tear profiling studies in the clinical monitoring of patients. PMID:22736947

Quantifying interindividual variability and asymmetry of face-selective regions: a probabilistic functional atlas.

PubMed

Zhen, Zonglei; Yang, Zetian; Huang, Lijie; Kong, Xiang-Zhen; Wang, Xu; Dang, Xiaobin; Huang, Yangyue; Song, Yiying; Liu, Jia

2015-06-01

Face-selective regions (FSRs) are among the most widely studied functional regions in the human brain. However, individual variability of the FSRs has not been well quantified. Here we use functional magnetic resonance imaging (fMRI) to localize the FSRs and quantify their spatial and functional variabilities in 202 healthy adults. The occipital face area (OFA), posterior and anterior fusiform face areas (pFFA and aFFA), posterior continuation of the superior temporal sulcus (pcSTS), and posterior and anterior STS (pSTS and aSTS) were delineated for each individual with a semi-automated procedure. A probabilistic atlas was constructed to characterize their interindividual variability, revealing that the FSRs were highly variable in location and extent across subjects. The variability of FSRs was further quantified on both functional (i.e., face selectivity) and spatial (i.e., volume, location of peak activation, and anatomical location) features. Considerable interindividual variability and rightward asymmetry were found in all FSRs on these features. Taken together, our work presents the first effort to characterize comprehensively the variability of FSRs in a large sample of healthy subjects, and invites future work on the origin of the variability and its relation to individual differences in behavioral performance. Moreover, the probabilistic functional atlas will provide an adequate spatial reference for mapping the face network. Copyright © 2015 Elsevier Inc. All rights reserved.

Heart rate variability is associated with social value orientation in males but not females.

PubMed

Lischke, Alexander; Mau-Moeller, Anett; Jacksteit, Robert; Pahnke, Rike; Hamm, Alfons O; Weippert, Matthias

2018-05-09

Phylogenetic and neurobiological theories suggest that inter-individual differences in high frequency heart rate variability (HF-HRV) are associated with inter-individual differences in social behavior and social cognition. To test these theories, we investigated whether individuals with high and low HF-HRV would show different preferences for cooperative behavior in social contexts. We recorded resting state HF-HRV in 84 healthy individuals before they completed the Social Value Orientation task, a well-established measure of cooperative preferences. HF-HRV was derived from short-term (300 s) and ultra-short-term (60 s, 120 s) recordings of participants' heart rate to determine the robustness of possible findings. Irrespective of recording length, we found a sex-dependent association between inter-individual differences in HF-HRV and inter-individual differences in social value orientation: The preference for cooperation was more pronounced among individuals with high as compared low HF-HRV, albeit only in male and not in female participants. These findings suggest that males with high HF-HRV are more inclined to engage in cooperative behavior than males with low HF-HRV.

Trajectories of Evening Fatigue in Oncology Outpatients Receiving Chemotherapy

PubMed Central

Wright, Fay; Melkus, Gail D’Eramo; Hammer, Marilyn; Schmidt, Brian L.; Knobf, M. Tish; Paul, Steven M.; Cartwright, Frances; Mastick, Judy; Cooper, Bruce A.; Chen, Lee-May; Melisko, Michelle; Levine, Jon D.; Kober, Kord; Aouizerat, Bradley E.; Miaskowski, Christine

2015-01-01

Context Fatigue is a distressing, persistent sense of physical tiredness that is not proportional to a person’s recent activity. Fatigue impacts patients’ treatment decisions and can limit their self-care activities. While significant interindividual variability in fatigue severity has been noted, little is known about predictors of interindividual variability in initial levels and trajectories of evening fatigue severity in oncology patients receiving chemotherapy (CTX). Objectives To determine whether demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of evening fatigue. Methods A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. Results A large amount of interindividual variability was found in the evening fatigue trajectories. A piecewise model fit the data best. Patients who were White, diagnosed with breast, gynecological, or lung cancer, and who had more years of education, child care responsibilities, lower functional status, and higher levels of sleep disturbance and depression reported higher levels of evening fatigue at enrollment. Conclusion This study identified both non-modifiable (e.g., ethnicity) and modifiable (e.g., child care responsibilities, depressive symptoms, sleep disturbance) risk factors for more severe evening fatigue. Using this information, clinicians can identify patients at higher risk for more severe evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors. PMID:25828560

Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

PubMed Central

Jiang, Xi-Ling; Samant, Snehal; Lesko, Lawrence J.; Schmidt, Stephan

2017-01-01

Acute coronary syndromes (ACS) remain life-threatening disorders that are associated with high morbidity and mortality. Dual-antiplatelet therapy with aspirin and clopidogrel has shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in response to clopidogrel treatment in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19 that affect clopidogrel’s pharmacokinetics. While FDA has issued a boxed warning for CYP2C19 poor metabolizers due to a potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug-drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability and how they are interrelated is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence clopidogrel’s pharmacokinetics and pharmacodynamics and how they mechanistically contribute to inter-individual differences in response to clopidogrel treatment. PMID:25559342

Heart rate variability is associated with psychosocial stress in distinct social domains.

PubMed

Lischke, Alexander; Jacksteit, Robert; Mau-Moeller, Anett; Pahnke, Rike; Hamm, Alfons O; Weippert, Matthias

2018-03-01

Psychosocial stress is associated with substantial morbidity and mortality. Accordingly, there is a growing interest in biomarkers that indicate whether individuals show adaptive (i.e., stress-buffering and health-promoting) or maladaptive (i.e., stress-escalating and health-impairing) stress reactions in social contexts. As heart rate variability (HRV) has been suggested to be a biomarker of adaptive behavior during social encounters, it may be possible that inter-individual differences in HRV are associated with inter-individual differences regarding stress in distinct social domains. To test this hypothesis, resting state HRV and psychosocial stress was assessed in 83 healthy community-dwelling individuals (age: 18-35years). HRV was derived from heart rate recordings during spontaneous and instructed breathing to assess the robustness of possible associations between inter-individual differences in HRV and inter-individual differences in psychosocial stress. Psychosocial stress was determined with a self-report questionnaire assessing stress in distinct social domains. A series of categorical and dimensional analyses revealed an association between inter-individual differences in HRV and inter-individual differences in psychosocial stress: Individuals with high HRV reported less stress in social life, but not in family life, work life or everyday life, than individuals with low HRV. On basis of these findings, it may be assumed that individuals with high HRV experience less psychosocial stress than individuals with low HRV. Although such an assumption needs to be corroborated by further findings, it seems to be consistent with previous findings showing that individuals with high HRV suffer less from stress and stress-related disorders than individuals with low HRV. Copyright © 2018 Elsevier Inc. All rights reserved.

The future prospects of pharmacogenetics in oral anticoagulation therapy

PubMed Central

Kamali, Farhad; Pirmohamed, Munir

2006-01-01

Coumarins are the mainstay of oral anticoagulation for the treatment and prophylaxis of thromboembolic disorders. They have a narrow therapeutic index and regular monitoring is therefore required to avoid serious adverse effects. There is wide interindividual variability in dosage requirements, which makes anticoagulation response unpredictable. Current dosing titrations are haphazard and inconvenient and poor initial control leads to morbidity, and occasional mortality, because of bleeding and further thromboembolism. Recent discoveries have helped to characterize the factors that contribute to the interindividual variability in responses to coumarins. Patient and environmental factors that affect anticoagulation response to coumarins include age, body size, dietary vitamin K status, concurrent disease and drug interactions. More recently, single nucleotide polymorphisms in the 2C9 isoform of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKOR) have been shown to make significant contributions to the variability in coumarin dosage requirements. Polymorphisms in other genes that mediate the actions of coumarins may also contribute to this variability. Racial and cultural differences influence dosage requirements, which can be explained, at least in part, by genetic and dietary factors. Incorporation of genetic and environmental factors could help in the prediction of more individualized loading and maintenance doses for safer anticoagulation therapy. PMID:16722840

Data-Driven User Feedback: An Improved Neurofeedback Strategy considering the Interindividual Variability of EEG Features.

PubMed

Han, Chang-Hee; Lim, Jeong-Hwan; Lee, Jun-Hak; Kim, Kangsan; Im, Chang-Hwan

2016-01-01

It has frequently been reported that some users of conventional neurofeedback systems can experience only a small portion of the total feedback range due to the large interindividual variability of EEG features. In this study, we proposed a data-driven neurofeedback strategy considering the individual variability of electroencephalography (EEG) features to permit users of the neurofeedback system to experience a wider range of auditory or visual feedback without a customization process. The main idea of the proposed strategy is to adjust the ranges of each feedback level using the density in the offline EEG database acquired from a group of individuals. Twenty-two healthy subjects participated in offline experiments to construct an EEG database, and five subjects participated in online experiments to validate the performance of the proposed data-driven user feedback strategy. Using the optimized bin sizes, the number of feedback levels that each individual experienced was significantly increased to 139% and 144% of the original results with uniform bin sizes in the offline and online experiments, respectively. Our results demonstrated that the use of our data-driven neurofeedback strategy could effectively increase the overall range of feedback levels that each individual experienced during neurofeedback training.

Data-Driven User Feedback: An Improved Neurofeedback Strategy considering the Interindividual Variability of EEG Features

PubMed Central

Lim, Jeong-Hwan; Lee, Jun-Hak; Kim, Kangsan

2016-01-01

It has frequently been reported that some users of conventional neurofeedback systems can experience only a small portion of the total feedback range due to the large interindividual variability of EEG features. In this study, we proposed a data-driven neurofeedback strategy considering the individual variability of electroencephalography (EEG) features to permit users of the neurofeedback system to experience a wider range of auditory or visual feedback without a customization process. The main idea of the proposed strategy is to adjust the ranges of each feedback level using the density in the offline EEG database acquired from a group of individuals. Twenty-two healthy subjects participated in offline experiments to construct an EEG database, and five subjects participated in online experiments to validate the performance of the proposed data-driven user feedback strategy. Using the optimized bin sizes, the number of feedback levels that each individual experienced was significantly increased to 139% and 144% of the original results with uniform bin sizes in the offline and online experiments, respectively. Our results demonstrated that the use of our data-driven neurofeedback strategy could effectively increase the overall range of feedback levels that each individual experienced during neurofeedback training. PMID:27631005

Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients

PubMed Central

Foster, David J R; Somogyi, Andrew A; Dyer, Kyle R; White, Jason M; Bochner, Felix

2000-01-01

Aims To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma α1-acid glycoprotein concentrations were quantified by radial immunoassay. Results (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCτSS, (167%) was significantly (P < 0.001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCτSS, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence. PMID:11069437

Inter-Individual Variability in Human Response to Low-Dose Ionizing Radiation, Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rocke, David

2016-08-01

In order to investigate inter-individual variability in response to low-dose ionizing radiation, we are working with three models, 1) in-vivo irradiated human skin, for which we have a realistic model, but with few subjects, all from a previous project, 2) ex-vivo irradiated human skin, for which we also have a realistic model, though with the limitations involved in keeping skin pieces alive in media, and 3) MatTek EpiDermFT skin plugs, which provides a more realistic model than cell lines, which is more controllable than human samples.

The Stationary-Gaze Task Should Not Be Systematically Used as the Control Task in Studies of Postural Control.

PubMed

Bonnet, Cédrick T; Szaffarczyk, Sébastien

2017-01-01

In studies of postural control, a control task is often used to understand significant effects obtained with experimental manipulations. This task should be the easiest task and (therefore) engage the lowest behavioral variability and cognitive workload. Since 1983, the stationary-gaze task is considered as the most relevant control task. Instead, the authors expected that free looking at small targets (white paper or images; visual angle: 12°) could be an easier task. To verify this assumption, 16 young individuals performed stationary-gaze, white-panel, and free-viewing 12° tasks in steady and relaxed stances. The stationary-gaze task led to significantly higher cognitive workload (mean score in the National Aeronotics and Space Administration Task Load Index questionnaire), higher interindividual body (head, neck, and lower back) linear variability, and higher interindividual body angular variability-not systematically yet-than both other tasks. There was more cognitive workload in steady than relaxed stances. The authors also tested if a free-viewing 24° task could lead to greater angular displacement, and hence greater body sway, than could the other tasks in relaxed stance. Unexpectedly, the participants mostly moved their eyes and not their body in this task. In the discussion, the authors explain why the stationary-gaze task may not be an ideal control task and how to choose this neutral task.

Sleep variability in military-related PTSD: a comparison to primary insomnia and healthy controls.

PubMed

Straus, Laura D; Drummond, Sean P A; Nappi, Carla M; Jenkins, Melissa M; Norman, Sonya B

2015-02-01

Sleep disturbances are prevalent in posttraumatic stress disorder (PTSD) and are associated with a number of adverse health consequences. Few studies have used comprehensive assessment methods to characterize sleep in Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OEF/OIF/OND) veterans with PTSD. OEF/OIF/OND veterans with PTSD and sleep disturbance (n = 45) were compared to patients with primary insomnia (n = 25) and healthy control subjects (n = 27). Participants were assessed using questionnaire-based measures as well as daily subjective and objective measures of sleep. The 3 groups were compared with regard to (a) group means, (b) intraindividual (i.e., night-to-night) variability of sleep, and (c) interindividual (i.e., within-group) variability of sleep. In terms of group means, only objective sleep efficiency was significantly worse with PTSD than with primary insomnia (d = 0.54). Those with PTSD differed from those with primary insomnia on measures of intraindividual as well as interindividual variability (d = 0.48-0.73). These results suggested sleep symptoms in OEF/OIF/OND veterans with PTSD are more variable across nights and less consistent across patients relative to sleep symptoms in insomnia patients without PTSD. These findings have implications for research, as well as for personalizing treatment for individuals with PTSD. Published 2015. This article is a US Government work and is in the public domain in the USA.

Changes in aerobic capacity and glycaemic control in response to reduced-exertion high-intensity interval training (REHIT) are not different between sedentary men and women.

PubMed

Metcalfe, Richard S; Tardif, Nicolas; Thompson, Dylan; Vollaard, Niels B J

2016-11-01

Previously it has been reported that reduced-exertion high-intensity interval training (REHIT; total training time of 3 × 10 min per week) improves maximal aerobic capacity in both sedentary men and women, but improves insulin sensitivity in men only. The aim of the present study was to determine whether there is a true sex difference in response to REHIT, or that these findings can be explained by the large interindividual variability in response inherent to all exercise training. Thirty-five sedentary participants (18 women; mean ± SD age for men and women, respectively: age, 33 ± 9 and 36 ± 9 years; body mass index, 25.1 ± 2.1 and 24.1 ± 3.5 kg·m -2 ; maximal aerobic capacity, 38.6 ± 8.3 and 31.6 ± 4.6 mL·kg -1 ·min -1 ) completed a 6-week REHIT programme consisting of eighteen 10-min unloaded cycling sessions with 1 (first session) or 2 (all other sessions) "all-out" 10-20-s sprints against a resistance of 5% of body mass. Maximal aerobic capacity and oral glucose tolerance test-derived insulin sensitivity were determined before and after training. REHIT was associated with an increase in maximal aerobic capacity (2.54 ± 0.65 vs. 2.78 ± 0.68 L·min -1 , main effect of time: p < 0.01), a trend toward reduced plasma insulin area-under-the-curve (AUC; 6.7 ± 4.8 vs. 6.1 ± 4.0 IU·min -1 ·mL -1 , p = 0.096), but no significant change in plasma glucose AUC or the Cederholm index of insulin sensitivity. Substantial interindividual variability in response to REHIT was observed for all variables, but there was no significant effect of sex. In conclusion, REHIT improves the key health marker of aerobic capacity within a minimal total training time-commitment. There is large interindividual variability in responses to REHIT, but sex differences in the responses are not apparent.

Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability

EPA Science Inventory

We incorporate inter-individual variability, including variability across demographic subgroups, into an open-source high-throughput (HT) toxicokinetics (TK) modeling framework for use in a next-generation risk prioritization approach. Risk prioritization involves rapid triage of...

How Plantar Exteroceptive Efficiency Modulates Postural and Oculomotor Control: Inter-Individual Variability.

PubMed

Foisy, Arnaud; Kapoula, Zoï

2016-01-01

In a previous experiment, we showed that among young and healthy subjects, thin plantar inserts improve postural control and modify vergence amplitudes. In this experiment, however, significant inter-individual variability was observed. We hypothesize that its origin could be attributed to a different reliance upon feet cutaneous afferents. In order to test this hypothesis, we re-analyzed the data relative to 31 young (age 25.7 ± 3.8) and healthy subjects who participated in the first experiment after having classified them into two groups depending on their Plantar Quotient (PQ = Surface area of CoPfoam/Surface area of CoPfirm ground × 100). Foam decreases the information arising from the feet, normally resulting in a PQ > 100. Hence, the PQ provides information on the weight of plantar cutaneous afferents used in postural control. Twelve people were Plantar-Independent Subjects, as indicated by a PQ < 100. These individuals did not behave like the Normal Plantar Quotient Subjects: they were almost insensitive to the plantar stimulations in terms of postural control and totally insensitive in terms of oculomotor control. We conclude that the inter-individual variability observed in our first experiment is explained by the subjects' degree of plantar reliance. We propose that plantar independence is a dysfunctional situation revealing inefficiency in plantar cutaneous afferents. The latter could be due to a latent somatosensory dysfunction generating a noise which prevents the CNS from correctly processing and using feet somatosensory afferents both for balance and vergence control: Plantar Irritating Stimulus. Considering the non-noxious nature and prevalence of this phenomenon, these results can be of great interest to researchers and clinicians who attempt to trigger postural or oculomotor responses through mechanical stimulation of the foot sole.

Inter-individual variability in the production of flavan-3-ol colonic metabolites: preliminary elucidation of urinary metabotypes.

PubMed

Mena, Pedro; Ludwig, Iziar A; Tomatis, Virginia B; Acharjee, Animesh; Calani, Luca; Rosi, Alice; Brighenti, Furio; Ray, Sumantra; Griffin, Julian L; Bluck, Les J; Del Rio, Daniele

2018-04-03

There is much information on the bioavailability of (poly)phenolic compounds following acute intake of various foods. However, there are only limited data on the effects of repeated and combined exposure to specific (poly)phenol food sources and the inter-individual variability in their bioavailability. This study evaluated the combined urinary excretion of (poly)phenols from green tea and coffee following daily consumption by healthy subjects in free-living conditions. The inter-individual variability in the production of phenolic metabolites was also investigated. Eleven participants consumed both tablets of green tea and green coffee bean extracts daily for 8 weeks and 24-h urine was collected on five different occasions. The urinary profile of phenolic metabolites and a set of multivariate statistical tests were used to investigate the putative existence of characteristic metabotypes in the production of flavan-3-ol microbial metabolites. (Poly)phenolic compounds in the green tea and green coffee bean extracts were absorbed and excreted after simultaneous consumption, with green tea resulting in more inter-individual variability in urinary excretion of phenolic metabolites. Three metabotypes in the production of flavan-3-ol microbial metabolites were tentatively defined, characterized by the excretion of different amounts of trihydroxyphenyl-γ-valerolactones, dihydroxyphenyl-γ-valerolactones, and hydroxyphenylpropionic acids. The selective production of microbiota-derived metabolites from flavan-3-ols and the putative existence of characteristic metabotypes in their production represent an important development in the study of the bioavailability of plant bioactives. These observations will contribute to better understand the health effects and individual differences associated with consumption of flavan-3-ols, arguably the main class of flavonoids in the human diet.

Assessment of metabolic phenotypic variability in children’s urine using 1H NMR spectroscopy

NASA Astrophysics Data System (ADS)

Maitre, Léa; Lau, Chung-Ho E.; Vizcaino, Esther; Robinson, Oliver; Casas, Maribel; Siskos, Alexandros P.; Want, Elizabeth J.; Athersuch, Toby; Slama, Remy; Vrijheid, Martine; Keun, Hector C.; Coen, Muireann

2017-04-01

The application of metabolic phenotyping in clinical and epidemiological studies is limited by a poor understanding of inter-individual, intra-individual and temporal variability in metabolic phenotypes. Using 1H NMR spectroscopy we characterised short-term variability in urinary metabolites measured from 20 children aged 8-9 years old. Daily spot morning, night-time and pooled (50:50 morning and night-time) urine samples across six days (18 samples per child) were analysed, and 44 metabolites quantified. Intraclass correlation coefficients (ICC) and mixed effect models were applied to assess the reproducibility and biological variance of metabolic phenotypes. Excellent analytical reproducibility and precision was demonstrated for the 1H NMR spectroscopic platform (median CV 7.2%). Pooled samples captured the best inter-individual variability with an ICC of 0.40 (median). Trimethylamine, N-acetyl neuraminic acid, 3-hydroxyisobutyrate, 3-hydroxybutyrate/3-aminoisobutyrate, tyrosine, valine and 3-hydroxyisovalerate exhibited the highest stability with over 50% of variance specific to the child. The pooled sample was shown to capture the most inter-individual variance in the metabolic phenotype, which is of importance for molecular epidemiology study design. A substantial proportion of the variation in the urinary metabolome of children is specific to the individual, underlining the potential of such data to inform clinical and exposome studies conducted early in life.

Nonsense-mediated mRNA decay: inter-individual variability and human disease

PubMed Central

Nguyen, Lam Son; Wilkinson, Miles; Gecz, Jozef

2013-01-01

Nonsense-Mediated mRNA Decay (NMD) is a regulatory pathway that functions to degrade transcripts containing premature termination codons (PTCs) and to maintain normal transcriptome homeostasis. Nonsense and frameshift mutations that generate PTCs cause approximately one-third of all known human genetic diseases and thus NMD has a potentially important role in human disease. In genetic disorders in which the affected genes carry PTC-generating mutations, NMD acts as a double-edge sword. While it can benefit the patient by degrading PTC-containing mRNAs that encode detrimental, dominant-negative truncated proteins, it can also make the disease worse when a PTC-containing mRNA is degraded that encodes a mutant but still functional protein. There is evidence that the magnitude of NMD varies between individuals, which, in turn, has been shown to correlate with both clinical presentations and the patients’ responses to drugs that promote read-through of PTCs. In this review, we examine the evidence supporting the existence of inter-individual variability in NMD efficiency and discuss the genetic factors that underlie this variability. We propose that inter-individual variability in NMD efficiency is a common phenomenon in human populations and that an individual’s NMD efficiency should be taken into consideration when testing, developing, and making therapeutic decisions for diseases caused by genes harboring PTCs. PMID:24239855

Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish.

PubMed

Román, Angel-Carlos; Vicente-Page, Julián; Pérez-Escudero, Alfonso; Carvajal-González, Jose M; Fernández-Salguero, Pedro M; de Polavieja, Gonzalo G

2018-04-25

Animals can show very different behaviors even in isogenic populations, but the underlying mechanisms to generate this variability remain elusive. We use the zebrafish (Danio rerio) as a model to test the influence of histone modifications on behavior. We find that laboratory and isogenic zebrafish larvae show consistent individual behaviors when swimming freely in identical wells or in reaction to stimuli. This behavioral inter-individual variability is reduced when we impair the histone deacetylation pathway. Individuals with high levels of histone H4 acetylation, and specifically H4K12, behave similarly to the average of the population, but those with low levels deviate from it. More precisely, we find a set of genomic regions whose histone H4 acetylation is reduced with the distance between the individual and the average population behavior. We find evidence that this modulation depends on a complex of Yin-yang 1 (YY1) and histone deacetylase 1 (HDAC1) that binds to and deacetylates these regions. These changes are not only maintained at the transcriptional level but also amplified, as most target regions are located near genes encoding transcription factors. We suggest that stochasticity in the histone deacetylation pathway participates in the generation of genetic-independent behavioral inter-individual variability.

Host‐related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans

PubMed Central

Desmarchelier, Charles; Dragsted, Lars O.; Nielsen, Charlotte S.; Stahl, Wilhelm; Rühl, Ralph; Keijer, Jaap; Borel, Patrick

2017-01-01

Carotenoid dietary intake and their endogenous levels have been associated with a decreased risk of several chronic diseases. There are indications that carotenoid bioavailability depends, in addition to the food matrix, on host factors. These include diseases (e.g. colitis), life‐style habits (e.g. smoking), gender and age, as well as genetic variations including single nucleotide polymorphisms that govern carotenoid metabolism. These are expected to explain interindividual differences that contribute to carotenoid uptake, distribution, metabolism and excretion, and therefore possibly also their association with disease risk. For instance, digestion enzymes fostering micellization (PNLIP, CES), expression of uptake/efflux transporters (SR‐BI, CD36, NPC1L1), cleavage enzymes (BCO1/2), intracellular transporters (FABP2), secretion into chylomicrons (APOB, MTTP), carotenoid metabolism in the blood and liver (LPL, APO C/E, LDLR), and distribution to target tissues such as adipose tissue or macula (GSTP1, StARD3) depend on the activity of these proteins. In addition, human microbiota, e.g. via altering bile‐acid concentrations, may play a role in carotenoid bioavailability. In order to comprehend individual, variable responses to these compounds, an improved knowledge on intra‐/interindividual factors determining carotenoid bioavailability, including tissue distribution, is required. Here, we highlight the current knowledge on factors that may explain such intra‐/interindividual differences. PMID:28101967

Neural Correlates of Interindividual Differences in Children’s Audiovisual Speech Perception

PubMed Central

Nath, Audrey R.; Fava, Eswen E.; Beauchamp, Michael S.

2011-01-01

Children use information from both the auditory and visual modalities to aid in understanding speech. A dramatic illustration of this multisensory integration is the McGurk effect, an illusion in which an auditory syllable is perceived differently when it is paired with an incongruent mouth movement. However, there are significant interindividual differences in McGurk perception: some children never perceive the illusion, while others always do. Because converging evidence suggests that the posterior superior temporal sulcus (STS) is a critical site for multisensory integration, we hypothesized that activity within the STS would predict susceptibility to the McGurk effect. To test this idea, we used blood-oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) in seventeen children aged 6 to 12 years to measure brain responses to three audiovisual stimulus categories: McGurk incongruent, non-McGurk incongruent and congruent syllables. Two separate analysis approaches, one using independent functional localizers and another using whole-brain voxel-based regression, showed differences in the left STS between perceivers and non-perceivers. The STS of McGurk perceivers responded significantly more than non-perceivers to McGurk syllables, but not to other stimuli, and perceivers’ hemodynamic responses in the STS were significantly prolonged. In addition to the STS, weaker differences between perceivers and non-perceivers were observed in the FFA and extrastriate visual cortex. These results suggest that the STS is an important source of interindividual variability in children’s audiovisual speech perception. PMID:21957257

Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins.

PubMed

Ternant, David; Paintaud, Gilles

2005-09-01

Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell's receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration-effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration-effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose-response relationships must be studied by PK-PD modelling.

Age differences and interindividual variation in cognition in community-dwelling elderly.

PubMed

Christensen, H; Mackinnon, A; Jorm, A F; Henderson, A S; Scott, L R; Korten, A E

1994-09-01

The cognitive test performance of 897 community-dwelling elderly Ss, aged 70 years and over, was examined for age trends and interindividual variation. Data were subjected to factor analysis, and 3 factors emerged (Crystallized Intelligence, Fluid Intelligence, and Memory). Over the age span sampled, Crystallized Intelligence, Fluid Intelligence, and Memory all decreased with the decrease being greatest for Fluid Intelligence and least for Crystallized Intelligence. Interindividual variation increased for Fluid Intelligence and Memory, but not for Crystallized Intelligence. These findings give support to the view that crystallized intelligence is lower in the very old and that there is a greater degree of variability in test performance with advancing age.

Pharmacogenetics of drug response in Parkinson's disease.

PubMed

Džoljić, Eleonora; Novaković, Ivana; Krajinovic, Maja; Grbatinić, Ivan; Kostić, Vladimir

2015-01-01

Parkinson's disease (PD) is a debilitating, demoralizing and financially devastating condition affecting 1% of population at the age of 60 years. Thus, very important issue to address is individual therapy optimization. Recent results have shown evidence that variable efficacy of treatment and risk of motor and mental complications could have genetic origin. Significant roles in that process play (pharmaco)genomic/genetic studies of PD. Variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in drug pathway signaling is an important factor determining inter-individual variability in drug responses. Interpersonal differences in drug responses are clearly documented although individualized treatment of PD is not widely known. Treatment with antiparkinsonian drugs is associated with the development of complications, such as L-DOPA-induced dyskinesia (LID), hallucinations and excessive daytime sleepiness. Carriers of specific genetic polymorphisms are particularly susceptible to development of some of these drug adverse effects. Pharmacogenomics aims to understand the relationship between genetic factors and inter-individual variations in drug responses, and to translate this information in therapy tailored to individual patient genetics. Relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. Thus, many genetic variations and polymorphisms in myriad of different proteins can influence individual response to anti-PD drugs.

Present status and perspective of pharmacogenetics in Mexico.

PubMed

Cuautle-Rodríguez, Patricia; Llerena, Adrián; Molina-Guarneros, Juan

2014-01-01

Drug costs account for up to 24% of the country's health expenditure and there are 13,000 registered drugs being prescribed. Diabetes is the main cause of death in the country, with over 85% of diabetic patients currently under drug treatment. The importance of knowing interindividual variability in drug metabolism on Mexican populations is thus evident. The purpose of this article is to provide an overlook of the current situation of pharmacogenetic research in Mexico, focusing on drug-metabolizing enzymes, and the possibility of developing a phenotyping cocktail for Mexican populations. So far, 21 pharmacogenetic studies on Mexican population samples (Mestizos and Amerindian) have been published. These have reported interindividual variability through phenotyping and/or genotyping cytochromes: CYP2D6, 2C19, 2C9, 2E1, and phase II enzymes UGT and NAT2. Some cytochromes with important clinical implications have not yet been phenotyped in Mexican populations. The development of a cocktail adapted to them could be a significant contribution to a larger knowledge on drug response variability at a lower price and shorter time. There are validated phenotyping cocktails that present several practical advantages, being valuable, safe, and inexpensive tools in drug metabolism characterization, which require only a single experiment to provide information on several cytochrome activities.

Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance

PubMed Central

Noetzli, Muriel; Guidi, Monia; Ebbing, Karsten; Eyer, Stephan; Wilhelm, Laurence; Michon, Agnès; Thomazic, Valérie; Stancu, Ioana; Alnawaqil, Abdel-Messieh; Bula, Christophe; Zumbach, Serge; Gaillard, Michel; Giannakopoulos, Panteleimon; von Gunten, Armin; Csajka, Chantal; Eap, Chin B

2014-01-01

Aims A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. Methods A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. Results The average donepezil clearance was 7.3 l h−1 with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. Conclusion The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment. PMID:24433464

Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance.

PubMed

Noetzli, Muriel; Guidi, Monia; Ebbing, Karsten; Eyer, Stephan; Wilhelm, Laurence; Michon, Agnès; Thomazic, Valérie; Stancu, Ioana; Alnawaqil, Abdel-Messieh; Bula, Christophe; Zumbach, Serge; Gaillard, Michel; Giannakopoulos, Panteleimon; von Gunten, Armin; Csajka, Chantal; Eap, Chin B

2014-07-01

A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment. © 2014 The British Pharmacological Society.

Could pharmacogenetic data explain part of the interindividual sensitivity to methadone-induced respiratory depression?

PubMed Central

Crettol, Séverine; Monnat, Martine; Eap, Chin B

2007-01-01

In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected. PMID:17338832

Investigating Inter-Individual Differences in Short-Term Intra-Individual Variability

ERIC Educational Resources Information Center

Wang, Lijuan; Hamaker, Ellen; Bergeman, C. S.

2012-01-01

Intra-individual variability over a short period of time may contain important information about how individuals differ from each other. In this article we begin by discussing diverse indicators for quantifying intra-individual variability and indicate their advantages and disadvantages. Then we propose an alternative method that models…

An analysis of diversity in the cognitive performance of elderly community dwellers: individual differences in change scores as a function of age.

PubMed

Christensen, H; Mackinnon, A J; Korten, A E; Jorm, A F; Henderson, A S; Jacomb, P; Rodgers, B

1999-09-01

This longitudinal study investigated whether age is associated with increases in interindividual variability across 4 ability domains using a sample of 426 elderly community dwellers followed over 3.5 years. Interindividual variability in change scores increased with age for memory, spatial functioning, and speed but not for crystallized intelligence for the full sample and in a subsample that excluded dementia or probable dementia cases. Hierarchical regression analyses indicated that being female, having weaker muscle strength, and having greater symptoms of illness and greater depression were associated with overall greater variability in cognitive scores. Having a higher level of education was associated with reduced variability. These findings are consistent with the view that there is a greater range of responses at older ages, that certain domains of intelligence are less susceptible to variation than others and that variables other than age affect cognitive performance in later life.

Interindividual Variability in Hepatic Organic Anion-Transporting Polypeptides and P-Glycoprotein (ABCB1) Protein Expression: Quantification by Liquid Chromatography Tandem Mass Spectroscopy and Influence of Genotype, Age, and Sex

PubMed Central

Prasad, Bhagwat; Evers, Raymond; Gupta, Anshul; Hop, Cornelis E. C. A.; Salphati, Laurent; Shukla, Suneet; Ambudkar, Suresh V.

2014-01-01

Interindividual variability in protein expression of organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified in frozen human livers (n = 64) and cryopreserved human hepatocytes (n = 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, and LC-MS/MS analyses were as described before by our laboratory. Briefly, total native membrane proteins, isolated from the liver tissue and cryopreserved hepatocytes, were trypsin digested and quantified by LC-MS/MS using signature peptide(s) unique to each transporter. The mean ± S.D. (maximum/minimum range in parentheses) protein expression (fmol/µg of membrane protein) in human liver tissue was OATP1B1- 2.0 ± 0.9 (7), OATP1B3- 1.1 ± 0.5 (8), OATP2B1- 1 1.7 ± 0.6 (5), and P-gp- 0.4 ± 0.2 (8). Transporter expression in the liver tissue was comparable to that in the cryopreserved hepatocytes. Most important is that livers with SLCO1B1 (encoding OATP1B1) haplotypes *14/*14 and *14/*1a [i.e., representing single nucleotide polymorphisms (SNPs), c.388A > G, and c.463C > A] had significantly higher (P < 0.0001) protein expression than the reference haplotype (*1a/*1a). Based on these genotype-dependent protein expression data, we predicted (using Simcyp) an up to ∼40% decrease in the mean area under the curve of rosuvastatin or repaglinide in subjects harboring these variant alleles compared with those harboring the reference alleles. SLCO1B3 (encoding OATP1B3) SNPs did not significantly affect protein expression. Age and sex were not associated with transporter protein expression. These data will facilitate the prediction of population-based human transporter-mediated drug disposition, drug-drug interactions, and interindividual variability through physiologically based pharmacokinetic modeling. PMID:24122874

Variability of mammary blood flow in lactating Holstein-Friesian cows during the first twelve weeks of lactation.

PubMed

Götze, A; Honnens, A; Flachowsky, G; Bollwein, H

2010-01-01

The goals of the present study were to measure mammary blood flow volume (BFV) during the first 12 wk of lactation in dairy cows by using color Doppler sonography and to determine what affects the mammary blood flow. Forty cows were examined via color Doppler sonography on d 1, 7, 14, 28, 56, and 84 after parturition (d 0). The total BFV (BFV(total)) to the 4 mammary glands was calculated by measuring time-averaged maximum velocities (TAMV) and cross-sectional areas (A) of the left and right pudendoepigastric trunks via transrectal color Doppler sonography. Because there were no significant differences in A, TAMV, and BFV between the right and left pudendoepigastric trunks, the means of A and TAMV, and the BFV(total) of both trunks were used for calculations. The intraindividual and interindividual variability of repeated BFV measures quantified by intraclass correlation coefficients were 96 and 98%, respectively. The BFV(total) ranged from 19.9 to 27.9 L/min, with a mean of 22.3+/-4.9 L/min. Interindividual differences in BFV values were attributable to variations in A and TAMV. The interindividual variability of the BFV(total), which was determined using the coefficients of variation of the BFV(total) on individual days, ranged from 16 to 28%. All the cows had similar changes in the BFV(total) during the study. Changes in BFV(total) were not correlated with changes in the mean of A, but there was a good correlation between changes in BFV(total) and in the mean of TAMV (r=0.94). The BFV(total) was highest on d 1 of lactation, decreased 28% by d 7, and remained at this level until d 28. By d 56, the BFV(total) had increased by 15% compared with d 14 and by 10% compared with d 28. The BFV(total) on d 84 was significantly different from all other days except d 56. There were moderate correlations between daily milk yield and BFV on individual days (0.24

Language, motor and cognitive development of extremely preterm children: modeling individual growth trajectories over the first three years of life.

PubMed

Sansavini, Alessandra; Pentimonti, Jill; Justice, Laura; Guarini, Annalisa; Savini, Silvia; Alessandroni, Rosina; Faldella, Giacomo

2014-01-01

Survival rate of extremely low gestational age (ELGA) newborns has increased over 80% in the last 15 years, but its consequences on the short- and longer-term developmental competencies may be severe. The aim of this study was to describe growth trajectories of linguistic, motor and cognitive skills among ELGA children, compared to full-term (FT) peers, from the first to the third year of life, a crucial period for development. Growth curve analysis was used to examine individual and group differences in terms of initial status at 12 months and rate of growth through the second and the third year of life with five points of assessment. Twenty-eight monolingual Italian children, of whom 17 were ELGA (mean GA 25.7 weeks) and 11 were FT children, were assessed through the BSID-III at 12, 18, 24, 30 and 36 months for language skills and at 12, 24 and 30 months for motor and cognitive skills. ELGA children presented significantly lower scores than FT peers in language, motor and cognitive skills and they did not overcome their disadvantage by 3 years, even if their corrected age was taken into account. Concerning growth curves, in motor development a significant increasing divergence was found showing a Matthew effect with the preterm sample falling further behind the FT sample. In linguistic and cognitive development, instead, a stable gap between the two samples was found. In addition, great inter-individual differences in rate of change were observed for language development in both samples. Our findings highlight the theoretical and clinical relevance of analyzing, through growth curve analyses, the developmental trajectories of ELGA children in language skills taking into account their inter-individual variability also across motor and cognitive domains. After reading this article, the reader will interpret: (a) characteristics and growth trajectories of ELGA children from the first to the third year of life with respect to FT children in language, motor and cognitive development; (b) the method of growth curve analyses to describe group as well as inter-individual trajectories; (c) the rate of inter-individual variability in language as well as motor and cognitive skills, which gives useful indications for early interventions. Copyright © 2014 Elsevier Inc. All rights reserved.

Ilaprazole for the treatment of gastro-esophageal reflux.

PubMed

Savarino, Edoardo; Ottonello, Andrea; Martinucci, Irene; Dulbecco, Pietro; Savarino, Vincenzo

2016-10-01

Despite the undoubted benefit of proton pump inhibitors (PPIs), they have several shortcomings, such as a slow onset of action and a remarkable inter-individual variability, that limit the complete success of these drugs. Recently, a new PPI, ilaprazole, has been developed and used in GERD patients. The present review provides an update on the following points: current knowledge of GERD mechanisms; limitations of actual therapies; pharmacokinetic profile and metabolism of ilaprazole; initial studies on the therapeutic efficacy of ilaprazole in GERD. Compared with all other approved PPIs, ilaprazole has shown an extended plasma half-life, a metabolism not significantly influenced by CYP2C19 genetic polymorphism and similar safety. This characteristics account for a low inter-individual variability, particularly in Asian populations, a higher suppression of gastric acid secretion, a more rapid acid control and consequent quicker symptom relief and a better effect on nocturnal acidity. However, clinical investigations assessing the efficacy of ilaprazole in the management of GERD are lacking and therefore the potential improvements achievable with ilaprazole in the current standard of care for acid-suppressing treatment must be confirmed in large and randomly controlled clinical trials enrolling patients with both erosive and non-erosive reflux disease.

Between-session intra-individual variability in sustained, selective, and integrational non-linguistic attention in aphasia.

PubMed

Villard, Sarah; Kiran, Swathi

2015-01-01

A number of studies have identified impairments in one or more types/aspects of attention processing in patients with aphasia (PWA) relative to healthy controls; person-to-person variability in performance on attention tasks within the PWA group has also been noted. Studies using non-linguistic stimuli have found evidence that attention is impaired in this population even in the absence of language processing demands. An underlying impairment in non-linguistic, or domain-general, attention processing could have implications for the ability of PWA to attend during therapy sessions, which in turn could impact long-term treatment outcomes. With this in mind, this study aimed to systematically examine the effect of task complexity on reaction time (RT) during a non-linguistic attention task, in both PWA and controls. Additional goals were to assess the effect of task complexity on between-session intra-individual variability (BS-IIV) in RT and to examine inter-individual differences in BS-IIV. Eighteen PWA and five age-matched neurologically healthy controls each completed a novel computerized non-linguistic attention task measuring five types of attention on each of four different non-consecutive days. A significant effect of task complexity on both RT and BS-IIV in RT was found for the PWA group, whereas the control group showed a significant effect of task complexity on RT but not on BS-IIV in RT. Finally, in addition to these group-level findings, it was noted that different patients exhibited different patterns of BS-IIV, indicating the existence of inter-individual variability in BS-IIV within the PWA group. Results may have implications for session-to-session fluctuations in attention during language testing and therapy for PWA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Population pharmacokinetic study of teicoplanin in severely neutropenic patients.

PubMed Central

Lortholary, O; Tod, M; Rizzo, N; Padoin, C; Biard, O; Casassus, P; Guillevin, L; Petitjean, O

1996-01-01

The teicoplanin pharmacokinetics (PK) of 30 febrile and severely neutropenic patients (polymorphonuclear count, < 500/mm3) with hematologic malignancies were compared with those determined for five healthy volunteers (HV). Neutropenic patients were given piperacillin combined with amikacin, and teicoplanin was added to the regimen the day fever developed in patients suspected of having a staphylococcal infection or 48 h later. Teicoplanin was given intravenously at a dosage of 6 mg/kg of body weight at 0, 12, and 24 h and once a day thereafter. Five to eleven blood samples per patient were collected. Teicoplanin concentrations were measured by liquid chromatography. A bicompartmental model was fitted to the data by a nonlinear mixed-effect-model approach. Multiple-linear regression analysis was applied in an attempt to correlate PK parameters to nine covariates. The mean trough concentrations of teicoplanin 48 h after the onset of treatment and 24 h after the last injection (last trough) +/- standard deviations were 8.8 +/- 4.1 and 17.5 +/- 13.5 mg/liter, respectively. A significant increase was noted in the mean rate of elimination clearance of teicoplanin in neutropenic patients compared with that of HV (0.86 versus 0.73 liter/h, P = 0.002), as was the case with rates of distribution clearance (5.89 versus 4.94 liter/h, P = 0.002); the mean half-life of distribution was significantly shorter in patients than in HV (0.43 versus 0.61 h, P = 0.002). In contrast, the volumes of the central compartment (ca. 5.8 liters for both groups), the volumes of distribution at steady state (HV, 37.6 liters; patients, 55.9 liters), and the elimination half-lives (HV, 39.6 h; patients, 52.7 h) were not significantly different between HV and neutropenic patients. Interindividual variabilities of rates of clearance (coefficient of variation [CV], 43%) and elimination half-lives (CV, 56%) were mainly explained by the variabilities among rates of creatinine clearance. Interindividual variabilities of the volumes of the central compartment (CV, 33%) and the volumes of distribution at steady state (CV = 51%) were correlated to interindividual variabilities among numbers of leukocytes and the ages of patients, respectively. On the basis of the population PK model of teicoplanin, simulations were made to optimize the dosing schedule. A supplemental 6 mg/kg dose of teicoplanin at 36 h resulted in a trough concentration at 48 h of 16.0 +/- 4.5 mg/liter, with only 7% of patients having a trough concentration of less than 10 mg/liter, compared with 46% of patients on the usual schedule. PMID:8723474

Variability and epistemic uncertainty in water ingestion rates and pharmacokinetic parameters, and impact on the association between perfluorooctanoate and preeclampsia in the C8 Health Project population.

PubMed

Avanasi, Raghavendhran; Shin, Hyeong-Moo; Vieira, Veronica M; Bartell, Scott M

2016-04-01

We recently utilized a suite of environmental fate and transport models and an integrated exposure and pharmacokinetic model to estimate individual perfluorooctanoate (PFOA) serum concentrations, and also assessed the association of those concentrations with preeclampsia for participants in the C8 Health Project (a cross-sectional study of over 69,000 people who were environmentally exposed to PFOA near a major U.S. fluoropolymer production facility located in West Virginia). However, the exposure estimates from this integrated model relied on default values for key independent exposure parameters including water ingestion rates, the serum PFOA half-life, and the volume of distribution for PFOA. The aim of the present study is to assess the impact of inter-individual variability and epistemic uncertainty in these parameters on the exposure estimates and subsequently, the epidemiological association between PFOA exposure and preeclampsia. We used Monte Carlo simulation to propagate inter-individual variability/epistemic uncertainty in the exposure assessment and reanalyzed the epidemiological association. Inter-individual variability in these parameters mildly impacted the serum PFOA concentration predictions (the lowest mean rank correlation between the estimated serum concentrations in our study and the original predicted serum concentrations was 0.95) and there was a negligible impact on the epidemiological association with preeclampsia (no change in the mean adjusted odds ratio (AOR) and the contribution of exposure uncertainty to the total uncertainty including sampling variability was 7%). However, when epistemic uncertainty was added along with the inter-individual variability, serum PFOA concentration predictions and their association with preeclampsia were moderately impacted (the mean AOR of preeclampsia occurrence was reduced from 1.12 to 1.09, and the contribution of exposure uncertainty to the total uncertainty was increased up to 33%). In conclusion, our study shows that the change of the rank exposure among the study participants due to variability and epistemic uncertainty in the independent exposure parameters was large enough to cause a 25% bias towards the null. This suggests that the true AOR of the association between PFOA and preeclampsia in this population might be higher than the originally reported AOR and has more uncertainty than indicated by the originally reported confidence interval. Copyright © 2016 Elsevier Inc. All rights reserved.

Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression

EPA Science Inventory

Traditional toxicological paradigms have relied on factors such as age, genotype, and disease status to explain variability in responsiveness to toxicant exposure; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are they modi...

To Each Their Own: Molecular Mechanisms of Inter-Individual Variability in Toxic Exposure Effects

EPA Science Inventory

Traditional approaches to identifying susceptible populations have relied on factors such as age, genotype, and disease status to explain variability in exposure outcomes; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are t...

Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

EPA Science Inventory

Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, inter-individual differences in the population are accounted for by default assumptions or, in rare cas...

Inter-Individual Variability in High-Throughput Risk Prioritization of Environmental Chemicals (Sot)

EPA Science Inventory

We incorporate realistic human variability into an open-source high-throughput (HT) toxicokinetics (TK) modeling framework for use in a next-generation risk prioritization approach. Risk prioritization involves rapid triage of thousands of environmental chemicals, most which have...

Inter-Individual Differences in Neurobehavioural Impairment following Sleep Restriction Are Associated with Circadian Rhythm Phase

PubMed Central

Sletten, Tracey L.; Segal, Ahuva Y.; Flynn-Evans, Erin E.; Lockley, Steven W.; Rajaratnam, Shantha M. W.

2015-01-01

Although sleep restriction is associated with decrements in daytime alertness and neurobehavioural performance, there are considerable inter-individual differences in the degree of impairment. This study examined the effects of short-term sleep restriction on neurobehavioural performance and sleepiness, and the associations between individual differences in impairments and circadian rhythm phase. Healthy adults (n = 43; 22 M) aged 22.5 ± 3.1 (mean ± SD) years maintained a regular 8:16 h sleep:wake routine for at least three weeks prior to laboratory admission. Sleep opportunity was restricted to 5 hours time-in-bed at home the night before admission and 3 hours time-in-bed in the laboratory, aligned by wake time. Hourly saliva samples were collected from 5.5 h before until 5 h after the pre-laboratory scheduled bedtime to assess dim light melatonin onset (DLMO) as a marker of circadian phase. Participants completed a 10-min auditory Psychomotor Vigilance Task (PVT), the Karolinska Sleepiness Scale (KSS) and had slow eye movements (SEM) measured by electrooculography two hours after waking. We observed substantial inter-individual variability in neurobehavioural performance, particularly in the number of PVT lapses. Increased PVT lapses (r = -0.468, p < 0.01), greater sleepiness (r = 0.510, p < 0.0001), and more slow eye movements (r = 0.375, p = 0.022) were significantly associated with later DLMO, consistent with participants waking at an earlier circadian phase. When the difference between DLMO and sleep onset was less than 2 hours, individuals were significantly more likely to have at least three attentional lapses the following morning. This study demonstrates that the phase of an individual’s circadian system is an important variable in predicting the degree of neurobehavioural performance impairment in the hours after waking following sleep restriction, and confirms that other factors influencing performance decrements require further investigation. PMID:26043207

Polymorphisms in HLA-DPB1 Are Associated With Differences in Rubella Virus–Specific Humoral Immunity After Vaccination

PubMed Central

Lambert, Nathaniel D.; Haralambieva, Iana H.; Kennedy, Richard B.; Ovsyannikova, Inna G.; Pankratz, Vernon Shane; Poland, Gregory A.

2015-01-01

Vaccination with live attenuated rubella virus induces a strong immune response in most individuals. However, small numbers of subjects never reach or maintain protective antibody levels, and there is a high degree of variability in immune response. We have previously described genetic polymorphisms in HLA and other candidate genes that are associated with interindividual differences in humoral immunity to rubella virus. To expand our previous work, we performed a genome-wide association study (GWAS) to discover single-nucleotide polymorphisms (SNPs) associated with rubella virus–specific neutralizing antibodies. We identified rs2064479 in the HLA-DPB1 genetic region as being significantly associated with humoral immune response variations after rubella vaccination (P = 8.62 × 10−8). All other significant SNPs in this GWAS were located near the HLA-DPB1 gene (P ≤ 1 × 10−7). These findings demonstrate that polymorphisms in HLA-DPB1 are strongly associated with interindividual differences in neutralizing antibody levels to rubella vaccination and represent a validation of our previous HLA work. PMID:25293367

Association of speed of onset and speed of recovery of depressive episodes in patients with major depression.

PubMed

Strauss, Maria; Mergl, Roland; Sander, Christian; Schönknecht, Peter; Hegerl, Ulrich

2015-01-01

Depressive episodes show large interindividual differences concerning their speed of onset and speed of recovery, which might suggest differences in underlying pathophysiological processes. The aim of the present study was to assess whether there is a relationship between the speed of onset and the speed of recovery from depressive episodes. The speed of onset and the speed of recovery from depression were assessed using a structured patient interview, the Onset of Depression Inventory (ODI). In total, 28 patients with bipolar depression and 91 patients with unipolar depression were included. The mean speed of onset of depression was significantly faster than the mean speed of recovery from depression (35.25, range 0-360 days vs. 59.60, range 0.13-720 days; Z = -3.40; p = 0.001). The correlation between these variables was positive, but numerically low (ρ = 0.22; p = 0.016). The speed of onset of the previous episode and that of the present episode were significantly correlated (ρ = 0.45; p < 0.001). Data are based on retrospective patient reports within a naturalistic study. While the speed of onset of depressive episodes has been found to show large interindividual variability and some intraindividual stability, the data of this study do not indicate that the neurobiological processes involved in the onset of and in the recovery from depressive episodes are closely linked. © 2014 S. Karger AG, Basel.

Intraindividual differences in executive functions during childhood: the role of emotions.

PubMed

Pnevmatikos, Dimitris; Trikkaliotis, Ioannis

2013-06-01

Intraindividual differences in executive functions (EFs) have been rarely investigated. In this study, we addressed the question of whether the emotional fluctuations that schoolchildren experience in their classroom settings could generate substantial intraindividual differences in their EFs and, more specifically, in the fundamental unifying component of EFs, their inhibition function. We designed an experimental research with ecological validity within the school setting where schoolchildren of three age groups (8-, 10-, and 12-year-olds) were involved. We executed three experiments. In Experiment 1, using a between-participants design, we isolated a classroom episode that, compared with the other episodes, generated significant differences in inhibitory function in a consequent Go/NoGo task. This was an episode that induced frustration after the experience of anxiety due to the uncertainty. Experiment 2, using a within-participants design, confirmed both the induced emotions from the episode and the intraindividual variability in schoolchildren's inhibition accuracy in the consequent Go/NoGo task. Experiment 3, again using a within-participants design, examined whether the same episode could generate intraindividual differences in a more demanding inhibition task, namely the anti-saccade task. The experiment confirmed the previous evidence; the episode generated high variability that in some age groups accounted for more than 1.5 standard deviations from the interindividual variability between the schoolchildren of the same age. Results showed that, regardless of their sex and the developmental progression in their inhibition with age, the variability induced within participants from the experienced frustration was very high compared with the interindividual variability of the same age group. Copyright © 2013 Elsevier Inc. All rights reserved.

Human variability in high-throughput risk prioritization of environmental chemicals (Texas AM U. webinar)

EPA Science Inventory

We incorporate inter-individual variability into an open-source high-throughput (HT) toxicokinetics (TK) modeling framework for use in a next-generation risk prioritization approach. Risk prioritization involves rapid triage of thousands of environmental chemicals, most which hav...

Emerging Approaches and Opportunities to inform Internal Dosimetry and Inter-individual Variability

EPA Science Inventory

This talk provided an update to EPA ORD scientists and program officers about planned research within the Chemical Safety for Sustainability program to address chemical toxicokinetics and strategies to understand better the range of variability across different populations and li...

Toxicology and senescence: Baseline variability and toluene effects on the motor function of aging brown Norway rats.

EPA Science Inventory

The rapidly expanding population of older adults raises concern in EPA over aging-related vulnerability to environmental exposures. Deficits in motor function are frequent with advancing age. An increase in interindividual variability is also commonly accepted. Increased variabil...

Comparison of propranolol and metoprolol in the management of hyperthyroidism.

PubMed

Murchison, L E; How, J; Bewsher, P D

1979-12-01

1 Propranolol and metoprolol were both effective in controlling the symptoms and signs of hyperthyroidism. 2 Propranolol caused a highly significant increase in serum reverse T3 concentrations with lesser changes in other serum thyroid hormone levels, whereas metoprolol did not have this effect. 3 Steady-state plasma propranolol and metoprolol levels showed marked inter-individual variation. Metoprolol concentrations showed relatively little intra-individual variability, and could be related to the clinical efficacy of the drug, whereas no such relationship was demonstrated for propranolol.

Reversed Priming Effects May Be Driven by Misperception Rather than Subliminal Processing.

PubMed

Sand, Anders

2016-01-01

A new paradigm for investigating whether a cognitive process is independent of perception was recently suggested. In the paradigm, primes are shown at an intermediate signal strength that leads to trial-to-trial and inter-individual variability in prime perception. Here, I used this paradigm and an objective measure of perception to assess the influence of prime identification responses on Stroop priming. I found that sensory states producing correct and incorrect prime identification responses were also associated with qualitatively different priming effects. Incorrect prime identification responses were associated with reversed priming effects but in contrast to previous studies, I interpret this to result from the (mis-)perception of primes rather than from a subliminal process. Furthermore, the intermediate signal strength also produced inter-individual variability in prime perception that strongly influenced priming effects: only participants who on average perceived the primes were Stroop primed. I discuss how this new paradigm, with a wide range of d' values, is more appropriate when regression analysis on inter-individual identification performance is used to investigate perception-dependent processing. The results of this study, in line with previous results, suggest that drawing conclusions about subliminal processes based on data averaged over individuals may be unwarranted.

Addressing the inter-individual variation in response to consumption of plant food bioactives: Towards a better understanding of their role in healthy aging and cardiometabolic risk reduction.

PubMed

Manach, Claudine; Milenkovic, Dragan; Van de Wiele, Tom; Rodriguez-Mateos, Ana; de Roos, Baukje; Garcia-Conesa, Maria Teresa; Landberg, Rikard; Gibney, Eileen R; Heinonen, Marina; Tomás-Barberán, Francisco; Morand, Christine

2017-06-01

Bioactive compounds in plant-based foods have health properties that contribute to the prevention of age-related chronic diseases, particularly cardiometabolic disorders. Conclusive proof and understanding of these benefits in humans is essential in order to provide effective dietary recommendations but, so far, the evidence obtained from human intervention trials is limited and contradictory. This is partly due to differences between individuals in the absorption, distribution, metabolism and excretion of bioactive compounds, as well as to heterogeneity in their biological response regarding cardiometabolic health outcomes. Identifying the main factors underlying inter-individual differences, as well as developing new and innovative methodologies to account for such variability constitute an overarching goal to ultimately optimize the beneficial health effects of plant food bioactives for each and every one of us. In this respect, this position paper from the COST Action FA1403-POSITIVe examines the main factors likely to affect the individual responses to consumption of plant food bioactives and presents perspectives for assessment and consideration of inter-individual variability. © 2016 The Authors. Molecular Nutrition & Food Research published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reversed Priming Effects May Be Driven by Misperception Rather than Subliminal Processing

PubMed Central

Sand, Anders

2016-01-01

A new paradigm for investigating whether a cognitive process is independent of perception was recently suggested. In the paradigm, primes are shown at an intermediate signal strength that leads to trial-to-trial and inter-individual variability in prime perception. Here, I used this paradigm and an objective measure of perception to assess the influence of prime identification responses on Stroop priming. I found that sensory states producing correct and incorrect prime identification responses were also associated with qualitatively different priming effects. Incorrect prime identification responses were associated with reversed priming effects but in contrast to previous studies, I interpret this to result from the (mis-)perception of primes rather than from a subliminal process. Furthermore, the intermediate signal strength also produced inter-individual variability in prime perception that strongly influenced priming effects: only participants who on average perceived the primes were Stroop primed. I discuss how this new paradigm, with a wide range of d′ values, is more appropriate when regression analysis on inter-individual identification performance is used to investigate perception-dependent processing. The results of this study, in line with previous results, suggest that drawing conclusions about subliminal processes based on data averaged over individuals may be unwarranted. PMID:26925016

Genome-wide interactions with dairy intake for body mass index in adults of European descent

USDA-ARS?s Scientific Manuscript database

Scope: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. Methods and results: We conducted a genome-wide interaction study to discover genetic variants that account f...

Interindividual registration and dose mapping for voxelwise population analysis of rectal toxicity in prostate cancer radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dréan, Gaël; Acosta, Oscar, E-mail: Oscar.Acosta@univ-rennes1.fr; Simon, Antoine

2016-06-15

Purpose: Recent studies revealed a trend toward voxelwise population analysis in order to understand the local dose/toxicity relationships in prostate cancer radiotherapy. Such approaches require, however, an accurate interindividual mapping of the anatomies and 3D dose distributions toward a common coordinate system. This step is challenging due to the high interindividual variability. In this paper, the authors propose a method designed for interindividual nonrigid registration of the rectum and dose mapping for population analysis. Methods: The method is based on the computation of a normalized structural description of the rectum using a Laplacian-based model. This description takes advantage of themore » tubular structure of the rectum and its centerline to be embedded in a nonrigid registration-based scheme. The performances of the method were evaluated on 30 individuals treated for prostate cancer in a leave-one-out cross validation. Results: Performance was measured using classical metrics (Dice score and Hausdorff distance), along with new metrics devised to better assess dose mapping in relation with structural deformation (dose-organ overlap). Considering these scores, the proposed method outperforms intensity-based and distance maps-based registration methods. Conclusions: The proposed method allows for accurately mapping interindividual 3D dose distributions toward a single anatomical template, opening the way for further voxelwise statistical analysis.« less

Inhibitory activity of aspirin on von Willebrand factor-induced platelet aggregation.

PubMed

Homoncik, M; Jilma, B; Eichelberger, B; Panzer, S

2000-09-01

The effect of aspirin (ASA) on vWF induced platelet - platelet interaction is unknown. We therefore tested the response of platelets to von Willebrand factor (vWF) coated beads induced platelet aggregation before and after i.v. and oral ASA. 1000 mg ASA was infused to 10 healthy individuals and after a wash-out period 7 volunteers received 100 mg ASA orally over a period of 11 days. Prior to ASA and in regular intervals thereafter we tested the reactivity to vWF-coated beads to assess platelet adhesion/aggregation and the fade-out time of ASA effects on platelets. Considerable interindividual variability in response to vWF-coated beads was observed, both before ASA and after treatment with ASA. The maximal response to vWF-coated beads (Tmax), the time lag, and the slope of the curve were significantly affected by i.v. ASA, whereas 100 mg of ASA had only inconstant effect on Tmax and slope. The absolute reduction of Tmax after ASA depended on the pre-ASA level, while the percentage of the reduction was similar in all individuals. Thus, platelet aggregation induced by vWF-coated beads is impaired by ASA. Furthermore, our data indicate a large interindividual variability of the response to ASA shortly after treatment induction, which becomes more constant after prolonged treatment.

Smoking and Female Sex: Independent Predictors of Human Vascular Smooth Muscle Cells Stiffening

PubMed Central

Dinardo, Carla Luana; Santos, Hadassa Campos; Vaquero, André Ramos; Martelini, André Ricardo; Dallan, Luis Alberto Oliveira; Alencar, Adriano Mesquita; Krieger, José Eduardo; Pereira, Alexandre Costa

2015-01-01

Aims Recent evidence shows the rigidity of vascular smooth muscle cells (VSMC) contributes to vascular mechanics. Arterial rigidity is an independent cardiovascular risk factor whose associated modifications in VSMC viscoelasticity have never been investigated. This study’s objective was to evaluate if the arterial rigidity risk factors aging, African ancestry, female sex, smoking and diabetes mellitus are associated with VMSC stiffening in an experimental model using a human derived vascular smooth muscle primary cell line repository. Methods Eighty patients subjected to coronary artery bypass surgery were enrolled. VSMCs were extracted from internal thoracic artery fragments and mechanically evaluated using Optical Magnetic Twisting Cytometry assay. The obtained mechanical variables were correlated with the clinical variables: age, gender, African ancestry, smoking and diabetes mellitus. Results The mechanical variables Gr, G’r and G”r had a normal distribution, demonstrating an inter-individual variability of VSMC viscoelasticity, which has never been reported before. Female sex and smoking were independently associated with VSMC stiffening: Gr (apparent cell stiffness) p = 0.022 and p = 0.018, R2 0.164; G’r (elastic modulus) p = 0.019 and p = 0.009, R2 0.184 and G”r (dissipative modulus) p = 0.011 and p = 0.66, R2 0.141. Conclusion Female sex and smoking are independent predictors of VSMC stiffening. This pro-rigidity effect represents an important element for understanding the vascular rigidity observed in post-menopausal females and smokers, as well as a potential therapeutic target to be explored in the future. There is a significant inter-individual variation of VSMC viscoelasticity, which is slightly modulated by clinical variables and probably relies on molecular factors. PMID:26661469

Heritability of Intraindividual Mean and Variability of Positive and Negative Affect.

PubMed

Zheng, Yao; Plomin, Robert; von Stumm, Sophie

2016-12-01

Positive affect (e.g., attentiveness) and negative affect (e.g., upset) fluctuate over time. We examined genetic influences on interindividual differences in the day-to-day variability of affect (i.e., ups and downs) and in average affect over the duration of a month. Once a day, 17-year-old twins in the United Kingdom ( N = 447) rated their positive and negative affect online. The mean and standard deviation of each individual's daily ratings across the month were used as the measures of that individual's average affect and variability of affect. Analyses revealed that the average of negative affect was significantly heritable (.53), but the average of positive affect was not; instead, the latter showed significant shared environmental influences (.42). Fluctuations across the month were significantly heritable for both negative affect (.54) and positive affect (.34). The findings support the two-factor theory of affect, which posits that positive affect is more situational and negative affect is more dispositional.

Heritability of Intraindividual Mean and Variability of Positive and Negative Affect

PubMed Central

Zheng, Yao; Plomin, Robert; von Stumm, Sophie

2016-01-01

Positive affect (e.g., attentiveness) and negative affect (e.g., upset) fluctuate over time. We examined genetic influences on interindividual differences in the day-to-day variability of affect (i.e., ups and downs) and in average affect over the duration of a month. Once a day, 17-year-old twins in the United Kingdom (N = 447) rated their positive and negative affect online. The mean and standard deviation of each individual’s daily ratings across the month were used as the measures of that individual’s average affect and variability of affect. Analyses revealed that the average of negative affect was significantly heritable (.53), but the average of positive affect was not; instead, the latter showed significant shared environmental influences (.42). Fluctuations across the month were significantly heritable for both negative affect (.54) and positive affect (.34). The findings support the two-factor theory of affect, which posits that positive affect is more situational and negative affect is more dispositional. PMID:27729566

Global Genetic Variations Predict Brain Response to Faces

PubMed Central

Dickie, Erin W.; Tahmasebi, Amir; French, Leon; Kovacevic, Natasa; Banaschewski, Tobias; Barker, Gareth J.; Bokde, Arun; Büchel, Christian; Conrod, Patricia; Flor, Herta; Garavan, Hugh; Gallinat, Juergen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Lawrence, Claire; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Nichols, Thomas; Lathrop, Mark; Loth, Eva; Pausova, Zdenka; Rietschel, Marcela; Smolka, Michal N.; Ströhle, Andreas; Toro, Roberto; Schumann, Gunter; Paus, Tomáš

2014-01-01

Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40–50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R2 = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R2 = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network. PMID:25122193

An IRT Model with a Parameter-Driven Process for Change

ERIC Educational Resources Information Center

Rijmen, Frank; De Boeck, Paul; van der Maas, Han L. J.

2005-01-01

An IRT model with a parameter-driven process for change is proposed. Quantitative differences between persons are taken into account by a continuous latent variable, as in common IRT models. In addition, qualitative inter-individual differences and auto-dependencies are accounted for by assuming within-subject variability with respect to the…

Genome-wide interactions with dairy intake for body mass index in adults of European descent

USDA-ARS?s Scientific Manuscript database

Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. We conducted a genome-wide interaction study to discover genetic variants that account for variation in BMI in the c...

Bioavailability and pharmacokinetic profile of grape pomace phenolic compounds in humans.

PubMed

Castello, Fabio; Costabile, Giuseppina; Bresciani, Letizia; Tassotti, Michele; Naviglio, Daniele; Luongo, Delia; Ciciola, Paola; Vitale, Marilena; Vetrani, Claudia; Galaverna, Gianni; Brighenti, Furio; Giacco, Rosalba; Del Rio, Daniele; Mena, Pedro

2018-05-15

Grape pomace, the major byproduct of the wine and juice industry, is a relevant source of bioactive phenolic compounds. However, polyphenol bioavailability in humans is not well understood, and the inter-individual variability in the production of phenolic metabolites has not been comprehensively assessed to date. The pharmacokinetic and excretive profiles of phenolic metabolites after the acute administration of a drink made from red grape pomace was here investigated in ten volunteers. A total of 35 and 28 phenolic metabolites were quantified in urine and plasma, respectively. The main circulating metabolites included phenyl-γ-valerolactones, hydroxybenzoic acids, simple phenols, hydroxyphenylpropionic acids, hydroxycinnamates, and (epi)catechin phase II conjugates. A high inter-individual variability was shown both in urine and plasma samples, and different patterns of circulating metabolites were unravelled by applying unsupervised multivariate analysis. Besides the huge variability in the production of microbial metabolites of colonic origin, an important variability was observed due to phase II conjugates. These results are of interest to further understand the potential health benefits of phenolic metabolites on individual basis. Copyright © 2018 Elsevier Inc. All rights reserved.

Polymorphisms in HLA-DPB1 are associated with differences in rubella virus-specific humoral immunity after vaccination.

PubMed

Lambert, Nathaniel D; Haralambieva, Iana H; Kennedy, Richard B; Ovsyannikova, Inna G; Pankratz, Vernon Shane; Poland, Gregory A

2015-03-15

Vaccination with live attenuated rubella virus induces a strong immune response in most individuals. However, small numbers of subjects never reach or maintain protective antibody levels, and there is a high degree of variability in immune response. We have previously described genetic polymorphisms in HLA and other candidate genes that are associated with interindividual differences in humoral immunity to rubella virus. To expand our previous work, we performed a genome-wide association study (GWAS) to discover single-nucleotide polymorphisms (SNPs) associated with rubella virus-specific neutralizing antibodies. We identified rs2064479 in the HLA-DPB1 genetic region as being significantly associated with humoral immune response variations after rubella vaccination (P = 8.62 × 10(-8)). All other significant SNPs in this GWAS were located near the HLA-DPB1 gene (P ≤ 1 × 10(-7)). These findings demonstrate that polymorphisms in HLA-DPB1 are strongly associated with interindividual differences in neutralizing antibody levels to rubella vaccination and represent a validation of our previous HLA work. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Functional relevance of interindividual differences in temporal lobe callosal pathways: a DTI tractography study.

PubMed

Westerhausen, René; Grüner, Renate; Specht, Karsten; Hugdahl, Kenneth

2009-06-01

The midsagittal corpus callosum is topographically organized, that is, with regard to their cortical origin several subtracts can be distinguished within the corpus callosum that belong to specific functional brain networks. Recent diffusion tensor tractography studies have also revealed remarkable interindividual differences in the size and exact localization of these tracts. To examine the functional relevance of interindividual variability in callosal tracts, 17 right-handed male participants underwent structural and diffusion tensor magnetic resonance imaging. Probabilistic tractography was carried out to identify the callosal subregions that interconnect left and right temporal lobe auditory processing areas, and the midsagittal size of this tract was seen as indicator of the (anatomical) strength of this connection. Auditory information transfer was assessed applying an auditory speech perception task with dichotic presentations of consonant-vowel syllables (e.g., /ba-ga/). The frequency of correct left ear reports in this task served as a functional measure of interhemispheric transfer. Statistical analysis showed that a stronger anatomical connection between the superior temporal lobe areas supports a better information transfer. This specific structure-function association in the auditory modality supports the general notion that interindividual differences in callosal topography possess functional relevance.

Cluster analysis and subgrouping to investigate inter-individual variability to non-invasive brain stimulation: a systematic review.

PubMed

Pellegrini, Michael; Zoghi, Maryam; Jaberzadeh, Shapour

2018-01-12

Cluster analysis and other subgrouping techniques have risen in popularity in recent years in non-invasive brain stimulation research in the attempt to investigate the issue of inter-individual variability - the issue of why some individuals respond, as traditionally expected, to non-invasive brain stimulation protocols and others do not. Cluster analysis and subgrouping techniques have been used to categorise individuals, based on their response patterns, as responder or non-responders. There is, however, a lack of consensus and consistency on the most appropriate technique to use. This systematic review aimed to provide a systematic summary of the cluster analysis and subgrouping techniques used to date and suggest recommendations moving forward. Twenty studies were included that utilised subgrouping techniques, while seven of these additionally utilised cluster analysis techniques. The results of this systematic review appear to indicate that statistical cluster analysis techniques are effective in identifying subgroups of individuals based on response patterns to non-invasive brain stimulation. This systematic review also reports a lack of consensus amongst researchers on the most effective subgrouping technique and the criteria used to determine whether an individual is categorised as a responder or a non-responder. This systematic review provides a step-by-step guide to carrying out statistical cluster analyses and subgrouping techniques to provide a framework for analysis when developing further insights into the contributing factors of inter-individual variability in response to non-invasive brain stimulation.

Analysis of manual segmentation in paranasal CT images.

PubMed

Tingelhoff, Kathrin; Eichhorn, Klaus W G; Wagner, Ingo; Kunkel, Maria E; Moral, Analia I; Rilk, Markus E; Wahl, Friedrich M; Bootz, Friedrich

2008-09-01

Manual segmentation is often used for evaluation of automatic or semi-automatic segmentation. The purpose of this paper is to describe the inter and intraindividual variability, the dubiety of manual segmentation as a gold standard and to find reasons for the discrepancy. We realized two experiments. In the first one ten ENT surgeons, ten medical students and one engineer outlined the right maxillary sinus and ethmoid sinuses manually on a standard CT dataset of a human head. In the second experiment two participants outlined maxillary sinus and ethmoid sinuses five times consecutively. Manual segmentation was accomplished with custom software using a line segmentation tool. The first experiment shows the interindividual variability of manual segmentation which is higher for ethmoidal sinuses than for maxillary sinuses. The variability can be caused by the level of experience, different interpretation of the CT data or different levels of accuracy. The second experiment shows intraindividual variability which is lower than interindividual variability. Most variances in both experiments appear during segmentation of ethmoidal sinuses and outlining hiatus semilunaris. Concerning the inter and intraindividual variances the segmentation result of one manual segmenter could not directly be used as gold standard for the evaluation of automatic segmentation algorithms.

Transcriptional Regulation of CYP2D6 Expression

PubMed Central

Pan, Xian; Ning, Miaoran

2017-01-01

CYP2D6-mediated drug metabolism exhibits large interindividual variability. Although genetic variations in the CYP2D6 gene are well known contributors to the variability, the sources of CYP2D6 variability in individuals of the same genotype remain unexplained. Accumulating data indicate that transcriptional regulation of CYP2D6 may account for part of CYP2D6 variability. Yet, our understanding of factors governing transcriptional regulation of CYP2D6 is limited. Recently, mechanistic studies of increased CYP2D6-mediated drug metabolism in pregnancy revealed two transcription factors, small heterodimer partner (SHP) and Krüppel-like factor 9, as a transcriptional repressor and an activator, respectively, of CYP2D6. Chemicals that increase SHP expression (e.g., retinoids and activators of farnesoid X receptor) were shown to downregulate CYP2D6 expression in the humanized mice as well as in human hepatocytes. This review summarizes the series of studies on the transcriptional regulation of CYP2D6 expression, potentially providing a basis to better understand the large interindividual variability in CYP2D6-mediated drug metabolism. PMID:27698228

Dietary intake is independently associated with the maximal capacity for fat oxidation during exercise.

PubMed

Fletcher, Gareth; Eves, Frank F; Glover, Elisa I; Robinson, Scott L; Vernooij, Carlijn A; Thompson, Janice L; Wallis, Gareth A

2017-04-01

Background: Substantial interindividual variability exists in the maximal rate of fat oxidation (MFO) during exercise with potential implications for metabolic health. Although the diet can affect the metabolic response to exercise, the contribution of a self-selected diet to the interindividual variability in the MFO requires further clarification. Objective: We sought to identify whether recent, self-selected dietary intake independently predicts the MFO in healthy men and women. Design: The MFO and maximal oxygen uptake ([Formula: see text]O 2 max) were determined with the use of indirect calorimetry in 305 healthy volunteers [150 men and 155 women; mean ± SD age: 25 ± 6 y; body mass index (BMI; in kg/m 2 ): 23 ± 2]. Dual-energy X-ray absorptiometry was used to assess body composition with the self-reported physical activity level (SRPAL) and dietary intake determined in the 4 d before exercise testing. To minimize potential confounding with typically observed sex-related differences (e.g., body composition), predictor variables were mean-centered by sex. In the analyses, hierarchical multiple linear regressions were used to quantify each variable's influence on the MFO. Results: The mean absolute MFO was 0.55 ± 0.19 g/min (range: 0.19-1.13 g/min). A total of 44.4% of the interindividual variability in the MFO was explained by the [Formula: see text]O 2 max, sex, and SRPAL with dietary carbohydrate (carbohydrate; negative association with the MFO) and fat intake (positive association) associated with an additional 3.2% of the variance. When expressed relative to fat-free mass (FFM), the MFO was 10.8 ± 3.2 mg · kg FFM -1 · min -1 (range: 3.5-20.7 mg · kg FFM -1 · min -1 ) with 16.6% of the variability explained by the [Formula: see text]O 2 max, sex, and SRPAL; dietary carbohydrate and fat intakes together explained an additional 2.6% of the variability. Biological sex was an independent determinant of the MFO with women showing a higher MFO [men: 10.3 ± 3.1 mg · kg FFM -1 · min -1 (3.5-19.9 mg · kg FFM -1 · min -1 ); women: 11.2 ± 3.3 mg · kg FFM -1 · min -1 (4.6-20.7 mg · kg FFM -1 · min -1 ); P < 0.05]. Conclusion: Considered alongside other robust determinants, dietary carbohydrate and fat intake make modest but independent contributions to the interindividual variability in the capacity to oxidize fat during exercise. This trial was registered at clinicaltrials.gov as NCT02070055.

Comparison of propranolol and metoprolol in the management of hyperthyroidism.

PubMed Central

Murchison, L E; How, J; Bewsher, P D

1979-01-01

1 Propranolol and metoprolol were both effective in controlling the symptoms and signs of hyperthyroidism. 2 Propranolol caused a highly significant increase in serum reverse T3 concentrations with lesser changes in other serum thyroid hormone levels, whereas metoprolol did not have this effect. 3 Steady-state plasma propranolol and metoprolol levels showed marked inter-individual variation. Metoprolol concentrations showed relatively little intra-individual variability, and could be related to the clinical efficacy of the drug, whereas no such relationship was demonstrated for propranolol. PMID:391258

Isogenic blood-brain barrier models based on patient-derived stem cells display inter-individual differences in cell maturation and functionality.

PubMed

Patel, Ronak; Page, Shyanne; Al-Ahmad, Abraham Jacob

2017-07-01

The blood-brain barrier (BBB) constitutes an important component of the neurovascular unit formed by specialized brain microvascular endothelial cells (BMECs) surrounded by astrocytes, pericytes, and neurons. Recently, isogenic in vitro models of the BBB based on human pluripotent stem cells have been documented, yet the impact of inter-individual variability on the yield and phenotype of such models remains to be documented. In this study, we investigated the impact of inter-individual variability on the yield and phenotype of isogenic models of the BBB, using patient-derived induced pluripotent stem cells (iPSCs). Astrocytes, BMECs, and neurons were differentiated from four asymptomatic patient-derived iPSCs (two males, two females). We differentiated such cells using existing differentiation protocols and quantified expression of cell lineage markers, as well as BBB phenotype, barrier induction, and formation of neurite processes. iPSC-derived BMECs showed barrier properties better than hCMEC/D3 monolayers; however, we noted differences in the expression and activity among iPSC lines. In addition, we noted differences in the differentiation efficiency of these cells into neural stem cells and progenitor cells (as noted by differences in expression of cell lineage markers). Such differences were reflected later in the terminal differentiation, as seen as ability to induce barrier function and to form neurite processes. Although we demonstrated our ability to obtain an isogenic model of the BBB with different patients' iPSCs, we also noted subtle differences in the expression of cell lineage markers and cell maturation processes, suggesting the presence of inter-individual polymorphisms. © 2017 International Society for Neurochemistry.

Interindividual Differences in Neonatal Imitation and the Development of Action Chains in Rhesus Macaques

ERIC Educational Resources Information Center

Ferrari, Pier Francesco; Paukner, Annika; Ruggiero, Angela; Darcey, Lisa; Unbehagen, Sarah; Suomi, Stephen J.

2009-01-01

The capacity to imitate facial gestures is highly variable in rhesus macaques and this variability may be related to differences in specific neurobehavioral patterns of development. This study evaluated the differential neonatal imitative response of 41 macaques in relation to the development of sensory, motor, and cognitive skills throughout the…

Impact of Flavonols on Cardiometabolic Biomarkers: A Meta-Analysis of Randomized Controlled Human Trials to Explore the Role of Inter-Individual Variability

PubMed Central

Menezes, Regina; Rodriguez-Mateos, Ana; Kaltsatou, Antonia; González-Sarrías, Antonio; Greyling, Arno; Giannaki, Christoforos; Andres-Lacueva, Cristina; Milenkovic, Dragan; Gibney, Eileen R.; Dumont, Julie; Schär, Manuel; Garcia-Aloy, Mar; Palma-Duran, Susana Alejandra; Ruskovska, Tatjana; Maksimova, Viktorija; Combet, Emilie; Pinto, Paula

2017-01-01

Several epidemiological studies have linked flavonols with decreased risk of cardiovascular disease (CVD). However, some heterogeneity in the individual physiological responses to the consumption of these compounds has been identified. This meta-analysis aimed to study the effect of flavonol supplementation on biomarkers of CVD risk such as, blood lipids, blood pressure and plasma glucose, as well as factors affecting their inter-individual variability. Data from 18 human randomized controlled trials were pooled and the effect was estimated using fixed or random effects meta-analysis model and reported as difference in means (DM). Variability in the response of blood lipids to supplementation with flavonols was assessed by stratifying various population subgroups: age, sex, country, and health status. Results showed significant reductions in total cholesterol (DM = −0.10 mmol/L; 95% CI: −0.20, −0.01), LDL cholesterol (DM = −0.14 mmol/L; 95% CI: −0.21, 0.07), and triacylglycerol (DM = −0.10 mmol/L; 95% CI: −0.18, 0.03), and a significant increase in HDL cholesterol (DM = 0.05 mmol/L; 95% CI: 0.02, 0.07). A significant reduction was also observed in fasting plasma glucose (DM = −0.18 mmol/L; 95% CI: −0.29, −0.08), and in blood pressure (SBP: DM = −4.84 mmHg; 95% CI: −5.64, −4.04; DBP: DM = −3.32 mmHg; 95% CI: −4.09, −2.55). Subgroup analysis showed a more pronounced effect of flavonol intake in participants from Asian countries and in participants with diagnosed disease or dyslipidemia, compared to healthy and normal baseline values. In conclusion, flavonol consumption improved biomarkers of CVD risk, however, country of origin and health status may influence the effect of flavonol intake on blood lipid levels. PMID:28208791

Intra-individual variability in tinnitus patients : current thoughts and perspectives.

PubMed

Dauman, N; Erlandsson, S; Lundlin, L; Dauman, R

2015-04-01

Most tinnitus studies have attempted to compare groups of individuals, thus revealing inter-individuals differences, i.e., variations between compared subjects. For methodological reasons, inter-individual studies cannot take into account the variability of tinnitus experience, which has been known for decades to be relevant in daily practice with tinnitus patients. The concept of intra-individual variability has been promoted in the research literature, in order to shed light on this aspect of individual perception. In previous studies, unrelated to hearing, the concept of intra-individual variability implied inclusion of the environment (i.e., physical and social interactions) as a factor of individual performance. In tinnitus research, we believe that the concept of variability (within a person) could find a place beside the concept of variation (between groups of subjects). In this paper, four perspectives of tinnitus experiences from the clinical and research fields are described: (1) ENT consultation; (2) short-term group psychotherapy; (3) psychodynamic psychotherapy; and (4) clinical psychological research. Intra-individual variability stresses the importance of defining tinnitus in a dynamic way, contrary to the current definition of tinnitus as the perception of sound(s). In clinical practice, it is useful to embrace the perspective of the perceiver of tinnitus, and to include social and cultural circumstances as well as audiological/physical changes.

Interindividual variability of electromyographic patterns and pedal force profiles in trained cyclists.

PubMed

Hug, François; Drouet, Jean Marc; Champoux, Yvan; Couturier, Antoine; Dorel, Sylvain

2008-11-01

The aim of this study was to determine whether high inter-individual variability of the electromyographic (EMG) patterns during pedaling is accompanied by variability in the pedal force application patterns. Eleven male experienced cyclists were tested at two submaximal power outputs (150 and 250 W). Pedal force components (effective and total forces) and index of mechanical effectiveness were measured continuously using instrumented pedals and were synchronized with surface electromyography signals measured in ten lower limb muscles. The intersubject variability of EMG and mechanical patterns was assessed using standard deviation, mean deviation, variance ratio and coefficient of cross-correlation (_R(0), with lag time = 0). The results demonstrated a high intersubject variability of EMG patterns at both exercise intensities for biarticular muscles as a whole (and especially for Gastrocnemius lateralis and Rectus femoris) and for one monoarticular muscle (Tibialis anterior). However, this heterogeneity of EMG patterns is not accompanied by a so high intersubject variability in pedal force application patterns. A very low variability in the three mechanical profiles (effective force, total force and index of mechanical effectiveness) was obtained in the propulsive downstroke phase, although a greater variability in these mechanical patterns was found during upstroke and around the top dead center, and at 250 W when compared to 150 W. Overall, these results provide additional evidence for redundancy in the neuromuscular system.

Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan.

PubMed

Kühne, Annett; Kaiser, Rolf; Schirmer, Markus; Heider, Ulrike; Muhlke, Sabine; Niere, Wiebke; Overbeck, Tobias; Hohloch, Karin; Trümper, Lorenz; Sezer, Orhan; Brockmöller, Jürgen

2007-07-01

Melphalan is widely used in the treatment of multiple myeloma. Pharmacokinetics of this alkylating drug shows high inter-individual variability. As melphalan is a phenylalanine derivative, the pharmacokinetic variability may be determined by genetic polymorphisms in the L-type amino acid transporters LAT1 (SLC7A5) and LAT2 (SLC7A8). Pharmacokinetics were analysed in 64 patients after first administration of intravenous melphalan. Severity of side effects was documented according to WHO criteria. Genomic DNA was analysed for polymorphisms in LAT1 and LAT2 by sequencing of the entire coding region, intron-exon boundaries and 2 kb upstream promoter region. Selected polymorphisms in the common heavy chain of both transporters, the protein 4F2hc (SLC3A2), were analysed by single nucleotide primer extension. Melphalan pharmacokinetics was highly variable with up to 6.2-fold differences in total clearance. A total of 44 polymorphisms were identified in LAT1 and 21 polymorphisms in LAT2. From all variants, only five were in the coding region and only one heterozygous non-synonymous polymorphism (Ala94Thr) was found in LAT2. Numerous polymorphisms were found in the LAT1 and LAT2 5'-flanking regions but did not correlate with expression of the respective genes. No significant correlations could be observed between the polymorphisms in 4F2hc, LAT1, and LAT2 with melphalan pharmacokinetics or with melphalan side effects. The study confirmed that these transporter genes are highly conserved, particularly in the coding sequences. Genetic variation in 4F2hc, LAT1, and LAT2 does not appear to be a major cause of inter-individual variability in pharmacokinetics and of adverse reactions to melphalan.

Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.

PubMed

Vandenberghe, Frederik; Guidi, Monia; Choong, Eva; von Gunten, Armin; Conus, Philippe; Csajka, Chantal; Eap, Chin B

2015-12-01

High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPARα, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM(®)). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. The cytochrome P450 (CYP) 2D6 phenotype explained 52% of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28% higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26% with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response. Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment.

Pharmacogenetics and outcome with antipsychotic drugs.

PubMed

Pouget, Jennie G; Shams, Tahireh A; Tiwari, Arun K; Müller, Daniel J

2014-12-01

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.

Pharmacogenetics and outcome with antipsychotic drugs

PubMed Central

Pouget, Jennie G.; Shams, Tahireh A.; Tiwari, Arun K.; Müller, Daniel J.

2014-01-01

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h2~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future. PMID:25733959

Engagement with the auditory processing system during targeted auditory cognitive training mediates changes in cognitive outcomes in individuals with schizophrenia.

PubMed

Biagianti, Bruno; Fisher, Melissa; Neilands, Torsten B; Loewy, Rachel; Vinogradov, Sophia

2016-11-01

Individuals with schizophrenia who engage in targeted cognitive training (TCT) of the auditory system show generalized cognitive improvements. The high degree of variability in cognitive gains maybe due to individual differences in the level of engagement of the underlying neural system target. 131 individuals with schizophrenia underwent 40 hours of TCT. We identified target engagement of auditory system processing efficiency by modeling subject-specific trajectories of auditory processing speed (APS) over time. Lowess analysis, mixed models repeated measures analysis, and latent growth curve modeling were used to examine whether APS trajectories were moderated by age and illness duration, and mediated improvements in cognitive outcome measures. We observed significant improvements in APS from baseline to 20 hours of training (initial change), followed by a flat APS trajectory (plateau) at subsequent time-points. Participants showed interindividual variability in the steepness of the initial APS change and in the APS plateau achieved and sustained between 20 and 40 hours. We found that participants who achieved the fastest APS plateau, showed the greatest transfer effects to untrained cognitive domains. There is a significant association between an individual's ability to generate and sustain auditory processing efficiency and their degree of cognitive improvement after TCT, independent of baseline neurocognition. APS plateau may therefore represent a behavioral measure of target engagement mediating treatment response. Future studies should examine the optimal plateau of auditory processing efficiency required to induce significant cognitive improvements, in the context of interindividual differences in neural plasticity and sensory system efficiency that characterize schizophrenia. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Weight-correction of carbon dioxide diffusion coefficient (DCO2 ) reduces its inter-individual variability and improves its correlation with blood carbon dioxide levels in neonates receiving high-frequency oscillatory ventilation.

PubMed

Belteki, Gusztav; Lin, Benjamin; Morley, Colin J

2017-10-01

Carbon-dioxide elimination during high-frequency oscillatory ventilation (HFOV) is thought to be proportional to the carbon dioxide diffusion coefficient (DCO 2 ) which is calculated as frequency x (tidal volume) 2 . DCO 2 can be used to as an indicator of CO 2 elimination but values obtained in different patients cannot be directly compared. To analyze the relationship between DCO 2 , the weight-corrected DCO 2 (DCO 2 corr) and blood gas PCO 2 values obtained from infants receiving HFOV. DCO 2 data were obtained from 14 infants at 1/s sampling rate and the mean DCO 2 was determined over 10 min periods preceding the time of the blood gas. DCO 2 corr was calculated by dividing the DCO 2 by the square of the body weight in kg. Weight-correction significantly reduced the inter-individual variability of DCO 2 . When data from all the babies were combined, standard DCO 2 showed no correlation with PCO 2 but DCO 2 corr showed a weak but statistically significant inverse correlation. The correlation was better when the endotracheal leak was <10%. There was significant inverse but weaker correlation between the HFOV tidal volume (VThf) and the PCO 2 . In any baby, DCO 2 corr >50 mL 2 /sec/kg 2 or VThf > 2.5 mL/kg was rarely needed to avoid hypercapnia. Weight-correction of DCO 2 values improved its comparability between patients. Weight-corrected DCO 2 correlated better with PCO 2 than uncorrected DCO 2 but the correlation was weak. © 2017 Wiley Periodicals, Inc.

Dietary intake is independently associated with the maximal capacity for fat oxidation during exercise12

PubMed Central

Eves, Frank F; Glover, Elisa I; Robinson, Scott L; Vernooij, Carlijn A

2017-01-01

Background: Substantial interindividual variability exists in the maximal rate of fat oxidation (MFO) during exercise with potential implications for metabolic health. Although the diet can affect the metabolic response to exercise, the contribution of a self-selected diet to the interindividual variability in the MFO requires further clarification. Objective: We sought to identify whether recent, self-selected dietary intake independently predicts the MFO in healthy men and women. Design: The MFO and maximal oxygen uptake (O2 max) were determined with the use of indirect calorimetry in 305 healthy volunteers [150 men and 155 women; mean ± SD age: 25 ± 6 y; body mass index (BMI; in kg/m2): 23 ± 2]. Dual-energy X-ray absorptiometry was used to assess body composition with the self-reported physical activity level (SRPAL) and dietary intake determined in the 4 d before exercise testing. To minimize potential confounding with typically observed sex-related differences (e.g., body composition), predictor variables were mean-centered by sex. In the analyses, hierarchical multiple linear regressions were used to quantify each variable’s influence on the MFO. Results: The mean absolute MFO was 0.55 ± 0.19 g/min (range: 0.19–1.13 g/min). A total of 44.4% of the interindividual variability in the MFO was explained by the O2 max, sex, and SRPAL with dietary carbohydrate (carbohydrate; negative association with the MFO) and fat intake (positive association) associated with an additional 3.2% of the variance. When expressed relative to fat-free mass (FFM), the MFO was 10.8 ± 3.2 mg · kg FFM−1 · min−1 (range: 3.5–20.7 mg · kg FFM−1 · min−1) with 16.6% of the variability explained by the O2 max, sex, and SRPAL; dietary carbohydrate and fat intakes together explained an additional 2.6% of the variability. Biological sex was an independent determinant of the MFO with women showing a higher MFO [men: 10.3 ± 3.1 mg · kg FFM−1 · min−1 (3.5–19.9 mg · kg FFM−1 · min−1); women: 11.2 ± 3.3 mg · kg FFM−1 · min−1 (4.6–20.7 mg · kg FFM−1 · min−1); P < 0.05]. Conclusion: Considered alongside other robust determinants, dietary carbohydrate and fat intake make modest but independent contributions to the interindividual variability in the capacity to oxidize fat during exercise. This trial was registered at clinicaltrials.gov as NCT02070055. PMID:28251936

Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I) - longitudinal investigations and differences to control groups.

PubMed

Schinkel, Christian; Scherens, A; Köller, M; Roellecke, G; Muhr, G; Maier, C

2009-03-17

The Complex Regional Pain Syndrome I (CRPS I) is a disease that might affect an extremity after trauma or operation. The pathogenesis remains yet unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response but neurogenic dysregulation also contributes to it. Some studies investigated the role inflammatory mediators and cytokines; however, few longitudinal studies exist and control groups except healthy controls were not investigated yet. To get further insights into the role of systemic inflammatory mediators in CRPS I, we investigated a variety of pro-, anti-, or neuro-inflammatory mediators such as C-Reactive Protein (CRP), White Blood Cell Count (WBC), Interleukins 4, 6, 8, 10, 11, 12 (p70), Interferon gamma, Tumor-Necrosis-Factor alpha (TNF-a) and its soluble Receptors I/II, soluble Selectins (E,L,P), Substance-P (SP), and Calcitonin Gene-Related Peptide (CGRP) at different time points in venous blood from patients with acute (AC) and chronic (CC) CRPS I, patients with forearm fractures (FR), with neuralgia (NE), and from healthy volunteers (C). No significant changes for serum parameters investigated in CRPS compared to control groups were found except for CC/C (CGRP p = 0.007), FR/C (CGRP p = 0.048) and AC/CC (IL-12 p = 0.02; TNFRI/II p = 0.01; SP p = 0.049). High interindividual variations were observed. No intra- or interindividual correlation of parameters with clinical course (e.g. chronification) or outcome was detectable. Although clinically appearing as inflammation in acute stages, local rather than systemic inflammatory responses seem to be relevant in CRPS. Variable results from different studies might be explained by unpredictable intermittent release of mediators from local inflammatory processes into the blood combined with high interindividual variabilities. A clinically relevant difference to various control groups was not notable in this pilot study. Determination of systemic inflammatory parameters is not yet helpful in diagnostic and follow-up of CRPS I.

Modeling spatial competition for light in plant populations with the porous medium equation.

PubMed

Beyer, Robert; Etard, Octave; Cournède, Paul-Henry; Laurent-Gengoux, Pascal

2015-02-01

We consider a plant's local leaf area index as a spatially continuous variable, subject to particular reaction-diffusion dynamics of allocation, senescence and spatial propagation. The latter notably incorporates the plant's tendency to form new leaves in bright rather than shaded locations. Applying a generalized Beer-Lambert law allows to link existing foliage to production dynamics. The approach allows for inter-individual variability and competition for light while maintaining robustness-a key weakness of comparable existing models. The analysis of the single plant case leads to a significant simplification of the system's key equation when transforming it into the well studied porous medium equation. Confronting the theoretical model to experimental data of sugar beet populations, differing in configuration density, demonstrates its accuracy.

Adjustment of sleep and the circadian temperature rhythm after flights across nine time zones

NASA Technical Reports Server (NTRS)

Gander, Philippa H.; Myhre, Grete; Graeber, R. Curtis; Lauber, John K.; Andersen, Harald T.

1989-01-01

The adjustment of sleep-wake patterns and the circadian temperature rhythm was monitored in nine Royal Norwegian Airforce volunteers operating P-3 aircraft during a westward training deployment across nine time zones. Subjects recorded all sleep and nap times, rated nightly sleep quality, and completed personality inventories. Rectal temperature, heart rate, and wrist activity were continuously monitored. Adjustment was slower after the return eastward flight than after the outbound westward flight. The eastward flight produced slower readjustment of sleep timing to local time and greater interindividual variability in the patterns of adjustment of sleep and temperature. One subject apparently exhibited resynchronization by partition, with the temperature rhythm undergoing the reciprocal 15-h delay. In contrast, average heart rates during sleep were significantly elevated only after westward flight. Interindividual differences in adjustment of the temperature rhythm were correlated with some of the personality measures. Larger phase delays in the overall temperature waveform (as measured on the 5th day after westward flight) were exhibited by extraverts, and less consistently by evening types.

High interindividual variability in dose-dependent reduction in speed of movement after exposing C. elegans to shock waves

PubMed Central

Angstman, Nicholas B.; Kiessling, Maren C.; Frank, Hans-Georg; Schmitz, Christoph

2015-01-01

In blast-related mild traumatic brain injury (br-mTBI) little is known about the connections between initial trauma and expression of individual clinical symptoms. Partly due to limitations of current in vitro and in vivo models of br-mTBI, reliable prediction of individual short- and long-term symptoms based on known blast input has not yet been possible. Here we demonstrate a dose-dependent effect of shock wave exposure on C. elegans using shock waves that share physical characteristics with those hypothesized to induce br-mTBI in humans. Increased exposure to shock waves resulted in decreased mean speed of movement while increasing the proportion of worms rendered paralyzed. Recovery of these two behavioral symptoms was observed during increasing post-traumatic waiting periods. Although effects were observed on a population-wide basis, large interindividual variability was present between organisms exposed to the same highly controlled conditions. Reduction of cavitation by exposing worms to shock waves in polyvinyl alcohol resulted in reduced effect, implicating primary blast effects as damaging components in shock wave induced trauma. Growing worms on NGM agar plates led to the same general results in initial shock wave effect in a standard medium, namely dose-dependence and high interindividual variability, as raising worms in liquid cultures. Taken together, these data indicate that reliable prediction of individual clinical symptoms based on known blast input as well as drawing conclusions on blast input from individual clinical symptoms is not feasible in br-mTBI. PMID:25705183

Inter-individual variability in the patterns of responses for electromyography and mechanomyography during cycle ergometry using an RPE-clamp model.

PubMed

Cochrane-Snyman, Kristen C; Housh, Terry J; Smith, Cory M; Hill, Ethan C; Jenkins, Nathaniel D M; Schmidt, Richard J; Johnson, Glen O

2016-09-01

To examine inter-individual variability versus composite models for the patterns of responses for electromyography (EMG) and mechanomyography (MMG) versus time relationships during moderate and heavy cycle ergometry using a rating of perceived exertion (RPE) clamp model. EMG amplitude (amplitude root-mean-square, RMS), EMG mean power frequency (MPF), MMG-RMS, and MMG-MPF were collected during two, 60-min rides at a moderate (RPE at the gas exchange threshold; RPEGET) and heavy (RPE at 15 % above the GET; RPEGET+15 %) intensity when RPE was held constant (clamped). Composite (mean) and individual responses for EMG and MMG parameters were compared during each 60-min ride. There was great inter-individual variability for each EMG and MMG parameters at RPEGET and RPEGET+15 %. Composite models showed decreases in EMG-RMS (r (2) = -0.92 and R (2) = 0.96), increases in EMG-MPF (R (2) = 0.90), increases in MMG-RMS (r (2) = 0.81 and 0.55), and either no change or a decrease (r (2) = 0.34) in MMG-MPF at RPEGET and RPEGET+15 %, respectively. The results of the present study indicated that there were differences between composite and individual patterns of responses for EMG and MMG parameters during moderate and heavy cycle ergometry at a constant RPE. Thus, composite models did not represent the unique muscle activation strategies exhibited by individual responses when cycling in the moderate and heavy intensity domains when using an RPE-clamp model.

Universality of human microbial dynamics

NASA Astrophysics Data System (ADS)

Bashan, Amir; Gibson, Travis E.; Friedman, Jonathan; Carey, Vincent J.; Weiss, Scott T.; Hohmann, Elizabeth L.; Liu, Yang-Yu

2016-06-01

Human-associated microbial communities have a crucial role in determining our health and well-being, and this has led to the continuing development of microbiome-based therapies such as faecal microbiota transplantation. These microbial communities are very complex, dynamic and highly personalized ecosystems, exhibiting a high degree of inter-individual variability in both species assemblages and abundance profiles. It is not known whether the underlying ecological dynamics of these communities, which can be parameterized by growth rates, and intra- and inter-species interactions in population dynamics models, are largely host-independent (that is, universal) or host-specific. If the inter-individual variability reflects host-specific dynamics due to differences in host lifestyle, physiology or genetics, then generic microbiome manipulations may have unintended consequences, rendering them ineffective or even detrimental. Alternatively, microbial ecosystems of different subjects may exhibit universal dynamics, with the inter-individual variability mainly originating from differences in the sets of colonizing species. Here we develop a new computational method to characterize human microbial dynamics. By applying this method to cross-sectional data from two large-scale metagenomic studies—the Human Microbiome Project and the Student Microbiome Project—we show that gut and mouth microbiomes display pronounced universal dynamics, whereas communities associated with certain skin sites are probably shaped by differences in the host environment. Notably, the universality of gut microbial dynamics is not observed in subjects with recurrent Clostridium difficile infection but is observed in the same set of subjects after faecal microbiota transplantation. These results fundamentally improve our understanding of the processes that shape human microbial ecosystems, and pave the way to designing general microbiome-based therapies.

[13C]Nandrolone excretion in trained athletes: interindividual variability in metabolism.

PubMed

Baume, Norbert; Avois, Lidia; Schweizer, Carine; Cardis, Christine; Dvorak, Jiri; Cauderay, Michel; Mangin, Patrice; Saugy, Martial

2004-02-01

Nandrolone is one of the most abused anabolic steroids, and its use in doping is increasing, as revealed by numerous positive cases during recent years in various sports. Different authors have reported the possible natural production of nandrolone metabolites in humans, and some of these authors argued that exhaustive exercise could increase nandrolone production in the body or induce dehydration and consequently lead to an increase of nandrolone metabolites in urine. Volunteers (n = 22) ingested two 25-mg doses of [(13)C]nandrolone at 24-h intervals and collected urine specimens for 5 days. The labeled nandrolone metabolites 19-norandrosterone and 19-noretiocholanolone were identified and quantified by gas chromatography-mass spectrometry. Interindividual variability was observed in nandrolone excretion patterns and kinetics, as well as for the noretiocholanolone:norandrosterone ratio. The amounts of nandrolone metabolites measured at the excretion peak varied between 1180 and 38 661 microg/L for norandrosterone and 576 and 12 328 microg/L for noretiocholanolone. At the end of the excretion period, the noretiocholanolone:norandrosterone ratio was sometimes >1. The analysis of numerous spot-urine samples allowed the determination of an acceptable correlation between urinary creatinine and specific gravity for placebo- and steroid-treated individuals: y = 0.0052ln(x) + 1.0178 (r(2) = 0.8142) and y = 0.0068ln(x) + 1.0172 (r(2) = 0.7730), respectively. The excretion kinetics and patterns of labeled nandrolone show interindividual variability. More investigations are currently underway to estimate the influence of exhaustive exercises on excretion of labeled nandrolone metabolites in urine.

Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men.

PubMed

Shumay, Elena; Logan, Jean; Volkow, Nora D; Fowler, Joanna S

2012-10-01

Human brain function is mediated by biochemical processes, many of which can be visualized and quantified by positron emission tomography (PET). PET brain imaging of monoamine oxidase A (MAO A)-an enzyme metabolizing neurotransmitters-revealed that MAO A levels vary widely between healthy men and this variability was not explained by the common MAOA genotype (VNTR genotype), suggesting that environmental factors, through epigenetic modifications, may mediate it. Here, we analyzed MAOA methylation in white blood cells (by bisulphite conversion of genomic DNA and subsequent sequencing of cloned DNA products) and measured brain MAO A levels (using PET and [(11)C]clorgyline, a radiotracer with specificity for MAO A) in 34 healthy non-smoking male volunteers. We found significant interindividual differences in methylation status and methylation patterns of the core MAOA promoter. The VNTR genotype did not influence the methylation status of the gene or brain MAO A activity. In contrast, we found a robust association of the regional and CpG site-specific methylation of the core MAOA promoter with brain MAO A levels. These results suggest that the methylation status of the MAOA promoter (detected in white blood cells) can reliably predict the brain endophenotype. Therefore, the status of MAOA methylation observed in healthy males merits consideration as a variable contributing to interindividual differences in behavior.

Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAOA enzyme in healthy men

PubMed Central

Shumay, Elena; Logan, Jean; Volkow, Nora D.; Fowler, Joanna S.

2012-01-01

Human brain function is mediated by biochemical processes, many of which can be visualized and quantified by positron emission tomography (PET). PET brain imaging of monoamine oxidase A (MAOA)—an enzyme metabolizing neurotransmitters—revealed that MAOA levels vary widely between healthy men and this variability was not explained by the common MAOA genotype (VNTR genotype), suggesting that environmental factors, through epigenetic modifications, may mediate it. Here, we analyzed MAOA methylation in white blood cells (by bisulphite conversion of genomic DNA and subsequent sequencing of cloned DNA products) and measured brain MAOA levels (using PET and [11C]clorgyline, a radiotracer with specificity for MAOA) in 34 healthy non-smoking male volunteers. We found significant interindividual differences in methylation status and methylation patterns of the core MAOA promoter. The VNTR genotype did not influence the methylation status of the gene or brain MAOA activity. In contrast, we found a robust association of the regional and CpG site-specific methylation of the core MAOA promoter with brain MAOA levels. These results suggest that the methylation status of the MAOA promoter (detected in white blood cells) can reliably predict the brain endophenotype. Therefore, the status of MAOA methylation observed in healthy males merits consideration as a variable contributing to interindividual differences in behavior. PMID:22948232

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

PubMed Central

Saruwatari, Junji; Ishitsu, Takateru; Nakagawa, Kazuko

2010-01-01

Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed. PMID:27713373

Engagement with the auditory processing system during targeted auditory cognitive training mediates changes in cognitive outcomes in individuals with schizophrenia

PubMed Central

Biagianti, Bruno; Fisher, Melissa; Neilands, Torsten B.; Loewy, Rachel; Vinogradov, Sophia

2016-01-01

BACKGROUND Individuals with schizophrenia who engage in targeted cognitive training (TCT) of the auditory system show generalized cognitive improvements. The high degree of variability in cognitive gains maybe due to individual differences in the level of engagement of the underlying neural system target. METHODS 131 individuals with schizophrenia underwent 40 hours of TCT. We identified target engagement of auditory system processing efficiency by modeling subject-specific trajectories of auditory processing speed (APS) over time. Lowess analysis, mixed models repeated measures analysis, and latent growth curve modeling were used to examine whether APS trajectories were moderated by age and illness duration, and mediated improvements in cognitive outcome measures. RESULTS We observed signifcant improvements in APS from baseline to 20 hours of training (initial change), followed by a flat APS trajectory (plateau) at subsequent time-points. Participants showed inter-individual variability in the steepness of the initial APS change and in the APS plateau achieved and sustained between 20–40 hours. We found that participants who achieved the fastest APS plateau, showed the greatest transfer effects to untrained cognitive domains. CONCLUSIONS There is a significant association between an individual's ability to generate and sustain auditory processing efficiency and their degree of cognitive improvement after TCT, independent of baseline neurocognition. APS plateau may therefore represent a behavioral measure of target engagement mediating treatment response. Future studies should examine the optimal plateau of auditory processing efficiency required to induce significant cognitive improvements, in the context of inter-individual differences in neural plasticity and sensory system efficiency that characterize schizophrenia. PMID:27617637

Analysis of the in vivo confocal Raman spectral variability in human skin

NASA Astrophysics Data System (ADS)

Mogilevych, Borys; dos Santos, Laurita; Rangel, Joao L.; Grancianinov, Karen J. S.; Sousa, Mariane P.; Martin, Airton A.

2015-06-01

Biochemical composition of the skin changes in each layer and, therefore, the skin spectral profile vary with the depth. In this work, in vivo Confocal Raman spectroscopy studies were performed at different skin regions and depth profile (from the surface down to 10 μm) of the stratum corneum, to verify the variability and reproducibility of the intra- and interindividual Raman data. The Raman spectra were collected from seven healthy female study participants using a confocal Raman system from Rivers Diagnostic, with 785 nm excitation line and a CCD detector. Measurements were performed in the volar forearm region, at three different points at different depth, with the step of 2 μm. For each depth point, three spectra were acquired. Data analysis included the descriptive statistics (mean, standard deviation and residual) and Pearson's correlation coefficient calculation. Our results show that inter-individual variability is higher than intraindividual variability, and variability inside the SC is higher than on the skin surface. In all these cases we obtained r values, higher than 0.94, which correspond to high correlation between Raman spectra. It reinforces the possibility of the data reproducibility and direct comparison of in vivo results obtained with different study participants of the same age group and phototype.

Genetic basis of inter-individual variability in the effects of exercise on the alleviation of lifestyle-related diseases

PubMed Central

Mori, Masayuki; Higuchi, Keiichi; Sakurai, Akihiro; Tabara, Yasuharu; Miki, Tetsuro; Nose, Hiroshi

2009-01-01

Habitual exercise training, including a high-intensity interval walking programme, improves cardiorespiratory fitness and alleviates lifestyle-related diseases, such as obesity, hypertension and dyslipidaemia. However, the extent of improvement has been shown to differ substantially among individuals for various exercise regimens. A body of literature has demonstrated that gene polymorphisms could account for the inter-individual variability in the improvement of risk factors for lifestyle-related diseases following exercise training. However, the fractions of the variability explained by the polymorphisms are small (∼5%). Also, it is likely that the effects of gene polymorphisms differ with exercise regimens and subject characteristics. These observations suggest the necessity for further studies to exhaustively identify such gene polymorphisms. More importantly, the physiological and molecular genetic mechanisms by which gene polymorphisms interact with exercise to influence the improvements of risk factors for lifestyle-related diseases differentially remain to be clarified. A better understanding of these issues should lead to more effective integration of exercise to optimize the treatment and management of individuals with lifestyle-related diseases. PMID:19736300

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics.

PubMed

Abubakar, Murtala B; Gan, Siew Hua

2016-01-01

The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effects and inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed. © 2016 S. Karger AG, Basel.

Inter-individual differences in sleep response to shift work in novice police officers - A prospective study.

PubMed

Lammers-van der Holst, Heidi M; Van Dongen, Hans P A; Drosopoulos, Spyridon; Kerkhof, Gerard A

2016-01-01

The aim of this longitudinal study on novice police officers was to investigate inter-individual differences in sleep response to shift work, and to identify potential baseline predictors thereof. A total of 42 subjects were assessed at baseline, prior to commencing shift work. They were re-assessed during three follow-up sessions within the first 2 years of shift work exposure after approximately 4, 12, and 20 months of rotating shift work. Wrist actigraphy and sleep logs were used to investigate nocturnal sleep at baseline and daytime sleep after night shifts during the follow-up sessions. Actigraphically estimated total sleep time and subjective sleep quality were analyzed as outcome variables, using mixed-effects analysis of variance. Systematic inter-individual differences were observed in the overall response of these outcome variables to shift work. In this sample, flexibility of sleeping habits and gender were found to be predictors of daytime total sleep time in the first 2 years of shift work exposure. Flexibility of sleeping habits and subjective quality of nighttime sleep prior to shift work were found to be predictors of subjective quality of daytime sleep. These results suggest that it may be possible to detect and even predict sleep deficiencies in response to shift work early on, which could be a basis for the development of individualized interventions to improve shift work tolerance.

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors.

PubMed

Lane, Steven; Al-Zubiedi, Sameh; Hatch, Ellen; Matthews, Ivan; Jorgensen, Andrea L; Deloukas, Panos; Daly, Ann K; Park, B Kevin; Aarons, Leon; Ogungbenro, Kayode; Kamali, Farhad; Hughes, Dyfrig; Pirmohamed, Munir

2012-01-01

Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2). Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Individual modulation of pain sensitivity under stress.

PubMed

Reinhardt, Tatyana; Kleindienst, Nikolaus; Treede, Rolf-Detlef; Bohus, Martin; Schmahl, Christian

2013-05-01

Stress has a strong influence on pain sensitivity. However, the direction of this influence is unclear. Recent studies reported both decreased and increased pain sensitivities under stress, and one hypothesis is that interindividual differences account for these differences. The aim of our study was to investigate the effect of stress on individual pain sensitivity in a relatively large female sample. Eighty female participants were included. Pain thresholds and temporal summation of pain were tested before and after stress, which was induced by the Mannheim Multicomponent Stress Test. In an independent sample of 20 women, correlation coefficients between 0.45 and 0.89 indicated relatively high test-retest reliability for pain measurements. On average, there were significant differences between pain thresholds under non-stress and stress conditions, indicating an increased sensitivity to pain under stress. No significant differences between non-stress and stress conditions were found for temporal summation of pain. On an individual basis, both decreased and increased pain sensitivities under stress conditions based on Jacobson's criteria for reliable change were observed. Furthermore, we found significant negative associations between pain sensitivity under non-stress conditions and individual change of pain sensitivity under stress. Participants with relatively high pain sensitivity under non-stress conditions became less sensitive under stress and vice versa. These findings support the view that pain sensitivity under stress shows large interindividual variability, and point to a possible dichotomy of altered pain sensitivity under stress. Wiley Periodicals, Inc.

DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.

PubMed

Nahid, Noor Ahmed; Apu, Mohd Nazmul Hasan; Islam, Md Reazul; Shabnaz, Samia; Chowdhury, Surid Mohammad; Ahmed, Maizbha Uddin; Nahar, Zabun; Islam, Md Siddiqul; Islam, Mohammad Safiqul; Hasnat, Abul

2018-01-01

Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients. Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. DPYD and MTHFR polymorphisms were assessed in peripheral leukocytes. Multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity and efficacy. Multivariate analyses showed that DPYD*2A polymorphism was a predictive factor (P = 0.023) for grade 3 and grade 4 5-fluorouracil-related toxicities. Although MTHFR C677T polymorphism might act as forecasters for grade 3 or grade 4 neutropenia, diarrhea, and mucositis, this polymorphism was found to increase significantly (P = 0.006) the response of 5-FU. DPYD*2A and MTHFR C677T polymorphisms could explain 5-FU toxicity or clinical outcome in Bangladeshi colorectal patients.

Temporal dynamics of circadian phase shifting response to consecutive night shifts in healthcare workers: role of light-dark exposure.

PubMed

Stone, Julia E; Sletten, Tracey L; Magee, Michelle; Ganesan, Saranea; Mulhall, Megan D; Collins, Allison; Howard, Mark; Lockley, Steven W; Rajaratnam, Shantha M W

2018-06-01

Shift work is highly prevalent and is associated with significant adverse health impacts. There is substantial inter-individual variability in the way the circadian clock responds to changing shift cycles. The mechanisms underlying this variability are not well understood. We tested the hypothesis that light-dark exposure is a significant contributor to this variability; when combined with diurnal preference, the relative timing of light exposure accounted for 71% of individual variability in circadian phase response to night shift work. These results will drive development of personalised approaches to manage circadian disruption among shift workers and other vulnerable populations to potentially reduce the increased risk of disease in these populations. Night shift workers show highly variable rates of circadian adaptation. This study examined the relationship between light exposure patterns and the magnitude of circadian phase resetting in response to night shift work. In 21 participants (nursing and medical staff in an intensive care unit) circadian phase was measured using 6-sulphatoxymelatonin at baseline (day/evening shifts or days off) and after 3-4 consecutive night shifts. Daily light exposure was examined relative to individual circadian phase to quantify light intensity in the phase delay and phase advance portions of the light phase response curve (PRC). There was substantial inter-individual variability in the direction and magnitude of phase shift after three or four consecutive night shifts (mean phase delay -1:08 ± 1:31 h; range -3:43 h delay to +3:07 h phase advance). The relative difference in the distribution of light relative to the PRC combined with diurnal preference accounted for 71% of the variability in phase shift. Regression analysis incorporating these factors estimated phase shift to within ±60 min in 85% of participants. No participants met criteria for partial adaptation to night work after three or four consecutive night shifts. Our findings provide evidence that the phase resetting that does occur is based on individual light exposure patterns relative to an individual's baseline circadian phase. Thus, a 'one size fits all' approach to promoting adaptation to shift work using light therapy, implemented without knowledge of circadian phase, may not be efficacious for all individuals. © 2018 Monash University. The Journal of Physiology © 2018 The Physiological Society.

HUMAN INTERINDIVIDUAL VARIABILITY IN SUSCEPTIBILITY TO AIRBORNE PARTICLES

EPA Science Inventory

Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This stu...

Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy

PubMed Central

Fisch, Adam S.; Perry, Christina G.; Stephens, Sarah H.; Horenstein, Richard B.; Shuldiner, Alan R.

2013-01-01

Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with the new diagnostic targets and therapeutic strategies on the horizon hold promise for more effective individualized anti-coagulation and anti-platelet therapy. PMID:23797323

Genetic characterization of Colombian Bahman cattle using microsatellites markers.

PubMed

Gómez, Y M; Fernandez, M; Rivera, D; Gómez, G; Bernal, J E

2013-07-01

Genetic structure and diversity of 3789 animals of the Brahman breed from 23 Colombian regions were assessed. Considering the Brahman Zebu cattle as a single population, the multilocus test based on the HW equilibrium, shows significant differences (P < 0.001). Genetic characterization made on the cattle population allowed to examine the genetic variability, calculating a H(o) = 0.6621. Brahman population in Colombia was a small subdivision within populations (F(it) = 0.045), a geographic subdivision almost non-existent or low differentiation (F(st) = 0.003) and the F(is) calculated (0.042) indicates no detriment to the variability in the population, despite the narrow mating takes place or there is a force that causes the variability is sustained without inbreeding actually affect the cattle population. The outcomes of multivariate analyses, Bayesian inferences and interindividual genetic distances suggested that there is no genetic sub-structure in the population, because of the high rate of animal migration among regions.

Incorporating Human Interindividual Biotransformation Variance in Health Risk Assessment

EPA Science Inventory

The protection of sensitive individuals within a population dictates that measures other than central tendencies be employed to estimate risk. The refinement of human health risk assessments for chemicals metabolized by the liver to reflect data on human variability can be accom...

The contribution of wine-derived monoterpene glycosides to retronasal odour during tasting.

PubMed

Parker, Mango; Black, Cory A; Barker, Alice; Pearson, Wes; Hayasaka, Yoji; Francis, I Leigh

2017-10-01

This study investigated the sensory significance of monoterpene glycosides during tasting, by retronasal perception of odorant aglycones released in-mouth. Monoterpene glycosides were isolated from Gewürztraminer and Riesling juices and wines, chemically characterised and studied using sensory time-intensity methodology, together with a synthesised monoterpene glucoside. When assessed in model wine at five times wine-like concentration, Gewürztraminer glycosides and geranyl glucoside gave significant fruity flavour, although at wine-like concentrations, or in the presence of wine volatiles, the effect was not significant. Gewürztraminer glycosides, geranyl glucoside and guaiacyl glucoside were investigated using a sensory panel (n=39), revealing large inter-individual variability, with 77% of panellists responding to at least one glycoside. The study showed for the first time that grape-derived glycosides can contribute perceptible fruity flavour, providing a means of enhancing flavour in wines, and confirms the results of previous studies that the effect is highly variable across individuals. Copyright © 2017 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bogen, K.T.; Conrado, C.L.; Robison, W.L.

A detailed analysis of uncertainty and interindividual variability in estimated doses was conducted for a rehabilitation scenario for Bikini Island at Bikini Atoll, in which the top 40 cm of soil would be removed in the housing and village area, and the rest of the island is treated with potassium fertilizer, prior to an assumed resettlement date of 1999. Predicted doses were considered for the following fallout-related exposure pathways: ingested Cesium-137 and Strontium-90, external gamma exposure, and inhalation and ingestion of Americium-241 + Plutonium-239+240. Two dietary scenarios were considered: (1) imported foods are available (IA), and (2) imported foods aremore » unavailable (only local foods are consumed) (IUA). Corresponding calculations of uncertainty in estimated population-average dose showed that after {approximately}5 y of residence on Bikini, the upper and lower 95% confidence limits with respect to uncertainty in this dose are estimated to be approximately 2-fold higher and lower than its population-average value, respectively (under both IA and IUA assumptions). Corresponding calculations of interindividual variability in the expected value of dose with respect to uncertainty showed that after {approximately}5 y of residence on Bikini, the upper and lower 95% confidence limits with respect to interindividual variability in this dose are estimated to be approximately 2-fold higher and lower than its expected value, respectively (under both IA and IUA assumptions). For reference, the expected values of population-average dose at age 70 were estimated to be 1.6 and 5.2 cSv under the IA and IUA dietary assumptions, respectively. Assuming that 200 Bikini resettlers would be exposed to local foods (under both IA and IUA assumptions), the maximum 1-y dose received by any Bikini resident is most likely to be approximately 2 and 8 mSv under the IA and IUA assumptions, respectively.« less

Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate.

PubMed

Joerger, Markus; Ferreri, Andrés J M; Krähenbühl, Stephan; Schellens, Jan H M; Cerny, Thomas; Zucca, Emanuele; Huitema, Alwin D R

2012-02-01

There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h. A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four. The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24) < 0.5 µmol l(-1) up to -35% in patients with MTX C(24) > 12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure. A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL). © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Use of Mechanistic Modeling to Assess Interindividual Variability and Interspecies Differences in Active Uptake in Human and Rat Hepatocytes

PubMed Central

Ménochet, Karelle; Kenworthy, Kathryn E.; Houston, J. Brian

2012-01-01

Interindividual variability in activity of uptake transporters is evident in vivo, yet limited data exist in vitro, confounding in vitro-in vivo extrapolation. The uptake kinetics of seven organic anion-transporting polypeptide substrates was investigated over a concentration range in plated cryopreserved human hepatocytes. Active uptake clearance (CLactive, u), bidirectional passive diffusion (Pdiff), intracellular binding, and metabolism were estimated for bosentan, pitavastatin, pravastatin, repaglinide, rosuvastatin, telmisartan, and valsartan in HU4122 donor using a mechanistic two-compartment model in Matlab. Full uptake kinetics of rosuvastatin and repaglinide were also characterized in two additional donors, whereas for the remaining drugs CLactive, u was estimated at a single concentration. The unbound affinity constant (Km, u) and Pdiff values were consistent across donors, whereas Vmax was on average up to 2.8-fold greater in donor HU4122. Consistency in Km, u values allowed extrapolation of single concentration uptake activity data and assessment of interindividual variability in CLactive across donors. The maximal contribution of active transport to total uptake differed among donors, for example, 85 to 96% and 68 to 87% for rosuvastatin and repaglinide, respectively; however, in all cases the active process was the major contributor. In vitro-in vivo extrapolation indicated a general underprediction of hepatic intrinsic clearance, an average empirical scaling factor of 17.1 was estimated on the basis of seven drugs investigated in three hepatocyte donors, and donor-specific differences in empirical factors are discussed. Uptake Km, u and CLactive, u were on average 4.3- and 7.1-fold lower in human hepatocytes compared with our previously published rat data. A strategy for the use of rat uptake data to facilitate the experimental design in human hepatocytes is discussed. PMID:22665271

PXR, CAR and HNF4alpha genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients.

PubMed

Hor, S Y; Lee, S C; Wong, C I; Lim, Y W; Lim, R C; Wang, L Z; Fan, L; Guo, J Y; Lee, H S; Goh, B C; Tan, T

2008-04-01

Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.

A Comparative Study of Finland and Chile: The Culture-Dependent Significance of the Individual and Interindividual Levels of the Mathematics-Related Affect

ERIC Educational Resources Information Center

Tuohilampi, Laura; Laine, Anu; Hannula, Markku S.; Varas, Leonor

2016-01-01

Mathematics-related affect is established regarding both individual and interindividual levels. However, the interaction between the levels has not been elaborated. Furthermore, it is known that people may draw either from intrinsic or extrinsic experiences to construct their identities depending on their cultural environment. Thus, affective…

Interindividual and intraindividual variations in postprandial glycemia peak time complicate precise recommendations for self-monitoring of glucose in persons with type 1 diabetes mellitus.

PubMed

Johansen, Mette Dencker; Gjerløv, Irene; Christiansen, Jens Sandahl; Hejlesen, Ole K

2012-03-01

In glycemic control, postprandial glycemia may be important to monitor and optimize as it reveals glycemic control quality, and postprandial hyperglycemia partly predicts late diabetic complications. Self-monitoring of blood glucose (SMBG) may be an appropriate technology to use, but recommendations on measurement time are crucial. We retrospectively analyzed interindividual and intraindividual variations in postprandial glycemic peak time. Continuous glucose monitoring (CGM) and carbohydrate intake were collected in 22 patients with type 1 diabetes mellitus. Meals were identified from carbohydrate intake data. For each meal, peak time was identified as time from meal to CGM zenith within 40-150 min after meal start. Interindividual (one-way Anova) and intraindividual (intraclass correlation coefficient) variation was calculated. Nineteen patients were included with sufficient meal data quality. Mean peak time was 87 ± 29 min. Mean peak time differed significantly between patients (p = 0.02). Intraclass correlation coefficient was 0.29. Significant interindividual and intraindividual variations exist in postprandial glycemia peak time, thus hindering simple and general advice regarding postprandial SMBG for detection of maximum values. © 2012 Diabetes Technology Society.

Seasonal Trends and Inter-Individual Heterogeneity: A multi-species record of Mg, Sr, Ba, & Mn in Planktic Foraminifera from the Modern Cariaco Basin

NASA Astrophysics Data System (ADS)

Davis, C. V.; Thunell, R.; Astor, Y. M.

2017-12-01

The trace element to calcium ratios (TE/Ca) of planktic foraminifera shells are a valuable tool for paleoceanographic reconstructions, and represent a combination of environmental, ecological and biological signals. We present here a three-year record (2010-2013) of TE/Ca (Mg, Sr, Ba, Mn) from four species of foraminifera (Orbulina universa, Globigerina ruber, Globigerinella siphonifera, and Globorotalia menardii) collected by plankton tow in the modern Cariaco basin. Each tow is paired with in situ measurements of water column properties, allowing a direct comparison between shell geochemistry and calcification environment. A combination of Laser Ablation and solution ICP-MS analyses are used to document seasonality, primarily due to the alternating influence of wind-driven coastal upwelling and riverine inputs, in shell TE/Ca. Individual shell data further allows for the quantification of trace element heterogeneity among individual shells within single tows. All TE/Ca ratios vary temporally and show inter-individual variability within single tows. The spread in TE/Ca differs between element and species, with Mg/Ca ratios being the most variable. Despite this, Mg/Ca still tracks temperature changes in G. ruber, O. universa, and G. menardii, with G. ruber most closely reproducing sea surface temperature. Some species show chamber-to-chamber differences in trace element ratios, with G. ruber Mg/Ca and Ba/Ca decreasing in younger chambers (but not other elements) and Mg/Ca, Mn/Ca and Ba/Ca decreasing in younger chambers in G. siphonifera. We find the original Mn/Ca to be variable both temporally and between species, with G. menardii in some samples having extremely high ratios (100 μmol/mol). Assessing seasonal trends and environmental drivers of TE/Ca variability and quantifying the extent of inter-individual heterogeneity in these species will inform the use of their shells as geochemical proxies.

Menaquinones content of human serum and feces

USDA-ARS?s Scientific Manuscript database

Bacterially-synthesized menaquinones (MKn) may contribute to vitamin K (VK) nutriture. There are limited data on interindividual variability in endogenous MK synthesis and its relation to circulating forms of VK. Serum and fecal VK concentrations were assessed in 13 healthy adults (45-65 yr) consumi...

Interindividual variability in sweat electrolyte concentration in marathoners.

PubMed

Lara, Beatriz; Gallo-Salazar, César; Puente, Carlos; Areces, Francisco; Salinero, Juan José; Del Coso, Juan

2016-01-01

Sodium (Na(+)) intake during exercise aims to replace the Na(+) lost by sweat to avoid electrolyte imbalances, especially in endurance disciplines. However, Na(+) needs can be very different among individuals because of the great inter-individual variability in sweat electrolyte concentration. The aim of this investigation was to determine sweat electrolyte concentration in a large group of marathoners. A total of 157 experienced runners (141 men and 16 women) completed a marathon race (24.4 ± 3.6 °C and 27.7 ± 4.8 % of humidity). During the race, sweat samples were collected by using sweat patches placed on the runners' forearms. Sweat electrolyte concentration was measured by using photoelectric flame photometry. As a group, sweat Na(+) concentration was 42.9 ± 18.7 mmol·L(-1) (minimal-maximal value = 7.0-95.5 mmol·L(-1)), sweat Cl(-) concentration was 32.2 ± 15.6 mmol·L(-1) (7.3-90.6 mmol·L(-1)) and sweat K(+) concentration was 6.0 ± 0.9 mmol·L(-1) (3.1-8.0 mmol·L(-1)). Women presented lower sweat Na(+) (33.9 ± 12.1 vs 44.0 ± 19.1 mmol·L(-1); P = 0.04) and sweat Cl(-) concentrations (22.9 ± 10.5 vs 33.2 ± 15.8 mmol·L(-1); P = 0.01) than men. A 20 % of individuals presented a sweat Na(+) concentration higher than 60 mmol·L(-1) while this threshold was not surpassed by any female marathoner. Sweat electrolyte concentration did not correlate to sweat rate, age, body characteristics, experience or training. Although there was a significant correlation between sweat Na(+) concentration and running pace (r = 0.18; P = 0.03), this association was weak to interpret that sweat Na(+) concentration increased with running pace. The inter-individual variability in sweat electrolyte concentration was not explained by any individual characteristics except for individual running pace and sex. An important portion (20 %) of marathoners might need special sodium intake recommendations due to their high sweat salt losses.

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo.

PubMed

Asakura, Mitsutoshi; Fukami, Tatsuki; Nakajima, Miki; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

2017-02-01

The main route of elimination of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is cyano group hydrolysis to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice coadministered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice. The area under the plasma concentration-time curve (AUC) value of M20.7 in mice coadministered with vildagliptin and sitagliptin was significantly lower than that in mice administered vildagliptin alone (P < 0.01). Although plasma DPP-4 expression level was increased 1.9-fold, hepatic DPP-4 activity was decreased in STZ-induced diabetic mice. The AUC values of M20.7 in STZ-induced diabetic mice were lower than those in control mice (P < 0.01). Additionally, the AUC values of M20.7 significantly positively correlated with hepatic DPP-4 activities in the individual mice (Rs = 0.943, P < 0.05). These findings indicated that DPP-4 greatly contributed to the hydrolysis of vildagliptin in vivo and that not plasma, but hepatic DPP-4 controlled pharmacokinetics of vildagliptin. Furthermore, enzyme assays of 23 individual human liver samples showed that there was a 3.6-fold interindividual variability in vildagliptin-hydrolyzing activities. Predetermination of the interindividual variability of hepatic vildagliptin-hydrolyzing activity might be useful for the prediction of blood vildagliptin concentrations in vivo. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Relative Composition of Fibrous Connective and Fatty/Glandular Tissue in Connective Tissue Grafts Depends on the Harvesting Technique but not the Donor Site of the Hard Palate.

PubMed

Bertl, Kristina; Pifl, Markus; Hirtler, Lena; Rendl, Barbara; Nürnberger, Sylvia; Stavropoulos, Andreas; Ulm, Christian

2015-12-01

Whether the composition of palatal connective tissue grafts (CTGs) varies depending on donor site or harvesting technique in terms of relative amounts of fibrous connective tissue (CT) and fatty/glandular tissue (FGT) is currently unknown and is histologically assessed in the present study. In 10 fresh human cadavers, tissue samples were harvested in the anterior and posterior palate and in areas close to (marginal) and distant from (apical) the mucosal margin. Mucosal thickness, lamina propria thickness (defined as the extent of subepithelial portion of the biopsy containing ≤25% or ≤50% FGT), and proportions of CT and FGT were semi-automatically estimated for the entire mucosa and for CTGs virtually harvested by split-flap (SF) preparation minimum 1 mm deep or after deepithelialization (DE). Palatal mucosal thickness, ranging from 2.35 to 6.89 mm, and histologic composition showed high interindividual variability. Lamina propria thickness (P >0.21) and proportions of CT (P = 0.48) and FGT (P = 0.15) did not differ significantly among the donor sites (anterior, posterior, marginal, apical). However, thicker palatal tissue was associated with higher FGT content (P <0.01) and thinner lamina propria (P ≤0.03). Independent of the donor site, DE-harvested CTG contained a significantly higher proportion of CT and a lower proportion of FGT than an SF-harvested CTG (P <0.04). Despite high interindividual variability in terms of relative tissue composition in the hard palate, DE-harvested CTG contains much larger amounts of CT and much lower amounts of FGT than SF-harvested CTG, irrespective of the harvesting site.

Personality Traits and Behavioral Syndromes in Differently Urbanized Populations of House Sparrows (Passer domesticus)

PubMed Central

Bókony, Veronika; Kulcsár, Anna; Tóth, Zoltán; Liker, András

2012-01-01

Urbanization creates novel environments for wild animals where selection pressures may differ drastically from those in natural habitats. Adaptation to urban life involves changes in various traits, including behavior. Behavioral traits often vary consistently among individuals, and these so-called personality traits can be correlated with each other, forming behavioral syndromes. Despite their adaptive significance and potential to act as constraints, little is known about the role of animal personality and behavioral syndromes in animals' adaptation to urban habitats. In this study we tested whether differently urbanized habitats select for different personalities and behavioral syndromes by altering the population mean, inter-individual variability, and correlations of personality traits. We captured house sparrows (Passer domesticus) from four different populations along the gradient of urbanization and assessed their behavior in standardized test situations. We found individual consistency in neophobia, risk taking, and activity, constituting three personality axes. On the one hand, urbanization did not consistently affect the mean and variance of these traits, although there were significant differences between some of the populations in food neophobia and risk taking (both in means and variances). On the other hand, both urban and rural birds exhibited a behavioral syndrome including object neophobia, risk taking and activity, whereas food neophobia was part of the syndrome only in rural birds. These results indicate that there are population differences in certain aspects of personality in house sparrows, some of which may be related to habitat urbanization. Our findings suggest that urbanization and/or other population-level habitat differences may not only influence the expression of personality traits but also alter their inter-individual variability and the relationships among them, changing the structure of behavioral syndromes. PMID:22574204

Water-induced thermogenesis and fat oxidation: a reassessment

PubMed Central

Charrière, N; Miles-Chan, J L; Montani, J-P; Dulloo, A G

2015-01-01

Background/Objectives: Drinking large amounts of water is often recommended for weight control. Whether water intake stimulates energy and fat metabolism is, however, controversial with some studies reporting that drinking half a litre or more of water increases resting energy expenditure (REE) by 10–30% and decreases respiratory quotient (RQ), whereas others report no significant changes in REE or RQ. The aim here was to reassess the concept of water-induced thermogenesis and fat oxidation in humans, with particular focus on interindividual variability in REE and RQ responses, comparison with a time-control Sham drink, and on the potential impact of gender, body composition and abdominal adiposity. Subjects/Methods: REE and RQ were measured in healthy young adults (n=27; body mass index range: 18.5–33.9 kg m−2), by ventilated hood indirect calorimetry for at least 30 min before and 130 min after ingesting 500 ml of purified (distilled) water at 21–22 °C or after Sham drinking, in a randomized cross-over design. Body composition and abdominal fat were assessed by bioimpedance techniques. Results: Drinking 500 ml of distilled water led to marginal increases in REE (<3% above baseline), independently of gender, but which were not significantly different from Sham drinking. RQ was found to fall after the water drink, independently of gender, but it also diminished to a similar extent in response to sham drinking. Interindividual variability in REE and RQ responses was not associated with body fatness, central adiposity or fat-free mass. Conclusions: This study conducted in young men and women varying widely in adiposity, comparing the ingestion of distilled water to Sham drinking, suggests that ingestion of purified water per se does not result in the stimulation of thermogenesis or fat oxidation. PMID:26690288

Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women

USDA-ARS?s Scientific Manuscript database

A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the estrogen receptor alpha gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT. We studied the effect of sin...

Key interindividual determinants in MDMA pharmacodynamics.

PubMed

Papaseit, E; Torrens, M; Pérez-Mañá, C; Muga, R; Farré, M

2018-02-01

MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.

ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors.

PubMed

Danilov, Sergei M; Tovsky, Stan I; Schwartz, David E; Dull, Randal O

2017-07-01

Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response. To investigate whether interindividual variability in the response to ACE inhibitors is explained by the "ACE phenotype"-for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. Due to the fact that "20% of patients do not respond to ACEI by blood pressure drop," the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.

On the nature of motor planning variables during arm pointing movement: Compositeness and speed dependence.

PubMed

Vu, Van Hoan; Isableu, Brice; Berret, Bastien

2016-07-22

The purpose of this study was to investigate the nature of the variables and rules underlying the planning of unrestrained 3D arm reaching. To identify whether the brain uses kinematic, dynamic and energetic values in an isolated manner or combines them in a flexible way, we examined the effects of speed variations upon the chosen arm trajectories during free arm movements. Within the optimal control framework, we uncovered which (possibly composite) optimality criterion underlays at best the empirical data. Fifteen participants were asked to perform free-endpoint reaching movements from a specific arm configuration at slow, normal and fast speeds. Experimental results revealed that prominent features of observed motor behaviors were significantly speed-dependent, such as the chosen reach endpoint and the final arm posture. Nevertheless, participants exhibited different arm trajectories and various degrees of speed dependence of their reaching behavior. These inter-individual differences were addressed using a numerical inverse optimal control methodology. Simulation results revealed that a weighted combination of kinematic, energetic and dynamic cost functions was required to account for all the critical features of the participants' behavior. Furthermore, no evidence for the existence of a speed-dependent tuning of these weights was found, thereby suggesting subject-specific but speed-invariant weightings of kinematic, energetic and dynamic variables during the motor planning process of free arm movements. This suggested that the inter-individual difference of arm trajectories and speed dependence was not only due to anthropometric singularities but also to critical differences in the composition of the subjective cost function. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of the Brain-Derived Neurotrophic Factor Val66Met polymorphism and resting brain functional connectivity on individual differences in tactile cognitive performance in healthy young adults.

PubMed

Yang, Xuejuan; Xu, Ziliang; Liu, Lin; Liu, Peng; Sun, Jinbo; Jin, Lingmin; Zhu, Yuanqiang; Fei, Ningbo; Qin, Wei

2017-07-28

Cognitive processes involve input from multiple sensory modalities and obvious differences in the level of cognitive function can be observed between individuals. Evidence to date understanding the biological basis of tactile cognitive variability, however, is limited compared with other forms of sensory cognition. Data from auditory and visual cognition research suggest that variations in both genetics and intrinsic brain function might contribute to individual differences in tactile cognitive performance. In the present study, by using the tactual performance test (TPT), a widely used neuropsychological assessment tool, we investigated the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and resting-state brain functional connectivity (FC) on interindividual variability in TPT performance in healthy, young Chinese adults. Our results showed that the BDNF genotypes and resting-state FC had significant effects on the variability in TPT performance, together accounting for 32.5% and 19.1% of the variance on TPT total score and Memory subitem score respectively. Having fewer Met alleles, stronger anticorrelations between left posterior superior temporal gyrus and somatosensory areas (right postcentral gyrus and right parietal operculum cortex), and greater positive correlation between left parietal operculum cortex and left central opercular cortex, all correspond with better performance of TPT task. And FC between left parietal operculum cortex and left central opercular cortex might be a mediator of the relationship between BDNF genotypes and Memory subitem score. These data demonstrate a novel contribution of intrinsic brain function to tactile cognitive capacity, and further confirm the genetic basis of tactile cognition. Our findings might also explain the interindividual differences in cognitive ability observed in those who are blind and/or deaf from a new perspective. Copyright © 2017. Published by Elsevier Ltd.

Gene Expression Signatures Characterized by Longitudinal Stability and Interindividual Variability Delineate Baseline Phenotypic Groups with Distinct Responses to Immune Stimulation.

PubMed

Scheid, Adam D; Van Keulen, Virginia P; Felts, Sara J; Neier, Steven C; Middha, Sumit; Nair, Asha A; Techentin, Robert W; Gilbert, Barry K; Jen, Jin; Neuhauser, Claudia; Zhang, Yuji; Pease, Larry R

2018-03-01

Human immunity exhibits remarkable heterogeneity among individuals, which engenders variable responses to immune perturbations in human populations. Population studies reveal that, in addition to interindividual heterogeneity, systemic immune signatures display longitudinal stability within individuals, and these signatures may reliably dictate how given individuals respond to immune perturbations. We hypothesize that analyzing relationships among these signatures at the population level may uncover baseline immune phenotypes that correspond with response outcomes to immune stimuli. To test this, we quantified global gene expression in peripheral blood CD4 + cells from healthy individuals at baseline and following CD3/CD28 stimulation at two time points 1 mo apart. Systemic CD4 + cell baseline and poststimulation molecular immune response signatures (MIRS) were defined by identifying genes expressed at levels that were stable between time points within individuals and differential among individuals in each state. Iterative differential gene expression analyses between all possible phenotypic groupings of at least three individuals using the baseline and stimulated MIRS gene sets revealed shared baseline and response phenotypic groupings, indicating the baseline MIRS contained determinants of immune responsiveness. Furthermore, significant numbers of shared phenotype-defining sets of determinants were identified in baseline data across independent healthy cohorts. Combining the cohorts and repeating the analyses resulted in identification of over 6000 baseline immune phenotypic groups, implying that the MIRS concept may be useful in many immune perturbation contexts. These findings demonstrate that patterns in complex gene expression variability can be used to define immune phenotypes and discover determinants of immune responsiveness. Copyright © 2018 by The American Association of Immunologists, Inc.

Characterizing Individual Differences in Functional Connectivity Using Dual-Regression and Seed-Based Approaches

PubMed Central

Smith, David V.; Utevsky, Amanda V.; Bland, Amy R.; Clement, Nathan; Clithero, John A.; Harsch, Anne E. W.; Carter, R. McKell; Huettel, Scott A.

2014-01-01

A central challenge for neuroscience lies in relating inter-individual variability to the functional properties of specific brain regions. Yet, considerable variability exists in the connectivity patterns between different brain areas, potentially producing reliable group differences. Using sex differences as a motivating example, we examined two separate resting-state datasets comprising a total of 188 human participants. Both datasets were decomposed into resting-state networks (RSNs) using a probabilistic spatial independent components analysis (ICA). We estimated voxelwise functional connectivity with these networks using a dual-regression analysis, which characterizes the participant-level spatiotemporal dynamics of each network while controlling for (via multiple regression) the influence of other networks and sources of variability. We found that males and females exhibit distinct patterns of connectivity with multiple RSNs, including both visual and auditory networks and the right frontal-parietal network. These results replicated across both datasets and were not explained by differences in head motion, data quality, brain volume, cortisol levels, or testosterone levels. Importantly, we also demonstrate that dual-regression functional connectivity is better at detecting inter-individual variability than traditional seed-based functional connectivity approaches. Our findings characterize robust—yet frequently ignored—neural differences between males and females, pointing to the necessity of controlling for sex in neuroscience studies of individual differences. Moreover, our results highlight the importance of employing network-based models to study variability in functional connectivity. PMID:24662574

Do PTK2 gene polymorphisms contribute to the interindividual variability in muscle strength and the response to resistance training? A preliminary report.

PubMed

Erskine, Robert M; Williams, Alun G; Jones, David A; Stewart, Claire E; Degens, Hans

2012-04-01

The protein tyrosine kinase-2 (PTK2) gene encodes focal adhesion kinase, a structural protein involved in lateral transmission of muscle fiber force. We investigated whether single-nucleotide polymorphisms (SNPs) of the PTK2 gene were associated with various indexes of human skeletal muscle strength and the interindividual variability in the strength responses to resistance training. We determined unilateral knee extension single repetition maximum (1-RM), maximum isometric voluntary contraction (MVC) knee joint torque, and quadriceps femoris muscle specific force (maximum force per unit physiological cross-sectional area) before and after 9 wk of knee extension resistance training in 51 untrained young men. All participants were genotyped for the PTK2 intronic rs7843014 A/C and 3'-untranslated region (UTR) rs7460 A/T SNPs. There were no genotype associations with baseline measures or posttraining changes in 1-RM or MVC. Although the training-induced increase in specific force was similar for all PTK2 genotypes, baseline specific force was higher in PTK2 rs7843014 AA and rs7460 TT homozygotes than in the respective rs7843014 C- (P = 0.016) and rs7460 A-allele (P = 0.009) carriers. These associations between muscle specific force and PTK2 SNPs suggest that interindividual differences exist in the way force is transmitted from the muscle fibers to the tendon. Therefore, our results demonstrate for the first time the impact of genetic variation on the intrinsic strength of human skeletal muscle.

Meta-analysis of genome-wide association studies for circulating phylloquinone concentrations

USDA-ARS?s Scientific Manuscript database

Background: Poor vitamin K status is linked to greater risk of several chronic diseases. Age, sex, and diet are determinants of circulating vitamin K; however, there is still large unexplained interindividual variability in vitamin K status. Although a strong genetic component has been hypothesized,...

Intergrating in Vitro and In Silico Approaches to Assess Inter-individual Toxicokinetic Variability

EPA Science Inventory

This educational talk provided an introduction to what is currently known to contribute to differences in how various populations and life stages metabolize chemicals to which they are exposed. These differences will impact how different populations may be affected following chem...

Revisiting the Dedifferentiation Hypothesis with Longitudinal Multi-Cohort Data

ERIC Educational Resources Information Center

de Frias, Cindy M.; Lovden, Martin; Lindenberger, Ulman; Nilsson, Lars-Goran

2007-01-01

The present longitudinal multi-cohort study examines whether interindividual variability in cognitive performance and change increases in old age, and whether associations among developments of different cognitive functions increase with adult age. Multivariate multiple-group latent growth modeling was applied to data from narrow cohorts separated…

Attitudes towards Foreign Accents among Adult Multilingual Language Users

ERIC Educational Resources Information Center

Dewaele, Jean-Marc; McCloskey, James

2015-01-01

The present study investigates inter-individual variation (linked to personality traits, multilingualism and sociobiographical variables) in the attitudes that 2035 multilinguals have of their own and others' foreign accent (FA). Data were collected through an online questionnaire. We found that multilinguals who were extraverted, emotionally…

Analytical and biological variability in biomarker measurement in the Hispanic Community Health Study/Study of Latinos.

PubMed

Thyagarajan, Bharat; Howard, Annie Green; Durazo-Arvizu, Ramon; Eckfeldt, John H; Gellman, Marc D; Kim, Ryung S; Liu, Kiang; Mendez, Armando J; Penedo, Frank J; Talavera, Gregory A; Youngblood, Marston E; Zhao, Lihui; Sotres-Alvarez, Daniela

2016-12-01

Biomarker variability, which includes within-individual variability (CV I ), between-individual variability (CV G ) and methodological variability (CV P + A ) is an important determinant of our ability to detect biomarker-disease associations. Estimates of CV I and CV G may be population specific and little data exists on biomarker variability in diverse Hispanic populations. Hence, we evaluated all 3 components of biomarker variability in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) using repeat blood collections (n=58) and duplicate blood measurements (n=761-929 depending on the biomarker). We estimated the index of individuality (II) ((CV I +CV P + A )/CV G ) for 41 analytes and evaluated differences in the II across sexes and age groups. Biomarkers such as fasting glucose, triglycerides and ferritin had substantially higher inter-individual variability and lower II in HCHS/SOL as compared to the published literature. We also found significant sex-specific differences in the II for neutrophil count, platelet count, hemoglobin, % eosinophils and fasting glucose. The II for fasting insulin, post oral glucose tolerance test glucose and cystatin C was significantly higher among the 18-44y age group as compared to the 45+y age group. The implications of these findings for determining biomarker-disease associations in Hispanic populations need to be evaluated in future studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Ocean acidification impacts on sperm mitochondrial membrane potential bring sperm swimming behaviour near its tipping point.

PubMed

Schlegel, Peter; Binet, Monique T; Havenhand, Jonathan N; Doyle, Christopher J; Williamson, Jane E

2015-04-01

Broadcast spawning marine invertebrates are susceptible to environmental stressors such as climate change, as their reproduction depends on the successful meeting and fertilization of gametes in the water column. Under near-future scenarios of ocean acidification, the swimming behaviour of marine invertebrate sperm is altered. We tested whether this was due to changes in sperm mitochondrial activity by investigating the effects of ocean acidification on sperm metabolism and swimming behaviour in the sea urchin Centrostephanus rodgersii. We used a fluorescent molecular probe (JC-1) and flow cytometry to visualize mitochondrial activity (measured as change in mitochondrial membrane potential, MMP). Sperm MMP was significantly reduced in ΔpH -0.3 (35% reduction) and ΔpH -0.5 (48% reduction) treatments, whereas sperm swimming behaviour was less sensitive with only slight changes (up to 11% decrease) observed overall. There was significant inter-individual variability in responses of sperm swimming behaviour and MMP to acidified seawater. We suggest it is likely that sperm exposed to these changes in pH are close to their tipping point in terms of physiological tolerance to acidity. Importantly, substantial inter-individual variation in responses of sperm swimming to ocean acidification may increase the scope for selection of resilient phenotypes, which, if heritable, could provide a basis for adaptation to future ocean acidification. © 2015. Published by The Company of Biologists Ltd.

On Older Listeners' Ability to Perceive Dynamic Pitch

ERIC Educational Resources Information Center

Shen, Jing; Wright, Richard; Souza, Pamela E.

2016-01-01

Purpose: Natural speech comes with variation in pitch, which serves as an important cue for speech recognition. The present study investigated older listeners' dynamic pitch perception with a focus on interindividual variability. In particular, we asked whether some of the older listeners' inability to perceive dynamic pitch stems from the higher…

1997 Toxic Hazards Research Annual Report

DTIC Science & Technology

1998-05-01

TYPE AND DATES COVERED I May 1998 Interim Report - October 1996-September 1997 4 . TITLE AND SUBTITLE 5. FUNDING NUMBERS 1997 Toxic Hazards Research... 4 3 TRICHLOROETHYLENE (TCE) CARCINOGENICITY PROJECT ......................... 7 3.1 SYNTHESIS AND...EXPERIMENTAL ERROR AND INTERINDIVIDUAL VARIABILITY .................. 20 J.Z. Byczkowski and J.C. Lipscomb 4 HALON REPLACEMENT TOXICITY PROJECT

Intra- and Inter-Individual Variability in Location Data for Two U.S. Health-Compromised Elderly Cohorts

EPA Science Inventory

This study provides descriptive statistical data on daily time spent in three locations of exposure assessment interest for two panel studies of health-compromised elderly individuals > 65 y old having multi-days of human activity data. The panel studies include individuals livi...

Intergenerational Grandparent/Grandchild Relations: The Socioeducational Role of Grandparents

ERIC Educational Resources Information Center

Bernal, Jeronimo Gonzalez; Anuncibay, Raquel de la Fuente

2008-01-01

Intergenerational relationships established between grandparents and grandchildren have aroused great scientific interest in recent years. It is true that, nowadays, different studies have been conducted in which the typology of these relationships has been researched. Studies have used variables such as intra- and interindividual styles in the…

Variations of Histone Modification Patterns: Contributions of Inter-plant Variability and Technical Factors

PubMed Central

Brabencová, Sylva; Ihnatová, Ivana; Potěšil, David; Fojtová, Miloslava; Fajkus, Jiří; Zdráhal, Zbyněk; Lochmanová, Gabriela

2017-01-01

Inter-individual variability of conspecific plants is governed by differences in their genetically determined growth and development traits, environmental conditions, and adaptive responses under epigenetic control involving histone post-translational modifications. The apparent variability in histone modifications among plants might be increased by technical variation introduced in sample processing during epigenetic analyses. Thus, to detect true variations in epigenetic histone patterns associated with given factors, the basal variability among samples that is not associated with them must be estimated. To improve knowledge of relative contribution of biological and technical variation, mass spectrometry was used to examine histone modification patterns (acetylation and methylation) among Arabidopsis thaliana plants of ecotypes Columbia 0 (Col-0) and Wassilewskija (Ws) homogenized by two techniques (grinding in a cryomill or with a mortar and pestle). We found little difference in histone modification profiles between the ecotypes. However, in comparison of the biological and technical components of variability, we found consistently higher inter-individual variability in histone mark levels among Ws plants than among Col-0 plants (grown from seeds collected either from single plants or sets of plants). Thus, more replicates of Ws would be needed for rigorous analysis of epigenetic marks. Regarding technical variability, the cryomill introduced detectably more heterogeneity in the data than the mortar and pestle treatment, but mass spectrometric analyses had minor apparent effects. Our study shows that it is essential to consider inter-sample variance and estimate suitable numbers of biological replicates for statistical analysis for each studied organism when investigating changes in epigenetic histone profiles. PMID:29270186

Variations of Histone Modification Patterns: Contributions of Inter-plant Variability and Technical Factors.

PubMed

Brabencová, Sylva; Ihnatová, Ivana; Potěšil, David; Fojtová, Miloslava; Fajkus, Jiří; Zdráhal, Zbyněk; Lochmanová, Gabriela

2017-01-01

Inter-individual variability of conspecific plants is governed by differences in their genetically determined growth and development traits, environmental conditions, and adaptive responses under epigenetic control involving histone post-translational modifications. The apparent variability in histone modifications among plants might be increased by technical variation introduced in sample processing during epigenetic analyses. Thus, to detect true variations in epigenetic histone patterns associated with given factors, the basal variability among samples that is not associated with them must be estimated. To improve knowledge of relative contribution of biological and technical variation, mass spectrometry was used to examine histone modification patterns (acetylation and methylation) among Arabidopsis thaliana plants of ecotypes Columbia 0 (Col-0) and Wassilewskija (Ws) homogenized by two techniques (grinding in a cryomill or with a mortar and pestle). We found little difference in histone modification profiles between the ecotypes. However, in comparison of the biological and technical components of variability, we found consistently higher inter-individual variability in histone mark levels among Ws plants than among Col-0 plants (grown from seeds collected either from single plants or sets of plants). Thus, more replicates of Ws would be needed for rigorous analysis of epigenetic marks. Regarding technical variability, the cryomill introduced detectably more heterogeneity in the data than the mortar and pestle treatment, but mass spectrometric analyses had minor apparent effects. Our study shows that it is essential to consider inter-sample variance and estimate suitable numbers of biological replicates for statistical analysis for each studied organism when investigating changes in epigenetic histone profiles.

Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1.

PubMed

Tran, Phuong; Yoo, Hee-Doo; Ngo, Lien; Cho, Hea-Young; Lee, Yong-Bok

2017-12-01

The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C > T, 2677G > T/A, and 3435C > T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800 mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Gabapentin showed considerable inter-individual variability (from 5.2- to 8.7-fold) in PK parameters. Serum concentration of gabapentin was well fitted by a one-compartment model with first-order absorption and lag time. An inhibitory Emax model was applied to describe the effect of dose on bioavailability. The oral clearance was estimated to be 11.1 L/h. The volume of distribution was characterized as 81.0 L. The absorption rate constant was estimated at 0.860 h -1 , and the lag time was predicted at 0.311 h. Oral bioavailability was estimated to be 68.8% at dose of 300 mg, 62.7% at dose of 400 mg, and 47.1% at dose of 800 mg. The creatinine clearance significantly influenced on the oral clearance (P < 0.005) and ABCB1 2677G > T/A genotypes significantly influenced on the absorption rate constant (P < 0.05) of gabapentin. However, ABCB1 1236C > T and 3435C > T genotypes showed no significant effect on gabapentin PK parameters. The results of the present study indicate that the oral bioavailability of gabapentin is decreased when its dosage is increased. In addition, ABCB1 2677G > T/A polymorphism can explain the substantial inter-individual variability in the absorption of gabapentin.

Morphology, morphometry and probability mapping of the pars opercularis of the inferior frontal gyrus: an in vivo MRI analysis.

PubMed

Tomaiuolo, F; MacDonald, J D; Caramanos, Z; Posner, G; Chiavaras, M; Evans, A C; Petrides, M

1999-09-01

The pars opercularis occupies the posterior part of the inferior frontal gyrus. Electrical stimulation or damage of this region interferes with language production. The present study investigated the morphology and morphometry of the pars opercularis in 108 normal adult human cerebral hemispheres by means of magnetic resonance imaging. The brain images were transformed into a standardized proportional steoreotaxic space (i.e. that of Talairach and Tournoux) in order to minimize interindividual brain size variability. There was considerable variability in the shape and location of the pars opercularis across brains and between cerebral hemispheres. There was no significant difference or correlation between left and right hemisphere grey matter volumes. There was also no significant difference between sex and side of asymmetry of the pars opercularis. A probability map of the pars opercularis was constructed by averaging its location and extent in each individual normalized brain into Talairach space to aid in localization of activity changes in functional neuroimaging studies.

Glomerular epithelial foot processes in normal man and rats. Distribution of true width and its intra- and inter-individual variation.

PubMed

Gundersen, H J; Seefeldt, T; Osterby, R

1980-01-01

The width of individual glomerular epithelial foot processes appears very different on electron micrographs. A method for obtainining distributions of the true width of foot processes from that of their apparent width on electron micrographs has been developed based on geometric probability theory pertaining to a specific geometric model. Analyses of foot process width in humans and rats show a remarkable interindividual invariance implying rigid control and therefore great biological significance of foot process width or a derivative thereof. The very low inter-individual variation of the true width, shown in the present paper, makes it possible to demonstrate slight changes in rather small groups of patients or experimental animals.

Genetics of human body size and shape: body proportions and indices.

PubMed

Livshits, Gregory; Roset, A; Yakovenko, K; Trofimov, S; Kobyliansky, E

2002-01-01

The study of the genetic component in morphological variables such as body height and weight, head and chest circumference, etc. has a rather long history. However, only a few studies investigated body proportions and configuration. The major aim of the present study was to evaluate the extent of the possible genetic effects on the inter-individual variation of a number of body configuration indices amenable to clear functional interpretation. Two ethnically different pedigree samples were used in the study: (1) Turkmenians (805 individuals) from Central Asia, and (2) Chuvasha (732 individuals) from the Volga riverside, Russian Federation. To achieve the aim of the present study we proposed three new indices, which were subjected to a statistical-genetic analysis using modified version of "FISHER" software. The proposed indices were: (1) an integral index of torso volume (IND#1), an index reflecting a predisposition of body proportions to maintain a balance in a vertical position (IND#2), and an index of skeletal extremities volume (IND#3). Additionally, the first two principal factors (PF1 and PF2) obtained on 19 measurements of body length and breadth were subjected to genetic analysis. Variance decomposition analysis that simultaneously assess the contribution of gender, age, additive genetic effects and effects of environment shared by the nuclear family members, was applied to fit variation of the above three indices, and PF1 and PF2. The raw familial correlation of all study traits and in both samples showed: (1) all marital correlations did not differ significantly from zero; (2) parent-offspring and sibling correlations were all positive and statistically significant. The parameter estimates obtained in variance analyses showed that from 40% to 75% of inter-individual variation of the studied traits (adjusted for age and sex) were attributable to genetic effects. For PF1 and PF2 in both samples, and for IND#2 (in Chuvasha pedigrees), significant common sib environmental effects were also detectable. Genetic factors substantially influence inter-individual differences in body shape and configuration in two studied samples. However, further studies are needed to clarify the extent of pleiotropy and epigenetic effects on various facets of the human physique.

Population pharmacokinetics of oxycodone in patients with cancer-related pain.

PubMed

Komatsu, Toshiaki; Kokubun, Hideya; Suzuki, Ai; Takayanagi, Risa; Yamada, Yasuhiko; Matoba, Motohiro; Yago, Kazuo

2012-09-01

Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

Characterizing individual differences in functional connectivity using dual-regression and seed-based approaches.

PubMed

Smith, David V; Utevsky, Amanda V; Bland, Amy R; Clement, Nathan; Clithero, John A; Harsch, Anne E W; McKell Carter, R; Huettel, Scott A

2014-07-15

A central challenge for neuroscience lies in relating inter-individual variability to the functional properties of specific brain regions. Yet, considerable variability exists in the connectivity patterns between different brain areas, potentially producing reliable group differences. Using sex differences as a motivating example, we examined two separate resting-state datasets comprising a total of 188 human participants. Both datasets were decomposed into resting-state networks (RSNs) using a probabilistic spatial independent component analysis (ICA). We estimated voxel-wise functional connectivity with these networks using a dual-regression analysis, which characterizes the participant-level spatiotemporal dynamics of each network while controlling for (via multiple regression) the influence of other networks and sources of variability. We found that males and females exhibit distinct patterns of connectivity with multiple RSNs, including both visual and auditory networks and the right frontal-parietal network. These results replicated across both datasets and were not explained by differences in head motion, data quality, brain volume, cortisol levels, or testosterone levels. Importantly, we also demonstrate that dual-regression functional connectivity is better at detecting inter-individual variability than traditional seed-based functional connectivity approaches. Our findings characterize robust-yet frequently ignored-neural differences between males and females, pointing to the necessity of controlling for sex in neuroscience studies of individual differences. Moreover, our results highlight the importance of employing network-based models to study variability in functional connectivity. Copyright © 2014 Elsevier Inc. All rights reserved.

Controlling stimulation strength and focality in electroconvulsive therapy via current amplitude and electrode size and spacing: comparison with magnetic seizure therapy.

PubMed

Deng, Zhi-De; Lisanby, Sarah H; Peterchev, Angel V

2013-12-01

Understanding the relationship between the stimulus parameters of electroconvulsive therapy (ECT) and the electric field characteristics could guide studies on improving risk/benefit ratio. We aimed to determine the effect of current amplitude and electrode size and spacing on the ECT electric field characteristics, compare ECT focality with magnetic seizure therapy (MST), and evaluate stimulus individualization by current amplitude adjustment. Electroconvulsive therapy and double-cone-coil MST electric field was simulated in a 5-shell spherical human head model. A range of ECT electrode diameters (2-5 cm), spacing (1-25 cm), and current amplitudes (0-900 mA) was explored. The head model parameters were varied to examine the stimulus current adjustment required to compensate for interindividual anatomical differences. By reducing the electrode size, spacing, and current, the ECT electric field can be more focal and superficial without increasing scalp current density. By appropriately adjusting the electrode configuration and current, the ECT electric field characteristics can be made to approximate those of MST within 15%. Most electric field characteristics in ECT are more sensitive to head anatomy variation than in MST, especially for close electrode spacing. Nevertheless, ECT current amplitude adjustment of less than 70% can compensate for interindividual anatomical variability. The strength and focality of ECT can be varied over a wide range by adjusting the electrode size, spacing, and current. If desirable, ECT can be made as focal as MST while using simpler stimulation equipment. Current amplitude individualization can compensate for interindividual anatomical variability.

Variability of PCB burden in 5 fish and sharks species of the French Mediterranean continental slope.

PubMed

Cresson, Pierre; Fabri, Marie Claire; Miralles, Françoise Marco; Dufour, Jean-Louis; Elleboode, Romain; Sevin, Karine; Mahé, Kelig; Bouchoucha, Marc

2016-05-01

Despite being generally located far from contamination sources, deep marine ecosystems are impacted by chemicals like PCB. The PCB contamination in five fish and shark species collected in the continental slope of the Gulf of Lions (NW Mediterranean Sea) was measured, with a special focus on intra- and interspecific variability and on the driving factors. Significant differences occurred between species. Higher values were measured in Scyliorhinus canicula, Galeus melastomus and Helicolenus dactylopterus and lower values in Phycis blennoides and Lepidorhombus boscii. These differences might be explained by specific abilities to accumulate and eliminate contaminant, mostly through cytochrome P450 pathway. Interindividual variation was also high and no correlation was observed between contamination and length, age or trophic level. Despite its major importance, actual bioaccumulation of PCB in deep fish is not as documented as in other marine ecosystems, calling for a better assessment of the factors driving individual bioaccumulation mechanisms and originating high variability in PCB contamination. Copyright © 2016 Elsevier Ltd. All rights reserved.

Variability of cholesterol accessibility in human red blood cells measured using a bacterial cholesterol-binding toxin

PubMed Central

Chakrabarti, Rima S; Ingham, Sally A; Kozlitina, Julia; Gay, Austin; Cohen, Jonathan C; Radhakrishnan, Arun; Hobbs, Helen H

2017-01-01

Cholesterol partitions into accessible and sequestered pools in cell membranes. Here, we describe a new assay using fluorescently-tagged anthrolysin O, a cholesterol-binding bacterial toxin, to measure accessible cholesterol in human red blood cells (RBCs). Accessible cholesterol levels were stable within individuals, but varied >10 fold among individuals. Significant variation was observed among ethnic groups (Blacks>Hispanics>Whites). Variation in accessibility of RBC cholesterol was unrelated to the cholesterol content of RBCs or plasma, but was associated with the phospholipid composition of the RBC membranes and with plasma triglyceride levels. Pronase treatment of RBCs only modestly altered cholesterol accessibility. Individuals on hemodialysis, who have an unexplained increase in atherosclerotic risk, had significantly higher RBC cholesterol accessibility. Our data indicate that RBC accessible cholesterol is a stable phenotype with significant inter-individual variability. Factors both intrinsic and extrinsic to the RBC contribute to variation in its accessibility. This assay provides a new tool to assess cholesterol homeostasis among tissues in humans. DOI: http://dx.doi.org/10.7554/eLife.23355.001 PMID:28169829

Association of sequence variations in vitamin K epoxide reductase and gamma-glutamyl carboxylas genes with biochemical measures of vitamin K status

USDA-ARS?s Scientific Manuscript database

Genetic factors, specifically the VKORC1 and GGCX genes, have been shown to contribute to the interindividual variability in response to the vitamin K-antagonist, warfarin, which influences the dose required to achieve the desired anticoagulation response. These differences in warfarin sensitivity ...

Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis.

PubMed

Joerger, Markus; Wilkins, Justin; Fagagnini, Stefania; Baldinger, Reto; Brenneisen, Rudolf; Schneider, Ursula; Goldman, Bea; Weber, Markus

2012-06-01

Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients. Nine patients received THC single oral doses of 5mg and 10mg, separated by a wash-out period of two weeks. Blood samples for the determination of THC, 11-nor-9-carboxy-THC (THC-COOH) and hydroxy-THC (THC-OH) were taken up to 8 hours after intake. Adverse events were assessed by visual analogue scales (VAS). Plasma concentrations of the active metabolite THC-OH were submitted to sequential pharmacokinetic-pharmacodynamic population modeling on individual heart rate as a proxy for THC's cardiovasculatory effects. Drowsiness, euphoria, orthostasis, sleepiness, vertigo and weakness were significantly more frequent in patients receiving 10mg compared to 5 mg THC. A marked interindividual variability was found for the absorption of oral THC (84%) and elimination of THC-COOH (45%). PK data did not support any clinically relevant deviation from linear PK in the investigated range of concentrations. Plasma concentrations of THC-OH were positively correlated with the individual heart rate. An E(max-model) was successfully fitted to individual heart rate, with a THC-OH plasma concentration of 3.2 x 10(-4) μmol/L for EC(50) and an E(max) of 93 bpm for heart rate. The higher 10mg dose of THC was dose-limiting in patients with ALS. High interindividual PK variability requires individuell titration of THC for potential therapeutic use in patients with ALS.

Changes in and predictors of pain characteristics in patients with head and neck cancer undergoing radiotherapy.

PubMed

Astrup, Guro Lindviksmoen; Rustøen, Tone; Miaskowski, Christine; Paul, Steven M; Bjordal, Kristin

2015-05-01

Pain is a common symptom in patients with head and neck cancer (HNC) that is associated with significant decrements in physical and psychological functioning. Only 4 studies have evaluated for changes in and predictors of different pain characteristics in these patients. In this longitudinal study of patients with HNC, changes in pain intensity (i.e., average pain, worst pain), pain interference with function, and pain relief were evaluated from the initiation of radiotherapy and through the following 6 months. Hierarchical linear modeling was used to evaluate for changes over time in these 4 pain characteristics, as well as to identify predictors of interindividual variability in each characteristic. Overall, pain intensity and interference with function scores were in the mild-to-moderate range, while pain relief scores were in the moderate range. The occurrence of pain, as well as scores for each pain characteristic, increased from the initiation to the completion of radiotherapy, followed by a gradual decrease to near pretreatment levels at 6 months. However, interindividual variability existed in patients' ratings of each pain characteristic. Predictors of more severe pain characteristic scores were more comorbidities, worse physical functioning, not having surgery before radiotherapy, difficulty swallowing, mouth sores, sleep disturbance, fatigue, more energy, and less social support. Patients with more depressive symptoms had better pain relief. Although some of the predictors cannot be modified (e.g., rrence of surgery), other predictors (e.g., symptoms) can be treated. Therefore, information about these predictors may result in decreased pain in patients with HNC.

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes.

PubMed

Teh, Ai Ling; Pan, Hong; Chen, Li; Ong, Mei-Lyn; Dogra, Shaillay; Wong, Johnny; MacIsaac, Julia L; Mah, Sarah M; McEwen, Lisa M; Saw, Seang-Mei; Godfrey, Keith M; Chong, Yap-Seng; Kwek, Kenneth; Kwoh, Chee-Keong; Soh, Shu-E; Chong, Mary F F; Barton, Sheila; Karnani, Neerja; Cheong, Clara Y; Buschdorf, Jan Paul; Stünkel, Walter; Kobor, Michael S; Meaney, Michael J; Gluckman, Peter D; Holbrook, Joanna D

2014-07-01

Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained ∼25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation. © 2014 Teh et al.; Published by Cold Spring Harbor Laboratory Press.

Laterality and grip strength influence hand bone micro-architecture in modern humans, an HRpQCT study.

PubMed

Reina, Nicolas; Cavaignac, Etienne; Trousdale, William H; Laffosse, Jean-Michel; Braga, José

2017-06-01

It is widely hypothesized that mechanical loading, specifically repetitive low-intensity tasks, influences the inner structure of cancellous bone. As such, there is likely a relationship between handedness and bone morphology. The aim of this study is to determine patterns in trabecular bone between dominant and non-dominant hands in modern humans. Seventeen healthy patients between 22 and 32 years old were included in the study. Radial carpal bones (lunate, capitate, scaphoid, trapezium, trapezoid, 1st, 2nd and 3rd metacarpals) were analyzed with high-resolution micro-computed tomography. Additionally, crush and pinch grip were recorded. Factorial analysis indicated that bone volume ratio, trabeculae number (Tb.N), bone surface to volume ratio (BS.BV), body weight, stature and crush grip were all positively correlated with principal components 1 and 2 explaining 78.7% of the variance. Volumetric and trabecular endostructural parameters (BV/TV, BS/BV or Tb.Th, Tb.N) explain the observed inter-individual variability better than anthropometric or clinical parameters. Factors analysis regressions showed correlations between these parameters and the dominant side for crush strength for the lunate (r 2 = 0.640, P < 0.0001), trapezium (r 2 = 0.836, P < 0.0001) and third metacarpal (r 2 = 0.763). However, despite a significant lateralization in grip strength for all patients, the endostructural variability between dominant and non-dominant sides was limited in perspective to inter-individual differences. In conclusion, handedness is unlikely to generate trabecular patterns of asymmetry. It appears, however, that crush strength can be considered for endostructural analysis in the modern human wrist. © 2017 Anatomical Society.

An in vitro evaluation of guanfacine as a substrate for P-glycoprotein

PubMed Central

Gillis, Nancy K; Zhu, Hao-Jie; Markowitz, John S

2011-01-01

Background With a US Food and Drug Administration-labeled indication to treat attention-deficit/hyperactivity disorder (ADHD), the nonstimulant guanfacine has become the preferred α2-agonist for ADHD treatment. However, significant interindividual variability has been observed in response to guanfacine. Consequently, hypotheses of a contributing interaction with the ubiquitously expressed drug transporter, P-glycoprotein (P-gp), have arisen. We performed an in vitro study to determine if guanfacine is indeed a substrate of P-gp. Methods Intracellular accumulation of guanfacine was compared between P-gp expressing LLC-PK1/MDR1 cells and P-gp-negative LLC-PK1 cells to evaluate the potential interaction between P-gp and guanfacine. Cellular retention of guanfacine was analyzed using a high-performance liquid chromatographic-ultraviolet method. Rhodamine6G, a known P-gp substrate, was included in the study as a positive control. Results At guanfacine concentrations of 50 μM and 5 μM, intracellular accumulation of guanfacine in LLC-PK1/MDR1 cells was, 35.9% ± 4.8% and 49.0% ± 28.3% respectively, of that in LLC-PK1 cells. In comparison, the concentration of rhodamine6G, the positive P-gp substrate, in LLC-PK1/MDR1 cells was only 5% of that in LLC-PK1 cells. Conclusion The results of the intracellular accumulation study suggest that guanfacine is, at best, a weak P-gp substrate. Therefore, it is unlikely that P-gp, or any genetic variants thereof, are a determining factor in the interindividual variability of response observed with guanfacine therapy. PMID:21931492

Reading and lexical-decision tasks generate different patterns of individual variability as a function of condition difficulty.

PubMed

Zoccolotti, Pierluigi; De Luca, Maria; Di Filippo, Gloria; Marinelli, Chiara Valeria; Spinelli, Donatella

2018-06-01

We reanalyzed previous experiments based on lexical-decision and reading-aloud tasks in children with dyslexia and control children and tested the prediction of the difference engine model (DEM) that mean condition reaction times (RTs) and standard deviations (SDs) would be linearly related (Myerson et al., 2003). Then we evaluated the slope and the intercept with the x-axis of these linear functions in comparison with previously reported values (i.e., slope of about 0.30 and intercept of about 300 ms). In the case of lexical decision, the parameters were close to these values; by contrast, in the case of reading aloud, a much steeper slope (0.66) and a greater intercept (482.6 ms) were found. Therefore, interindividual variability grows at a much faster rate as a function of condition difficulty for reading than for lexical-decision tasks (or for other tasks reported in the literature). According to the DEM, the slope of the regression that relates means and SDs indicates the degree of correlation among the durations of the stages of processing. We propose that the need for a close coupling between orthographic and phonological processing in reading is what drives the particularly strong relationship between performance and interindividual variability that we observed in reading tasks.

Deferasirox pharmacokinetic and toxicity correlation in β-thalassaemia major treatment.

PubMed

Allegra, Sarah; De Francia, Silvia; Cusato, Jessica; Pirro, Elisa; Massano, Davide; Piga, Antonio; D'Avolio, Antonio

2016-11-01

Deferasirox adverse effects include the following: gastrointestinal disturbance, mild elevations in serum creatinine levels and intermittent proteinuria; these events are dose-dependent and reversible with drug discontinuation, but this solution can lead to an inadequate iron chelation. For these reasons, interindividual variability of drug plasma concentration could help the clinical management of deferasirox dosage. We sought to describe deferasirox plasma exposure in a cohort of 60 adult patients. A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from β-thalassaemia adult patients. Samples obtained before and after 2, 4, 6 and 24 h drug administration were evaluated. Associations between variables were tested using the Pearson test. Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive correlation was found between deferasirox area under the concentration curve over 24 h and serum creatinine (r = 0.314; P = 0.018) and between area and drug dose (r = 0.311; P = 0.016). Moreover, a negative correlation resulted among area under the concentration curve over 24 h and serum ferritin (r = -0.291; P = 0.026) and among drug half-life and its dose (r = -0.319; P = 0.013). Treatment decision based on the individual characteristics could strongly contribute to minimize toxicity and increase efficacy of deferasirox therapy. © 2016 Royal Pharmaceutical Society.

EDUCATION ENHANCES THE ACUITY OF THE NON-VERBAL APPROXIMATE NUMBER SYSTEM

PubMed Central

Piazza, Manuela; Pica, Pierre; Izard, Véronique; Spelke, Elizabeth; Dehaene, Stanislas

2015-01-01

All humans share a universal, evolutionarily ancient approximate number system (ANS) that estimates and combines the number of objects in sets with ratio-limited precision. Inter-individual variability in the acuity of the ANS correlates with mathematical achievement, but the causes of this correlation have never been established. We acquired psychophysical measures of ANS acuity in child and adult members of an indigene group in the Amazon, the Mundurucu, who have a very restricted numerical lexicon and highly variable access to mathematical education. By comparing Mundurucu subjects with or without access to schooling, we demonstrate that education significantly enhances the acuity with which sets of concrete objects are estimated. These results speak in favor of an important effect of culture and education on basic number perception. We hypothesize that symbolic and non-symbolic numerical thinking mutually enhance one another over the course of mathematics instruction. PMID:23625879

An Exploratory Analysis of Personality, Attitudes, and Study Skills on the Learning Curve within a Team-based Learning Environment

PubMed Central

Henry, Teague; Campbell, Ashley

2015-01-01

Objective. To examine factors that determine the interindividual variability of learning within a team-based learning environment. Methods. Students in a pharmacokinetics course were given 4 interim, low-stakes cumulative assessments throughout the semester and a cumulative final examination. Students’ Myers-Briggs personality type was assessed, as well as their study skills, motivations, and attitudes towards team-learning. A latent curve model (LCM) was applied and various covariates were assessed to improve the regression model. Results. A quadratic LCM was applied for the first 4 assessments to predict final examination performance. None of the covariates examined significantly impacted the regression model fit except metacognitive self-regulation, which explained some of the variability in the rate of learning. There were some correlations between personality type and attitudes towards team learning, with introverts having a lower opinion of team-learning than extroverts. Conclusion. The LCM could readily describe the learning curve. Extroverted and introverted personality types had the same learning performance even though preference for team-learning was lower in introverts. Other personality traits, study skills, or practice did not significantly contribute to the learning variability in this course. PMID:25861101

An exploratory analysis of personality, attitudes, and study skills on the learning curve within a team-based learning environment.

PubMed

Persky, Adam M; Henry, Teague; Campbell, Ashley

2015-03-25

To examine factors that determine the interindividual variability of learning within a team-based learning environment. Students in a pharmacokinetics course were given 4 interim, low-stakes cumulative assessments throughout the semester and a cumulative final examination. Students' Myers-Briggs personality type was assessed, as well as their study skills, motivations, and attitudes towards team-learning. A latent curve model (LCM) was applied and various covariates were assessed to improve the regression model. A quadratic LCM was applied for the first 4 assessments to predict final examination performance. None of the covariates examined significantly impacted the regression model fit except metacognitive self-regulation, which explained some of the variability in the rate of learning. There were some correlations between personality type and attitudes towards team learning, with introverts having a lower opinion of team-learning than extroverts. The LCM could readily describe the learning curve. Extroverted and introverted personality types had the same learning performance even though preference for team-learning was lower in introverts. Other personality traits, study skills, or practice did not significantly contribute to the learning variability in this course.

The Effect of microRNAs in the Regulation of Human CYP3A4: a Systematic Study using a Mathematical Model

NASA Astrophysics Data System (ADS)

Wei, Zhiyun; Jiang, Songshan; Zhang, Yiting; Wang, Xiaofei; Peng, Xueling; Meng, Chunjie; Liu, Yichen; Wang, Honglian; Guo, Luo; Qin, Shengying; He, Lin; Shao, Fengmin; Zhang, Lirong; Xing, Qinghe

2014-03-01

CYP3A4 metabolizes more than 50% of the drugs on the market. The large inter-individual differences of CYP3A4 expression may contribute to the variability of human drug responses. Post-transcriptional regulation of CYP3A4 is poorly understood, whereas transcriptional regulation has been studied much more thoroughly. In this study, we used multiple software programs to predict miRNAs that might bind to CYP3A4 and identified 112 potentially functional miRNAs. Then a luciferase reporter system was used to assess the effect of the overexpression of each potentially functional miRNA in HEK 293T cells. Fourteen miRNAs that significantly decreased reporter activity were measured in human liver samples (N = 27) as candidate miRNAs. To establish a more effective way to analyze in vivo data for miRNA candidates, the relationship between functional miRNA and target mRNA was modeled mathematically. Taking advantage of this model, we found that hsa-miR-577, hsa-miR-1, hsa-miR-532-3p and hsa-miR-627 could significantly downregulate the translation efficiency of CYP3A4 mRNA in liver. This study used in silico, in vitro and in vivo methods to progressively screen functional miRNAs for CYP3A4 and to enhance our understanding of molecular events underlying the large inter-individual differences of CYP3A4 expression in human populations.

The Continuity of College Students' Autonomous Learning Motivation and Its Predictors: A Three-Year Longitudinal Study

ERIC Educational Resources Information Center

Pan, Yingqiu; Gauvain, Mary

2012-01-01

This study examined change in Chinese students' autonomous learning motivation in the first three years of college and how this change is accounted for by intra- and inter-individual variables. The sample included 633 (328 female) college freshmen. Results showed that students' autonomous learning motivation decreased over years in college.…

Interannual variations in the hatching pattern, larval growth and otolith size of a sand-dwelling fish from central Chile

NASA Astrophysics Data System (ADS)

Rodríguez-Valentino, Camilo; Landaeta, Mauricio F.; Castillo-Hidalgo, Gissella; Bustos, Claudia A.; Plaza, Guido; Ojeda, F. Patricio

2015-09-01

The interannual variation (2010-2013) of larval abundance, growth and hatching patterns of the Chilean sand stargazer Sindoscopus australis (Pisces: Dactyloscopidae) was investigated through otolith microstructure analysis from samples collected nearshore (<500 m from shore) during austral late winter-early spring off El Quisco bay, central Chile. In the studied period, the abundance of larval stages in the plankton samples varied from 2.2 to 259.3 ind. 1000 m-3; larval abundance was similar between 2010 and 2011, and between 2012 and 2013, but increased significantly from 2011 to 2012. The estimated growth rates increased twice, from 0.09 to 0.21 mm day-1, between 2011 and 2013. Additionally, otolith size (radius, perimeter and area), related to body length of larvae, significantly decreased from 2010 to 2012, but increases significantly in 2013. Although the mean values of microincrement widths of sagitta otoliths were similar between 2010 and 2011 (around 0.6-0.7 μm), the interindividual variability increases in 2011 and 2013, suggesting large environmental variability experienced by larvae during these years. Finally, the hatching pattern of S. australis changed significantly from semi-lunar to lunar cycle after 2012.

The Differential role of parenting, peers, and temperament for explaining interindividual differences in 18-months-olds' comforting and helping.

PubMed

Schuhmacher, Nils; Collard, Jenny; Kärtner, Joscha

2017-02-01

This study analyzes temperamental and social correlates of 18-month-olds' (N=58) instrumental helping (i.e., handing over out-of-reach objects) and comforting (i.e., alleviating experimenter's distress). While out-of-reach helping as a basic type of prosocial behavior was not associated with any of the social and temperamental variables, comforting was associated with maternal responsible parenting, day care attendance, and temperamental fear, accounting for 34% of the total variance in a corresponding regression model. The data of the present study suggest that, while simple instrumental helping seems to be a robust developmental phenomenon, comforting is associated with specific social experiences and child temperament that constitute interindividual differences and thereby help to explain the domain-specific development of prosociality. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabolic effects of resistance or high-intensity interval training among glycemic control-nonresponsive children with insulin resistance.

PubMed

Álvarez, C; Ramírez-Campillo, R; Ramírez-Vélez, R; Martínez, C; Castro-Sepúlveda, M; Alonso-Martínez, A; Izquierdo, M

2018-01-01

Little evidence exists on which variables of body composition or muscular strength mediates more glucose control improvements taking into account inter-individual metabolic variability to different modes of exercise training. We examined 'mediators' to the effects of 6-weeks of resistance training (RT) or high-intensity interval training (HIT) on glucose control parameters in physically inactive schoolchildren with insulin resistance (IR). Second, we also determined both training-induce changes and the prevalence of responders (R) and non-responders (NR) to decrease the IR level. Fifty-six physically inactive children diagnosed with IR followed a RT or supervised HIT program for 6 weeks. Participants were classified based on ΔHOMA-IR into glycemic control R (decrease in homeostasis model assessment-IR (HOMA-IR) <3.0 after intervention) and NRs (no changes or values HOMA-IR⩾3.0 after intervention). The primary outcome was HOMA-IR associated with their mediators; second, the training-induced changes to glucose control parameters; and third the report of R and NR to improve body composition, cardiovascular, metabolic and performance variables. Mediation analysis revealed that improvements (decreases) in abdominal fat by the waist circumference can explain more the effects (decreases) of HOMA-IR in physically inactive schoolchildren under RT or HIT regimes. The same analysis showed that increased one-maximum repetition leg-extension was correlated with the change in HOMA-IR (β=-0.058; P=0.049). Furthermore, a change in the waist circumference fully mediated the dose-response relationship between changes in the leg-extension strength and HOMA-IR (β'=-0.004; P=0.178). RT or HIT were associated with significant improvements in body composition, muscular strength, blood pressure and cardiometabolic parameters irrespective of improvement in glycemic control response. Both glucose control RT-R and HIT-R (respectively), had significant improvements in mean HOMA-IR, mean muscular strength leg-extension and mean measures of adiposity. The improvements in the lower body strength and the decreases in waist circumference can explain more the effects of the improvements in glucose control of IR schoolchildren in R group after 6 weeks of RT or HIT, showing both regimes similar effects on body composition or muscular strength independent of interindividual metabolic response variability.

Presence and inter-individual variability of carboxylesterases (CES1 and CES2) in human lung.

PubMed

Gabriele, Morena; Puccini, Paola; Lucchi, Marco; Vizziello, Anna; Gervasi, Pier Giovanni; Longo, Vincenzo

2018-04-01

Lungs are pharmacologically active organs and the pulmonary drug metabolism is of interest for inhaled drugs design. Carboxylesterases (CESs) are enzymes catalyzing the hydrolysis of many structurally different ester, amide and carbamate chemicals, including prodrugs. For the first time, the presence, kinetics, inhibition and inter-individual variations of the major liver CES isozymes (CES1 and CES2) were investigated in cytosol and microsomes of human lungs from 20 individuals using 4-nitrophenyl acetate (pNPA), 4-methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD) as substrates the rates of hydrolysis (V max ) for pNPA and 4-MUA, unlike FD, were double in microsomes than in cytosol. In these cellular fractions, the V max of pNPA, as CES1 marker, were much greater (30-50-fold) than those of FD, as a specific CES2 marker. Conversely, the K m values were comparable suggesting the involvement of the same enzymes. Inhibition studies revealed that the FD hydrolysis was inhibited by bis-p-nitrophenylphosphate, phenylmethanesulfonyl fluoride, and loperamide (specific for CES2), whereas the pNPA and 4-MUA hydrolysis inhibition was limited. Inhibitors selective for other esterases missed having any effect on above-mentioned activities. In cytosol and microsomes of 20 lung samples, inter-individual variations were found for the hydrolysis of pNPA (2.5-5-fold), FD or 4-MUA (8-15-fold). Similar variations were also observed in CES1 and CES2 gene expression, although determined in a small number (n = 9) of lung samples. The identification of CES1 and CES2 and their variability in human lungs are important for drug metabolism and design of prodrugs which need to be activated in this organ. Copyright © 2018 Elsevier Inc. All rights reserved.

Broca Pars Triangularis Constitutes a "Hub" of the Language-Control Network during Simultaneous Language Translation.

PubMed

Elmer, Stefan

2016-01-01

Until now, several branches of research have fundamentally contributed to a better understanding of the ramifications of bilingualism, multilingualism, and language expertise on psycholinguistic-, cognitive-, and neural implications. In this context, it is noteworthy to mention that from a cognitive perspective, there is a strong convergence of data pointing to an influence of multilingual speech competence on a variety of cognitive functions, including attention, short-term- and working memory, set shifting, switching, and inhibition. In addition, complementary neuroimaging findings have highlighted a specific set of cortical and subcortical brain regions which fundamentally contribute to administrate cognitive control in the multilingual brain, namely Broca's area, the middle-anterior cingulate cortex, the inferior parietal lobe, and the basal ganglia. However, a disadvantage of focusing on group analyses is that this procedure only enables an approximation of the neural networks shared within a population while at the same time smoothing inter-individual differences. In order to address both commonalities (i.e., within group analyses) and inter-individual variability (i.e., single-subject analyses) in language control mechanisms, here I measured five professional simultaneous interpreters while the participants overtly translated or repeated sentences with a simple subject-verb-object structure. Results demonstrated that pars triangularis was commonly activated across participants during backward translation (i.e., from L2 to L1), whereas the other brain regions of the "control network" showed a strong inter-individual variability during both backward and forward (i.e., from L1 to L2) translation. Thus, I propose that pars triangularis plays a crucial role within the language-control network and behaves as a fundamental processing entity supporting simultaneous language translation.

Population nutrikinetics of green tea extract.

PubMed

Scholl, Catharina; Lepper, Anna; Lehr, Thorsten; Hanke, Nina; Schneider, Katharina Luise; Brockmöller, Jürgen; Seufferlein, Thomas; Stingl, Julia Carolin

2018-01-01

Green tea polyphenols may contribute to the prevention of cancer and other diseases. To learn more about the pharmacokinetics and interindividual variation of green tea polyphenols after oral intake in humans we performed a population nutrikinetic study of standardized green tea extract. 84 healthy participants took green tea extract capsules standardized to 150 mg epigallocatechin-gallate (EGCG) twice a day for 5 days. On day 5 catechin plasma concentrations were analyzed using non-compartmental and population pharmacokinetic methods. A strong between-subject variability in catechin pharmacokinetics was found with maximum plasma concentrations varying more than 6-fold. The AUCs of EGCG, EGC and ECG were 877.9 (360.8-1576.5), 35.1 (8.0-87.4), and 183.6 (55.5-364.6) h*μg/L respectively, and the elimination half lives were 2.6 (1.8-3.8), 3.9 (0.9-10.7) and 1.8 (0.8-2.9) h, respectively. Genetic polymorphisms in genes of the drug transporters MRP2 and OATP1B1 could at least partly explain the high variability in pharmacokinetic parameters. The observed variability in catechin plasma levels might contribute to interindividual variation in benefical and adverse effects of green tea polyphenols. Our data could help to gain a better understanding of the causes of variability of green tea effects and to improve the design of studies on the effects of green tea polyphenols in different health conditions. ClinicalTrials.gov: NCT01360320.

Glutamatergic model psychoses: prediction error, learning, and inference.

PubMed

Corlett, Philip R; Honey, Garry D; Krystal, John H; Fletcher, Paul C

2011-01-01

Modulating glutamatergic neurotransmission induces alterations in conscious experience that mimic the symptoms of early psychotic illness. We review studies that use intravenous administration of ketamine, focusing on interindividual variability in the profundity of the ketamine experience. We will consider this individual variability within a hypothetical model of brain and cognitive function centered upon learning and inference. Within this model, the brains, neural systems, and even single neurons specify expectations about their inputs and responding to violations of those expectations with new learning that renders future inputs more predictable. We argue that ketamine temporarily deranges this ability by perturbing both the ways in which prior expectations are specified and the ways in which expectancy violations are signaled. We suggest that the former effect is predominantly mediated by NMDA blockade and the latter by augmented and inappropriate feedforward glutamatergic signaling. We suggest that the observed interindividual variability emerges from individual differences in neural circuits that normally underpin the learning and inference processes described. The exact source for that variability is uncertain, although it is likely to arise not only from genetic variation but also from subjects' previous experiences and prior learning. Furthermore, we argue that chronic, unlike acute, NMDA blockade alters the specification of expectancies more profoundly and permanently. Scrutinizing individual differences in the effects of acute and chronic ketamine administration in the context of the Bayesian brain model may generate new insights about the symptoms of psychosis; their underlying cognitive processes and neurocircuitry.

The rs662 polymorphism of paraoxonase 1 affects the difference in the inhibition of butyrylcholinesterase activity by organophosphorus pesticides in human blood.

PubMed

Nam, Dae Cheol; Ha, Yu Mi; Park, Min Kyu; Cho, Sung Kweon

2016-08-01

Organophosphorus pesticides (OPs) are a human health hazard. OPs inhibit acetylcholinesterase (AChE) at nerve endings and accumulate acetylcholine (ACh) at these sites. High levels of ACh and long exposure promote cholinergic crisis. The hydrolysis of OPs by serum paraoxonase 1 (PON1) plays a role in cholinergic crisis in humans. Human serum PON1 can break down organophosphate before binding to ChE. We investigated the effect of PON1 polymorphisms on AChE activity after OP treatment. 50 healthy volunteers were randomly recruited with informed consent. We investigated butyrylcholinesterase (BuChE) activity changes in plasma as a biomarker of AChE after OP treatment in human blood samples immediately following blood sampling. After the standardization of BuChE activity in human blood, we correlated changes in BuChE activity with changes in blood pH. We analyzed the PON1 polymorphisms (rs854560 and rs662) of 50 participants to retrospectively investigate the interindividual variability of changes in BuChE activity. Changes in BuChE activity are strongly correlated with pH changes after OP treatment (R2 = 0.913). We used changes in pH as a surrogate marker for BuChE inhibition after OP treatment. OP treatment significantly decreased BuChE activity by 56.4 ± 5.1% (p < 0.001). The degree of BuChE inhibition was significantly different in the PON1 rs662 genotype (56.10 ± 4.74% vs. 57.96 ± 5.67% vs. 52.34 ± 1.51%; GG vs. GA vs. AA, respectively). Changes in pH can be used as a surrogate marker for the detection of BuChE inhibition after OP exposure. The rs662 polymorphism of PON1 may explain the inter-individual variability in BuChE inhibition.

Population Pharmacokinetic-Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats.

PubMed

Kobuchi, Shinji; Ito, Yukako; Sakaeda, Toshiyuki

2017-08-01

Myelosuppression is a dose-limiting toxicity of 5-fluorouracil (5-FU). Predicting the inter- and intra-patient variability in pharmacokinetics and toxicities of 5-FU may contribute to the individualized medicine. This study aimed to establish a population pharmacokinetic-pharmacodynamic model that could evaluate the inter- and intra-individual variability in the plasma 5-FU concentration, 5-FU-induced body weight loss and myelosuppression in rats. Plasma 5-FU concentrations, body weight loss, and blood cell counts in rats following the intravenous administration of various doses of 5-FU for 4 days were used to develop the population pharmacokinetic-pharmacodynamic model. The population pharmacokinetic model consisting of a two-compartment model with Michaelis-Menten elimination kinetics successfully characterized the individual and population predictions of the plasma concentration of 5-FU and provided credible parameter estimates. The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively. The population pharmacokinetic-pharmacodynamic model adequately described the individual complete time-course of alterations in body weight loss, erythrocyte, leukocyte, and lymphocyte counts in rats treated with various doses of 5-FU. The inter-individual variability of the drug effects in the pharmacodynamic model for body weight loss was 82.6%, which was relatively high. The results of the present study suggest that not only individual fluctuations in the 5-FU concentration but also the cell sensitivity would affect the onset and degree of 5-FU-induced toxicity. This population pharmacokinetic-pharmacodynamic model could evaluate the inter- and intra-individual variability in drug-induced toxicity and guide the assessments of novel anticancer agents in drug development.

Assessing human variability in kinetics for exposures to multiple environmental chemicals: a physiologically based pharmacokinetic modeling case study with dichloromethane, benzene, toluene, ethylbenzene, and m-xylene.

PubMed

Valcke, Mathieu; Haddad, Sami

2015-01-01

The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease.

PubMed

Ma, Yanjiao; Xue, Ling; Chen, Xin; Kang, Yingbo; Wang, Yong; Wang, Liqing

2018-05-18

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of - 3860G > A, - 163C > A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h) = 4.530 × (FFM/56.1) 0.75  × 0.713 CYP1A2*1B , the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.

Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses.

PubMed

García-Conesa, María-Teresa; Chambers, Karen; Combet, Emilie; Pinto, Paula; Garcia-Aloy, Mar; Andrés-Lacueva, Cristina; de Pascual-Teresa, Sonia; Mena, Pedro; Konic Ristic, Alekxandra; Hollands, Wendy J; Kroon, Paul A; Rodríguez-Mateos, Ana; Istas, Geoffrey; Kontogiorgis, Christos A; Rai, Dilip K; Gibney, Eileen R; Morand, Christine; Espín, Juan Carlos; González-Sarrías, Antonio

2018-02-28

Understanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total-cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation.

Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses

PubMed Central

Chambers, Karen; Andrés-Lacueva, Cristina; Konic Ristic, Aleksandra; Hollands, Wendy J.; Kroon, Paul A.; Rodríguez-Mateos, Ana; Istas, Geoffrey; Kontogiorgis, Christos A.; Morand, Christine; Espín, Juan Carlos

2018-01-01

Understanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total-cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation. PMID:29495642

Large inter-individual and intra-individual variability in the effect of perceptual load

PubMed Central

Yeshurun, Yaffa

2017-01-01

This study examined whether the recurrent difficulty to replicate results obtained with paradigms measuring distractor processing as a function of perceptual load is due to individual differences. We first reanalyzed, at the individual level, the data of eight previously reported experiments. These reanalyses revealed substantial inter-individual differences, with particularly low percentage of participants whose performance matched the load theory’s predictions (i.e., larger distractor interference with low than high levels of load). Moreover, frequently the results were opposite to the theory's predictions–larger interference in the high than low load condition; and often a reversed compatibility effect emerged–better performance in the incompatible than neutral condition. Subsequently, seven observers participated in five identical experimental sessions. If the observed inter-individual differences are due to some stable trait or perceptual capacity, similar results should have emerged in all sessions of a given participant. However, all seven participants showed large between-sessions variations with similar patterns to those found between participants. These findings question the theoretical foundation implemented with these paradigms, as none of the theories suggested thus far can account for such inter- and intra-individual differences. Thus, these paradigms should be used with caution until further research will provide better understanding of what they actually measure. PMID:28406997

Pharmacogenetics in type 2 diabetes: influence on response to oral hypoglycemic agents

PubMed Central

Dawed, Adem Yesuf; Zhou, Kaixin; Pearson, Ewan Robert

2016-01-01

Type 2 diabetes is one of the leading causes of morbidity and mortality, consuming a significant proportion of public health spending. Oral hypoglycemic agents (OHAs) are the frontline treatment approaches after lifestyle changes. However, huge interindividual variation in response to OHAs results in unnecessary treatment failure. In addition to nongenetic factors, genetic factors are thought to contribute to much of such variability, highlighting the importance of the potential of pharmacogenetics to improve therapeutic outcome. Despite the presence of conflicting results, significant progress has been made in an effort to identify the genetic markers associated with pharmacokinetics, pharmacodynamics, and ultimately therapeutic response and/or adverse outcomes to OHAs. As such, this article presents a comprehensive review of current knowledge on pharmacogenetics of OHAs and provides insights into knowledge gaps and future directions. PMID:27103840

The circadian body temperature rhythm in the elderly: effect of single daily melatonin dosing.

PubMed

Gubin, D G; Gubin, G D; Waterhouse, J; Weinert, D

2006-01-01

The present study is part of a more extensive investigation dedicated to the study and treatment of age-dependent changes/disturbances in the circadian system in humans. It was performed in the Tyumen Elderly Veteran House and included 97 subjects of both genders, ranging from 63 to 91 yrs of age. They lived a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted 3 wks. After 1 control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen) daily at 22:30 h for 2 wks. The other 34 subjects were given placebo. Axillary temperature was measured using calibrated mercury thermometers at 03:00, 08:00, 11:00, 14:00, 17:00, and 23:00 h each of the first and third week. Specially trained personnel took the measurements, avoiding disturbing the sleep of the subjects. To evaluate age-dependent changes, data obtained under similar conditions on 58 young adults (both genders, 17 to 39 yrs of age) were used. Rhythm characteristics were estimated by means of cosinor analyses, and intra- and inter-individual variability by analysis of variance (ANOVA). In both age groups, the body temperature underwent daily changes. The MESOR (36.38+/-0.19 degrees C vs. 36.17+/-0.21 degrees C) and circadian amplitude (0.33+/-0.01 degrees C vs. 0.26+/-0.01 degrees C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001). The mean circadian acrophase was similar in both age groups (17.19+/-1.66 vs. 16.93+/-3.08 h). However, the inter-individual differences were higher in the older group, with individual values varying between 10:00 and 23:00 h. It was mainly this phase variability that caused a decrease in the inter-daily rhythm stability and lower group amplitude. With melatonin treatment, the MESOR was lower by 0.1 degrees C and the amplitude increased to 0.34+/-0.01 degrees C, a similar value to that found in young adults. This was probably due to the increase of the inter-daily rhythm stability. The mean acrophase did not change (16.93 vs. 16.75 h), although the inter-individual variability decreased considerably. The corresponding standard deviations (SD) of the group acrophases were 3.08 and 1.51 h (p<0.01). A highly significant correlation between the acrophase before treatment and the phase change under melatonin treatment indicates that this is due to a synchronizing effect of melatonin. Apart from the difference in MESOR, the body temperature rhythm in the elderly subjects undergoing melatonin treatment was not significantly different from that of young adults. The data clearly show that age-dependent changes mainly concern rhythm stability and synchronization with the 24 h day. A single daily melatonin dose stabilizes/synchronizes the body temperature rhythm, most probably via hypothermic and sleep-improving effects.

The relevance of the urinary concentration of ephedrines in anti-doping analysis: determination of pseudoephedrine, cathine, and ephedrine after administration of over-the-counter medicaments.

PubMed

Strano-Rossi, Sabina; Leone, Daniele; de la Torre, Xavier; Botrè, Francesco

2009-08-01

This article describes a method for the detection and quantitation of cathine, pseudoephedrine, ephedrine, and methylephedrine in urine, using their deuterated analogues as internal standards and derivatization to form the corresponding trimethylsilyl derivatives after a simple liquid-liquid extraction. The study was designed to evaluate whether the urinary cutoff values set by the World Anti-Doping Agency for the banned ephedrines (cathine >5 microg/mL, ephedrine and methylephedrine >10 microg/mL) can be exceeded after the normal self-administration of common over-the-counter medicaments containing nonbanned ephedrines. The present method, after validation, has been applied on real urine samples obtained from 9 healthy volunteers taking different doses of over-the-counter preparations containing ephedrines. Results obtained from excretion studies show high interindividual differences in the urinary concentrations of both pseudoephedrine and cathine, not dependent on body weight or sex nor, in some instances, on the administered dose. The same typical therapeutic dose of pseudoephedrine (60 mg) produced a urinary concentration of more than 5 microg/mL for cathine and of more than 100 microg/mL for pseudoephedrine in 2 of 9 subjects only. When a dose of 120 mg was administered, cathine concentration exceeded 5 microg/mL in 4 of 7 subject, and also concentrations of pseudoephedrine above 100 microg/mL. After administration of 5 x 120 mg of pseudoephedrine (120 mg administered every 7 days for 5 weeks) to one of the subjects exceeding the urinary threshold values, the urinary concentration of cathine and pseudoephedrine exceeded 5 microg/mL (peak concentration 14.8 microg/mL) and 100 microg/mL (peak concentration 275 microg/mL), respectively. When the same subject took 180 mg of pseudoephedrine, the urinary concentration values were below 5 microg/mL for ephedrine and 100 microg/mL for pseudoephedrine. In the case of ephedrine administration in a sustained-release formulation containing 12 mg of ephedrine, 2 of 3 subjects exceeded the urinary cutoff value of 10 microg/mL. The high interindividual variability is still significant even if the urinary concentration values are adjusted by specific gravity and/or creatinine. These results confirm a high interindividual variability in the urinary concentration of ephedrines after the administration of the same therapeutic dose of a preparation.

A large population-based association study between HLA and KIR genotypes and measles vaccine antibody responses.

PubMed

Ovsyannikova, Inna G; Schaid, Daniel J; Larrabee, Beth R; Haralambieva, Iana H; Kennedy, Richard B; Poland, Gregory A

2017-01-01

Human antibody response to measles vaccine is highly variable in the population. Host genes contribute to inter-individual antibody response variation. The killer cell immunoglobulin-like receptors (KIR) are recognized to interact with HLA molecules and possibly influence humoral immune response to viral antigens. To expand on and improve our previous work with HLA genes, and to explore the genetic contribution of KIR genes to the inter-individual variability in measles vaccine-induced antibody responses, we performed a large population-based study in 2,506 healthy immunized subjects (ages 11 to 41 years) to identify HLA and KIR associations with measles vaccine-induced neutralizing antibodies. After correcting for the large number of statistical tests of allele effects on measles-specific neutralizing antibody titers, no statistically significant associations were found for either HLA or KIR loci. However, suggestive associations worthy of follow-up in other cohorts include B*57:01, DQB1*06:02, and DRB1*15:05 alleles. Specifically, the B*57:01 allele (1,040 mIU/mL; p = 0.0002) was suggestive of an association with lower measles antibody titer. In contrast, the DQB1*06:02 (1,349 mIU/mL; p = 0.0004) and DRB1*15:05 (2,547 mIU/mL; p = 0.0004) alleles were suggestive of an association with higher measles antibodies. Notably, the associations with KIR genotypes were strongly nonsignificant, suggesting that KIR loci in terms of copy number and haplotypes are not likely to play a major role in antibody response to measles vaccination. These findings refine our knowledge of the role of HLA and KIR alleles in measles vaccine-induced immunity.

Human variability in mercury toxicokinetics and steady state biomarker ratios.

PubMed

Bartell, S M; Ponce, R A; Sanga, R N; Faustman, E M

2000-10-01

Regulatory guidelines regarding methylmercury exposure depend on dose-response models relating observed mercury concentrations in maternal blood, cord blood, and maternal hair to developmental neurobehavioral endpoints. Generalized estimates of the maternal blood-to-hair, blood-to-intake, or hair-to-intake ratios are necessary for linking exposure to biomarker-based dose-response models. Most assessments have used point estimates for these ratios; however, significant interindividual and interstudy variability has been reported. For example, a maternal ratio of 250 ppm in hair per mg/L in blood is commonly used in models, but a 1990 WHO review reports mean ratios ranging from 140 to 370 ppm per mg/L. To account for interindividual and interstudy variation in applying these ratios to risk and safety assessment, some researchers have proposed representing the ratios with probability distributions and conducting probabilistic assessments. Such assessments would allow regulators to consider the range and like-lihood of mercury exposures in a population, rather than limiting the evaluation to an estimate of the average exposure or a single conservative exposure estimate. However, no consensus exists on the most appropriate distributions for representing these parameters. We discuss published reviews of blood-to-hair and blood-to-intake steady state ratios for mercury and suggest statistical approaches for combining existing datasets to form generalized probability distributions for mercury distribution ratios. Although generalized distributions may not be applicable to all populations, they allow a more informative assessment than point estimates where individual biokinetic information is unavailable. Whereas development and use of these distributions will improve existing exposure and risk models, additional efforts in data generation and model development are required.

Genome-Wide Association Study of L-Arginine and Dimethylarginines Reveals Novel Metabolic Pathway for Symmetric Dimethylarginine

PubMed Central

Lüneburg, Nicole; Lieb, Wolfgang; Zeller, Tanja; Chen, Ming-Huei; Maas, Renke; Carter, Angela M.; Xanthakis, Vanessa; Glazer, Nicole L; Schwedhelm, Edzard; Seshadri, Sudha; Ikram, M. Arfan; Longstreth, W.T.; Fornage, Myriam; König, Inke R.; Loley, Christina; Ojeda, Francisco M.; Schillert, Arne; Wang, Thomas J.; Sticht, Heinrich; Kittel, Anja; König, Jörg; Benjamin, Emelia J.; Sullivan, Lisa M.; Bernges, Isabel; Anderssohn, Maike; Ziegler, Andreas; Gieger, Christian; Illig, Thomas; Meisinger, Christa; Wichmann, H.-Erich; Wild, Philipp S.; Schunkert, Heribert; Psaty, Bruce M.; Wiggins, Kerri L.; Heckbert, Susan R.; Smith, Nicholas; Lackner, Karl; Lunetta, Kathryn L.; Blankenberg, Stefan; Erdmann, Jeanette; Munzel, Thomas; Grant, Peter J.; Vasan, Ramachandran S.; Böger, Rainer H.

2016-01-01

Background Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers. Methods and Results This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (FHS (n=2992), GHS (n=4354) and MONICA/KORA F3 (n=581)) and identified replicated loci (DDAH1, MED23, Arg1 and AGXT2) associated with the inter-individual variability in ADMA, L-arginine and SDMA. Experimental in-silico and in-vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants and various cardiometabolic risk factors. AGXT2 variants were not associated with post-stroke survival in the Leeds study, nor were they associated with incident stroke in the CHARGE consortium. Conclusion These GWAS support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and L-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation. PMID:25245031

Hair analysis for long-term monitoring of buprenorphine intake in opiate withdrawal.

PubMed

Pirro, Valentina; Fusari, Ivana; Di Corcia, Daniele; Gerace, Enrico; De Vivo, Enrico; Salomone, Alberto; Vincenti, Marco

2014-12-01

Buprenorphine (BUP) is a psychoactive pharmaceutical drug largely used to treat opiate addiction. Short-term therapeutic monitoring is supported by toxicological analysis of blood and urine samples, whereas long-term monitoring by means of hair analysis is rarely used. Aim of this work was to develop and validate a highly sensitive ultrahigh-performance liquid chromatography tandem mass spectrometry method to detect BUP and norbuprenorphine (NBUP) in head hair. Interindividual correlation between oral dosage of BUP and head hair concentration was investigated. Furthermore, an intra-individual study by means of segmental analysis was performed on subjects with variable maintenance dosage. Hair samples from a population of 79 patients in treatment for opiate addiction were analyzed. The validated ultrahigh-performance liquid chromatography tandem mass spectrometry protocol allowed to obtain limits of detection and quantification at 0.6 and 2.2 pg/mg for BUP and 5.0 and 17 pg/mg for NBUP, respectively. Validation criteria were satisfied, assuring selective analyte identification, high detection capability, and precise and accurate quantification. Significant positive correlation was found between constant oral BUP dosage (1-32 mg/d) and the summed up head hair concentrations of BUP and NBUP. Nevertheless, substantial interindividual variability limits the chance to predict the oral dosage taken by each subject from the measured concentrations in head hair. In contrast, strong correlation was observed in the results of intra-individual segmental analysis, which proved reliable to detect oral dosage variations during therapy. Remarkably, all hair samples yielded BUP concentrations higher than 10 pg/mg, even when the lowest dosage was administered. Thus, these results support the selection of 10 pg/mg as a cutoff value.

Environmental impact of omnivorous, ovo-lacto-vegetarian, and vegan diet.

PubMed

Rosi, Alice; Mena, Pedro; Pellegrini, Nicoletta; Turroni, Silvia; Neviani, Erasmo; Ferrocino, Ilario; Di Cagno, Raffaella; Ruini, Luca; Ciati, Roberto; Angelino, Donato; Maddock, Jane; Gobbetti, Marco; Brighenti, Furio; Del Rio, Daniele; Scazzina, Francesca

2017-07-21

Food and beverage consumption has a great impact on the environment, although there is a lack of information concerning the whole diet. The environmental impact of 153 Italian adults (51 omnivores, 51 ovo-lacto-vegetarians, 51 vegans) and the inter-individual variability within dietary groups were assessed in a real-life context. Food intake was monitored with a 7-d dietary record to calculate nutritional values and environmental impacts (carbon, water, and ecological footprints). The Italian Mediterranean Index was used to evaluate the nutritional quality of each diet. The omnivorous choice generated worse carbon, water and ecological footprints than other diets. No differences were found for the environmental impacts of ovo-lacto-vegetarians and vegans, which also had diets more adherent to the Mediterranean pattern. A high inter-individual variability was observed through principal component analysis, showing that some vegetarians and vegans have higher environmental impacts than those of some omnivores. Thus, regardless of the environmental benefits of plant-based diets, there is a need for thinking in terms of individual dietary habits. To our knowledge, this is the first time environmental impacts of three dietary regimens are evaluated using individual recorded dietary intakes rather than hypothetical diet or diets averaged over a population.

Individual differences in visual motion perception and neurotransmitter concentrations in the human brain.

PubMed

Takeuchi, Tatsuto; Yoshimoto, Sanae; Shimada, Yasuhiro; Kochiyama, Takanori; Kondo, Hirohito M

2017-02-19

Recent studies have shown that interindividual variability can be a rich source of information regarding the mechanism of human visual perception. In this study, we examined the mechanisms underlying interindividual variability in the perception of visual motion, one of the fundamental components of visual scene analysis, by measuring neurotransmitter concentrations using magnetic resonance spectroscopy. First, by psychophysically examining two types of motion phenomena-motion assimilation and contrast-we found that, following the presentation of the same stimulus, some participants perceived motion assimilation, while others perceived motion contrast. Furthermore, we found that the concentration of the excitatory neurotransmitter glutamate-glutamine (Glx) in the dorsolateral prefrontal cortex (Brodmann area 46) was positively correlated with the participant's tendency to motion assimilation over motion contrast; however, this effect was not observed in the visual areas. The concentration of the inhibitory neurotransmitter γ-aminobutyric acid had only a weak effect compared with that of Glx. We conclude that excitatory process in the suprasensory area is important for an individual's tendency to determine antagonistically perceived visual motion phenomena.This article is part of the themed issue 'Auditory and visual scene analysis'. © 2017 The Author(s).

Inter-individual variability and genetic influences on cytokine responses against bacterial and fungal pathogens

PubMed Central

Li, Yang; Oosting, Marije; Deelen, Patrick; Ricaño-Ponce, Isis; Smeekens, Sanne; Jaeger, Martin; Matzaraki, Vasiliki; Swertz, Morris A.; Xavier, Ramnik J.; Franke, Lude; Wijmenga, Cisca; Joosten, Leo A.B.; Kumar, Vinod; Netea, Mihai G.

2016-01-01

Little is known about the inter-individual variation of cytokine responses to different pathogens in healthy individuals. To systematically describe cytokine responses elicited by distinct pathogens, and to determine the impact of genetic variation on cytokine production, we profiled cytokines produced by peripheral blood mononuclear cells from 197 individuals of European origin from the 200 Functional Genomics (200FG) cohort within the Human Functional Genomics Study (www.humanfunctionalgenomics.org), obtained over three different years. By comparing bacteria- and fungi-induced cytokine profiles, we show that most cytokine responses are organized around a physiological response to specific pathogens, rather than around a particular immune pathway or cytokine. We then correlated genome-wide SNP genotypes with cytokine abundance and identified six cytokine QTLs. Among them, a cytokine QTL at NAA35-GOLM1 locus markedly modulates IL-6 production in response to multiple pathogens, and associated with susceptibility to candidemia. Furthermore, the cytokine QTLs we identified are enriched among SNPs previously associated with infectious diseases and heart diseases. These data reveal and begin to explain the variability in cytokine production by human immune cells in response to pathogens. PMID:27376574

Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes.

PubMed

Rietschel, Liz; Streit, Fabian; Zhu, Gu; McAloney, Kerrie; Frank, Josef; Couvy-Duchesne, Baptiste; Witt, Stephanie H; Binz, Tina M; McGrath, John; Hickie, Ian B; Hansell, Narelle K; Wright, Margaret J; Gillespie, Nathan A; Forstner, Andreas J; Schulze, Thomas G; Wüst, Stefan; Nöthen, Markus M; Baumgartner, Markus R; Walker, Brian R; Crawford, Andrew A; Colodro-Conde, Lucía; Medland, Sarah E; Martin, Nicholas G; Rietschel, Marcella

2017-11-10

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.

CYP1A2 and NAT2 phenotyping and 3-aminobiphenyl and 4-aminobiphenyl hemoglobin adduct levels in smokers and non-smokers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sarkar, Mohamadi; Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298; Stabbert, Regina

Some aromatic amines are considered to be putative bladder carcinogens. Hemoglobin (Hb) adducts of 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP) have been used as biomarkers of exposure to aromatic amines from cigarette smoke. One of the goals of this study was to determine intra- and inter-individual variability in 3-ABP and 4-ABP Hb adducts and to explore the predictability of ABP Hb adduct levels based on caffeine phenotyping. The study was conducted in adult smokers (S, n = 65) and non-smokers (NS, n 65). The subjects were phenotyped for CYP1A2 and NAT2 using urinary caffeine metabolites. Blood samples were collected twice withinmore » 6 weeks and adducts measured by GC/MS. The levels of 4-ABP Hb adducts were significantly (p < 0.0001) greater in S (34.5 {+-} 21.06 pg/g Hb) compared to NS (6.3 {+-} 3.02 pg/g Hb). The levels of 3-ABP Hb adducts were below the limit of quantification (BLOQ) in most (82%) of the NS and about 10-fold lower in S (3.6 {+-} 3.29 pg/g Hb) compared to 4-ABP Hb adducts. No differences were observed in the adduct levels between weeks 1 and 6 in the smokers, suggesting that a single sample would be adequate to monitor cigarette smoke exposure. The regression model developed with CYP1A2, NAT2 phenotype and number of cigarettes smoked (NCIG) accounted for 47% of the variability in 3-ABP adducts, whereas 32% variability in 4-ABP adducts was accounted by CYP1A2 and NCIG. The ratio of 4-ABP Hb adducts in adult S:NS was {approx} 5:1, whereas 3-ABP Hb adducts levels were BLOQ in some S, exhibited large interindividual variability ({approx} 91% compared to 57% for 4-ABP Hb) and poor dose response relationship. Therefore, 4-ABP Hb adduct levels may be a more useful biomarker of aminobiphenyl exposure from cigarette smoke.« less

Solving the puzzle of collective action through inter-individual differences

PubMed Central

von Rueden, Chris; Gavrilets, Sergey; Glowacki, Luke

2015-01-01

Models of collective action infrequently account for differences across individuals beyond a limited set of strategies, ignoring variation in endowment (e.g. physical condition, wealth, knowledge, personality, support), individual costs of effort, or expected gains from cooperation. However, behavioural research indicates these inter-individual differences can have significant effects on the dynamics of collective action. The papers contributed to this theme issue evaluate how individual differences affect the propensity to cooperate, and how they can catalyse others’ likelihood of cooperation (e.g. via leadership). Many of the papers emphasize the relationship between individual decisions and socio-ecological context, particularly the effect of group size. All together, the papers in this theme issue provide a more complete picture of collective action, by embracing the reality of inter-individual variation and its multiple roles in the success or failure of collective action. PMID:26503677

Individual Variability in Reproductive Success Determines Winners and Losers under Ocean Acidification: A Case Study with Sea Urchins

PubMed Central

Schlegel, Peter; Havenhand, Jon N.; Gillings, Michael R.; Williamson, Jane E.

2012-01-01

Background Climate change will lead to intense selection on many organisms, particularly during susceptible early life stages. To date, most studies on the likely biotic effects of climate change have focused on the mean responses of pooled groups of animals. Consequently, the extent to which inter-individual variation mediates different selection responses has not been tested. Investigating this variation is important, since some individuals may be preadapted to future climate scenarios. Methodology/Principal Findings We examined the effect of CO2-induced pH changes (“ocean acidification”) in sperm swimming behaviour on the fertilization success of the Australasian sea urchin Heliocidaris erythrogramma, focusing on the responses of separate individuals and pairs. Acidification significantly decreased the proportion of motile sperm but had no effect on sperm swimming speed. Subsequent fertilization experiments showed strong inter-individual variation in responses to ocean acidification, ranging from a 44% decrease to a 14% increase in fertilization success. This was partly explained by the significant relationship between decreases in percent sperm motility and fertilization success at ΔpH = 0.3, but not at ΔpH = 0.5. Conclusions and Significance The effects of ocean acidification on reproductive success varied markedly between individuals. Our results suggest that some individuals will exhibit enhanced fertilization success in acidified oceans, supporting the concept of ‘winners’ and ‘losers’ of climate change at an individual level. If these differences are heritable it is likely that ocean acidification will lead to selection against susceptible phenotypes as well as to rapid fixation of alleles that allow reproduction under more acidic conditions. This selection may ameliorate the biotic effects of climate change if taxa have sufficient extant genetic variation upon which selection can act. PMID:23300876

Changes in Physiological Parameters after Combined Exercise according to the I/D Polymorphism of hUCP2 Gene in Middle-Aged Obese Females

PubMed Central

DUK OH, Sang

2014-01-01

Abstract Background The purpose of this study was to determine whether a 45 bp insertion/deletion (I/D) polymorphism in human uncoupling protein 2 (hUCP2) gene was associated with changes in several cardiovascular risk and physical fitness factors in response to combined exercise during 12 weeks in Korean middle-aged women. The changes in physiological parameters after combined exercise during 12 weeks were compared between each genotype subgroups of hUCP2 gene to clarify the inter-individual differences in exercised-induced changes according to genetic predisposition. Methods A total of 185 women aged over 40 years living in Seoul, Korea were participated in this study, and analyzed before and after 12 weeks on combined exercise including aerobic exercise and strength training for body composition, hemodynamic parameters, physical fitness and metabolic variables. A 45 bp I/D polymorphism in hUCP2 gene was genotyped by polymerase chain reaction (PCR) amplification and agarose gel electrophoresis method. Results Combined exercise program during 12 weeks indicated the significant health-promoting effects for our participants on multiple body composition, hemodynamic parameters, physical fitness factors and metabolic parameters, respectively. With respect to a 45 bp I/D polymorphism in hUCP2 gene, this polymorphism was significantly associated with baseline %body fat of our participants (P <.05). Moreover, this polymorphism was significantly associated with the changes in %body fat and serum triglyceride(TG) level after combined exercise program during 12 weeks(P <.05). Conclusion Our data suggest that a 45 bp I/D polymorphism in hUCP2 gene may at least in part contribute to the inter-individual differences on the changes in some clinical and metabolic parameters following combined exercise in middle-aged women. PMID:25909061

Evaluation of analgesic effect and absorption of buprenorphine after buccal administration in cats with oral disease.

PubMed

Stathopoulou, Thaleia-Rengina; Kouki, Maria; Pypendop, Bruno H; Johnston, Atholl; Papadimitriou, Serafeim; Pelligand, Ludovic

2017-09-01

Objectives The objective of this study was to evaluate the analgesic effect and absorption of buprenorphine after buccal administration in cats with oral disease. Methods Six adult client-owned cats with chronic gingivostomatitis (weighing 5.1 ± 1.1 kg) were recruited for a randomised, prospective, blinded, saline-controlled, crossover study. Pain scores, dental examination, stomatitis score and buccal pH measurement were conducted on day 1 under sedation in all cats. On day 2, animals were randomised into two groups and administered one of the two treatments buccally (group A received buprenorphine 0.02 mg/kg and group B received 0.9% saline) and vice versa on day 3. Pain scores and food consumption were measured at 30, 90 and 360 mins after the administration of buprenorphine. Blood samples were taken at the same time and plasma buprenorphine concentration was measured by liquid chromatography-mass spectrometry. Data were statistically analysed as non-parametric and the level of significance was set as P <0.05. Results There were no major side effects after buprenorphine administration. Buccal pH values ranged between 8.5 and 9.1 and the stomatitis disease activity index between 10 and 22 (17.8 ± 4.5) with the scale ranging from 0-30. The maximum buprenorphine plasma concentration (14.8 ng/ml) was observed 30 mins after administration and there was low inter-individual variability. There was a significant difference between baseline pain scores compared with pain scores after buprenorphine ( P <0.05 ) and between the saline and buprenorphine group at 30 mins ( P = 0.04) and 90 mins ( P = 0.04). There was also a significant effect of the stomatitis index on the pain score. Regarding the pharmacokinetic parameters, cats with stomatitis showed lower bioavailability and shorter absorption half-life after buccal administration of buprenorphine compared with normal cats in previous studies. Conclusions and relevance Buccal administration of buprenorphine in cats with gingivostomatitis produces an analgesic effect and low inter-individual variability in plasma concentration, and it can be incorporated in their multimodal analgesia plan.

Dopaminergic modulation of hemodynamic signal variability and the functional connectome during cognitive performance.

PubMed

Alavash, Mohsen; Lim, Sung-Joo; Thiel, Christiane; Sehm, Bernhard; Deserno, Lorenz; Obleser, Jonas

2018-05-15

Dopamine underlies important aspects of cognition, and has been suggested to boost cognitive performance. However, how dopamine modulates the large-scale cortical dynamics during cognitive performance has remained elusive. Using functional MRI during a working memory task in healthy young human listeners, we investigated the effect of levodopa (l-dopa) on two aspects of cortical dynamics, blood oxygen-level-dependent (BOLD) signal variability and the functional connectome of large-scale cortical networks. We here show that enhanced dopaminergic signaling modulates the two potentially interrelated aspects of large-scale cortical dynamics during cognitive performance, and the degree of these modulations is able to explain inter-individual differences in l-dopa-induced behavioral benefits. Relative to placebo, l-dopa increased BOLD signal variability in task-relevant temporal, inferior frontal, parietal and cingulate regions. On the connectome level, however, l-dopa diminished functional integration across temporal and cingulo-opercular regions. This hypo-integration was expressed as a reduction in network efficiency and modularity in more than two thirds of the participants and to different degrees. Hypo-integration co-occurred with relative hyper-connectivity in paracentral lobule and precuneus, as well as posterior putamen. Both, l-dopa-induced BOLD signal variability modulation and functional connectome modulations proved predictive of an individual's l-dopa-induced benefits in behavioral performance, namely response speed and perceptual sensitivity. Lastly, l-dopa-induced modulations of BOLD signal variability were correlated with l-dopa-induced modulation of nodal connectivity and network efficiency. Our findings underline the role of dopamine in maintaining the dynamic range of, and communication between, cortical systems, and their explanatory power for inter-individual differences in benefits from dopamine during cognitive performance. Copyright © 2018 Elsevier Inc. All rights reserved.

Interindividual Responses of Appetite to Acute Exercise: A Replicated Crossover Study.

PubMed

Goltz, Fernanda R; Thackray, Alice E; King, James A; Dorling, James L; Atkinson, Greg; Stensel, David J

2018-04-01

Acute exercise transiently suppresses appetite, which coincides with alterations in appetite-regulatory hormone concentrations. Individual variability in these responses is suspected, but replicated trials are needed to quantify them robustly. We examined the reproducibility of appetite and appetite-regulatory hormone responses to acute exercise and quantified the individual differences in responses. Fifteen healthy, recreationally active men completed two control (60-min resting) and two exercise (60-min fasted treadmill running at 70% peak oxygen uptake) conditions in randomized sequences. Perceived appetite and circulating concentrations of acylated ghrelin and total peptide YY (PYY) were measured immediately before and after the interventions. Interindividual differences were explored by correlating the two sets of response differences between exercise and control conditions. Within-participant covariate-adjusted linear mixed models were used to quantify participant-condition interactions. Compared with control, exercise suppressed mean acylated ghrelin concentrations and appetite perceptions (all ES = 0.62-1.47, P < 0.001) and elevated total PYY concentrations (ES = 1.49, P < 0.001). For all variables, the standard deviation of the change scores was substantially greater in the exercise versus control conditions. Moderate-to-large positive correlations were observed between the two sets of control-adjusted exercise responses for all variables (r = 0.54-0.82, P ≤ 0.036). After adjusting for baseline measurements, participant-condition interactions were present for all variables (P ≤ 0.053). Our replicated crossover study allowed, for the first time, the interaction between participant and acute exercise response in appetite parameters to be quantified. Even after adjustment for individual baseline measurements, participants demonstrated individual differences in perceived appetite and hormone responses to acute exercise bouts beyond any random within-subject variability over time.

Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine.

PubMed

Aarts, Esther; van Holstein, Mieke; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

2015-02-01

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3'-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD.

Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine

PubMed Central

Aarts, Esther; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

2015-01-01

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3′-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD. PMID:25485641

[Environmental and genetic factors associated with psychoactive medication use in adult females. A population-based twin study].

PubMed

Rosagro Escámez, Francisco; González-Javier, Francisca; Ordoñana, Juan R

2013-01-01

Our objective is to determine the prevalence and factors associated to psychotropic medication consumption in a sample of adult females. Additionally, this study seeks to analyze the relative contribution of environmental and genetic factors to psychoactive medication use. Sample consists of a population-based cohort comprising 437 pairs of female twins born between 1940 and 1966. Information is collected through individual interviews, and it includes employment status, educational level, partner status, menopause, presence of mental disorders and psychoactive medication use. Logistic regression models are applied. The relative contribution of genetic and environmental factors to interindividual variation is analyzed through the classical twin design. In the past month, 34.0% of the women interviewed had consumed psychoactive medication. Consumption increases with age, in women out of the labor market, menopausal, and reporting a history of mental disorders. When controlling for age, all variables lost significance, except the presence of mental health problems. Heritability estimates for psychoactive medication use was 52%. This estimate is similar (46%) for consumption in the two categories studied. There is a high prevalence of psychoactive medication use in this sample. This consumption is mainly associated with age and presence of mental disorders. About half of the interindividual variation in psychotropic medication use is attributable to genetic factors, while the rest of the variance would be due to environmental factors unique to each individual.

The Effect of microRNAs in the Regulation of Human CYP3A4: a Systematic Study using a Mathematical Model

PubMed Central

Wei, Zhiyun; Jiang, Songshan; Zhang, Yiting; Wang, Xiaofei; Peng, Xueling; Meng, Chunjie; Liu, Yichen; Wang, Honglian; Guo, Luo; Qin, Shengying; He, Lin; Shao, Fengmin; Zhang, Lirong; Xing, Qinghe

2014-01-01

CYP3A4 metabolizes more than 50% of the drugs on the market. The large inter-individual differences of CYP3A4 expression may contribute to the variability of human drug responses. Post-transcriptional regulation of CYP3A4 is poorly understood, whereas transcriptional regulation has been studied much more thoroughly. In this study, we used multiple software programs to predict miRNAs that might bind to CYP3A4 and identified 112 potentially functional miRNAs. Then a luciferase reporter system was used to assess the effect of the overexpression of each potentially functional miRNA in HEK 293T cells. Fourteen miRNAs that significantly decreased reporter activity were measured in human liver samples (N = 27) as candidate miRNAs. To establish a more effective way to analyze in vivo data for miRNA candidates, the relationship between functional miRNA and target mRNA was modeled mathematically. Taking advantage of this model, we found that hsa-miR-577, hsa-miR-1, hsa-miR-532-3p and hsa-miR-627 could significantly downregulate the translation efficiency of CYP3A4 mRNA in liver. This study used in silico, in vitro and in vivo methods to progressively screen functional miRNAs for CYP3A4 and to enhance our understanding of molecular events underlying the large inter-individual differences of CYP3A4 expression in human populations. PMID:24594634

Inflammatory Pathway Genes Associated with Inter-Individual Variability in the Trajectories of Morning and Evening Fatigue in Patients Receiving Chemotherapy

PubMed Central

Wright, Fay; Hammer, Marilyn; Paul, Steven M.; Aouizerat, Bradley E.; Kober, Kord M.; Conley, Yvette P.; Cooper, Bruce A.; Dunn, Laura B.; Levine, Jon D.; Melkus, Gail DEramo; Miaskowski, Christine

2017-01-01

Fatigue, a highly prevalent and distressing symptom during chemotherapy (CTX), demonstrates diurnal and interindividual variability in severity. Little is known about the associations between variations in genes involved in inflammatory processes and morning and evening fatigue severity during CTX. The purposes of this study, in a sample of oncology patients (N=543) with breast, gastrointestinal (GI), gynecological (GYN), or lung cancer who received two cycles of CTX, were to determine whether variations in genes involved in inflammatory processes were associated with inter-individual variability in initial levels as well as in the trajectories of morning and evening fatigue. Patients completed the Lee Fatigue Scale to determine morning and evening fatigue severity a total of six times over two cycles of CTX. Using a whole exome array, 309 single nucleotide polymorphisms among the 64 candidate genes that passed all quality control filters were evaluated using hierarchical linear modeling (HLM). Based on the results of the HLM analyses, the final SNPs were evaluated for their potential impact on protein function using two bioinformational tools. The following inflammatory pathways were represented: chemokines (3 genes); cytokines (12 genes); inflammasome (11 genes); Janus kinase/signal transducers and activators of transcription (JAK/STAT, 10 genes); mitogen-activated protein kinase/jun amino-terminal kinases (MAPK/JNK, 3 genes); nuclear factor-kappa beta (NFkB, 18 genes); and NFkB and MAP/JNK (7 genes). After controlling for self-reported and genomic estimates of race and ethnicity, polymorphisms in six genes from the cytokine (2 genes); inflammasome (2 genes); and NFkB (2 genes) pathways were associated with both morning and evening fatigue. Polymorphisms in six genes from the inflammasome (1 gene); JAK/STAT (1 gene); and NFkB (4 genes) pathways were associated with only morning fatigue. Polymorphisms in three genes from the inflammasome (2 genes) and the NFkB (1 gene) pathways were associated with only evening fatigue. Taken together, these findings add to the growing body of evidence that suggests that morning and evening fatigue are distinct symptoms. PMID:28110208

Baseline Chromatin Modification Levels May Predict ...

EPA Pesticide Factsheets

Traditional toxicological paradigms have relied on factors such as age, genotype, and disease status to explain variability in responsiveness to toxicant exposure; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are they modifiable factors that can be leveraged to mitigate the exposure effects. Unlike these factors, the epigenome is dynamic and shaped by an individual's environment. We sought to determine whether baseline levels of specific chromatin modifications correlated with the interindividual variability in their ozone (03)-mediated induction in an air-liquid interface model using primary human bronchial epithelial cells from a panel of 11 donors. We characterized the relationship between the baseline abundance of 6 epigenetic markers with established roles as key regulators of gene expression-histone H3 lysine 4 trimethylation (H3K4me3), H3K27 acetylation (H3K27ac), pan­acetyl H4 (H4ac), histone H3K27 di/trimethylation (H3K27me2/3), unmodified H3, and5-hydroxymethylcytosine (5-hmC)-and the variability in the 03-induced expression of IL-8, IL-6, COX2, and HMOX1. Baseline levels of H3K4me3, H3K27me2/3, and 5-hmC, but not H3K27ac, H4ac, and total H3, correlated with the interindividual variability in 03-mediated induction of HMOX1 and COX2. In contrast, none of the chromatin modifications that we examined correlated with the induction of IL-8 and IL-6. From these findings, we propose an "epigenetic see

An integrated workflow to assess technical and biological variability of cell population frequencies in human peripheral blood by flow cytometry

PubMed Central

Burel, Julie G.; Qian, Yu; Arlehamn, Cecilia Lindestam; Weiskopf, Daniela; Zapardiel-Gonzalo, Jose; Taplitz, Randy; Gilman, Robert H.; Saito, Mayuko; de Silva, Aruna D.; Vijayanand, Pandurangan; Scheuermann, Richard H.; Sette, Alessandro; Peters, Bjoern

2016-01-01

In the context of large-scale human system immunology studies, controlling for technical and biological variability is crucial to ensure that experimental data support research conclusions. Here, we report on a universal workflow to evaluate both technical and biological variation in multiparameter flow cytometry, applied to the development of a 10-color panel to identify all major cell populations and T cell subsets in cryopreserved PBMC. Replicate runs from a control donation and comparison of different gating strategies assessed technical variability associated with each cell population and permitted the calculation of a quality control score. Applying our panel to a large collection of PBMC samples, we found that most cell populations showed low intra-individual variability over time. In contrast, certain subpopulations such as CD56 T cells and Temra CD4 T cells were associated with high inter-individual variability. Age but not gender had a significant effect on the frequency of several populations, with a drastic decrease in naïve T cells observed in older donors. Ethnicity also influenced a significant proportion of immune cell population frequencies, emphasizing the need to account for these co-variates in immune profiling studies. Finally, we exemplify the usefulness of our workflow by identifying a novel cell-subset signature of latent tuberculosis infection. Thus, our study provides a universal workflow to establish and evaluate any flow cytometry panel in systems immunology studies. PMID:28069807

An Integrated Workflow To Assess Technical and Biological Variability of Cell Population Frequencies in Human Peripheral Blood by Flow Cytometry.

PubMed

Burel, Julie G; Qian, Yu; Lindestam Arlehamn, Cecilia; Weiskopf, Daniela; Zapardiel-Gonzalo, Jose; Taplitz, Randy; Gilman, Robert H; Saito, Mayuko; de Silva, Aruna D; Vijayanand, Pandurangan; Scheuermann, Richard H; Sette, Alessandro; Peters, Bjoern

2017-02-15

In the context of large-scale human system immunology studies, controlling for technical and biological variability is crucial to ensure that experimental data support research conclusions. In this study, we report on a universal workflow to evaluate both technical and biological variation in multiparameter flow cytometry, applied to the development of a 10-color panel to identify all major cell populations and T cell subsets in cryopreserved PBMC. Replicate runs from a control donation and comparison of different gating strategies assessed the technical variability associated with each cell population and permitted the calculation of a quality control score. Applying our panel to a large collection of PBMC samples, we found that most cell populations showed low intraindividual variability over time. In contrast, certain subpopulations such as CD56 T cells and Temra CD4 T cells were associated with high interindividual variability. Age but not gender had a significant effect on the frequency of several populations, with a drastic decrease in naive T cells observed in older donors. Ethnicity also influenced a significant proportion of immune cell population frequencies, emphasizing the need to account for these covariates in immune profiling studies. We also exemplify the usefulness of our workflow by identifying a novel cell-subset signature of latent tuberculosis infection. Thus, our study provides a universal workflow to establish and evaluate any flow cytometry panel in systems immunology studies. Copyright © 2017 by The American Association of Immunologists, Inc.

Stevens-Johnson syndrome and toxic epidermal necrolysis: an update on pharmacogenetics studies in drug-induced severe skin reaction.

PubMed

Rufini, Sara; Ciccacci, Cinzia; Politi, Cristina; Giardina, Emiliano; Novelli, Giuseppe; Borgiani, Paola

2015-11-01

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening drug reactions involving skin and membranes mucous, which are associated with significant morbidity and mortality and triggered, especially by drug exposure. Different studies have demonstrated that drug response is a multifactorial character and that the interindividual variability in this response depends on both environmental and genetic factors. The last ones have a relevant significance. In fact, the identification of new specific genetic markers involved in the response to drugs, will be of great utility to establish a more personalized therapeutic approach and to prevent the appearance of these adverse reactions. In this review, we summarize recent progresses in the Pharmacogenetics studies related to Stevens-Johnson syndrome/toxic epidermal necrolysis reporting the major genetic factors identified in the last years as associated with the disease and highlighting the use of some of these genomic variants in the clinical practice.

Single-Cell Memory Regulates a Neural Circuit for Sensory Behavior.

PubMed

Kobayashi, Kyogo; Nakano, Shunji; Amano, Mutsuki; Tsuboi, Daisuke; Nishioka, Tomoki; Ikeda, Shingo; Yokoyama, Genta; Kaibuchi, Kozo; Mori, Ikue

2016-01-05

Unveiling the molecular and cellular mechanisms underlying memory has been a challenge for the past few decades. Although synaptic plasticity is proven to be essential for memory formation, the significance of "single-cell memory" still remains elusive. Here, we exploited a primary culture system for the analysis of C. elegans neurons and show that a single thermosensory neuron has an ability to form, retain, and reset a temperature memory. Genetic and proteomic analyses found that the expression of the single-cell memory exhibits inter-individual variability, which is controlled by the evolutionarily conserved CaMKI/IV and Raf pathway. The variable responses of a sensory neuron influenced the neural activity of downstream interneurons, suggesting that modulation of the sensory neurons ultimately determines the behavioral output in C. elegans. Our results provide proof of single-cell memory and suggest that the individual differences in neural responses at the single-cell level can confer individuality. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Variability in emotional responsiveness and coping style during active avoidance as a window onto psychological vulnerability to stress.

PubMed

Gorka, Adam X; LaBar, Kevin S; Hariri, Ahmad R

2016-05-01

Individual differences in coping styles are associated with psychological vulnerability to stress. Recent animal research suggests that coping styles reflect trade-offs between proactive and reactive threat responses during active avoidance paradigms, with proactive responses associated with better stress tolerance. Based on these preclinical findings, we developed a novel instructed active avoidance paradigm to characterize patterns of proactive and reactive responses using behavioral, motoric, and autonomic measures in humans. Analyses revealed significant inter-individual variability not only in the magnitude of general emotional responsiveness but also the likelihood to specifically express proactive or reactive responses. In men but not women, individual differences in general emotional responsiveness were linked to increased trait anxiety while proactive coping style was linked to increased trait aggression. These patterns are consistent with preclinical findings and suggest that instructed active avoidance paradigms may be useful in assessing psychological vulnerability to stress using objective behavioral measures. Copyright © 2016. Published by Elsevier Inc.

Analysis of the contribution of experimental bias, experimental noise, and inter-subject biological variability on the assessment of developmental trajectories in diffusion MRI studies of the brain.

PubMed

Sadeghi, Neda; Nayak, Amritha; Walker, Lindsay; Okan Irfanoglu, M; Albert, Paul S; Pierpaoli, Carlo

2015-04-01

Metrics derived from the diffusion tensor, such as fractional anisotropy (FA) and mean diffusivity (MD) have been used in many studies of postnatal brain development. A common finding of previous studies is that these tensor-derived measures vary widely even in healthy populations. This variability can be due to inherent inter-individual biological differences as well as experimental noise. Moreover, when comparing different studies, additional variability can be introduced by different acquisition protocols. In this study we examined scans of 61 individuals (aged 4-22 years) from the NIH MRI study of normal brain development. Two scans were collected with different protocols (low and high resolution). Our goal was to separate the contributions of biological variability and experimental noise to the overall measured variance, as well as to assess potential systematic effects related to the use of different protocols. We analyzed FA and MD in seventeen regions of interest. We found that biological variability for both FA and MD varies widely across brain regions; biological variability is highest for FA in the lateral part of the splenium and body of the corpus callosum along with the cingulum and the superior longitudinal fasciculus, and for MD in the optic radiations and the lateral part of the splenium. These regions with high inter-individual biological variability are the most likely candidates for assessing genetic and environmental effects in the developing brain. With respect to protocol-related effects, the lower resolution acquisition resulted in higher MD and lower FA values for the majority of regions compared with the higher resolution protocol. However, the majority of the regions did not show any age-protocol interaction, indicating similar trajectories were obtained irrespective of the protocol used. Published by Elsevier Inc.

Systematic Therapeutic Drug Monitoring for Linezolid: Variability and Clinical Impact

PubMed Central

Valerio, Maricela; Muñoz, Patricia; Alcalá, Luis; García-González, Xandra; Burillo, Almudena; Sanjurjo, María; Grau, Santiago

2017-01-01

ABSTRACT Linezolid serum trough (Cmin) and peak (Cmax) levels were determined prospectively in 90 patients. Adequate exposure was defined as a Cmin of 2 to 8 mg/liter. Therapy was empirical (73.3%) or targeted (26.7%). Wide interindividual variability in linezolid Cmin levels was recorded (0.1 to 25.2 μg/ml). Overall, 65.5% of the patients had out-of-range, 41.1% had subtherapeutic, and 24.4% had supratherapeutic trough levels. We did not find a correlation between abnormal levels and adverse events, in-hospital mortality, or overall poor outcome. PMID:28739788

Agreement in DNA methylation levels from the Illumina 450K array across batches, tissues, and time

PubMed Central

Forest, Marie; O'Donnell, Kieran J.; Voisin, Greg; Gaudreau, Helene; MacIsaac, Julia L.; McEwen, Lisa M.; Silveira, Patricia P.; Steiner, Meir; Kobor, Michael S.; Meaney, Michael J.; Greenwood, Celia M.T.

2018-01-01

ABSTRACT Epigenome-wide association studies (EWAS) have focused primarily on DNA methylation as a chemically stable and functional epigenetic modification. However, the stability and accuracy of the measurement of methylation in different tissues and extraction types is still being actively studied, and the longitudinal stability of DNA methylation in commonly studied peripheral tissues is of great interest. Here, we used data from two studies, three tissue types, and multiple time points to assess the stability of DNA methylation measured with the Illumina Infinium HumanMethylation450 BeadChip array. Redundancy analysis enabled visual assessment of agreement of replicate samples overall and showed good agreement after removing effects of tissue type, age, and sex. At the probe level, analysis of variance contrasts separating technical and biological replicates clearly showed better agreement between technical replicates versus longitudinal samples, and suggested increased stability for buccal cells versus blood or blood spots. Intraclass correlations (ICCs) demonstrated that inter-individual variability is of similar magnitude to within-sample variability at many probes; however, as inter-individual variability increased, so did ICC. Furthermore, we were able to demonstrate decreasing agreement in methylation levels with time, despite a maximal sampling interval of only 576 days. Finally, at 6 popular candidate genes, there was a large range of stability across probes. Our findings highlight important sources of technical and biological variation in DNA methylation across different tissues over time. These data will help to inform longitudinal sampling strategies of future EWAS. PMID:29381404

Organic Isothiocyanates: Dietary Modulators of Doxorubicin Resistance in Breast Cancer

DTIC Science & Technology

2004-06-01

al. (30) have dem- isothiocyanates: chemistry and mechanisms. Cancer Res. 54: onstrated the inhibition of renal clearance of colchicine by 1976s-1981s... Chemistry , Uni- possibility of flip-flop kinetics (absorption being slower versity at Buffalo) for his assistance in internal standard than elimination) in...Anticarcinogenic activities of organic sult fi’om interindividual variability and limited subject isothiocyanates: chemistry and mechanisms, Cancer Res. 54 (1994

Effects of aircraft noise on the equilibrium of airport residents: Supplementary analyses to the study carried out around Orly

NASA Technical Reports Server (NTRS)

Francois, J.

1981-01-01

The effects of aircraft noise on humans living near airports were studied. Two main questions were considered: do residents give evidence of psychological or physiological disturbances in unusually intense noise sectors; and do personality or health factors account for the high interindividual variability of annoyance? The methodology used and results obtained are presented. Samples of the survey questionnaires are included.

Dealing with consumer differences in liking during repeated exposure to food; typical dynamics in rating behavior.

PubMed

Dalenberg, Jelle R; Nanetti, Luca; Renken, Remco J; de Wijk, René A; Ter Horst, Gert J

2014-01-01

Consumers show high interindividual variability in food liking during repeated exposure. To investigate consumer liking during repeated exposure, data is often interpreted on a product level by averaging results over all consumers. However, a single product may elicit inconsistent behaviors in consumers; averaging will mix and hide possible subgroups of consumer behaviors, leading to a misinterpretation of the results. To deal with the variability in consumer liking, we propose to use clustering on data from consumer-product combinations to investigate the nature of the behavioral differences within the complete dataset. The resulting behavioral clusters can then be used to describe product acceptance. To test this approach we used two independent data sets in which young adults were repeatedly exposed to drinks and snacks, respectively. We found that five typical consumer behaviors existed in both datasets. These behaviors differed both in the average level of liking as well as its temporal dynamics. By investigating the distribution of a single product across typical consumer behaviors, we provide more precise insight in how consumers divide in subgroups based on their product liking (i.e. product modality). This work shows that taking into account and using interindividual differences can unveil information about product acceptance that would otherwise be ignored.

Dealing with Consumer Differences in Liking during Repeated Exposure to Food; Typical Dynamics in Rating Behavior

PubMed Central

Dalenberg, Jelle R.; Nanetti, Luca; Renken, Remco J.; de Wijk, René A.; ter Horst, Gert J.

2014-01-01

Consumers show high interindividual variability in food liking during repeated exposure. To investigate consumer liking during repeated exposure, data is often interpreted on a product level by averaging results over all consumers. However, a single product may elicit inconsistent behaviors in consumers; averaging will mix and hide possible subgroups of consumer behaviors, leading to a misinterpretation of the results. To deal with the variability in consumer liking, we propose to use clustering on data from consumer-product combinations to investigate the nature of the behavioral differences within the complete dataset. The resulting behavioral clusters can then be used to describe product acceptance. To test this approach we used two independent data sets in which young adults were repeatedly exposed to drinks and snacks, respectively. We found that five typical consumer behaviors existed in both datasets. These behaviors differed both in the average level of liking as well as its temporal dynamics. By investigating the distribution of a single product across typical consumer behaviors, we provide more precise insight in how consumers divide in subgroups based on their product liking (i.e. product modality). This work shows that taking into account and using interindividual differences can unveil information about product acceptance that would otherwise be ignored. PMID:24667832

Role of self-emulsifying drug delivery systems in optimizing the oral delivery of hydrophilic macromolecules and reducing interindividual variability.

PubMed

AboulFotouh, Khaled; Allam, Ayat A; El-Badry, Mahmoud; El-Sayed, Ahmed M

2018-07-01

Self-emulsifying drug delivery systems (SEDDS) have been widely employed to improve the oral bioavailability of poorly soluble drugs. In the past few years, SEDDS were extensively investigated to overcome various barriers encountered in the oral delivery of hydrophilic macromolecules (e.g., protein/peptide therapeutics and plasmid DNA (pDNA)), as well as in lowering the effect of food on drugs' bioavailability. However, the main mechanism(s) by which SEDDS could achieve such promising effects remains not fully understood. This review summarizes the recent progress in the use of SEDDS for protecting protein therapeutics and/or pDNA against enzymatic degradation and increasing the oral bioavailability of various drug substances regardless of the dietary condition. Understanding the underlying mechanism(s) of such promising applications will aid in the future development of rationally designed SEDDS. Entrapment of hydrophilic macromolecules in the oil phase of the formed emulsion is critical for protection of the loaded cargoes against enzymatic degradation and the enhancement of oral bioavailability. On the other hand, drug administration as a preconcentrated solution in the SEDDS preconcentrate allows the process of drug absorption to occur independently of the dietary condition, and thus reducing interindividual variability that results from concomitant food intake. Copyright © 2018 Elsevier B.V. All rights reserved.

The influence of redox status on inter-individual variability in the response of human peripheral blood lymphocytes to ionizing radiation.

PubMed

Pajic, Jelena; Rovcanin, Branislav; Kekic, Dusan; Jovicic, Dubravka; Milovanovic, Aleksandar P S

2018-04-30

Ionizing radiation (IR) can act on atomic structures, producing damage to biomolecules. Earlier investigations evaluating individual radiosensitivity in vitro were focused on cytogenetic biomarkers (chromosomal aberrations - CA and micronuclei - MN). Since IR can also cause oxidative damage by producing reactive oxygen species, the main goal of this investigation was to establish the influence of redox status on CA and MN frequency in human peripheral blood lymphocytes. Blood samples from 56 healthy donors were irradiated at doses of 0, 0.75, 1.5 and 3 Gy and then analyzed cytogenetically and biochemically. The results showed inter-individual variability in all analyzed parameters, as well as dose-dependent increases in almost all of them. Correlation analysis indicated no association between CA, MN and oxidative stress parameters. However, findings for overall response (HRR) parameters showed that donors with lower values for parameters of antioxidant status had increased levels of cytogenetic damage and higher responses to irradiation and vice versa. Besides well-established cytogenetic biomarkers of radiation exposure, our results indicated promising future use for biochemical oxidative status parameters in routine radiation protection practice, since together they can provide a complete radiation response profile in cases of continuous low-dose exposure, as well as in a radiation emergency.

The impact of the matrix of red beet products and interindividual variability on betacyanins bioavailability in humans.

PubMed

Wiczkowski, Wieslaw; Romaszko, Ewa; Szawara-Nowak, Dorota; Piskula, Mariusz K

2018-06-01

The influence of the matrix of red beetroot products and interindividual variability on betacyanins bioavailability in humans was studied. In a randomized crossover study 12 volunteers consumed red beet juice and crunchy slices containing betanin and isobetanin. Betalains were analyzed by the HPLC-DAD-MS. Urine samples examined after the consumption of both products contained not only native betacyanins but also their aglycones. In case of juice, the highest betacyanins urine excretion rate was observed within the first 2 h (64 nmol/h), while in case of crunchy slices within the period of 2-4 h (66 nmol/h). Among volunteers, the average total betacyanins excretion rate ranged from 18.54 to 67.96 nmol/h and, 13.15 to 63.58 nmol/h for red beet juice and crunchy slices, respectively. In total, approximately 0.3% of betacyanins (ranging from 0.12 to 0.58%) ingested from both products was excreted. The study showed that betacyanins bioavailability from juice and crunchy slices is similar, with the matrix of products consumed having an impact on betacyanins excretion profile, and the phenotype of volunteers affecting betacyanins excretion rate. Copyright © 2018 Elsevier Ltd. All rights reserved.

Scaling left ventricular mass in adolescent boys aged 11-15 years.

PubMed

Valente-Dos-Santos, João; Coelho-E-Silva, Manuel J; Ferraz, António; Castanheira, Joaquim; Ronque, Enio R; Sherar, Lauren B; Elferink-Gemser, Marije T; Malina, Robert M

2014-01-01

Normalizing left ventricular mass (LVM) for inter-individual variation in body size is a central issue in human biology. During the adolescent growth spurt, variability in body size descriptors needs to be interpreted in combination with biological maturation. To examine the contribution of biological maturation, stature, sitting height, body mass, fat-free mass (FFM) and fat mass (FM) to inter-individual variability in LVM in boys, using proportional allometric modelling. The cross-sectional sample included 110 boys of 11-15 years (12.9-1.0 years). Stature, sitting height, body mass, cardiac chamber dimensions and LVM were measured. Age at peak height velocity (APHV) was predicted and used as an indicator of biological maturation. Percentage fat was estimated from triceps and subscapular skinfolds; FM and FFM were derived. Exponents for body size descriptors were k = 2.33 for stature, k = 2.18 for sitting height, k = 0.68 for body mass, k = 0.17 for FM and k = 0.80 for FFM (adjusted R(2 )= 19-62%). The combination of body descriptors and APHV increased the explained variance in LVM (adjusted R(2)( )= 56-69%). Stature, FM and FFM are the best combination for normalizing LVM in adolescent boys; when body composition is not available, an indicator of biological maturity should be included with stature.

Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1

PubMed Central

Yoo, Hee-Doo; Cho, Hea-Young; Lee, Yong-Bok

2010-01-01

AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h−1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h−1. Absorption rate constant was estimated at 0.24 h−1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. PMID:20078610

Smoking and diabetes. Epigenetics involvement in osseointegration.

PubMed

Razzouk, Sleiman; Sarkis, Rami

2013-03-01

Bone quality is a poorly defined parameter for successful implant placement, which largely depends upon many environmental and genetic factors unique to every individual. Smoking and diabetes are among the environmental factors that most impact osseointegration. However, there is an inter-individual variability of bone response in smokers and diabetic patients. Recent data on gene-environment interactions highlight the major role of epigenetic changes to induce a specific phenotype. Histone acetylation and DNA methylation are the main events that occur and modulate the gene expression. In this paper, we emphasize the impact of epigenetics on diabetes and smoking and describe their significance in bone healing. Also, we underscore the importance of adopting a new approach in clinical management for implant placement by customizing the treatment according to the patient's specific characteristics.

Engagement in adolescent career preparation: social support, personality and the development of choice decidedness and congruence.

PubMed

Hirschi, Andreas; Niles, Spencer G; Akos, Patrick

2011-02-01

This longitudinal panel study investigated predictors and outcomes of active engagement in career preparation among 349 Swiss adolescents from the beginning to the end of eighth grade. Latent variable structural equation modeling was applied. The results showed that engagement in terms of self- and environmental-exploration and active career planning related positively to interindividual increases in career decidedness and choice congruence. More perceived social support, early goal decidedness, and particular personality traits predicted more engagement. Support and personality impacted outcomes only mediated through engagement. Early decidedness and congruence were significant predictors of their respective later levels. Implications for practice are presented. Copyright © 2009 The Association for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

VO2 and VCO2 variabilities through indirect calorimetry instrumentation.

PubMed

Cadena-Méndez, Miguel; Escalante-Ramírez, Boris; Azpiroz-Leehan, Joaquín; Infante-Vázquez, Oscar

2013-01-01

The aim of this paper is to understand how to measure the VO2 and VCO2 variabilities in indirect calorimetry (IC) since we believe they can explain the high variation in the resting energy expenditure (REE) estimation. We propose that variabilities should be separately measured from the VO2 and VCO2 averages to understand technological differences among metabolic monitors when they estimate the REE. To prove this hypothesis the mixing chamber (MC) and the breath-by-breath (BbB) techniques measured the VO2 and VCO2 averages and their variabilities. Variances and power spectrum energies in the 0-0.5 Hertz band were measured to establish technique differences in steady and non-steady state. A hybrid calorimeter with both IC techniques studied a population of 15 volunteers that underwent the clino-orthostatic maneuver in order to produce the two physiological stages. The results showed that inter-individual VO2 and VCO2 variabilities measured as variances were negligible using the MC while variabilities measured as spectral energies using the BbB underwent 71 and 56% (p < 0.05), increase respectively. Additionally, the energy analysis showed an unexpected cyclic rhythm at 0.025 Hertz only during the orthostatic stage, which is new physiological information, not reported previusly. The VO2 and VCO2 inter-individual averages increased to 63 and 39% by the MC (p < 0.05) and 32 and 40% using the BbB (p < 0.1), respectively, without noticeable statistical differences among techniques. The conclusions are: (a) metabolic monitors should simultaneously include the MC and the BbB techniques to correctly interpret the steady or non-steady state variabilities effect in the REE estimation, (b) the MC is the appropriate technique to compute averages since it behaves as a low-pass filter that minimizes variances, (c) the BbB is the ideal technique to measure the variabilities since it can work as a high-pass filter to generate discrete time series able to accomplish spectral analysis, and (d) the new physiological information in the VO2 and VCO2 variabilities can help to understand why metabolic monitors with dissimilar IC techniques give different results in the REE estimation.

Systematic evaluation of the impact of stimulation intensity on neuroplastic after-effects induced by transcranial direct current stimulation.

PubMed

Jamil, Asif; Batsikadze, Giorgi; Kuo, Hsiao-I; Labruna, Ludovica; Hasan, Alkomiet; Paulus, Walter; Nitsche, Michael A

2017-02-15

Applications of transcranial direct current stimulation to modulate human neuroplasticity have increased in research and clinical settings. However, the need for longer-lasting effects, combined with marked inter-individual variability, necessitates a deeper understanding of the relationship between stimulation parameters and physiological effects. We systematically investigated the full DC intensity range (0.5-2.0 mA) for both anodal and cathodal tDCS in a sham-controlled repeated measures design, monitoring changes in motor-cortical excitability via transcranial magnetic stimulation up to 2 h after stimulation. For both tDCS polarities, the excitability after-effects did not linearly correlate with increasing DC intensity; effects of lower intensities (0.5, 1.0 mA) showed equal, if not greater effects in motor-cortical excitability. Further, while intra-individual responses showed good reliability, inter-individual sensitivity to TMS accounted for a modest percentage of the variance in the early after-effects of 1.0 mA anodal tDCS, which may be of practical relevance for future optimizations. Contemporary non-invasive neuromodulatory techniques, such as transcranial direct current stimulation (tDCS), have shown promising potential in both restituting impairments in cortical physiology in clinical settings, as well as modulating cognitive abilities in the healthy population. However, neuroplastic after-effects of tDCS are highly dependent on stimulation parameters, relatively short lasting, and not expectedly uniform between individuals. The present study systematically investigates the full range of current intensity between 0.5 and 2.0 mA on left primary motor cortex (M1) plasticity, as well as the impact of individual-level covariates on explaining inter-individual variability. Thirty-eight healthy subjects were divided into groups of anodal and cathodal tDCS. Five DC intensities (sham, 0.5, 1.0, 1.5 and 2.0 mA) were investigated in separate sessions. Using transcranial magnetic stimulation (TMS), 25 motor-evoked potentials (MEPs) were recorded before, and 10 time points up to 2 h following 15 min of tDCS. Repeated-measures ANOVAs indicated a main effect of intensity for both anodal and cathodal tDCS. With anodal tDCS, all active intensities resulted in equivalent facilitatory effects relative to sham while for cathodal tDCS, only 1.0 mA resulted in sustained excitability diminution. An additional experiment conducted to assess intra-individual variability revealed generally good reliability of 1.0 mA anodal tDCS (ICC(2,1) = 0.74 over the first 30 min). A post hoc analysis to discern sources of inter-individual variability confirmed a previous finding in which individual TMS SI 1mV (stimulus intensity for 1 mV MEP amplitude) sensitivity correlated negatively with 1.0 mA anodal tDCS effects on excitability. Our study thus provides further insights on the extent of non-linear intensity-dependent neuroplastic after-effects of anodal and cathodal tDCS. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Cumulative biomedical risk and social cognition in the second year of life: prediction and moderation by responsive parenting.

PubMed

Wade, Mark; Madigan, Sheri; Akbari, Emis; Jenkins, Jennifer M

2015-01-01

At 18 months, children show marked variability in their social-cognitive skill development, and the preponderance of past research has focused on constitutional and contextual factors in explaining this variability. Extending this literature, the current study examined whether cumulative biomedical risk represents another source of variability in social cognition at 18 months. Further, we aimed to determine whether responsive parenting moderated the association between biomedical risk and social cognition. A prospective community birth cohort of 501 families was recruited at the time of the child's birth. Cumulative biomedical risk was measured as a count of 10 prenatal/birth complications. Families were followed up at 18 months, at which point social-cognitive data was collected on children's joint attention, empathy, cooperation, and self-recognition using previously validated tasks. Concurrently, responsive maternal behavior was assessed through observational coding of mother-child interactions. After controlling for covariates (e.g., age, gender, child language, socioeconomic variables), both cumulative biomedical risk and maternal responsivity significantly predicted social cognition at 18 months. Above and beyond these main effects, there was also a significant interaction between biomedical risk and maternal responsivity, such that higher biomedical risk was significantly associated with compromised social cognition at 18 months, but only in children who experienced low levels of responsive parenting. For those receiving comparatively high levels of responsive parenting, there was no apparent effect of biomedical risk on social cognition. This study shows that cumulative biomedical risk may be one source of inter-individual variability in social cognition at 18 months. However, positive postnatal experiences, particularly high levels of responsive parenting, may protect children against the deleterious effects of these risks on social cognition.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

PubMed Central

Hawwa, Ahmed F; Collier, Paul S; Millership, Jeff S; McCarthy, Anthony; Dempsey, Sid; Cairns, Carole; McElnay, James C

2008-01-01

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTThe cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself.Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDSThe first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed.The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates.The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype. PMID:18823306

The genetic basis for interindividual immune response variation to measles vaccine: new understanding and new vaccine approaches

PubMed Central

Haralambieva, Iana H; Ovsyannikova, Inna G; Pankratz, V Shane; Kennedy, Richard B; Jacobson, Robert M; Poland, Gregory A

2013-01-01

The live-attenuated measles vaccine is effective, but measles outbreaks still occur in vaccinated populations. This warrants elucidation of the determinants of measles vaccine-induced protective immunity. Interindividual variability in markers of measles vaccine-induced immunity, including neutralizing antibody levels, is regulated in part by host genetic factor variations. This review summarizes recent advances in our understanding of measles vaccine immunogenetics relative to the perspective of developing better measles vaccines. Important genetic regulators of measles vaccine-induced immunity, such as HLA class I and HLA class II genotypes, single nucleotide polymorphisms in cytokine/cytokine receptor genes (IL12B, IL12RB1, IL2, IL10) and the cell surface measles virus receptor CD46 gene, have been identified and independently replicated. New technologies present many opportunities for identification of novel genetic signatures and genetic architectures. These findings help explain a variety of immune response-related phenotypes and promote a new paradigm of ‘vaccinomics’ for novel vaccine development. PMID:23256739

CK-MM gene polymorphism does not influence the blood CK activity levels after exhaustive eccentric exercise.

PubMed

Yamin, C; Oliveira, J; Meckel, Y; Eynon, N; Sagiv, M; Ayalon, M; Alves, A J; Duarte, J A

2010-03-01

Gene variants, such as creatine kinase (CK) polymorphisms, have been suggested to explain the inter-individual blood CK response to eccentric exercise. However, since this association is still doubtful, the purpose of this study was to analyse the relationship between the magnitudes of the CK response to exercise with the occurrence of muscle CK-MM NcoI polymorphism in young healthy subjects. Blood CK activity was assessed in 70 subjects immediately before and 3, 24, 48, 72, 96, 120, 168 h after strenuous eccentric exercise. Based on the amount of CK release by each subject, the sample was distributed in quartiles and the genotype and allele frequency distribution was compared among quartiles. Despite the inter-individual variability of CK response observed between subjects, there were no differences in genotype and allele frequencies among quartiles. The results allowed us to conclude that CK response after exhaustive eccentric exercise is not associated with CK-MM Ncol polymorphism. Georg Thieme Verlag KG Stuttgart.New York.

Linking unfounded beliefs to genetic dopamine availability

PubMed Central

Schmack, Katharina; Rössler, Hannes; Sekutowicz, Maria; Brandl, Eva J.; Müller, Daniel J.; Petrovic, Predrag; Sterzer, Philipp

2015-01-01

Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val158met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world. PMID:26483654

Space availability in confined sheep during pregnancy, effects in movement patterns and use of space.

PubMed

Averós, Xavier; Lorea, Areta; Beltrán de Heredia, Ignacia; Arranz, Josune; Ruiz, Roberto; Estevez, Inma

2014-01-01

Space availability is essential to grant the welfare of animals. To determine the effect of space availability on movement and space use in pregnant ewes (Ovis aries), 54 individuals were studied during the last 11 weeks of gestation. Three treatments were tested (1, 2, and 3 m2/ewe; 6 ewes/group). Ewes' positions were collected for 15 minutes using continuous scan samplings two days/week. Total and net distance, net/total distance ratio, maximum and minimum step length, movement activity, angular dispersion, nearest, furthest and mean neighbour distance, peripheral location ratio, and corrected peripheral location ratio were calculated. Restriction in space availability resulted in smaller total travelled distance, net to total distance ratio, maximum step length, and angular dispersion but higher movement activity at 1 m2/ewe as compared to 2 and 3 m2/ewe (P<0.01). On the other hand, nearest and furthest neighbour distances increased from 1 to 3 m2/ewe (P<0.001). Largest total distance, maximum and minimum step length, and movement activity, as well as lowest net/total distance ratio and angular dispersion were observed during the first weeks (P<0.05) while inter-individual distances increased through gestation. Results indicate that movement patterns and space use in ewes were clearly restricted by limitations of space availability to 1 m2/ewe. This reflected in shorter, more sinuous trajectories composed of shorter steps, lower inter-individual distances and higher movement activity potentially linked with higher restlessness levels. On the contrary, differences between 2 and 3 m2/ewe, for most variables indicate that increasing space availability from 2 to 3 m2/ewe would appear to have limited benefits, reflected mostly in a further increment in the inter-individual distances among group members. No major variations in spatial requirements were detected through gestation, except for slight increments in inter-individual distances and an initial adaptation period, with ewes being restless and highly motivated to explore their new environment.

Individual variability in reproductive success determines winners and losers under ocean acidification: a case study with sea urchins.

PubMed

Schlegel, Peter; Havenhand, Jon N; Gillings, Michael R; Williamson, Jane E

2012-01-01

Climate change will lead to intense selection on many organisms, particularly during susceptible early life stages. To date, most studies on the likely biotic effects of climate change have focused on the mean responses of pooled groups of animals. Consequently, the extent to which inter-individual variation mediates different selection responses has not been tested. Investigating this variation is important, since some individuals may be preadapted to future climate scenarios. We examined the effect of CO(2)-induced pH changes ("ocean acidification") in sperm swimming behaviour on the fertilization success of the Australasian sea urchin Heliocidaris erythrogramma, focusing on the responses of separate individuals and pairs. Acidification significantly decreased the proportion of motile sperm but had no effect on sperm swimming speed. Subsequent fertilization experiments showed strong inter-individual variation in responses to ocean acidification, ranging from a 44% decrease to a 14% increase in fertilization success. This was partly explained by the significant relationship between decreases in percent sperm motility and fertilization success at ΔpH = 0.3, but not at ΔpH = 0.5. The effects of ocean acidification on reproductive success varied markedly between individuals. Our results suggest that some individuals will exhibit enhanced fertilization success in acidified oceans, supporting the concept of 'winners' and 'losers' of climate change at an individual level. If these differences are heritable it is likely that ocean acidification will lead to selection against susceptible phenotypes as well as to rapid fixation of alleles that allow reproduction under more acidic conditions. This selection may ameliorate the biotic effects of climate change if taxa have sufficient extant genetic variation upon which selection can act.

Changes in glucose disposal after a caloric restriction-induced weight loss program in obese postmenopausal women: characteristics of positive and negative responders in a Montreal-Ottawa New Emerging Team study.

PubMed

Myette-Côté, Étienne; Doucet, Éric; Prud'homme, Denis; Rabasa-Lhoret, Rémi; Lavoie, Jean-Marc; Brochu, Martin

2015-01-01

This study aims to investigate individual characteristics that explain interindividual variations in glucose disposal in response to a 6-month weight loss program in obese postmenopausal women. The cohort was divided into tertiles based on changes in glucose disposal after weight loss. Only women in the upper tertile (positive responders: Δ glucose disposal ≥ 0.92 mg/kg/min; n = 19) and lower tertile (negative responders: Δ glucose disposal ≤ -0.23 mg/kg/min; n = 19) were considered for analyses. Outcome measures included body weight, lean body mass (LBM), LBM index (= LBM / height [m]), fat mass (FM), FM index (= FM / height [m]), visceral fat, subcutaneous abdominal fat, high-sensitivity C-reactive protein (hsCRP) levels, interleukin-6, lipid profile, physical activity levels, fasting blood glucose and insulin levels, glucose disposal by hyperinsulinemic-euglycemic clamp technique, and resting blood pressure. At baseline, positive responders had higher triglycerides and hsCRP levels and lower glucose disposal (0.01 < P < 0.05) than negative responders. Except for visceral fat, the entire cohort showed significant decreases in all measures of body composition (P < 0.005) after weight loss, with greater decreases in body weight, body mass index, and FM index in positive responders (P < 0.005). Finally, data revealed that only positive responders showed decreases in LBM, LBM index, and hsCRP levels after weight loss (P between 0.01 and 0.001). An important interindividual variability in changes in glucose disposal after weight loss is observed. Interestingly, participants who display improvements in glucose disposal also show significant decreases in LBM, LBM index, and hsCRP after weight loss.

Effect of urban traffic, individual habits, and genetic polymorphisms on background urinary 1-hydroxypyrene excretion.

PubMed

Cocco, Pierluigi; Moore, Patrick S; Ennas, Maria G; Tocco, Maria G; Ibba, Antonio; Mattuzzi, Silvia; Meloni, Michele; Monne, Maria; Piras, Giovanna; Collu, Stefania; Satta, Giannina; Zucca, Mariagrazia; Scarpa, Aldo; Flore, Costantino

2007-01-01

Potential sources of exposure to polycyclic aromatic hydrocarbons (PAHs) and genetic polymorphisms were investigated in relation to their contribution to interindividual variation in baseline levels of urinary 1-hydroxypyrene (1-OHP) excretion in subjects without occupational exposure to PAHs. Urinary excretion of 1-OHP was measured in 114 subjects, including 48 women and 66 men. Questionnaire information was collected on possible environmental and individual sources of PAH exposure. A subset of 70 individuals also was evaluated for a single-nucleotide polymorphism (Ex7+295C-->T) in the cytochrome P-450 1A2 (CYP1A2) gene, and 61 of these also were evaluated for the glutathione transferase T1 (GSTT1) gene polymorphism. 1-OHP values did not show a significant seasonal variability and were unaffected by age; education; body mass index; smoking status, including passive smoking; or the C-->T base substitution in position 295 of exon 7 of the CYP1A2 gene. After reciprocal adjustment with logistic regression, living in a heavily trafficked urban area (odds ratio, 4.9; 95% confidence interval, 1.0-24.9), and frequent intake of grilled meat (odds ratio, 6.9; 95% confidence interval, 1.1-43.5) were significant predictors of background urinary 1-OHP levels of 0.50 microg/g creatinine or greater. Elevated risks also were associated with daily alcohol intake greater than 65 g and the nonnull GSTT1 genotype. Our study shows that exposure to urban traffic, dietary habits, and the nonnull GSTT1 genotype may contribute to interindividual variation in background levels of 1-OHP urinary excretion in subjects without occupational exposure to PAHs.

Contributions of Human Cytochrome P450 Enzymes to Glyburide Metabolism*

PubMed Central

Zhou, Lin; Naraharisetti, Suresh B.; Liu, Li; Wang, Honggang; Lin, Yvonne S.; Isoherranen, Nina; Unadkat, Jashvant D.; Hebert, Mary F.; Mao, Qingcheng

2011-01-01

Glyburide (GLB) is a widely used oral sulfonylurea for the treatment of gestational diabetes. Therapeutic use of GLB is often complicated by a substantial inter-individual variability in the pharmacokinetics and pharmacodynamics of the drug in human populations, which might be caused by inter-individual variations in factors such as GLB metabolism. Therefore, there has been a continued interest in identifying human cytochrome P450 (CYP) isoforms that play a major role in the metabolism of GLB. However, contrasting data are available in the present literature in this regard. In the present study, we systematically investigated the contributions of various human CYP isoforms (CYP3A4, CYP3A5, CYP2C8, CYP2C9, and CYP2C19) to in vitro metabolism of GLB. GLB depletion and metabolite formation in human liver microsomes were most significantly inhibited by the CYP3A inhibitor ketoconazole compared with the inhibitors of other CYP isoforms. Furthermore, multiple correlation analysis between GLB depletion and individual CYP activities was performed, demonstrating a significant correlation between GLB depletion and the CYP3A probe activity in 16 individual human liver microsomal preparations, but not between GLB depletion and the CYP2C19, CYP2C8, or CYP2C9 probe activity. By using recombinant supersomes overexpressing individual human CYP isoforms, we found that GLB could be depleted by all the enzymes tested; however, the intrinsic clearance (Vmax/Km) of CYP3A4 for GLB depletion was 4 – 17 times greater than that of other CYP isoforms. These results confirm that human CYP3A4 is the major enzyme invovled in the in vitro metabolism of GLB. PMID:20437462

Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation.

PubMed

Takama, H; Tanaka, H; Nakashima, D; Ueda, R; Takaue, Y

2006-02-01

A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration-time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7-53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.

The Stability of Social Desirability: A Latent Change Analysis.

PubMed

Haberecht, Katja; Schnuerer, Inga; Gaertner, Beate; John, Ulrich; Freyer-Adam, Jennis

2015-08-01

Social desirability has been shown to be stable in samples with higher school education. However, little is known about the stability of social desirability in more heterogeneous samples differing in school education. This study aimed to investigate the stability of social desirability and which factors predict interindividual differences in intraindividual change. As part of a randomized controlled trial, 1,243 job seekers with unhealthy alcohol use were systematically recruited at three job agencies. A total of 1,094 individuals (87.8%) participated in at least one of two follow-ups (6 and 15 months after baseline) and constitute this study's sample. The Social Desirability Scale-17 was applied. Two latent change models were conducted: Model 1 tested for interindividual differences in intraindividual change of social desirability between both follow-ups; Model 2 included possible predictors (age, sex, education, current employment status) of interindividual differences in intraindividual change. Model 1 revealed a significant decrease of social desirability over time. Model 2 revealed school education to be the only significant predictor of change. These findings indicate that stability of social desirability may depend on school education. It may not be as stable in individuals with higher school education as in individuals with lower education. © 2014 Wiley Periodicals, Inc.

A review on therapeutic drug monitoring of immunosuppressant drugs.

PubMed

Mohammadpour, Niloufar; Elyasi, Sepideh; Vahdati, Naser; Mohammadpour, Amir Hooshang; Shamsara, Jamal

2011-11-01

: Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency, inflammation and infection, gender, age, polymorphism and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid. CYCLOSPORINE: Therapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity. MYCOPHENOLIC ACID MPA: Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic. SIROLIMUS: A recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l(-1) in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations. TACROLIMUS: Sudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.

Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect.

PubMed

Solymosi, Tamás; Ötvös, Zsolt; Angi, Réka; Ordasi, Betti; Jordán, Tamás; Molnár, László; McDermott, John; Zann, Vanessa; Church, Ann; Mair, Stuart; Filipcsei, Genovéva; Heltovics, Gábor; Glavinas, Hristos

2017-10-01

Zytiga (abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect in men. The unfavorable pharmacokinetic properties are attributed to the inadequate and variable dissolution of the compound. Using a continuous flow precipitation technology, a novel AA formulation has been developed with improved solubility and dissolution characteristics. The current study was performed to evaluate the pharmacokinetics and safety of this novel formulation in healthy volunteers. The study was conducted in 11 healthy men aged 47-57 years. All subjects received 3 consecutive single doses of the novel formulation of AA (100 and 200 mg in the fasted state and 200 mg in the fed state). Data were compared with pharmacokinetic and safety data reported for 1000 mg Zytiga, the marketed drug. The novel formulation of AA allows rapid absorption of the compound with t max values within 1 hour. Based on AUC values, a ~250 mg dose of the novel formulation is predicted to give the same exposure as 1000 mg Zytiga in the fasted state. The significant positive food effect was also eliminated; actually, a slight, but statistically significant negative food effect was observed. Variability of exposure was significantly reduced when compared to Zytiga. AA administered in the novel formulation was well tolerated with no IMP-related safety AEs reported. The novel formulation might allow a 75% dose reduction with significant reduction of inter-individual variability. The negative food effect observed requires further investigations; however, elimination of the significant positive food effect could be adequate to negate the restriction of a food label.

Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes.

PubMed

Takayama, Kazuo; Morisaki, Yuta; Kuno, Shuichi; Nagamoto, Yasuhito; Harada, Kazuo; Furukawa, Norihisa; Ohtaka, Manami; Nishimura, Ken; Imagawa, Kazuo; Sakurai, Fuminori; Tachibana, Masashi; Sumazaki, Ryo; Noguchi, Emiko; Nakanishi, Mahito; Hirata, Kazumasa; Kawabata, Kenji; Mizuguchi, Hiroyuki

2014-11-25

Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPS-HLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drug-metabolizing capacity and drug responsiveness.

Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals

PubMed Central

Goodrich, Jaclyn M.; Wang, Yi; Gillespie, Brenda; Werner, Robert; Franzblau, Alfred; Basu, Niladri

2012-01-01

Mercury is a potent toxicant of concern to both the general public and occupationally exposed workers (e.g., dentists). Recent studies suggest that several genes mediating the toxicokinetics of mercury are polymorphic in humans and may influence inter-individual variability in mercury accumulation. This work hypothesizes that polymorphisms in key glutathione synthesizing enzyme, glutathione s-transferase, and selenoprotein genes underlie inter-individual differences in mercury body burden as assessed by analytical mercury measurement in urine and hair, biomarkers of elemental mercury and methylmercury, respectively. Urine and hair samples were collected from a population of dental professionals (n=515), and total mercury content was measured. Average urine (1.06±1.24 ug/L) and hair mercury levels (0.49±0.63 ug/g) were similar to national U.S. population averages. Taqman assays were used to genotype DNA from buccal swab samples at 15 polymorphic sites in genes implicated in mercury metabolism. Linear regression modeling assessed the ability of polymorphisms to modify the relationship between mercury biomarker levels and exposure sources (e.g., amalgams, fish consumption). Five polymorphisms were significantly associated with urine mercury levels (GSTT1 deletion), hair mercury levels (GSTP1-105, GSTP1-114, GSS 5’), or both (SEPP1 3’UTR). Overall, this study suggests that polymorphisms in selenoproteins and glutathione-related genes may influence elimination of mercury in the urine and hair or mercury retention following exposures to elemental mercury (via dental amalgams) and methylmercury (via fish consumption). PMID:21967774

Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses.

PubMed

Chung, Jee-Eun; Lee, Kyung Eun; Chang, Byung Chul; Gwak, Hye Sun

2018-01-30

The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses. Copyright © 2017. Published by Elsevier B.V.

Use of a probabilistic PBPK/PD model to calculate Data Derived Extrapolation Factors for chlorpyrifos.

PubMed

Poet, Torka S; Timchalk, Charles; Bartels, Michael J; Smith, Jordan N; McDougal, Robin; Juberg, Daland R; Price, Paul S

2017-06-01

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model combined with Monte Carlo analysis of inter-individual variation was used to assess the effects of the insecticide, chlorpyrifos and its active metabolite, chlorpyrifos oxon in humans. The PBPK/PD model has previously been validated and used to describe physiological changes in typical individuals as they grow from birth to adulthood. This model was updated to include physiological and metabolic changes that occur with pregnancy. The model was then used to assess the impact of inter-individual variability in physiology and biochemistry on predictions of internal dose metrics and quantitatively assess the impact of major sources of parameter uncertainty and biological diversity on the pharmacodynamics of red blood cell acetylcholinesterase inhibition. These metrics were determined in potentially sensitive populations of infants, adult women, pregnant women, and a combined population of adult men and women. The parameters primarily responsible for inter-individual variation in RBC acetylcholinesterase inhibition were related to metabolic clearance of CPF and CPF-oxon. Data Derived Extrapolation Factors that address intra-species physiology and biochemistry to replace uncertainty factors with quantitative differences in metrics were developed in these same populations. The DDEFs were less than 4 for all populations. These data and modeling approach will be useful in ongoing and future human health risk assessments for CPF and could be used for other chemicals with potential human exposure. Copyright © 2017 Elsevier Inc. All rights reserved.

Nature and Nurture of Human Pain

PubMed Central

2013-01-01

Humans are very different when it comes to pain. Some get painful piercings and tattoos; others can not stand even a flu shot. Interindividual variability is one of the main characteristics of human pain on every level including the processing of nociceptive impulses at the periphery, modification of pain signal in the central nervous system, perception of pain, and response to analgesic strategies. As for many other complex behaviors, the sources of this variability come from both nurture (environment) and nature (genes). Here, I will discuss how these factors contribute to human pain separately and via interplay and how epigenetic mechanisms add to the complexity of their effects. PMID:24278778

An in vitro study to assess the impact of tetracycline on the human intestinal microbiome.

PubMed

Jung, Ji Young; Ahn, Youngbeom; Khare, Sangeeta; Gokulan, Kuppan; Piñeiro, Silvia A; Cerniglia, Carl E

2018-02-01

The human intestinal microbiome, a generally stable ecosystem, could be potentially altered by the ingestion of antimicrobial drug residues in foods derived from animals. Data and the scientific published literature on the effects of antimicrobial residues on the human intestinal microbiome are reviewed by national regulatory authorities as part of the human food safety evaluation of veterinary antimicrobial agents used in food-producing animals. In this study, we determined if tetracycline, at low residue concentrations, could impact the human intestinal microbiome structure and the resistance-gene profile, following acute and subchronic exposure. The effects of 0.15, 1.5, 15, and 150 μg/ml of tetracycline, after 24 h and 40 days of exposure, in 3% human fecal suspensions, collected from three individuals (A, B, and C) were investigated using in vitro batch cultures. Results were variable, with either no change or minor changes in total bacterial 16S rRNA gene copies after exposure of fecal samples to tetracycline, because of the inter-individual variation of human gastrointestinal tract microbiota. Bacterial community analysis using rRNA-based pyrosequencing revealed that Firmicutes and Bacteroidetes were the predominant phyla in the three fecal samples; the ratio of phylotypes varied among individuals. The evaluation of bacterial community changes at the genus level, from control to tetracycline-treated fecal samples, suggested that tetracycline under the conditions of this study could lead to slight differences in the composition of intestinal microbiota. The genus Bacteroides (of the Bacteroidetes) was consistently altered from 1.68 to 5.70% and 4.82-8.22% at tetracycline concentrations of 0.15 μg/ml or above at both time points for individual A, respectively, and increased 5.13-13.50% and 10.92-22.18% for individual B, respectively. Clostridium family XI increased 3.50-25.34% in the presence of tetracycline at 40 days for individual C. Principal Component Analysis (PCA) confirmed the pyrosequencing findings of inter-individual variability of the ratio of phylotypes and the effect of tetracycline. Among the 23 tetracycline resistance genes (TRGs) screened, four tet genes (tetO, Q, W, and X) were major TRGs in control and tetracycline-dosed fecal samples. A variable to slight increase of copy number of TRGs appeared to be related to tetracycline treatment, interindividual variability and duration of exposure. Despite, the inherent variability of the intestinal microbiota observed among or within individuals, this pilot study contributes to the knowledge base of the impact of low residue concentrations of tetracycline on the human intestinal microbiome on the potential for antimicrobial resistance. Published by Elsevier Ltd.

Individual differences in error monitoring in healthy adults: psychological symptoms and antisocial personality characteristics.

PubMed

Chang, Wen-Pin; Davies, Patricia L; Gavin, William J

2010-10-01

Recent studies have investigated the relationship between psychological symptoms and personality traits and error monitoring measured by error-related negativity (ERN) and error positivity (Pe) event-related potential (ERP) components, yet there remains a paucity of studies examining the collective simultaneous effects of psychological symptoms and personality traits on error monitoring. This present study, therefore, examined whether measures of hyperactivity-impulsivity, depression, anxiety and antisocial personality characteristics could collectively account for significant interindividual variability of both ERN and Pe amplitudes, in 29 healthy adults with no known disorders, ages 18-30 years. The bivariate zero-order correlation analyses found that only the anxiety measure was significantly related to both ERN and Pe amplitudes. However, multiple regression analyses that included all four characteristic measures while controlling for number of segments in the ERP average revealed that both depression and antisocial personality characteristics were significant predictors for the ERN amplitudes whereas antisocial personality was the only significant predictor for the Pe amplitude. These findings suggest that psychological symptoms and personality traits are associated with individual variations in error monitoring in healthy adults, and future studies should consider these variables when comparing group difference in error monitoring between adults with and without disabilities. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Factors affecting variability in the urinary biomarker 1,6-hexamethylene diamine in workers exposed to 1,6-hexamethylene diisocyanate.

PubMed

Gaines, Linda G T; Fent, Kenneth W; Flack, Sheila L; Thomasen, Jennifer M; Whittaker, Stephen G; Nylander-French, Leena A

2011-01-01

Although urinary 1,6-hexamethylene diamine (HDA) is a useful biomarker of exposure to 1,6-hexamethylene diisocyanate (HDI), a large degree of unexplained intra- and inter-individual variability exists between estimated HDI exposure and urine HDA levels. We investigated the effect of individual and workplace factors on urine HDA levels using quantitative dermal and inhalation exposure data derived from a survey of automotive spray painters exposed to HDI. Painters' dermal and breathing-zone HDI-exposures were monitored over an entire workday for up to three separate workdays, spaced approximately one month apart. One urine sample was collected before the start of work with HDI-containing paints, and multiple samples were collected throughout the workday. Using mixed effects multiple linear regression modeling, coverall use resulted in significantly lower HDA levels (p = 0.12), and weekday contributed to significant variability in HDA levels (p = 0.056). We also investigated differences in urine HDA levels stratified by dichotomous and classification covariates using analysis of variance. Use of coveralls (p = 0.05), respirator type worn (p = 0.06), smoker status (p = 0.12), paint-booth type (p = 0.02), and more than one painter at the shop (p = 0.10) were all found to significantly affect urine HDA levels adjusted for creatinine concentration. Coverall use remained significant (p = 0.10), even after adjusting for respirator type. These results indicate that the variation in urine HDA level is mainly due to workplace factors and that appropriate dermal and inhalation protection is required to prevent HDI exposure.

The contribution of individual and pairwise combinations of SNPs in the APOA1 and APOC3 genes to interindividual HDL-C variability.

PubMed

Brown, C M; Rea, T J; Hamon, S C; Hixson, J E; Boerwinkle, E; Clark, A G; Sing, C F

2006-07-01

Apolipoproteins (apo) A-I and C-III are components of high-density lipoprotein-cholesterol (HDL-C), a quantitative trait negatively correlated with risk of cardiovascular disease (CVD). We analyzed the contribution of individual and pairwise combinations of single nucleotide polymorphisms (SNPs) in the APOA1/APOC3 genes to HDL-C variability to evaluate (1) consistency of published single-SNP studies with our single-SNP analyses; (2) consistency of single-SNP and two-SNP phenotype-genotype relationships across race-, gender-, and geographical location-dependent contexts; and (3) the contribution of single SNPs and pairs of SNPs to variability beyond that explained by plasma apo A-I concentration. We analyzed 45 SNPs in 3,831 young African-American (N=1,858) and European-American (N=1,973) females and males ascertained by the Coronary Artery Risk Development in Young Adults (CARDIA) study. We found three SNPs that significantly impact HDL-C variability in both the literature and the CARDIA sample. Single-SNP analyses identified only one of five significant HDL-C SNP genotype relationships in the CARDIA study that was consistent across all race-, gender-, and geographical location-dependent contexts. The other four were consistent across geographical locations for a particular race-gender context. The portion of total phenotypic variance explained by single-SNP genotypes and genotypes defined by pairs of SNPs was less than 3%, an amount that is miniscule compared to the contribution explained by variability in plasma apo A-I concentration. Our findings illustrate the impact of context-dependence on SNP selection for prediction of CVD risk factor variability.

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

PubMed

Sassen, Sebastiaan D T; Mathôt, Ron A A; Pieters, Rob; Kloos, Robin Q H; de Haas, Valérie; Kaspers, Gertjan J L; van den Bos, Cor; Tissing, Wim J E; Te Loo, Maroeska; Bierings, Marc B; Kollen, Wouter J W; Zwaan, Christian M; van der Sluis, Inge M

2017-03-01

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m 2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM ® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher ( P <0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m 2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl). Copyright© Ferrata Storti Foundation.

Genetic variation in alpha2-adrenoreceptors and heart rate recovery after exercise

PubMed Central

Kohli, Utkarsh; Diedrich, André; Kannankeril, Prince J.; Muszkat, Mordechai; Sofowora, Gbenga G.; Hahn, Maureen K.; English, Brett A.; Blakely, Randy D.; Stein, C. Michael

2015-01-01

Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular outcomes. HRR is mediated by both parasympathetic reactivation and sympathetic withdrawal and is highly heritable. We examined whether common genetic variants in adrenergic and cholinergic receptors and transporters affect HRR. In our study 126 healthy subjects (66 Caucasians, 56 African Americans) performed an 8 min step-wise bicycle exercise test with continuous computerized ECG recordings. We fitted an exponential curve to the postexercise R-R intervals for each subject to calculate the recovery constant (kr) as primary outcome. Secondary outcome was the root mean square residuals averaged over 1 min (RMS1min), a marker of parasympathetic tone. We used multiple linear regressions to determine the effect of functional candidate genetic variants in autonomic pathways (6 ADRA2A, 1 ADRA2B, 4 ADRA2C, 2 ADRB1, 3 ADRB2, 2 NET, 2 CHT, and 1 GRK5) on the outcomes before and after adjustment for potential confounders. Recovery constant was lower (indicating slower HRR) in ADRA2B 301–303 deletion carriers (n = 54, P = 0.01), explaining 3.6% of the interindividual variability in HRR. ADRA2A Asn251Lys, ADRA2C rs13118771, and ADRB1 Ser49Gly genotypes were associated with RMS1min. Genetic variability in adrenergic receptors may be associated with HRR after exercise. However, most of the interindividual variability in HRR remained unexplained by the variants examined. Noncandidate gene-driven approaches to study genetic contributions to HRR in larger cohorts will be of interest. PMID:26058836

Using GAMM to examine inter-individual heterogeneity in thermal performance curves for Natrix natrix indicates bet hedging strategy by mothers.

PubMed

Vickers, Mathew J; Aubret, Fabien; Coulon, Aurélie

2017-01-01

The thermal performance curve (TPC) illustrates the dependence on body- and therefore environmental- temperature of many fitness-related aspects of ectotherm ecology and biology including foraging, growth, predator avoidance, and reproduction. The typical thermal performance curve model is linear in its parameters despite the well-known, strong, non-linearity of the response of performance to temperature. In addition, it is usual to consider a single model based on few individuals as descriptive of a species-level response to temperature. To overcome these issues, we used generalized additive mixed modeling (GAMM) to estimate thermal performance curves for 73 individual hatchling Natrix natrix grass snakes from seven clutches, taking advantage of the structure of GAMM to demonstrate that almost 16% of the deviance in thermal performance curves is attributed to inter-individual variation, while only 1.3% is attributable to variation amongst clutches. GAMM allows precise estimation of curve characteristics, which we used to test hypotheses on tradeoffs thought to constrain the thermal performance curve: hotter is better, the specialist-generalist trade off, and resource allocation/acquisition. We observed a negative relationship between maximum performance and performance breadth, indicating a specialist-generalist tradeoff, and a positive relationship between thermal optimum and maximum performance, suggesting "hotter is better". There was a significant difference among matrilines in the relationship between Area Under the Curve and maximum performance - relationship that is an indicator of evenness in acquisition or allocation of resources. As we used unfed hatchlings, the observed matriline effect indicates divergent breeding strategies among mothers, with some mothers provisioning eggs unequally resulting in some offspring being better than others, while other mothers provisioned the eggs more evenly, resulting in even performance throughout the clutch. This observation is reminiscent of bet-hedging strategies, and implies the possibility for intra-clutch variability in the TPCs to buffer N. natrix against unpredictable environmental variability. Copyright © 2016 Elsevier Ltd. All rights reserved.

Implications of intercorrelation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: a case study with repaglinide.

PubMed

Doki, Kosuke; Darwich, Adam S; Achour, Brahim; Tornio, Aleksi; Backman, Janne T; Rostami-Hodjegan, Amin

2018-05-01

Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolizing enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 intercorrelation on the predicted interindividual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically based pharmacokinetic (PBPK) modelling. PBPK modelling and simulation were employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming intercorrelations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict PK parameters in the presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study. Coefficient of variation (CV) of oral clearance was 52.5% in the absence of intercorrelation between CYP3A4-CYP2C8 abundances, which increased to 54.2% when incorporating intercorrelation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0% in the absence of intercorrelation between enzymes to 43.8% when incorporating intercorrelation: these CVs were associated with 5th/95th percentiles (2.48-11.29 vs. 2.49-9.69). The range of predicted DDI was larger in the absence of intercorrelation (1.55-77.06) than when incorporating intercorrelation (1.79-25.15), which was closer to clinical observations (2.6-12). The present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating intercorrelation led to more consistent estimation of extreme values than those observed in interindividual variabilities of clearance and DDI. As the intercorrelations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance. © 2018 The British Pharmacological Society.

Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers.

PubMed

Zhang, Dong-mei; Wang, Kun; Zhao, Xia; Li, Yun-fei; Zheng, Qing-shan; Wang, Zi-ning; Cui, Yi-min

2012-11-01

To investigate the population pharmacokinetics (PK) and pharmacodynamics (PD) of bivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinese subjects. Thirty-six young healthy volunteers were randomly assigned into 4 groups received bivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Blood samples were collected to measure bivalirudin plasma concentration and activated clotting time (ACT). Population PK-PD analysis was performed using the nonlinear mixed-effects model software NONMEM. The final models were validated with bootstrap and prediction-corrected visual predictive check (pcVPC) approaches. The final PK model was a two-compartment model without covariates. The typical PK population values of clearance (CL), apparent distribution volume of the central-compartment (V(1)), inter-compartmental clearance (Q) and apparent distribution volume of the peripheral compartment (V(2)) were 0.323 L·h(-1)·kg(-1), 0.086 L/kg, 0.0957 L·h(-1)·kg(-1), and 0.0554 L/kg, respectively. The inter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and 15.6%, respectively. The final PK-PD model was a sigmoid E(max) model without the Hill coefficient. In this model, a covariate, red blood cell count (RBC(*)), had a significant effect on the EC(50) value. The typical PD population values of maximum effect (E(max)), EC(50), baseline ACT value (E(0)) and the coefficient of RBC(*) on EC(50) were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of E(max), EC(50), and E(0) were 6.80%, 46.4%, and 4.10%, respectively. Population PK-PD models of bivalirudin in healthy young Chinese subjects have been developed, which may provide a reference for future use of bivalirudin in China.

Beyond the group mind: a quantitative review of the interindividual-intergroup discontinuity effect.

PubMed

Wildschut, Tim; Pinter, Brad; Vevea, Jack L; Insko, Chester A; Schopler, John

2003-09-01

This quantitative review of 130 comparisons of interindividual and intergroup interactions in the context of mixed-motive situations reveals that intergroup interactions are generally more competitive than interindividual interactions. The authors identify 4 moderators of this interindividual-intergroup discontinuity effect, each based on the theoretical perspective that the discontinuity effect flows from greater fear and greed in intergroup relative to interindividual interactions. Results reveal that each moderator shares a unique association with the magnitude of the discontinuity effect. The discontinuity effect is larger when (a) participants interact with an opponent whose behavior is unconstrained by the experimenter or constrained by the experimenter to be cooperative rather than constrained by the experimenter to be reciprocal, (b) group members make a group decision rather than individual decisions, (c) unconstrained communication between participants is present rather than absent, and (d) conflict of interest is severe rather than mild.

Variability of attention processes in ADHD: observations from the classroom.

PubMed

Rapport, Mark D; Kofler, Michael J; Alderson, R Matt; Timko, Thomas M; Dupaul, George J

2009-05-01

Classroom- and laboratory-based efforts to study the attentional problems of children with ADHD are incongruent in elucidating attentional deficits; however, none have explored within- or between-minute variability in the classroom attentional processing in children with ADHD. High and low attention groups of ADHD children defined via cluster analysis, and 36 typically developing children, were observed while completing academic assignments in their general education classrooms. All children oscillated between attentive and inattentive states; however, children in both ADHD groups switched states more frequently and remained attentive for shorter durations relative to typically developing children. Overall differences in attention and optimal ability to maintain attention among the groups are consistent with laboratory studies of increased ADHD-related interindividual and intergroup variability but inconsistent with laboratory results of increased intra-individual variability and attention decrements over time.

Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants

PubMed Central

Stage, C; Bergmann, TK; Ferrero‐Milliani, L; Bjerre, D; Thomsen, R; Dalhoff, KP; Rasmussen, HB; Jürgens, G

2016-01-01

The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d‐MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two‐compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d‐MPH plasma exposure. PMID:27754602

Beware the yellow slimming pill: fatal 2,4-dinitrophenol overdose.

PubMed

Holborow, Alexander; Purnell, Richard M; Wong, Jenny Frederina

2016-04-04

An industrial chemical, 2,4-dinitrophenol (DNP), has found use as a weight loss drug. It is extremely toxic in overdose and has a narrow therapeutic window with significant interindividual variability in metabolism. The rise in internet-based sales and distribution of this drug has seen an increased incidence of both accidental and intentional overdose presenting to emergency departments across the UK. No antidote currently exists and overdose is often fatal despite management based on current recommendations. We report a case of intentional overdose of DNP in a young man and discuss the current treatment guidelines. The case highlights the need for an increased awareness among frontline medical staff of the effects of DNP poisoning and questions the need for a more aggressive approach in the management of acute toxicity. 2016 BMJ Publishing Group Ltd.

Inter-individual variation and temperature-dependent antipredator behavior in the snake Tomodon dorsatus (Dipsadidae).

PubMed

Citadini, Jessyca Michele; Navas, Carlos Arturo

2013-07-01

Although many studies assessed the influence of temperature on the behavior of ectotermic vertebrates, little attention has been given to interindividual variation in the defensive responses of reptiles. In the present study we investigated the defensive behavior of the snake Tomodon dorsatus, in order to test the hypotheses that (1) individuals differ in their antipredator behavior consistently with the concept of behavioral syndromes, (2) temperature influences the defensive behavior, and (3) these two factors interact with each other. There was significant interindividual variation in defensive behavior, as well as consistently aggressive, passive or evasive behaviors. Temperature influenced aggressiveness, which was slightly higher when body temperature was lower, but this trend was only evident in animals with aggressive disposition. Our results corroborate the hypothesis of interaction between individuality of behavior and temperature-dependent defensive behavior in T. dorsatus. These results, together with results from previous studies, suggest that the evolution of temperature-dependent defensive behavior differs among lineages of ectothermic tetrapods. This article is part of a Special Issue entitled: insert SI title. Copyright © 2013 Elsevier B.V. All rights reserved.

Plasma and Urinary Phenolic Profiles after Acute and Repetitive Intake of Wild Blueberry.

PubMed

Feliciano, Rodrigo P; Istas, Geoffrey; Heiss, Christian; Rodriguez-Mateos, Ana

2016-08-25

Recent studies have shown that blueberries may have cardiovascular and cognitive health benefits. In this work, we investigated the profile of plasma and urine (poly)phenol metabolites after acute and daily consumption of wild blueberries for 30 days in 18 healthy men. The inter-individual variability in plasma and urinary polyphenol levels was also investigated. Blood samples were collected at baseline and 2 h post-consumption on day 1 and day 30. Twenty-four-hour urine was also collected on both days. A total of 61 phenolic metabolites were quantified in plasma at baseline, of which 43 increased after acute or chronic consumption of blueberries over one month. Benzoic and catechol derivatives represented more than 80% of the changes in phenolic profile after 2 h consumption on day 1, whereas hippuric and benzoic derivatives were the major compounds that increased at 0 and 2 h on day 30, respectively. The total (poly)phenol urinary excretion remained unchanged after 30 days of wild blueberry intake. The inter-individual variability ranged between 40%-48% in plasma and 47%-54% in urine. Taken together, our results illustrate that blueberry (poly)phenols are absorbed and extensively metabolized by phase II enzymes and by the gut microbiota, leading to a whole array of metabolites that may be responsible for the beneficial effects observed after blueberry consumption.

Polymorphisms in genes involved in fatty acid β-oxidation interact with dietary fat intakes to modulate the plasma TG response to a fish oil supplementation.

PubMed

Bouchard-Mercier, Annie; Rudkowska, Iwona; Lemieux, Simone; Couture, Patrick; Vohl, Marie-Claude

2014-03-18

A large inter-individual variability in the plasma triglyceride (TG) response to an omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has been observed. The objective was to examine gene-diet interaction effects on the plasma TG response after a fish oil supplementation, between single-nucleotide polymorphisms (SNPs) within genes involved in fatty acid β-oxidation and dietary fat intakes. Two hundred and eight (208) participants were recruited in the greater Quebec City area. The participants completed a six-week fish oil supplementation (5 g fish oil/day: 1.9-2.2 g EPA and 1.1 g DHA). Dietary fat intakes were measured using three-day food records. SNPs within RXRA, CPT1A, ACADVL, ACAA2, ABCD2, ACOX1 and ACAA1 genes were genotyped using TAQMAN methodology. Gene-diet interaction effects on the plasma TG response were observed for SNPs within RXRA (rs11185660, rs10881576 and rs12339187) and ACOX1 (rs17583163) genes. For rs11185660, fold changes in RXRA gene expression levels were different depending on SFA intakes for homozygotes T/T. Gene-diet interaction effects of SNPs within genes involved in fatty acid β-oxidation and dietary fat intakes may be important in understanding the inter-individual variability in plasma TG levels and in the plasma TG response to a fish oil supplementation.

Interindividual Variability in Metabolism of [6]-Shogaol by Gut Microbiota.

PubMed

Wang, Pei; Wang, Ronghui; Zhu, Yingdong; Sang, Shengmin

2017-11-08

[6]-Shogaol (6S), one of the major bioactive components in dry ginger, is attracting considerable attention because of its wide spectrum of biological activities, but its metabolic fate is still not fully understood. In the present study, the microbial metabolism of 6S was examined for the first time in in vitro batch fecal fermentation system and in mice. Two major microbial metabolites were detected and identified as 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9) and 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11). Our results indicated that reductions of the double bond and the ketone group are the major metabolic pathways of 6S by the human gut microbiota. We also observed the interindividual variability in the metabolism of M11 to M9 by human gut microbiota. In addition, we demonstrated that the glucuronidated form of 6S and its metabolites could be rapidly deconjugated by human gut microbiota and in mice, which can be regarded as a reactive process taking place in the intestinal tract. To our knowledge, this is the first report involving the identification of the microbial metabolites of 6S in an in vitro fermentation system, and the first demonstration of the critical role of gut microbiota in producing the bioactive free form of 6S and its metabolites in the intestinal tract in mice.

[Cognitive capacity in advanced age: initial results of the Berlin Aging Study].

PubMed

Lindenberger, U; Baltes, P B

1995-01-01

This study reports data on intellectual functioning in old and very old age from the Berlin Aging Study (N = 516; age range = 70-103 years; mean age = 85 years). A psychometric battery of 14 tests was used to assess five cognitive abilities: reasoning, memory, and perceptual speed from the broad fluid-mechanical as well as knowledge and fluency from the broad crystallized-pragmatic domains. Cognitive abilities had a negative linear relationship with age, with more pronounced age-based reductions in fluid-mechanical than crystallized-pragmatic abilities. At the same time, ability intercorrelations formed a highly positive manifold, and did not follow the fluid-crystallized distinction. Interindividual variability was of about equal magnitude across the entire age range studied. There was, however, no evidence for substantial sex differences. As to origins of individual differences, indicators of sensory and sensorimotor functioning were more powerful predictors of intellectual functioning than cultural-biographical variables, and the two sets of predictors were, consistent with theoretical expectations, differentially related to measures of fluid-mechanical (perceptual speed) and crystallized pragmatic (knowledge) functioning. Results, in general indicative of sizeable and general losses with age, are consistent with the view that aging-induced biological influences are a prominent source of individual differences in intellectual functioning in old and very old age. Longitudinal follow-ups are underway to examine the role of cohort effects, selective mortality, and interindividual differences in change trajectories.

Plasticity, Variability and Age in Second Language Acquisition and Bilingualism

PubMed Central

Birdsong, David

2018-01-01

Much of what is known about the outcome of second language acquisition and bilingualism can be summarized in terms of inter-individual variability, plasticity and age. The present review looks at variability and plasticity with respect to their underlying sources, and at age as a modulating factor in variability and plasticity. In this context we consider critical period effects vs. bilingualism effects, early and late bilingualism, nativelike and non-nativelike L2 attainment, cognitive aging, individual differences in learning, and linguistic dominance in bilingualism. Non-uniformity is an inherent characteristic of both early and late bilingualism. This review shows how plasticity and age connect with biological and experiential sources of variability, and underscores the value of research that reveals and explains variability. In these ways the review suggests how plasticity, variability and age conspire to frame fundamental research issues in L2 acquisition and bilingualism, and provides points of reference for discussion of the present Frontiers in Psychology Research Topic. PMID:29593590

Managing neurobehavioral capability when social expediency trumps biological imperatives

PubMed Central

Spaeth, Andrea M.; Goel, Namni; Dinges, David F.

2013-01-01

Sleep, which is evolutionarily conserved across species, is a biological imperative that cannot be ignored or replaced. However, the percentage of habitually sleep-restricted adults has increased in recent decades. Extended work hours and commutes, shift work schedules, and television viewing are particularly potent social factors that influence sleep duration. Chronic partial sleep restriction, a product of these social expediencies, leads to the accumulation of sleep debt over time and consequently increases sleep propensity, decreases alertness, and impairs critical aspects of cognitive functioning. Significant interindividual variability in the neurobehavioral responses to sleep restriction exists—this variability is stable and phenotypic—suggesting a genetic basis. Identifying vulnerability to sleep loss is essential as many adults cannot accurately judge their level of impairment in response to sleep restriction. Indeed, the consequences of impaired performance and the lack of insight due to sleep loss can be catastrophic. In order to cope with the effects of social expediencies on biological imperatives, identification of biological (including genetic) and behavioral markers of sleep loss vulnerability as well as development of technological approaches for fatigue management are critical. PMID:22877676

Influence of environmental and genetic factors on CYP1A2 activity in individuals of South Asian and European ancestry.

PubMed

Perera, V; Gross, A S; McLachlan, A J

2012-10-01

The drug-metabolizing enzyme CYP1A2 contributes to the metabolism of a number of commonly used medicines and displays wide interindividual variability. The aim of this study was to investigate CYP1A2 activity in a population of South Asian ancestry and compare it with a population of European ancestry. CYP1A2 activity was determined using the 4 h paraxanthine/caffeine saliva concentration ratio following a 100-mg oral dose of caffeine in healthy individuals of South Asian (n = 166) and European (n = 166) ancestry. Participants were surveyed for extrinsic ethnic factors and genotyped for polymorphisms in CYP1A2 and related genes. Significantly lower CYP1A2 activity was observed in South Asian participants (median: 0.42; range: 0.10-1.06) as compared with European participants (0.54; 0.12-1.64) (P < 0.01). Multiple linear regression indicated that 41% of the variability in CYP1A2 activity could be explained by the diet, lifestyle, and genetic factors studied.

Interindividual variability in the prevalence of OPRM1 and CYP2B6 gene variations may identify drug-susceptible populations.

PubMed

Bunten, H; Liang, W J; Pounder, D J; Seneviratne, C; Osselton, D

2011-09-01

Methadone is used worldwide for the treatment of heroin addiction; however, fatal poisonings are increasingly reported. The prevalence of CYP2B6 and μ-opioid receptor (OPRM1) gene variations were examined between a postmortem population where the deaths were associated with methadone and a live nondrug-using control population using Taqman™ SNP Genotyping assays. The CYP2B6*6 allele was higher in the postmortem population, but the difference was not significant (P = 0.92). The CYP2B6 T750C promoter variation was similar in frequency for both populations. Linkage between T750C and CYP2B6*6 was identified for both populations (P < 0.01). The prevalence of the OPRM1 A118G variation was significantly higher in the control population (P = 0.0046), which might indicate a protective mechanism against opioid toxicity. Individual susceptibility to methadone may be determined by screening for CYP2B6*6.

Comparative Analysis of Arterial Parameters Variations Associated with Inter-Individual Variations in Peripheral and Aortic Blood Pressure: Cross-Sectional Study in Healthy Subjects Aged 2-84 years.

PubMed

Zócalo, Yanina; Curcio, Santiago; García-Espinosa, Victoria; Chiesa, Pedro; Giachetto, Gustavo; Bia, Daniel

2017-12-01

The association between arterial parameters and blood pressure (BP) interindividual variations could depend on the arterial segment, BP component (systolic, SBP; diastolic, DBP; pulse pressure, PP) and/or on whether central (cBP) or peripheral (pBP) BP variations are considered. To assess and compare arterial parameters variations associated with interindividual variations in cBP and pBP. Healthy subjects (n = 923; 488 males, 2-84 years) were included. pBP and cBP waves were obtained (Mobil-O-Graph; SphygmoCor). Arterial diameter, intima-media thickness, local elastic modulus (carotid, CEM; brachial, BEM; femoral, FEM) and regional (carotid-radial and carotid-femoral pulse wave velocity; crPWV and cfPWV) arterial stiffness were determined. Associations between BP and arterial parameters interindividual variations were analyzed and compared (correlations; linear regressions; slopes comparisons) considering data transformed into z-scores. Given a variation in z-cSBP or z-pSBP, z-CEM, z-FEM and z-cfPWV (stiffness indexes), were among the parameters with major BP-associated variations. z-crPWV and z-cfPWV, rather than local stiffness indexes were the parameters with major variations associated with z-DBP variations. z-cPP or z-pPP were associated with z-CEM and z-FEM variations, but not with brachial or regional stiffness variations. Most of the arterial parameters-BP slopes did not show significant differences when considering a variation in z-cSBP and z-pSBP. z-CEM and z-FEM were mainly associated with z-cPP and z-pPP variations, respectively. Disregard of age and sex, the variations in arterial parameters associated with BP interindividual variations showed differences depending on whether variations were central or peripheral; in SBP, DBP or PP and depending on the arterial segment considered.

Ethnicity-Dependent and -Independent Heterogeneity in Healthy Normal Breast Hierarchy Impacts Tumor Characterization

PubMed Central

Nakshatri, Harikrishna; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima

2015-01-01

Recent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast. Ethnicity and genetic predisposition are partly responsible for this heterogeneity, evidenced by the finding that CD44+/CD24- and PROCR+/EpCAM- multi-potent stem cells were elevated significantly in African American women compared with Caucasians. ALDEFLUOR+ luminal stem/progenitor cells were lower in BRCA1-mutation carriers compared with cells from healthy donors (p = 0.0014). Moreover, tumor and adjoining-normal breast cells of the same patients showed distinct CD49f+/EpCAM+ progenitor, CD271+/EpCAM- basal, and ALDEFLUOR+ cell profiles. These inter-individual differences in the rate of differentiation in the normal breast may contribute to a substantial proportion of transcriptome, epigenome, and signaling pathway alterations and consequently has the potential to spuriously magnify the extent of documented tumor-specific gene expression. Therefore, comparative analysis of phenotypically defined subpopulations of normal and tumor cells on an individual basis may be required to identify cancer-specific aberrations. PMID:26311223

Ethnicity-Dependent and -Independent Heterogeneity in Healthy Normal Breast Hierarchy Impacts Tumor Characterization.

PubMed

Nakshatri, Harikrishna; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima

2015-08-27

Recent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast. Ethnicity and genetic predisposition are partly responsible for this heterogeneity, evidenced by the finding that CD44+/CD24- and PROCR+/EpCAM- multi-potent stem cells were elevated significantly in African American women compared with Caucasians. ALDEFLUOR+ luminal stem/progenitor cells were lower in BRCA1-mutation carriers compared with cells from healthy donors (p = 0.0014). Moreover, tumor and adjoining-normal breast cells of the same patients showed distinct CD49f+/EpCAM+ progenitor, CD271+/EpCAM- basal, and ALDEFLUOR+ cell profiles. These inter-individual differences in the rate of differentiation in the normal breast may contribute to a substantial proportion of transcriptome, epigenome, and signaling pathway alterations and consequently has the potential to spuriously magnify the extent of documented tumor-specific gene expression. Therefore, comparative analysis of phenotypically defined subpopulations of normal and tumor cells on an individual basis may be required to identify cancer-specific aberrations.

Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder.

PubMed

Ermer, James C; Adeyi, Ben A; Pucci, Michael L

2010-12-01

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmotic-release formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile. The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.

Mixed conditional logistic regression for habitat selection studies.

PubMed

Duchesne, Thierry; Fortin, Daniel; Courbin, Nicolas

2010-05-01

1. Resource selection functions (RSFs) are becoming a dominant tool in habitat selection studies. RSF coefficients can be estimated with unconditional (standard) and conditional logistic regressions. While the advantage of mixed-effects models is recognized for standard logistic regression, mixed conditional logistic regression remains largely overlooked in ecological studies. 2. We demonstrate the significance of mixed conditional logistic regression for habitat selection studies. First, we use spatially explicit models to illustrate how mixed-effects RSFs can be useful in the presence of inter-individual heterogeneity in selection and when the assumption of independence from irrelevant alternatives (IIA) is violated. The IIA hypothesis states that the strength of preference for habitat type A over habitat type B does not depend on the other habitat types also available. Secondly, we demonstrate the significance of mixed-effects models to evaluate habitat selection of free-ranging bison Bison bison. 3. When movement rules were homogeneous among individuals and the IIA assumption was respected, fixed-effects RSFs adequately described habitat selection by simulated animals. In situations violating the inter-individual homogeneity and IIA assumptions, however, RSFs were best estimated with mixed-effects regressions, and fixed-effects models could even provide faulty conclusions. 4. Mixed-effects models indicate that bison did not select farmlands, but exhibited strong inter-individual variations in their response to farmlands. Less than half of the bison preferred farmlands over forests. Conversely, the fixed-effect model simply suggested an overall selection for farmlands. 5. Conditional logistic regression is recognized as a powerful approach to evaluate habitat selection when resource availability changes. This regression is increasingly used in ecological studies, but almost exclusively in the context of fixed-effects models. Fitness maximization can imply differences in trade-offs among individuals, which can yield inter-individual differences in selection and lead to departure from IIA. These situations are best modelled with mixed-effects models. Mixed-effects conditional logistic regression should become a valuable tool for ecological research.

Changes in creatine kinase, lactate dehydrogenase and aspartate aminotransferase in saliva samples after an intense exercise: a pilot study.

PubMed

Barranco, Tomas; Tvarijonaviciute, Asta; Tecles, Fernando; Carrillo, Jose M; Sánchez-Resalt, Cristina; Jimenez-Reyes, Pedro; Rubio, Monica; García-Balletbó, Monserrat; Cerón, Jose J; Cugat, Ramon

2018-06-01

The aim of this study was to evaluate changes in the enzymes creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) in saliva before and after an intense exercise consisting of a futsal match. CK, LDH and AST were analyzed in saliva and serum samples of eleven, injury-free, amateur young men before and 30 minutes, 12 hours and 36 hours after a futsal match. A significant increase in CK, LDH and AST was observed after the game in serum samples. In saliva, although a high interindividual variability was found with some individuals no showing increases, significant increases in CK and LDH were observed after the game. No significant changes were observed in saliva AST after the game. Our study showed for first time that CK and LDH can increase in saliva after an intensive exercise consisting on a futsal match. Results suggest that measurements of CK and LDH in saliva could be potentially used to evaluate possible muscle stress or damage in cases of intensive exercise.

Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation

PubMed Central

Ruiz, Jesus; Herrero, María José; Bosó, Virginia; Megías, Juan Eduardo; Hervás, David; Poveda, Jose Luis; Escrivá, Juan; Pastor, Amparo; Solé, Amparo; Aliño, Salvador Francisco

2015-01-01

Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation. PMID:26307985

Auditory Multi-Stability: Idiosyncratic Perceptual Switching Patterns, Executive Functions and Personality Traits

PubMed Central

Farkas, Dávid; Denham, Susan L.; Bendixen, Alexandra; Tóth, Dénes; Kondo, Hirohito M.; Winkler, István

2016-01-01

Multi-stability refers to the phenomenon of perception stochastically switching between possible interpretations of an unchanging stimulus. Despite considerable variability, individuals show stable idiosyncratic patterns of switching between alternative perceptions in the auditory streaming paradigm. We explored correlates of the individual switching patterns with executive functions, personality traits, and creativity. The main dimensions on which individual switching patterns differed from each other were identified using multidimensional scaling. Individuals with high scores on the dimension explaining the largest portion of the inter-individual variance switched more often between the alternative perceptions than those with low scores. They also perceived the most unusual interpretation more often, and experienced all perceptual alternatives with a shorter delay from stimulus onset. The ego-resiliency personality trait, which reflects a tendency for adaptive flexibility and experience seeking, was significantly positively related to this dimension. Taking these results together we suggest that this dimension may reflect the individual’s tendency for exploring the auditory environment. Executive functions were significantly related to some of the variables describing global properties of the switching patterns, such as the average number of switches. Thus individual patterns of perceptual switching in the auditory streaming paradigm are related to some personality traits and executive functions. PMID:27135945

Qiviut cortisol in muskoxen as a potential tool for informing conservation strategies

PubMed Central

Navarro-Gonzalez, Nora; Wynne-Edwards, Katherine; Peacock, Stephanie; Leclerc, Lisa-Marie; Tomaselli, Matilde; Davison, Tracy; Carlsson, Anja

2017-01-01

Abstract Muskoxen (Ovibos moschatus) are increasingly subject to multiple new stressors associated with unprecedented climate change and increased anthropogenic activities across much of their range. Hair may provide a measurement of stress hormones (glucocorticoids) over periods of weeks to months. We developed a reliable method to quantify cortisol in the qiviut (wooly undercoat) of muskoxen using liquid chromatography coupled to tandem mass spectrometry. We then applied this technique to determine the natural variability in qiviut cortisol levels among 150 wild muskoxen, and to assess differences between sexes, seasons and years of collection. Qiviut samples were collected from the rump of adult muskoxen by subsistence and sport hunters in seven different locations in Nunavut and the Northwest Territories between 2013 and 2016. Results showed a high inter-individual variability in qiviut cortisol concentrations, with levels ranging from 3.5 to 48.9 pg/mg (median 11.7 pg/mg). Qiviut cortisol levels were significantly higher in males than females, and varied seasonally (summer levels were significantly lower than in fall and winter), and by year (levels significantly increased from 2013 to 2015). These differences may reflect distinct environmental conditions and the diverse stressors experienced, as well as physiological and/or behavioural characteristics. Quantification of qiviut cortisol may serve as a valuable tool for monitoring health and informing conservation and management efforts. PMID:28948023

How Much Does AMH Really Vary in Normal Women?

PubMed Central

La Marca, Antonio; Grisendi, Valentina; Griesinger, Georg

2013-01-01

Anti-Mullerian Hormone (AMH) is an ovarian hormone expressed in growing follicles that have undergone recruitment from the primordial follicle pool but have not yet been selected for dominance. It is considered an accurate marker of ovarian reserve, able to reflect the size of the ovarian follicular pool of a woman of reproductive age. In comparison to other hormonal biomarkers such as serum FSH, low intra- and intermenstrual cycle variability have been proposed for AMH. This review summarizes the knowledge regarding within-subject variability, with particular attention on AMH intracycle variability. Moreover the impact of ethnicity, body mass index, and smoking behaviour on AMH interindividual variability will be reviewed. Finally changes in AMH serum levels in two conditions of ovarian quiescence, namely contraceptives use and pregnancy, will be discussed. The present review aims at guiding researchers and clinicians in interpreting AMH values and fluctuations in various research and clinical scenarios. PMID:24348558

The Neural Underpinnings of Cognitive Flexibility and their Disruption in Psychotic Illness

PubMed Central

Waltz, James A.

2016-01-01

Schizophrenia has long been associated with a variety of cognitive deficits, including reduced cognitive flexibility. More recent findings, however, point to tremendous inter-individual variability among patients on measures of cognitive flexibility/set-shifting. With an eye toward shedding light on potential sources of variability in set-shifting abilities among schizophrenia patients, I examine the neural substrates of underlying probabilistic reversal learning (PRL) – a paradigmatic measure of cognitive flexibility – as well as neuromodulatory influences upon these systems. Finally, I report on behavioral and neuroimaging studies of PRL in schizophrenia patients, discussing the potentially influences of illness profile and antipsychotic medications on cognitive flexibility in schizophrenia. PMID:27282085

Variable expressivity of the phenotype in two families with brachydactyly type E, craniofacial dysmorphism, short stature and delayed bone age caused by novel heterozygous mutations in the PTHLH gene.

PubMed

Jamsheer, Aleksander; Sowińska-Seidler, Anna; Olech, Ewelina M; Socha, Magdalena; Kozłowski, Kazimierz; Pyrkosz, Antoni; Trzeciak, Tomasz; Materna-Kiryluk, Anna; Latos-Bieleńska, Anna

2016-05-01

Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms.

Genetic Influences on Response to Alcohol and Response to Pharmacotherapies for Alcoholism

PubMed Central

Enoch, Mary-Anne

2014-01-01

Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5′ and 3′ functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs / ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage. PMID:24220019

Integration of white matter network is associated with interindividual differences in psychologically mediated placebo response in migraine patients.

PubMed

Liu, Jixin; Ma, Shaohui; Mu, Junya; Chen, Tao; Xu, Qing; Dun, Wanghuan; Tian, Jie; Zhang, Ming

2017-10-01

Individual differences of brain changes of neural communication and integration in the modular architecture of the human brain network exist for the repeated migraine attack and physical or psychological stressors. However, whether the interindividual variability in the migraine brain connectome predicts placebo response to placebo treatment is still unclear. Using DTI and graph theory approaches, we systematically investigated the topological organization of white matter networks in 71 patients with migraine without aura (MO) and 50 matched healthy controls at three levels: global network measure, nodal efficiency, and nodal intramodule/intermodule efficiency. All patients participated in an 8-week sham acupuncture treatment to induce analgesia. In our results, 30% (n = 21) of patients had 50% change in migraine days from baseline after placebo treatment. At baseline, abnormal increased network integration was found in MO patients as compared with the HC group, and the increased global efficiency before starting clinical treatment was associated with their following placebo response. For nodal efficiency, significantly increased within-subnetwork nodal efficiency and intersubnetwork connectivity of the hippocampus and middle frontal gyrus in patients' white matter network were correlated with the responses of follow-up placebo treatment. Our findings suggested that the trait-like individual differences in pain-related maladaptive stress interfered with and diminished the capacity of chronic pain modulation differently, and the placebo response for treatment could be predicted from a prior white matter network modular structure in migraineurs. Hum Brain Mapp 38:5250-5259, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism.

PubMed

Enoch, Mary-Anne

2014-08-01

Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5' and 3' functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs/ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage. Published by Elsevier Inc.

Probing the limits of alpha power lateralisation as a neural marker of selective attention in middle-aged and older listeners.

PubMed

Tune, Sarah; Wöstmann, Malte; Obleser, Jonas

2018-02-11

In recent years, hemispheric lateralisation of alpha power has emerged as a neural mechanism thought to underpin spatial attention across sensory modalities. Yet, how healthy ageing, beginning in middle adulthood, impacts the modulation of lateralised alpha power supporting auditory attention remains poorly understood. In the current electroencephalography study, middle-aged and older adults (N = 29; ~40-70 years) performed a dichotic listening task that simulates a challenging, multitalker scenario. We examined the extent to which the modulation of 8-12 Hz alpha power would serve as neural marker of listening success across age. With respect to the increase in interindividual variability with age, we examined an extensive battery of behavioural, perceptual and neural measures. Similar to findings on younger adults, middle-aged and older listeners' auditory spatial attention induced robust lateralisation of alpha power, which synchronised with the speech rate. Notably, the observed relationship between this alpha lateralisation and task performance did not co-vary with age. Instead, task performance was strongly related to an individual's attentional and working memory capacity. Multivariate analyses revealed a separation of neural and behavioural variables independent of age. Our results suggest that in age-varying samples as the present one, the lateralisation of alpha power is neither a sufficient nor necessary neural strategy for an individual's auditory spatial attention, as higher age might come with increased use of alternative, compensatory mechanisms. Our findings emphasise that explaining interindividual variability will be key to understanding the role of alpha oscillations in auditory attention in the ageing listener. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS

PubMed Central

Nettekoven, Charlotte; Volz, Lukas J.; Leimbach, Martha; Pool, Eva-Maria; Rehme, Anne K.; Eickhoff, Simon B.; Fink, Gereon R.; Grefkes, Christian

2016-01-01

The responsiveness to non-invasive neuromodulation protocols shows high inter-individual variability, the reasons of which remain poorly understood. We here tested whether the response to intermittent theta-burst stimulation (iTBS) – an effective repetitive transcranial magnetic stimulation (rTMS) protocol for increasing cortical excitability – depends on network properties of the cortical motor system. We furthermore investigated whether the responsiveness to iTBS is dose-dependent. To this end, we used a sham-stimulation controlled, single-blinded within-subject design testing for the relationship between iTBS aftereffects and (i) motor-evoked potentials (MEPs) as well as (ii) resting-state functional connectivity (rsFC) in 16 healthy subjects. In each session, three blocks of iTBS were applied, separated by 15 min. We found that non-responders (subjects not showing an MEP increase of ≥10% after one iTBS block) featured stronger rsFC between the stimulated primary motor cortex (M1) and premotor areas before stimulation compared to responders. However, only the group of responders showed increases in rsFC and MEPs, while most non-responders remained close to baseline levels after all three blocks of iTBS. Importantly, there was still a large amount of variability in both groups. Our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) depends upon the pre-interventional network connectivity of the stimulated region. Of note, increasing iTBS dose did not turn non-responders into responders. The finding that higher levels of pre-interventional connectivity precluded a response to iTBS could reflect a ceiling effect underlying non-responsiveness to iTBS at the systems level. PMID:26052083

Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS.

PubMed

Nettekoven, Charlotte; Volz, Lukas J; Leimbach, Martha; Pool, Eva-Maria; Rehme, Anne K; Eickhoff, Simon B; Fink, Gereon R; Grefkes, Christian

2015-09-01

The responsiveness to non-invasive neuromodulation protocols shows high inter-individual variability, the reasons of which remain poorly understood. We here tested whether the response to intermittent theta-burst stimulation (iTBS) - an effective repetitive transcranial magnetic stimulation (rTMS) protocol for increasing cortical excitability - depends on network properties of the cortical motor system. We furthermore investigated whether the responsiveness to iTBS is dose-dependent. To this end, we used a sham-stimulation controlled, single-blinded within-subject design testing for the relationship between iTBS aftereffects and (i) motor-evoked potentials (MEPs) as well as (ii) resting-state functional connectivity (rsFC) in 16 healthy subjects. In each session, three blocks of iTBS were applied, separated by 15min. We found that non-responders (subjects not showing an MEP increase of ≥10% after one iTBS block) featured stronger rsFC between the stimulated primary motor cortex (M1) and premotor areas before stimulation compared to responders. However, only the group of responders showed increases in rsFC and MEPs, while most non-responders remained close to baseline levels after all three blocks of iTBS. Importantly, there was still a large amount of variability in both groups. Our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) depends upon the pre-interventional network connectivity of the stimulated region. Of note, increasing iTBS dose did not turn non-responders into responders. The finding that higher levels of pre-interventional connectivity precluded a response to iTBS could reflect a ceiling effect underlying non-responsiveness to iTBS at the systems level. Copyright © 2015 Elsevier Inc. All rights reserved.

Sweating Rate and Sweat Sodium Concentration in Athletes: A Review of Methodology and Intra/Interindividual Variability.

PubMed

Baker, Lindsay B

2017-03-01

Athletes lose water and electrolytes as a consequence of thermoregulatory sweating during exercise and it is well known that the rate and composition of sweat loss can vary considerably within and among individuals. Many scientists and practitioners conduct sweat tests to determine sweat water and electrolyte losses of athletes during practice and competition. The information gleaned from sweat testing is often used to guide personalized fluid and electrolyte replacement recommendations for athletes; however, unstandardized methodological practices and challenging field conditions can produce inconsistent/inaccurate results. The primary objective of this paper is to provide a review of the literature regarding the effect of laboratory and field sweat-testing methodological variations on sweating rate (SR) and sweat composition (primarily sodium concentration [Na + ]). The simplest and most accurate method to assess whole-body SR is via changes in body mass during exercise; however, potential confounding factors to consider are non-sweat sources of mass change and trapped sweat in clothing. In addition, variability in sweat [Na + ] can result from differences in the type of collection system used (whole body or localized), the timing/duration of sweat collection, skin cleaning procedure, sample storage/handling, and analytical technique. Another aim of this paper is to briefly review factors that may impact intra/interindividual variability in SR and sweat [Na + ] during exercise, including exercise intensity, environmental conditions, heat acclimation, aerobic capacity, body size/composition, wearing of protective equipment, sex, maturation, aging, diet, and/or hydration status. In summary, sweat testing can be a useful tool to estimate athletes' SR and sweat Na + loss to help guide fluid/electrolyte replacement strategies, provided that data are collected, analyzed, and interpreted appropriately.

Allometric modelling of peak oxygen uptake in male soccer players of 8-18 years of age.

PubMed

Valente-Dos-Santos, João; Coelho-E-Silva, Manuel J; Tavares, Óscar M; Brito, João; Seabra, André; Rebelo, António; Sherar, Lauren B; Elferink-Gemser, Marije T; Malina, Robert M

2015-03-01

Peak oxygen uptake (VO2peak) is routinely scaled as mL O2 per kilogram body mass despite theoretical and statistical limitations of using ratios. To examine the contribution of maturity status and body size descriptors to age-associated inter-individual variability in VO2peak and to present static allometric models to normalize VO2peak in male youth soccer players. Total body and estimates of total and regional lean mass were measured with dual energy X-ray absorptiometry in a cross-sectional sample of Portuguese male soccer players. The sample was divided into three age groups for analysis: 8-12 years, 13-15 years and 16-18 years. VO2peak was estimated using an incremental maximal exercise test on a motorized treadmill. Static allometric models were used to normalize VO2peak. The independent variables with the best statistical fit explained 72% in the younger group (lean body mass: k = 1.07), 52% in mid-adolescent players (lean body mass: k = 0.93) and 31% in the older group (body mass: k = 0.51) of variance in VO2peak. The inclusion of the exponential term pubertal status marginally increased the explained variance in VO2peak (adjusted R(2 )= 36-75%) and provided statistical adjustments to the size descriptors coefficients. The allometric coefficients and exponents evidenced the varying inter-relationship among size descriptors and maturity status with aerobic fitness from early to late-adolescence. Lean body mass, lean lower limbs mass and body mass combined with pubertal status explain most of the inter-individual variability in VO2peak among youth soccer players.

Choice of surrogate tissue influences neonatal EWAS findings.

PubMed

Lin, Xinyi; Teh, Ai Ling; Chen, Li; Lim, Ives Yubin; Tan, Pei Fang; MacIsaac, Julia L; Morin, Alexander M; Yap, Fabian; Tan, Kok Hian; Saw, Seang Mei; Lee, Yung Seng; Holbrook, Joanna D; Godfrey, Keith M; Meaney, Michael J; Kobor, Michael S; Chong, Yap Seng; Gluckman, Peter D; Karnani, Neerja

2017-12-05

Epigenomes are tissue specific and thus the choice of surrogate tissue can play a critical role in interpreting neonatal epigenome-wide association studies (EWAS) and in their extrapolation to target tissue. To develop a better understanding of the link between tissue specificity and neonatal EWAS, and the contributions of genotype and prenatal factors, we compared genome-wide DNA methylation of cord tissue and cord blood, two of the most accessible surrogate tissues at birth. In 295 neonates, DNA methylation was profiled using Infinium HumanMethylation450 beadchip arrays. Sites of inter-individual variability in DNA methylation were mapped and compared across the two surrogate tissues at birth, i.e., cord tissue and cord blood. To ascertain the similarity to target tissues, DNA methylation profiles of surrogate tissues were compared to 25 primary tissues/cell types mapped under the Epigenome Roadmap project. Tissue-specific influences of genotype on the variable CpGs were also analyzed. Finally, to interrogate the impact of the in utero environment, EWAS on 45 prenatal factors were performed and compared across the surrogate tissues. Neonatal EWAS results were tissue specific. In comparison to cord blood, cord tissue showed higher inter-individual variability in the epigenome, with a lower proportion of CpGs influenced by genotype. Both neonatal tissues were good surrogates for target tissues of mesodermal origin. They also showed distinct phenotypic associations, with effect sizes of the overlapping CpGs being in the same order of magnitude. The inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS. This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875 .

Natural history of acute and chronic hepatitis C.

PubMed

Maasoumy, Benjamin; Wedemeyer, Heiner

2012-08-01

Hepatitis C virus (HCV) infection remains a major global health burden. Hepatitis C causes significant liver-related morbidity and mortality due to hepatic decompensation and development of hepatocellular carcinoma. In addition, extra-hepatic manifestations of hepatitis C are frequent. There is a very large interindividual variability in the natural history of both acute and chronic hepatitis C which can be explained in part by a combination of various host, viral and environmental factors. Successful antiviral treatment can prevent short- and long-term complications of HCV infection in many patients. Still, the relative contribution of distinct risk factors for disease progression in different phases of HCV infection needs to be better defined. Personalized treatment approaches for HCV infection should consider individual risk profiles to avoid both under- and over-treatment - which will remain important also in upcoming era of interferon-free treatment of hepatitis C. Copyright © 2012. Published by Elsevier Ltd.

Observed differences in learning ability of heart rate self-regulation as a function of hypnotic susceptibility

NASA Technical Reports Server (NTRS)

Cowings, P. S.

1977-01-01

Three groups of eight male and female subjects (aged 20-27 yr) categorized by low and high hypnotic susceptibility were taught to control their heart rates by means of an appropriate autogenic therapy/biofeedback technique. The experimental groups were trained by autogenic therapy and biofeedback, while the control group received only biofeedback. Significant differences are observed in all psychological test scores between subjects of high and low hypnotic susceptibility. The results confirm that (1) there are qualitative and quantitative differences between the performance of individuals with high and low hypnotic susceptibility; (2) interindividual-variability tests yield data relevant to individual performance in visceral learning tasks; (3) the combined autogenic therapy/biofeedback/verbal feedback technique is suitable for conditioning large stable autonomic responses in humans; and (4) this kind of conditioning is effective in eliminating or alleviating physiological reactions to some environmental stressors.

Space Availability in Confined Sheep during Pregnancy, Effects in Movement Patterns and Use of Space

PubMed Central

Averós, Xavier; Lorea, Areta; Beltrán de Heredia, Ignacia; Arranz, Josune; Ruiz, Roberto; Estevez, Inma

2014-01-01

Space availability is essential to grant the welfare of animals. To determine the effect of space availability on movement and space use in pregnant ewes (Ovis aries), 54 individuals were studied during the last 11 weeks of gestation. Three treatments were tested (1, 2, and 3 m2/ewe; 6 ewes/group). Ewes' positions were collected for 15 minutes using continuous scan samplings two days/week. Total and net distance, net/total distance ratio, maximum and minimum step length, movement activity, angular dispersion, nearest, furthest and mean neighbour distance, peripheral location ratio, and corrected peripheral location ratio were calculated. Restriction in space availability resulted in smaller total travelled distance, net to total distance ratio, maximum step length, and angular dispersion but higher movement activity at 1 m2/ewe as compared to 2 and 3 m2/ewe (P<0.01). On the other hand, nearest and furthest neighbour distances increased from 1 to 3 m2/ewe (P<0.001). Largest total distance, maximum and minimum step length, and movement activity, as well as lowest net/total distance ratio and angular dispersion were observed during the first weeks (P<0.05) while inter-individual distances increased through gestation. Results indicate that movement patterns and space use in ewes were clearly restricted by limitations of space availability to 1 m2/ewe. This reflected in shorter, more sinuous trajectories composed of shorter steps, lower inter-individual distances and higher movement activity potentially linked with higher restlessness levels. On the contrary, differences between 2 and 3 m2/ewe, for most variables indicate that increasing space availability from 2 to 3 m2/ewe would appear to have limited benefits, reflected mostly in a further increment in the inter-individual distances among group members. No major variations in spatial requirements were detected through gestation, except for slight increments in inter-individual distances and an initial adaptation period, with ewes being restless and highly motivated to explore their new environment. PMID:24733027

Reticulocyte profile in top-level alpine skiers during four consecutive competitive seasons.

PubMed

Banfi, Giuseppe; Tavana, Rodolfo; Freschi, Marco; Lundby, Carsten

2010-06-01

The role of reticulocytes (Ret) in sports medicine became clear when the count of immature erythrocytes was introduced in protocols used for anti-doping purposes. Because specific research regarding seasonal variations in Ret is lacking, we assessed Ret (and [Hb]) in top-level male and female skiers during four consecutive competitive seasons. A difference (P < 0.05) between males and females was found for [Hb] and Ret values: [Hb] was lower and Ret was higher in females. The difference was maintained across all four competitive seasons. Marked within-subject differences in [Hb], Ret and immature reticulocyte fraction values were noted; the within-subject variability was greater than the between-subject variability in both genders. For instance, a difference for Ret was consistently shown between first and second blood drawings, i.e. between basal value, before the start of training and competition, and the value at middle of season, when training workload was at highest level. Unlike Ret%, the analysis of variance showed significant changes in [Hb] values across competitive seasons for both genders. Comparison between consecutive seasons (e.g., 2005-2006 vs. 2006-2007) showed significant differences for both parameters. The behaviour of [Hb] and Ret during the various seasons was parallel in females, whereas a discrepancy existed in males. In general, inter-individual variability is quite high, thus, Ret and [Hb] modifications should be referred only to the single athlete. We confirm the validity of the use of Ret counts for anti-doping purposes.

In vitro Production of IL-6 and IFN-γ is Influenced by Dietary Variables and Predicts Upper Respiratory Tract Infection Incidence and Severity Respectively in Young Adults

PubMed Central

Meng, Huicui; Lee, Yujin; Ba, Zhaoyong; Fleming, Jennifer A.; Furumoto, Emily J.; Roberts, Robert F.; Kris-Etherton, Penny M.; Rogers, Connie J.

2015-01-01

Assessment of immune responses in healthy adults following dietary or lifestyle interventions is challenging due to significant inter-individual variability. Thus, gaining a better understanding of host factors that contribute to the heterogeneity in immunity is necessary. To address this question, healthy adults [n = 36, 18–40 years old, body mass index (BMI) 20–35 kg/m2] were recruited. Dietary intake was obtained via 3-day dietary recall records, physical activity level was evaluated using the International Physical Activity Questionnaire, and peripheral blood mononuclear cells were isolated from peripheral blood. Expression of activation markers on unstimulated immune subsets was assessed by flow cytometry. T-cell proliferation and cytokine secretion was assessed following in vitro stimulation with anti-CD3 or lipopolysaccharide. Furthermore, the incidence and severity of cold or flu symptoms were obtained from self-reported upper respiratory tract infection (URTI) questionnaires. The relationship between activation marker expression on T cells and T-cell effector functions; and in vitro cytokine secretion and URTI was determined by linear or logistic regression. CD69 and CD25 expression on unstimulated T cells was significantly associated with T-cell proliferation and interleukin-2 secretion. Incidence and severity of cold or flu symptoms was significantly associated with in vitro interleukin-6 and interferon-gamma secretion, respectively. Furthermore, host factors (e.g., age, BMI, physical activity, and diet) contributed significantly to the relationship between activation marker expression and T-cell effector function, and cytokine secretion and cold and flu status. In conclusion, these results suggest that lifestyle and dietary factors are important variables that contribute to immune responses and should be included in human clinical trials that assess immune endpoints. PMID:25788896

Does oxygen delivery explain interindividual variation in forearm critical impulse?

PubMed

Kellawan, J Mikhail; Bentley, Robert F; Bravo, Michael F; Moynes, Jackie S; Tschakovsky, Michael E

2014-11-01

Within individuals, critical power appears sensitive to manipulations in O2 delivery. We asked whether interindividual differences in forearm O2 delivery might account for a majority of the interindividual differences in forearm critical force impulse (critical impulse), the force analog of critical power. Ten healthy men (24.6 ± 7.10 years) completed a maximal effort rhythmic handgrip exercise test (1 sec contraction-2 sec relaxation) for 10 min. The average of contraction impulses over the last 30 sec quantified critical impulse. Forearm brachial artery blood flow (FBF; echo and Doppler ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured continuously. O2 delivery (FBF arterial oxygen content (venous blood [hemoglobin] and oxygen saturation from pulse oximetry)) and forearm vascular conductance (FVC; FBF·MAP(-1)) were calculated. There was a wide range in O2 delivery (59.98-121.15 O2 mL·min(-1)) and critical impulse (381.5-584.8 N) across subjects. During maximal effort exercise, O2 delivery increased rapidly, plateauing well before the declining forearm impulse and explained most of the interindividual differences in critical impulse (r(2) = 0.85, P < 0.01). Both vasodilation (r(2) = 0.64, P < 0.001) and the exercise pressor response (r(2) = 0.33, P < 0.001) independently contributed to interindividual differences in FBF. In conclusion, interindividual differences in forearm O2 delivery account for most of the interindividual variation in critical impulse. Furthermore, individual differences in pressor response play an important role in determining differences in O2 delivery in addition to vasodilation. The mechanistic origins of this vasodilatory and pressor response heterogeneity across individuals remain to be determined. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Does oxygen delivery explain interindividual variation in forearm critical impulse?

PubMed Central

Kellawan, J. Mikhail; Bentley, Robert F.; Bravo, Michael F.; Moynes, Jackie S.; Tschakovsky, Michael E.

2014-01-01

Abstract Within individuals, critical power appears sensitive to manipulations in O2 delivery. We asked whether interindividual differences in forearm O2 delivery might account for a majority of the interindividual differences in forearm critical force impulse (critical impulse), the force analog of critical power. Ten healthy men (24.6 ± 7.10 years) completed a maximal effort rhythmic handgrip exercise test (1 sec contraction‐2 sec relaxation) for 10 min. The average of contraction impulses over the last 30 sec quantified critical impulse. Forearm brachial artery blood flow (FBF; echo and Doppler ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured continuously. O2 delivery (FBF arterial oxygen content (venous blood [hemoglobin] and oxygen saturation from pulse oximetry)) and forearm vascular conductance (FVC; FBF·MAP−1) were calculated. There was a wide range in O2 delivery (59.98–121.15 O2 mL·min−1) and critical impulse (381.5–584.8 N) across subjects. During maximal effort exercise, O2 delivery increased rapidly, plateauing well before the declining forearm impulse and explained most of the interindividual differences in critical impulse (r2 = 0.85, P < 0.01). Both vasodilation (r2 = 0.64, P < 0.001) and the exercise pressor response (r2 = 0.33, P < 0.001) independently contributed to interindividual differences in FBF. In conclusion, interindividual differences in forearm O2 delivery account for most of the interindividual variation in critical impulse. Furthermore, individual differences in pressor response play an important role in determining differences in O2 delivery in addition to vasodilation. The mechanistic origins of this vasodilatory and pressor response heterogeneity across individuals remain to be determined. PMID:25413323

A new approach for the quantification of synchrony of multivariate non-stationary psychophysiological variables during emotion eliciting stimuli

PubMed Central

Kelava, Augustin; Muma, Michael; Deja, Marlene; Dagdagan, Jack Y.; Zoubir, Abdelhak M.

2015-01-01

Emotion eliciting situations are accompanied by changes of multiple variables associated with subjective, physiological and behavioral responses. The quantification of the overall simultaneous synchrony of psychophysiological reactions plays a major role in emotion theories and has received increased attention in recent years. From a psychometric perspective, the reactions represent multivariate non-stationary intra-individual time series. In this paper, a new time-frequency based latent variable approach for the quantification of the synchrony of the responses is presented. The approach is applied to empirical data, collected during an emotion eliciting situation. The results are compared with a complementary inter-individual approach of Hsieh et al. (2011). Finally, the proposed approach is discussed in the context of emotion theories, and possible future applications and limitations are provided. PMID:25653624

Pharmacogenomics in pediatric rheumatology.

PubMed

Becker, Mara L

2012-09-01

Despite major advancements in therapeutics, variability in drug response remains a challenge in both adults and children diagnosed with rheumatic disease. The genetic contribution to interindividual variability has emerged as a promising avenue of exploration; however, challenges remain in making this knowledge relevant in the clinical realm. New genetic associations in patients with rheumatic disease have been reported for disease modifying antirheumatic drugs, antimetabolites and biologic drugs. However, many of these findings are in need of replication, and few have taken into account the concept of ontogeny, specific to pediatrics. In the current era in which we practice, genetic variation will undoubtedly contribute to variability in therapeutic response and may be a factor that will ultimately impact individualized care. However, preliminary studies have shown that there are many hurdles that need to be overcome as we explore pharmacogenomic associations specifically in the field of pediatric rheumatology.

Polymorphisms in Genes Involved in Fatty Acid β-Oxidation Interact with Dietary Fat Intakes to Modulate the Plasma TG Response to a Fish Oil Supplementation

PubMed Central

Bouchard-Mercier, Annie; Rudkowska, Iwona; Lemieux, Simone; Couture, Patrick; Vohl, Marie-Claude

2014-01-01

A large inter-individual variability in the plasma triglyceride (TG) response to an omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has been observed. The objective was to examine gene-diet interaction effects on the plasma TG response after a fish oil supplementation, between single-nucleotide polymorphisms (SNPs) within genes involved in fatty acid β-oxidation and dietary fat intakes. Two hundred and eight (208) participants were recruited in the greater Quebec City area. The participants completed a six-week fish oil supplementation (5 g fish oil/day: 1.9–2.2 g EPA and 1.1 g DHA). Dietary fat intakes were measured using three-day food records. SNPs within RXRA, CPT1A, ACADVL, ACAA2, ABCD2, ACOX1 and ACAA1 genes were genotyped using TAQMAN methodology. Gene-diet interaction effects on the plasma TG response were observed for SNPs within RXRA (rs11185660, rs10881576 and rs12339187) and ACOX1 (rs17583163) genes. For rs11185660, fold changes in RXRA gene expression levels were different depending on SFA intakes for homozygotes T/T. Gene-diet interaction effects of SNPs within genes involved in fatty acid β-oxidation and dietary fat intakes may be important in understanding the inter-individual variability in plasma TG levels and in the plasma TG response to a fish oil supplementation. PMID:24647074

The genetic theory of infectious diseases: a brief history and selected illustrations.

PubMed

Casanova, Jean-Laurent; Abel, Laurent

2013-01-01

Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases.

The Genetic Theory of Infectious Diseases: A Brief History and Selected Illustrations

PubMed Central

Casanova, Jean-Laurent; Abel, Laurent

2016-01-01

Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases. PMID:23724903

Sperm function and assisted reproduction technology

PubMed Central

MAAß, GESA; BÖDEKER, ROLF‐HASSO; SCHEIBELHUT, CHRISTINE; STALF, THOMAS; MEHNERT, CLAAS; SCHUPPE, HANS‐CHRISTIAN; JUNG, ANDREAS; SCHILL, WOLF‐BERNHARD

2005-01-01

The evaluation of different functional sperm parameters has become a tool in andrological diagnosis. These assays determine the sperm's capability to fertilize an oocyte. It also appears that sperm functions and semen parameters are interrelated and interdependent. Therefore, the question arose whether a given laboratory test or a battery of tests can predict the outcome in in vitro fertilization (IVF). One‐hundred and sixty‐one patients who underwent an IVF treatment were selected from a database of 4178 patients who had been examined for male infertility 3 months before or after IVF. Sperm concentration, motility, acrosin activity, acrosome reaction, sperm morphology, maternal age, number of transferred embryos, embryo score, fertilization rate and pregnancy rate were determined. In addition, logistic regression models to describe fertilization rate and pregnancy were developed. All the parameters in the models were dichotomized and intra‐ and interindividual variability of the parameters were assessed. Although the sperm parameters showed good correlations with IVF when correlated separately, the only essential parameter in the multivariate model was morphology. The enormous intra‐ and interindividual variability of the values was striking. In conclusion, our data indicate that the andrological status at the end of the respective treatment does not necessarily represent the status at the time of IVF. Despite a relatively low correlation coefficient in the logistic regression model, it appears that among the parameters tested, the most reliable parameter to predict fertilization is normal sperm morphology. (Reprod Med Biol 2005; 4: 7–30) PMID:29699207

Integrating Growth Variability of the Ilium, Fifth Lumbar Vertebra, and Clavicle with Multivariate Adaptive Regression Splines Models for Subadult Age Estimation.

PubMed

Corron, Louise; Marchal, François; Condemi, Silvana; Telmon, Norbert; Chaumoitre, Kathia; Adalian, Pascal

2018-05-31

Subadult age estimation should rely on sampling and statistical protocols capturing development variability for more accurate age estimates. In this perspective, measurements were taken on the fifth lumbar vertebrae and/or clavicles of 534 French males and females aged 0-19 years and the ilia of 244 males and females aged 0-12 years. These variables were fitted in nonparametric multivariate adaptive regression splines (MARS) models with 95% prediction intervals (PIs) of age. The models were tested on two independent samples from Marseille and the Luis Lopes reference collection from Lisbon. Models using ilium width and module, maximum clavicle length, and lateral vertebral body heights were more than 92% accurate. Precision was lower for postpubertal individuals. Integrating punctual nonlinearities of the relationship between age and the variables and dynamic prediction intervals incorporated the normal increase in interindividual growth variability (heteroscedasticity of variance) with age for more biologically accurate predictions. © 2018 American Academy of Forensic Sciences.

Variations of the liver standardized uptake value in relation to background blood metabolism: An 2-[18F]Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography study in a large population from China.

PubMed

Liu, Guobing; Hu, Yan; Zhao, Yanzhao; Yu, Haojun; Hu, Pengcheng; Shi, Hongcheng

2018-05-01

To investigate the influence of background blood metabolism on liver uptake of 2-[F]fluoro-2-deoxy-D-glucose (F-FDG) and search for an appropriate corrective method.Positron emission tomography/computed tomography (PET/CT) and common serological biochemical tests of 633 healthy people were collected retrospectively. The mean standardized uptake value (SUV) of the liver, liver artery, and portal vein (i.e., SUVL, SUVA, and SUVP) were measured. SUVL/A was calculated as SUVL/SUVA, while SUVL/P was calculated as SUVL/SUVP. SUV of liver parenchyma (SUVLP) was calculated as SUVL - .3 × (.75 × SUVP + .25 × SUVA). The coefficients of variation (CV) of SUVL, SUVL/A, SUVL/P, and SUVLP were compared to assess their interindividual variations. Univariate and multivariate analyses were performed to identify vulnerabilities of these SUV indexes to common factors assessed using serological liver functional tests.SUVLP was significantly larger than SUVL (2.19 ± .497 vs 1.88 ± .495, P < .001), while SUVL/P was significantly smaller than SUVL (1.72 ± .454 vs 1.88 ± .495, P < .001). The difference between SUVL/A and SUVL was not significant (1.83 ± .500 vs 1.88 ± .495, P = .130). The CV of SUVLP (22.7%) was significantly smaller than that of SUVL (22.7%:26.3%, P < .001), while the CVs of SUVL/A (27.2%) and SUVL/P (26.4%) were not different from that of SUVL (P = .429 and .929, respectively). Fewer variables independently influenced SUVLP than influenced SUVL, SUVL/A, and SUVL/P; Only aspartate aminotransferase, body mass index, and total cholesterol, all P-values <.05.The activity of background blood influences the variation of liver SUV. SUVLP might be an alternative corrective method to reduce this influence, as its interindividual variation and vulnerability to effects from common factors of serological liver functional tests are relatively lower than the commonly used SUVL.

Analysis of copy number variations in Holstein-Friesian cow genomes based on whole-genome sequence data.

PubMed

Mielczarek, M; Frąszczak, M; Giannico, R; Minozzi, G; Williams, John L; Wojdak-Maksymiec, K; Szyda, J

2017-07-01

Thirty-two whole genome DNA sequences of cows were analyzed to evaluate inter-individual variability in the distribution and length of copy number variations (CNV) and to functionally annotate CNV breakpoints. The total number of deletions per individual varied between 9,731 and 15,051, whereas the number of duplications was between 1,694 and 5,187. Most of the deletions (81%) and duplications (86%) were unique to a single cow. No relation between the pattern of variant sharing and a family relationship or disease status was found. The animal-averaged length of deletions was from 5,234 to 9,145 bp and the average length of duplications was between 7,254 and 8,843 bp. Highly significant inter-individual variation in length and number of CNV was detected for both deletions and duplications. The majority of deletion and duplication breakpoints were located in intergenic regions and introns, whereas fewer were identified in noncoding transcripts and splice regions. Only 1.35 and 0.79% of the deletion and duplication breakpoints were observed within coding regions. A gene with the highest number of deletion breakpoints codes for protein kinase cGMP-dependent type I, whereas the T-cell receptor α constant gene had the most duplication breakpoints. The functional annotation of genes with the largest incidence of deletion/duplication breakpoints identified 87/112 Kyoto Encyclopedia of Genes and Genomes pathways, but none of the pathways were significantly enriched or depleted with breakpoints. The analysis of Gene Ontology (GO) terms revealed that a cluster with the highest enrichment score among genes with many deletion breakpoints was represented by GO terms related to ion transport, whereas the GO term cluster mostly enriched among the genes with many duplication breakpoints was related to binding of macromolecules. Furthermore, when considering the number of deletion breakpoints per gene functional category, no significant differences were observed between the "housekeeping" and "strong selection" categories, but genes representing the "low selection pressure" group showed a significantly higher number of breakpoints. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Inter-individual variation in nutrient balancing in the honeybee (Apis mellifera).

PubMed

Reade, Abbie J; Naug, Dhruba

2016-12-01

The Geometric Framework approach in nutritional ecology postulates that animals attempt to balance the consumption of different nutrients rather than simply maximizing energetic gain. The intake target with respect to each nutrient maximizes fitness in a specific dimension and any difference between individuals in intake target therefore represents alternative behavioral and fitness maximization strategies. Nutritional interactions are a central component of all social groups and any inter-individual variation in intake target should therefore have a significant influence on social dynamics. Using the honeybee colony as an experimental model, we quantified differences in the carbohydrate intake target of individual foragers using a capillary feeder (CAFE) assay. Our results show that the bees did not simply maximize their net energetic gain, but combined sugar and water in their diet in a way that brought them to an intake target equivalent to a 33% sucrose solution. Although the mean intake target with respect to the nutrients sucrose and water was the same under different food choice regimens, there was significant inter-individual variation in intake target and the manner in which individuals reached this target, a variation which suggests different levels of tolerance to nutrient imbalance. We discuss our results in the context of how colony performance may be influenced by the different nutrient balancing strategies of individual members and how such nutritional constraints could have contributed to the evolution of sociality. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structural Organization of the Corpus Callosum Predicts Attentional Shifts after Continuous Theta Burst Stimulation.

PubMed

Chechlacz, Magdalena; Humphreys, Glyn W; Sotiropoulos, Stamatios N; Kennard, Christopher; Cazzoli, Dario

2015-11-18

Repetitive transcranial magnetic stimulation (rTMS) applied over the right posterior parietal cortex (PPC) in healthy participants has been shown to trigger a significant rightward shift in the spatial allocation of visual attention, temporarily mimicking spatial deficits observed in neglect. In contrast, rTMS applied over the left PPC triggers a weaker or null attentional shift. However, large interindividual differences in responses to rTMS have been reported. Studies measuring changes in brain activation suggest that the effects of rTMS may depend on both interhemispheric and intrahemispheric interactions between cortical loci controlling visual attention. Here, we investigated whether variability in the structural organization of human white matter pathways subserving visual attention, as assessed by diffusion magnetic resonance imaging and tractography, could explain interindividual differences in the effects of rTMS. Most participants showed a rightward shift in the allocation of spatial attention after rTMS over the right intraparietal sulcus (IPS), but the size of this effect varied largely across participants. Conversely, rTMS over the left IPS resulted in strikingly opposed individual responses, with some participants responding with rightward and some with leftward attentional shifts. We demonstrate that microstructural and macrostructural variability within the corpus callosum, consistent with differential effects on cross-hemispheric interactions, predicts both the extent and the direction of the response to rTMS. Together, our findings suggest that the corpus callosum may have a dual inhibitory and excitatory function in maintaining the interhemispheric dynamics that underlie the allocation of spatial attention. The posterior parietal cortex (PPC) controls allocation of attention across left versus right visual fields. Damage to this area results in neglect, characterized by a lack of spatial awareness of the side of space contralateral to the brain injury. Transcranial magnetic stimulation over the PPC is used to study cognitive mechanisms of spatial attention and to examine the potential of this technique to treat neglect. However, large individual differences in behavioral responses to stimulation have been reported. We demonstrate that the variability in the structural organization of the corpus callosum accounts for these differences. Our findings suggest novel dual mechanism of the corpus callosum function in spatial attention and have broader implications for the use of stimulation in neglect rehabilitation. Copyright © 2015 the authors 0270-6474/15/3515353-16$15.00/0.

Population Pharmacokinetics of Artesunate and Dihydroartemisinin following Intra-Rectal Dosing of Artesunate in Malaria Patients

PubMed Central

Simpson, Julie A; Agbenyega, Tsiri; Barnes, Karen I; Perri, Gianni Di; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif; McIlleron, Helen; Miller, Raymond; Molyneux, Malcolm; Mwenechanya, James; Navaratnam, Visweswaran; Nosten, Francois; Olliaro, Piero; Pang, Lorrin; Ribeiro, Isabela; Tembo, Madalitso; van Vugt, Michele; Ward, Steve; Weerasuriya, Kris; Win, Kyaw; White, Nicholas J

2006-01-01

Background Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. Methods and Findings Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36–1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0–6h were observed. Conclusions The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations. PMID:17132053

Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance and metabolism

PubMed Central

Kharasch, Evan D.; Regina, Karen J.; Blood, Jane; Friedel, Christina

2015-01-01

Background Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. Methods Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n=21), CYP2B6*1/*6 (n=20), and CYP2B6*6/*6 (n=17), and also CYP2B6*1/*4 (n=1), CYP2B6*4/*6 (n=3), CYP2B6*5/*5 (n=2) subjects received single doses of intravenous and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. Results Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1, and R-methadone apparent oral clearance was 25 and 30% lower. R- and S-methadone apparent oral clearance was 3- and 4-fold greater in CYP2B6*4 carriers. Intravenous and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with CYP2B6*1 homozygotes, and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African-Americans due to the CYP2B6*6 genetic polymorphism. Conclusions CYP2B6 polymorphisms influence methadone plasma concentrations, due to altered methadone metabolism and thus clearance. Genetic influence is greater for oral than intravenous, and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions. PMID:26389554

Contributors to dietary glycaemic index and glycaemic load in the Netherlands: the role of beer.

PubMed

Sluik, Diewertje; Atkinson, Fiona S; Brand-Miller, Jennie C; Fogelholm, Mikael; Raben, Anne; Feskens, Edith J M

2016-04-14

Diets high in glycaemic index (GI) and glycaemic load (GL) have been associated with a higher diabetes risk. Beer explained a large proportion of variation in GI in a Finnish and an American study. However, few beers have been tested according to International Organization for Standardization (ISO) methodology. We tested the GI of beer and estimated its contribution to dietary GI and GL in the Netherlands. GI testing of pilsner beer (Pilsner Urquell) was conducted at The University of Sydney according to ISO international standards with glucose as the reference food. Subsequently, GI and GL values were assigned to 2556 food items in the 2011 Dutch food composition table using a six-step methodology and consulting four databases. This table was linked to dietary data from 2106 adults in the Dutch National Food Consumption Survey 2007-2010. Stepwise linear regression identified contribution to inter-individual variation in dietary GI and GL. The GI of pilsner beer was 89 (SD 5). Beer consumption contributed to 9·6 and 5·3% inter-individual variation in GI and GL, respectively. Other foods that contributed to the inter-individual variation in GI and GL included potatoes, bread, soft drinks, sugar, candy, wine, coffee and tea. The results were more pronounced in men than in women. In conclusion, beer is a high-GI food. Despite its relatively low carbohydrate content (approximately 4-5 g/100 ml), it still made a contribution to dietary GL, especially in men. Next to potatoes, bread, sugar and sugar-sweetened beverages, beer captured a considerable proportion of between-person variability in GI and GL in the Dutch diet.

Intra- and Interindividual Variability in the Behavioral, Affective, and Perceptual Effects of Alcohol Consumption in a Social Context.

PubMed

Franzen, Minita; Sadikaj, Gentiana; Moskowitz, Debbie S; Ostafin, Brian D; Aan Het Rot, Marije

2018-05-01

We examined the influence of interindividual differences in alcohol use on the intraindividual associations of drinking occurrence with interpersonal behaviors, affect, and perceptions of others during naturally occurring social interactions. For 14 consecutive days, 219 psychology freshmen (55% female; M age  = 20.7 years, SD = 2.18) recorded their behaviors, affect, and perceptions in social interactions soon after an interpersonal event occurred. Interpersonal behaviors and perceptions were assessed in terms of dominance-submissiveness and agreeableness-quarrelsomeness. Participants also reported the number of alcoholic drinks consumed within 3 hours of each interaction. We considered the intraindividual associations of (i) having a drinking episode and (ii) the number of drinks during an episode with behaviors, affect, and perceptions and examined interindividual differences in drinking frequency and intensity during social interactions as potential moderators of these associations. Social drinking frequency and intensity moderated the associations between drinking episode and behaviors, affect, and perceptions in social interactions. During a drinking episode, more frequent social drinkers perceived others as more dominant than less frequent social drinkers. During a drinking episode in which more alcohol was consumed than usual, more frequent social drinkers also reported behaving more dominantly and experiencing less pleasant affect. As more frequent social drinkers had different interpersonal responses to drinking than less frequent social drinkers, including when they had consumed larger amounts of alcohol than usual, our results suggest a differential susceptibility to the effects of alcohol during naturally occurring social interactions among drinkers with varying drinking frequency. Copyright © 2018 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals, Inc. on behalf of Research Society on Alcoholism.

Influence of multiple injections of human chorionic gonadotropin (hCG) on urine and serum endogenous steroids concentrations.

PubMed

Strahm, Emmanuel; Marques-Vidal, Pedro; Pralong, François; Dvorak, Jiri; Saugy, Martial; Baume, Norbert

2011-12-10

Since it is established that human chorionic gonadotropin (hCG) affects testosterone production and release in the human body, the use of this hormone as a performance enhancing drug has been prohibited by the World Anti-Doping Agency. Nowadays, the only validated biomarker of a hCG doping is its direct quantification in urine. However, this specific parameter is subjected to large inter-individual variability and its determination is directly dependent on the reliability of hCG immunoassays used. In order to counteract these weaknesses, new biomarkers need to be evidenced. To address this issue, a pilot clinical study was performed on 10 volunteers submitted to 3 subsequent hCG injections. Blood and urine samples were collected during two weeks in order to follow the physiological effects on related compounds such as the steroid profile or hormones involved in the hypothalamo-pituitary axis. The hCG pharmacokinetic observed in all subjects was, as expected, prone to important inter-individual variations. Using ROC plots, level of testosterone and testosterone on luteinizing hormone ratio in both blood and urine were found to be the most relevant biomarker of a hCG abuse, regardless of inter-individual variations. In conclusion, this study showed the crucial importance of reliable quantification methods to assess low differences in hormonal patterns. In regard to these results and to anti-doping requirements and constraints, blood together with urine matrix should be included in the anti-doping testing program. Together with a longitudinal follow-up approach it could constitute a new strategy to detect a hCG abuse, applicable to further forms of steroid or other forbidden drug manipulation. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The marine side of a terrestrial carnivore: intra-population variation in use of allochthonous resources by arctic foxes.

PubMed

Tarroux, Arnaud; Bêty, Joël; Gauthier, Gilles; Berteaux, Dominique

2012-01-01

Inter-individual variation in diet within generalist animal populations is thought to be a widespread phenomenon but its potential causes are poorly known. Inter-individual variation can be amplified by the availability and use of allochthonous resources, i.e., resources coming from spatially distinct ecosystems. Using a wild population of arctic fox as a study model, we tested hypotheses that could explain variation in both population and individual isotopic niches, used here as proxy for the trophic niche. The arctic fox is an opportunistic forager, dwelling in terrestrial and marine environments characterized by strong spatial (arctic-nesting birds) and temporal (cyclic lemmings) fluctuations in resource abundance. First, we tested the hypothesis that generalist foraging habits, in association with temporal variation in prey accessibility, should induce temporal changes in isotopic niche width and diet. Second, we investigated whether within-population variation in the isotopic niche could be explained by individual characteristics (sex and breeding status) and environmental factors (spatiotemporal variation in prey availability). We addressed these questions using isotopic analysis and bayesian mixing models in conjunction with linear mixed-effects models. We found that: i) arctic fox populations can simultaneously undergo short-term (i.e., within a few months) reduction in both isotopic niche width and inter-individual variability in isotopic ratios, ii) individual isotopic ratios were higher and more representative of a marine-based diet for non-breeding than breeding foxes early in spring, and iii) lemming population cycles did not appear to directly influence the diet of individual foxes after taking their breeding status into account. However, lemming abundance was correlated to proportion of breeding foxes, and could thus indirectly affect the diet at the population scale.

The Marine Side of a Terrestrial Carnivore: Intra-Population Variation in Use of Allochthonous Resources by Arctic Foxes

PubMed Central

Tarroux, Arnaud; Bêty, Joël; Gauthier, Gilles; Berteaux, Dominique

2012-01-01

Inter-individual variation in diet within generalist animal populations is thought to be a widespread phenomenon but its potential causes are poorly known. Inter-individual variation can be amplified by the availability and use of allochthonous resources, i.e., resources coming from spatially distinct ecosystems. Using a wild population of arctic fox as a study model, we tested hypotheses that could explain variation in both population and individual isotopic niches, used here as proxy for the trophic niche. The arctic fox is an opportunistic forager, dwelling in terrestrial and marine environments characterized by strong spatial (arctic-nesting birds) and temporal (cyclic lemmings) fluctuations in resource abundance. First, we tested the hypothesis that generalist foraging habits, in association with temporal variation in prey accessibility, should induce temporal changes in isotopic niche width and diet. Second, we investigated whether within-population variation in the isotopic niche could be explained by individual characteristics (sex and breeding status) and environmental factors (spatiotemporal variation in prey availability). We addressed these questions using isotopic analysis and Bayesian mixing models in conjunction with linear mixed-effects models. We found that: i) arctic fox populations can simultaneously undergo short-term (i.e., within a few months) reduction in both isotopic niche width and inter-individual variability in isotopic ratios, ii) individual isotopic ratios were higher and more representative of a marine-based diet for non-breeding than breeding foxes early in spring, and iii) lemming population cycles did not appear to directly influence the diet of individual foxes after taking their breeding status into account. However, lemming abundance was correlated to proportion of breeding foxes, and could thus indirectly affect the diet at the population scale. PMID:22900021

The stress response and exploratory behaviour in Yucatan minipigs (Sus scrofa): Relations to sex and social rank.

PubMed

Adcock, Sarah J J; Martin, Gerard M; Walsh, Carolyn J

2015-12-01

According to the coping styles hypothesis, an individual demonstrates an integrated behavioural and physiological response to environmental challenge that is consistent over time and across situations. Individual consistency in behavioural responses to challenge has been documented across the animal kingdom. Comparatively few studies, however, have examined inter-individual variation in the physiological response, namely glucocorticoid and catecholamine levels, the stress hormones secreted by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, respectively. Variation in coping styles between individuals may be explained in part by differences in social rank and sex. Using 20 Yucatan minipigs (Sus scrofa) we: (1) investigated the existence of consistent inter-individual variation in exploratory behaviour and the hormonal stress response, and tested for correlations as predicted by the coping styles hypothesis; and (2) evaluated whether inter-individual behavioural and hormonal variation is related to social rank and sex. Salivary stress biomarkers (cortisol, alpha-amylase, chromogranin A) were assessed in the presence and absence of a stressor consisting of social isolation in a crate for 10 min. Principal components analysis on a set of behavioural variables revealed two traits, which we labelled exploratory tendency and neophobia. Neither exploratory tendency nor neophobia predicted the physiological stress response. Subordinate pigs exhibited higher catecholamine levels compared to dominant conspecifics. We observed sex differences in the repeatability of salivary stress markers and reactivity of the stress systems. The results do not provide support for the existence of behavioural-physiological coping styles in pigs. Sex is an important determinant of the physiological stress response and warrants consideration in research addressing behavioural and hormonal variation. Copyright © 2015 Elsevier Inc. All rights reserved.

Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.

PubMed

Picker-Minh, Sylvie; Mignot, Cyril; Doummar, Diane; Hashem, Mais; Faqeih, Eissa; Josset, Patrice; Dubern, Béatrice; Alkuraya, Fowzan S; Kraemer, Nadine; Kaindl, Angela M

2016-04-29

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) has been recently linked to biallelic mutation of the peptidyl-tRNA hydrolase 2 gene PTRH2. Two index patients with IMNEPD in the original report had multiple neurological symptoms such as postnatal microcephaly, intellectual disability, developmental delay, sensorineural deafness, cerebellar atrophy, ataxia, and peripheral neuropathy. In addition, distal muscle weakness and abnormalities of thyroid, pancreas, and liver were found. Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. We thereby hope to better define IMNEPD and promote recognition and diagnosis of this novel disease entity.

Pharmacogenetics of schizophrenia.

PubMed

Reynolds, Gavin P; Templeman, Lucy A; Godlewska, Beata R

2006-08-01

There is substantial unexplained interindividual variability in the drug treatment of schizophrenia. A substantial proportion of patients respond inadequately to antipsychotic drugs, and many experience limiting side effects. As genetic factors are likely to contribute to this variability, the pharmacogenetics of schizophrenia has attracted substantial effort. The approaches have mainly been limited to association studies of polymorphisms in candidate genes, which have been indicated by the pharmacology of antipsychotic drugs. Although some advances have been made, particularly in understanding the pharmacogenetics of some limiting side effects, genetic prediction of symptom response remains elusive. Nevertheless, with improvements in defining the response phenotype in carefully assessed and homogeneous subject groups, the near future is likely to see the identification of genetic predictors of outcome that may inform the choice of pharmacotherapy.

The intra-individual reproducibility of flash-evoked potentials in a sample of children.

PubMed

Schellberg, D; Gasser, T; Köhler, W

1987-07-01

Visual evoked potentials (VEPs) to flash stimuli were recorded twice from 26 children aged 10-13 years, with an intersession interval of about 10 months. Test-retest reliability was poor for recordings taken from scalp locations overlying non-specific cortex and somewhat better for specific cortex. The size of consistency coefficients (i.e. correlations within session) showed that noise and artefacts were not the decisive factors which lower reliability. A comparison with retest correlations of broad band parameters of the EEG at rest for the same sample showed, to our surprise, smaller retest reliability for VEP parameters. Variability of the VEP in children over time seems to be a substantial as its well-known inter-individual variability.

Preparation of a standardised faecal slurry for ex-vivo microbiota studies which reduces inter-individual donor bias.

PubMed

O'Donnell, Michelle M; Rea, Mary C; O'Sullivan, Órla; Flynn, Cal; Jones, Beth; McQuaid, Albert; Shanahan, Fergus; Ross, R Paul

2016-10-01

In-vitro gut fermentation systems provide suitable models for studying gut microbiota composition and functionality. However, such methods depend on the availability of donors and the assumption of reproducibility between microbial communities before experimental treatments commence. The aim of this study was to develop a frozen standardised inoculum (FSI) which minimizes inter-individual variation and to determine its stability over time using culture-dependent and culture-independent techniques. A method for the preparation difference of a FSI is described which involves pooling the faecal samples, centrifugation and pelleting of the cell biomass and finally homogenising the cell pellets with phosphate buffer and glycerol. Using this approach, no significant difference in total anaerobe cell viability was observed between the fresh standardised inoculum (before freezing) and the 12days post freezing FSI. Moreover, Quantitative PCR revealed no significant alterations in the estimated bacterial numbers in the FSI preparations for any of the phyla. MiSeq sequencing revealed minute differences in the relative abundance at phylum, family and genus levels between the FSI preparations. Differences in the microbiota denoted as significant were limited between preparations in the majority of cases to changes in percentage relative abundance of ±0.5%. The independently prepared FSIs revealed a high degree of reproducibility in terms of microbial composition between the three preparations. This study provides a method to produce a standardised human faecal inoculum suitable for freezing. Based on culture-dependent and independent analysis, the method ensures a degree of reproducibility between preparations by lessening the effect of inter-individual variation among the donors, thereby making the system more suitable for the accurate interpretation of the effects of experimental treatments. Copyright © 2016 Elsevier B.V. All rights reserved.

Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe

PubMed Central

Urquhart, Bradley L.; Ware, Joseph A.; Tirona, Rommel G.; Ho, Richard H.; Leake, Brenda F.; Schwarz, Ute I.; Zaher, Hani; Palandra, Joe; Gregor, Jamie C.; Dresser, George K.; Kim, Richard B.

2014-01-01

Breast cancer resistance protein (BCRP) is an efflux transporter expressed in tissues that act as barriers to drug entry. Given that single nucleotide polymorphisms (SNPs) in the ABCG2 gene encoding BCRP are common, the possibility exists that these genetic variants may be a determinant of interindividual variability in drug response. The objective of this study is to confirm the human BCRP-mediated transport of sulfasalazine in vitro, evaluate interindividual variation in BCRP expression in human intestine and to determine the role of ABCG2 SNPs to drug disposition in healthy patients using sulfasalazine as a novel in vivo probe. To evaluate these objectives, pinch biopsies were obtained from 18 patients undergoing esophagogastro–duodenoscopy or colonoscopy for determination of BCRP expression in relation to genotype. Wild-type and variant BCRP were expressed in a heterologous expression system to evaluate the effect of SNPs on cell-surface trafficking. A total of 17 healthy individuals participated in a clinical investigation to determine the effect of BCRP SNPs on sulfasalazine pharmacokinetics. In vitro, the cell surface protein expression of the common BCRP 421 C>A variant was reduced in comparison with the wild-type control. Intestinal biopsy samples revealed that BCRP protein and mRNA expression did not significantly differ between patients with 34GG/421CC versus patients with 34GG/421CA genotypes. Remarkably, in subjects with 34GG/421CA genotype, sulfasalazine area under the concentration-time curve was 2.4-fold greater compared with 34GG/421CC subjects (P<0.05). This study links commonly occurring SNPs in BCRP with significantly increased oral sulfasalazine plasma exposure in humans. Accordingly, sulfasalazine may prove to have utility as in vivo probe for assessing the clinical impact of BCRP for the disposition and efficacy of drugs. PMID:18408567

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

PubMed Central

Ruslami, R.; Later-Nijland, H.; Mooren, F.; Teulen, M.; Apriani, L.; Koenderink, J. B.; Russel, F. G.; Burger, D. M.; Alisjahbana, B.; Wieringa, F.; van Crevel, R.; Aarnoutse, R. E.

2015-01-01

Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m2), malnourished (BMI of <18.5 kg/m2), and well-nourished (BMI of ≥18.5 kg/m2) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0–24 (geometric mean, 59.2 versus 48.2 h · mg/liter; P = 0.02) and higher unbound AUC0–24 (geometric mean, 6.2 versus 4.8 h · mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships. PMID:25801554

Impact of childhood adversity on the onset and course of subclinical psychosis symptoms--results from a 30-year prospective community study.

PubMed

Rössler, Wulf; Hengartner, Michael P; Ajdacic-Gross, Vladeta; Haker, Helene; Angst, Jules

2014-03-01

The study objective was to examine childhood adversity in association with intra-individual changes and inter-individual differences in subclinical psychosis in a representative community cohort over a 30-year period of observation. We analyzed two psychosis syndromes derived from the SCL-90-R - schizotypal signs and schizophrenia nuclear symptoms - in 335 participants. Participants were repeatedly assessed between 1978 (around age 20) and 2008 (around age 50). We focused specifically on inter-individual differences and intra-individual changes over time by applying structural equation modeling, generalized linear models, and generalized estimating equations. Several weak inter-individual differences revealed that increased schizotypal signs are related to various childhood adversities, such as being repeatedly involved in fights and parents having severe conflicts among themselves. We also found a significant positive association between schizotypal signs and the total number of adversities a subject experienced. This pointed toward a modest dose-response relationship. The intra-individual change in schizotypal signs over time was rather weak, although some adjustment did occur. In contrast, inter-individual schizophrenia nuclear symptoms were mainly unrelated to childhood adversity. However, some striking intra-individual changes in distress were noted over time, especially those linked with severe punishment and the total adversity score. In conclusion, we have confirmed previous positive findings about the association between childhood adversity and subsequent subclinical psychosis symptoms: An increase in adversity is weakly related to an increase of the psychosis symptom load. However, depending on the kind of adversity experienced the psychosis symptom load decreases gradually in adult life. Copyright © 2014 Elsevier B.V. All rights reserved.

High internal noise and poor external noise filtering characterize perception in autism spectrum disorder.

PubMed

Park, Woon Ju; Schauder, Kimberly B; Zhang, Ruyuan; Bennetto, Loisa; Tadin, Duje

2017-12-14

An emerging hypothesis postulates that internal noise is a key factor influencing perceptual abilities in autism spectrum disorder (ASD). Given fundamental and inescapable effects of noise on nearly all aspects of neural processing, this could be a critical abnormality with broad implications for perception, behavior, and cognition. However, this proposal has been challenged by both theoretical and empirical studies. A crucial question is whether and how internal noise limits perception in ASD, independently from other sources of perceptual inefficiency, such as the ability to filter out external noise. Here, we separately estimated internal noise and external noise filtering in ASD. In children and adolescents with and without ASD, we computationally modeled individuals' visual orientation discrimination in the presence of varying levels of external noise. The results revealed increased internal noise and worse external noise filtering in individuals with ASD. For both factors, we also observed high inter-individual variability in ASD, with only the internal noise estimates significantly correlating with severity of ASD symptoms. We provide evidence for reduced perceptual efficiency in ASD that is due to both increased internal noise and worse external noise filtering, while highlighting internal noise as a possible contributing factor to variability in ASD symptoms.

Patterns and Predictors of Tic Suppressibility in Youth With Tic Disorders

PubMed Central

Conelea, Christine A.; Wellen, Brianna; Woods, Douglas W.; Greene, Deanna J.; Black, Kevin J.; Specht, Matthew; Himle, Michael B.; Lee, Han-Joo; Capriotti, Matthew

2018-01-01

Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression. PMID:29875706

Patterns and Predictors of Tic Suppressibility in Youth With Tic Disorders.

PubMed

Conelea, Christine A; Wellen, Brianna; Woods, Douglas W; Greene, Deanna J; Black, Kevin J; Specht, Matthew; Himle, Michael B; Lee, Han-Joo; Capriotti, Matthew

2018-01-01

Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression.

Deferasirox pharmacokinetic evaluation in β-thalassaemia paediatric patients.

PubMed

Allegra, Sarah; Cusato, Jessica; De Francia, Silvia; Pirro, Elisa; Massano, Davide; Piga, Antonio; D'Avolio, Antonio

2017-05-01

Iron chelation in the transfusion-dependent anaemias management is essential to prevent end-organ damage and to improve survival. Deferasirox is a once-daily orally active tridentate selective iron chelator which pharmacokinetic disposition could influence treatment efficacy and toxicity. Therapeutic drug monitoring is an important tool for optimizing drug utilization and doses. A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from paediatric patients with β-thalassaemia. Samples obtained after 5 days of washout or in naïve patients before and after 2, 4, 6 and 24 h drug administration were evaluated. Associations between variables were tested using the Pearson test. Twenty paediatric patients were enrolled; they were mainly men (13.65%), with median age of 6.35 years and body mass index of 15.45 kg/m 2 . Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive, but not significant, correlation (r = 0.363; P = 0.115) was found between deferasirox area under the concentration curve over 24 h (AUC) and drug dose. Monitoring plasma deferasirox concentrations appears beneficial for guiding appropriate patient treatment, enhancing effectiveness and minimizing toxicity. © 2016 Royal Pharmaceutical Society.

Neuroanatomical correlates of brain-computer interface performance.

PubMed

Kasahara, Kazumi; DaSalla, Charles Sayo; Honda, Manabu; Hanakawa, Takashi

2015-04-15

Brain-computer interfaces (BCIs) offer a potential means to replace or restore lost motor function. However, BCI performance varies considerably between users, the reasons for which are poorly understood. Here we investigated the relationship between sensorimotor rhythm (SMR)-based BCI performance and brain structure. Participants were instructed to control a computer cursor using right- and left-hand motor imagery, which primarily modulated their left- and right-hemispheric SMR powers, respectively. Although most participants were able to control the BCI with success rates significantly above chance level even at the first encounter, they also showed substantial inter-individual variability in BCI success rate. Participants also underwent T1-weighted three-dimensional structural magnetic resonance imaging (MRI). The MRI data were subjected to voxel-based morphometry using BCI success rate as an independent variable. We found that BCI performance correlated with gray matter volume of the supplementary motor area, supplementary somatosensory area, and dorsal premotor cortex. We suggest that SMR-based BCI performance is associated with development of non-primary somatosensory and motor areas. Advancing our understanding of BCI performance in relation to its neuroanatomical correlates may lead to better customization of BCIs based on individual brain structure. Copyright © 2015 Elsevier Inc. All rights reserved.

Accountability Accentuates Interindividual-Intergroup Discontinuity by Enforcing Parochialism.

PubMed

Wildschut, Tim; van Horen, Femke; Hart, Claire

2015-01-01

Interindividual-intergroup discontinuity is the tendency for relations between groups to be more competitive than relations between individuals. We examined whether the discontinuity effect arises in part because group members experience normative pressure to favor the ingroup (parochialism). Building on the notion that accountability enhances normative pressure, we hypothesized that the discontinuity effect would be larger when accountability is present (compared to absent). A prisoner's dilemma game experiment supported this prediction. Specifically, intergroup (compared to interindividual) interaction activated an injunctive ingroup-favoring norm, and accountability enhanced the influence of this norm on competitive behavior.

Prediction of early weight gain during psychotropic treatment using a combinatorial model with clinical and genetic markers.

PubMed

Vandenberghe, Frederik; Saigí-Morgui, Núria; Delacrétaz, Aurélie; Quteineh, Lina; Crettol, Séverine; Ansermot, Nicolas; Gholam-Rezaee, Mehdi; von Gunten, Armin; Conus, Philippe; Eap, Chin B

2016-12-01

Psychotropic drugs can induce significant (>5%) weight gain (WG) already after 1 month of treatment, which is a good predictor for major WG at 3 and 12 months. The large interindividual variability of drug-induced WG can be explained in part by genetic and clinical factors. The aim of this study was to determine whether extensive analysis of genes, in addition to clinical factors, can improve prediction of patients at risk for more than 5% WG at 1 month of treatment. Data were obtained from a 1-year naturalistic longitudinal study, with weight monitoring during weight-inducing psychotropic treatment. A total of 248 Caucasian psychiatric patients, with at least baseline and 1-month weight measures, and with compliance ascertained were included. Results were tested for replication in a second cohort including 32 patients. Age and baseline BMI were associated significantly with strong WG. The area under the curve (AUC) of the final model including genetic (18 genes) and clinical variables was significantly greater than that of the model including clinical variables only (AUCfinal: 0.92, AUCclinical: 0.75, P<0.0001). Predicted accuracy increased by 17% with genetic markers (Accuracyfinal: 87%), indicating that six patients must be genotyped to avoid one misclassified patient. The validity of the final model was confirmed in a replication cohort. Patients predicted before treatment as having more than 5% WG after 1 month of treatment had 4.4% more WG over 1 year than patients predicted to have up to 5% WG (P≤0.0001). These results may help to implement genetic testing before starting psychotropic drug treatment to identify patients at risk of important WG.

Short-term quality of life after subthalamic stimulation depends on non-motor symptoms in Parkinson's disease.

PubMed

Dafsari, Haidar Salimi; Weiß, Luisa; Silverdale, Monty; Rizos, Alexandra; Reddy, Prashanth; Ashkan, Keyoumars; Evans, Julian; Reker, Paul; Petry-Schmelzer, Jan Niklas; Samuel, Michael; Visser-Vandewalle, Veerle; Antonini, Angelo; Martinez-Martin, Pablo; Ray-Chaudhuri, K; Timmermann, Lars

2018-02-24

Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in advanced Parkinson's disease (PD). However, considerable inter-individual variability has been observed for QoL outcome. We hypothesized that demographic and preoperative NMS characteristics can predict postoperative QoL outcome. In this ongoing, prospective, multicenter study (Cologne, Manchester, London) including 88 patients, we collected the following scales preoperatively and on follow-up 6 months postoperatively: PDQuestionnaire-8 (PDQ-8), NMSScale (NMSS), NMSQuestionnaire (NMSQ), Scales for Outcomes in PD (SCOPA)-motor examination, -complications, and -activities of daily living, levodopa equivalent daily dose. We dichotomized patients into "QoL responders"/"non-responders" and screened for factors associated with QoL improvement with (1) Spearman-correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions using aforementioned "responders/non-responders" as dependent variable. All outcomes improved significantly on follow-up. However, approximately 44% of patients were categorized as "QoL non-responders". Spearman-correlations, linear and logistic regression analyses were significant for NMSS and NMSQ but not for SCOPA-motor examination. Post-hoc, we identified specific NMS (flat moods, difficulties experiencing pleasure, pain, bladder voiding) as significant contributors to QoL outcome. Our results provide evidence that QoL improvement after STN-DBS depends on preoperative NMS characteristics. These findings are important in the advising and selection of individuals for DBS therapy. Future studies investigating motor and non-motor PD clusters may enable stratifying QoL outcomes and help predict patients' individual prospects of benefiting from DBS. Copyright © 2018. Published by Elsevier Inc.

Transoesophageal spinal cord stimulation for motor-evoked potentials monitoring: feasibility, safety and stability.

PubMed

Tsuda, Kazumasa; Shiiya, Norihiko; Takahashi, Daisuke; Ohkura, Kazuhiro; Yamashita, Katsushi; Kando, Yumi

2015-08-01

Specificity of transcranial motor-evoked potentials (MEPs) is low because amplitude fluctuation is common, which seems due to several technical and fundamental reasons including difficulty in electrodes positioning and fixation for transcranial stimulation and susceptibility to anaesthesia. This study aimed to investigate the feasibility, safety and stability of our novel technique of transoesophageal spinal cord stimulation to improve the stability of MEPs. Ten anaesthetized adult beagle dogs were used. Transoesophageal stimulation was performed between the oesophageal luminal surface electrode (cathode) and a subcutaneous needle electrode (anode) at the fourth to fifth thoracic vertebra level. Stimulation was achieved with a train of five pulses delivered at 2.0-ms intervals. Compound muscle action potentials were recorded from four limbs and external anal sphincter muscles. Stability to anaesthetic agents was tested at varying speeds of propofol and remifentanil, and effects of varying concentration of sevoflurane inhalation were also evaluated. Transoesophageal MEPs could be recorded without difficulty in all dogs. Fluoroscopic evaluation showed that electrodes misalignment up to 5 cm cranially or caudally could be tolerated. Stimulus intensity to achieve maximum amplitude of hindlimb muscle potentials on both sides was significantly lower by transoesophageal stimulation than by transcranial stimulation (383 ± 41 vs 533 ± 121 V, P = 0.02) and had less interindividual variability. Latency of transoesophageal MEPs was shorter than that of transcranial MEPs at every recording point. No arrhythmia was provoked during stimulation. Animals that were allowed to recover showed no neurological abnormality. In the two sacrificed animals, the explanted oesophagus showed no mucosal injury. Stability to varying dose of anaesthetic agents was similar between transoesophageal and transcranial stimulation, except for the potentials of forelimbs by transoesophageal stimulation that were resistant to anaesthetic depression. Transoesophageal stimulation for MEPs monitoring was feasible without difficulty and safe. Although its stability to anaesthetic agents was similar to that of transcranial stimulation, its technical ease and small interindividual variability warrants further studies on the response to spinal cord ischaemia. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Polymorphisms in the dopamine receptor 2 gene region influence improvements during working memory training in children and adolescents.

PubMed

Söderqvist, Stina; Matsson, Hans; Peyrard-Janvid, Myriam; Kere, Juha; Klingberg, Torkel

2014-01-01

Studying the effects of cognitive training can lead to finding better treatments, but it can also be a tool for investigating factors important for brain plasticity and acquisition of cognitive skills. In this study, we investigated how single-nucleotide polymorphisms (SNPs) and ratings of intrinsic motivation were associated to interindividual differences in improvement during working memory training. The study included 256 children aged 7-19 years who were genotyped for 13 SNPs within or near eight candidate genes previously implicated in learning: COMT, SLC6A3 (DAT1), DRD4, DRD2, PPP1R1B (DARPP32), MAOA, LMX1A, and BDNF. Ratings on the intrinsic motivation inventory were also available for 156 of these children. All participants performed at least 20 sessions of working memory training, and performance during the training was logged and used as the outcome variable. We found that two SNPs, rs1800497 and rs2283265, located near and within the dopamine receptor 2 (DRD2) gene, respectively, were significantly associated with improvements during training (p < .003 and p < .0004, respectively). Scores from a questionnaire regarding intrinsic motivation did not correlate with training outcome. However, we observed both the main effect of genotype at those two loci as well as the interaction between genotypes and ratings of intrinsic motivation (perceived competence). Both SNPs have previously been shown to affect DRD2 receptor density primarily in the BG. Our results suggest that genetic variation is accounting for some interindividual differences in how children acquire cognitive skills and that part of this effect is also seen on intrinsic motivation. Moreover, they suggest that dopamine D2 transmission in the BG is a key factor for cognitive plasticity.

Pharmacokinetics of oral hydrocortisone - Results and implications from a randomized controlled trial.

PubMed

Werumeus Buning, Jorien; Touw, Daan J; Brummelman, Pauline; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Kamp, Jasper; Wolffenbuttel, Bruce H R; van Beek, André P

2017-06-01

This study aimed at comparing pharmacokinetics of two different doses of hydrocortisone (HC) in patients with secondary adrenal insufficiency (SAI). Forty-six patients with SAI participated in this randomized double-blind crossover study. Patients received two different doses of HC (0.2-0.3mg HC/kg body weight/day and 0.4-0.6mg HC/kg body weight/day). One- and two-compartment population models for plasma free cortisol, plasma total cortisol and salivary cortisol were parameterized. The individual pharmacokinetic parameters clearance (CL), volume of distribution (V d ), elimination half-life (t 1/2 ), maximum concentration (C max ), and area under the curve (AUC) were calculated. The one-compartment models gave a better description of the data compared to the two-compartment models. Weight-adjusted dosing reduced variability in cortisol exposure with comparable AUCs between weight groups. However, there was large inter-individual variation in CL and V d of plasma free cortisol, plasma total cortisol and salivary cortisol. As a consequence, AUC 24h varied more than 10 fold. Cortisol exposure was increased with the higher dose, but this was dose proportional only for free cortisol concentrations and not for total cortisol. Cortisol concentrations after a doubling of the dose were only dose proportional for free cortisol. HC pharmacokinetics can differ up to 10-fold inter-individually and individual adjustment of treatment doses may be necessary. Doubling of the HC dose in fast metabolizers (patients that showed relative low AUC and thus high clearance compared to other patients), does not result in significantly enhanced exposure during large parts of the day and these patients may need other management strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

Feedback suppression of meal-induced glucagon-like peptide-1 (GLP-1) secretion mediated through elevations in intact GLP-1 caused by dipeptidyl peptidase-4 inhibition: a randomized, prospective comparison of sitagliptin and vildagliptin treatment.

PubMed

Baranov, Oleg; Kahle, Melanie; Deacon, Carolyn F; Holst, Jens J; Nauck, Michael A

2016-11-01

To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. A total of 24 patients (12 on a diet/exercise regimen, 12 on metformin) were treated, in randomized order, for 7-9 days, with either vildagliptin (50 mg twice daily = 100 mg/d), sitagliptin (100 mg once daily in those on diet, 50 mg twice daily in those on metformin treatment = 100 mg/d) or placebo (twice daily). A mixed-meal test was performed. Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide concentrations were doubled by both DPP-4 inhibitors. Meal-related total GLP-1 responses were reduced by vildagliptin and sitagliptin treatment alike in the majority of patients (vildagliptin: p = 0.0005; sitagliptin: p = 0.019), but with substantial inter-individual variation. L-cell feedback appeared to be more pronounced in those whose intact GLP-1 relative to total GLP-1 increased more, and who had greater reductions in fasting plasma glucose after DPP-4 inhibition. K-cell feedback inhibition overall was not significant. There were no differences in any of the clinical variables (glycaemia, insulin and glucagon secretory responses) between vildagliptin and sitagliptin treatment. Vildagliptin and sitagliptin affected incretin hormones, glucose concentrations, insulin and glucagon secretion in a similar manner. Inter-individual variations in L-cell feedback inhibition may indicate heterogeneity in the clinical response to DPP-4 inhibition. © 2016 John Wiley & Sons Ltd.

Simulation of interindividual differences in inactivation of reactive para-benzoquinone imine metabolites of diclofenac by glutathione S-transferases in human liver cytosol.

PubMed

den Braver, Michiel W; Zhang, Yongjie; Venkataraman, Harini; Vermeulen, Nico P E; Commandeur, Jan N M

2016-07-25

Diclofenac is a widely prescribed NSAID that causes severe idiosyncratic drug induced liver injury (IDILI) in a small part of the patient population. Formation of protein-reactive metabolites is considered to play a role in the development of diclofenac-induced IDILI. Therefore, a high hepatic activity of enzymes involved in bioactivation of diclofenac is expected to increase the risk for liver injury. However, the extent of covalent protein binding may also be determined by activity of protective enzymes, such as glutathione S-transferases (GSTs). This is supported by an association study in which a correlation was found between NSAID-induced IDILI and the combined null genotypes of GSTM1 and GSTT1. In the present study, the activity of 10 different recombinant human GSTs in inactivation of protein-reactive quinoneimine (QI) metabolites of diclofenac was tested. Both at low and high GSH concentrations, high activities of GSTA1-1, A2-2, A3-3, M1-1, M3-3 and P1-1 in the inactivation of these QIs were found. By using the expression levels of GSTs in livers of 22 donors, a 6-fold variation in GST-dependent inactivation of reactive diclofenac metabolites was predicted. Moreover, it was shown in vitro that GSTs can strongly increase the efficiency of GSH to protect against the alkylation of the model thiol N-acetylcysteine by reactive diclofenac metabolites. The results of this study demonstrate that variability of GST expression may significantly contribute to the inter-individual differences in susceptibility to diclofenac-induced liver injury. In addition, expression levels of GSTs in in vitro models for hepatotoxicity may be important factors determining sensitivity to diclofenac cytotoxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In vivo maximal fascicle-shortening velocity during plantar flexion in humans.

PubMed

Hauraix, Hugo; Nordez, Antoine; Guilhem, Gaël; Rabita, Giuseppe; Dorel, Sylvain

2015-12-01

Interindividual variability in performance of fast movements is commonly explained by a difference in maximal muscle-shortening velocity due to differences in the proportion of fast-twitch fibers. To provide a better understanding of the capacity to generate fast motion, this study aimed to 1) measure for the first time in vivo the maximal fascicle-shortening velocity of human muscle; 2) evaluate the relationship between angular velocity and fascicle-shortening velocity from low to maximal angular velocities; and 3) investigate the influence of musculo-articular features (moment arm, tendinous tissues stiffness, and muscle architecture) on maximal angular velocity. Ultrafast ultrasound images of the gastrocnemius medialis were obtained from 31 participants during maximal isokinetic and light-loaded plantar flexions. A strong linear relationship between fascicle-shortening velocity and angular velocity was reported for all subjects (mean R(2) = 0.97). The maximal shortening velocity (V(Fmax)) obtained during the no-load condition (NLc) ranged between 18.8 and 43.3 cm/s. V(Fmax) values were very close to those of the maximal shortening velocity (V(max)), which was extrapolated from the F-V curve (the Hill model). Angular velocity reached during the NLc was significantly correlated with this V(Fmax) (r = 0.57; P < 0.001). This finding was in agreement with assumptions about the role of muscle fiber type, whereas interindividual comparisons clearly support the fact that other parameters may also contribute to performance during fast movements. Nevertheless, none of the biomechanical features considered in the present study were found to be directly related to the highest angular velocity, highlighting the complexity of the upstream mechanics that lead to maximal-velocity muscle contraction. Copyright © 2015 the American Physiological Society.

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

PubMed

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-06-18

To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini-Hochberg criterion for a 10% false discovery rate. Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

Repair of O6-alkylguanines in the nuclear DNA of human lymphocytes and leukaemic cells: analysis at the single-cell level.

PubMed Central

Thomale, J.; Seiler, F.; Müller, M. R.; Seeber, S.; Rajewsky, M. F.

1994-01-01

Inter-individual and cell-cell variability of repair of O6-alkylguanines (O6-AlkGua) in nuclear DNA was studied at the single-cell level in peripheral lymphocytes from healthy donors and in leukaemic cells isolated from patients with chronic lymphatic leukaemia (CLL) or acute myeloid leukaemia (AML). Cells were pulse exposed to N-ethyl- or N-(n-)butyl-N-nitrosourea in vitro, and O6-AlkGua residues in DNA were quantified using an anti-(O6-AlkGua) monoclonal antibody and electronically intensified fluorescence. The kinetics of O6-AlkGua elimination revealed considerable inter-individual differences in O6-ethylguanine (O6-EtGua) half-life (t1/2) values in DNA, ranging from 1.5 to 4.5 h (five AML patients), from 0.8 to 2.8 h (five CLL patients) and from 1.2 to 7.3 h (five healthy donors). The elimination from DNA of equimolar amounts of O6-butylguanine was generally 3-5 times slower in comparison with O6-EtGua. The t1/2 values of individual samples varied in parallel for both DNA alkylation products. Upon preincubation with O6-benzylguanine, the activity of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AT) in both lymphocytes and leukaemic blasts was reduced to < or = 1%. However, while the rate of O6-EtGua elimination from DNA was decelerated it was not abolished, suggesting the possible involvement of additional repair systems that might be co-regulated with AT. Within individual samples, no major cell subpopulations were observed whose repair kinetics would differ significantly from the remaining cells. Images Figure 1 PMID:8142257

Money talks: neural substrate of modulation of fairness by monetary incentives

PubMed Central

Zhou, Yuan; Wang, Yun; Rao, Li-Lin; Yang, Liu-Qing; Li, Shu

2014-01-01

A unique feature of the human species is compliance with social norms, e.g., fairness, even though this normative decision means curbing self-interest. However, sometimes people prefer to pursue wealth at the expense of moral goodness. Specifically, deviations from a fairness-related normative choice have been observed in the presence of a high monetary incentive. The neural mechanism underlying this deviation from the fairness-related normative choice has yet to be determined. In order to address this issue, using functional magnetic resonance imaging we employed an ultimatum game (UG) paradigm in which fairness and a proposed monetary amount were orthogonally varied. We found evidence for a significant modulation by the proposed amount on fairness in the right lateral prefrontal cortex (PFC) and the bilateral insular cortices. Additionally, the insular subregions showed dissociable modulation patterns. Inter-individual differences in the modulation effects in the left inferior frontal gyrus (IFG) accounted for inter-individual differences in the behavioral modulation effect as measured by the rejection rate, supporting the concept that the PFC plays a critical role in making fairness-related normative decisions in a social interaction condition. Our findings provide neural evidence for the modulation of fairness by monetary incentives as well as accounting for inter-individual differences. PMID:24834034

Application of in Vitro Biotransformation Data and ...

EPA Pesticide Factsheets

The adverse biological effects of toxic substances are dependent upon the exposure concentration and the duration of exposure. Pharmacokinetic models can quantitatively relate the external concentration of a toxicant in the environment to the internal dose of the toxicant in the target tissues of an exposed organism. The exposure concentration of a toxic substance is usually not the same as the concentration of the active form of the toxicant that reaches the target tissues following absorption, distribution, and biotransformation of the parent toxicant. Biotransformation modulates the biological activity of chemicals through bioactivation and detoxication pathways. Many toxicants require biotransformation to exert their adverse biological effects. Considerable species differences in biotransformation and other pharmacokinetic processes can make extrapolation of toxicity data from laboratory animals to humans problematic. Additionally, interindividual differences in biotransformation among human populations with diverse genetics and lifestyles can lead to considerable variability in the bioactivation of toxic chemicals. Compartmental pharmacokinetic models of animals and humans are needed to understand the quantitative relationships between chemical exposure and target tissue dose as well as animal to human differences and interindividual differences in human populations. The data-based compartmental pharmacokinetic models widely used in clinical pharmacology ha

Inter-individual differences in audio-motor learning of piano melodies and white matter fiber tract architecture.

PubMed

Engel, Annerose; Hijmans, Brenda S; Cerliani, Leonardo; Bangert, Marc; Nanetti, Luca; Keller, Peter E; Keysers, Christian

2014-05-01

Humans vary substantially in their ability to learn new motor skills. Here, we examined inter-individual differences in learning to play the piano, with the goal of identifying relations to structural properties of white matter fiber tracts relevant to audio-motor learning. Non-musicians (n = 18) learned to perform three short melodies on a piano keyboard in a pure audio-motor training condition (vision of their own fingers was occluded). Initial learning times ranged from 17 to 120 min (mean ± SD: 62 ± 29 min). Diffusion-weighted magnetic resonance imaging was used to derive the fractional anisotropy (FA), an index of white matter microstructural arrangement. A correlation analysis revealed that higher FA values were associated with faster learning of piano melodies. These effects were observed in the bilateral corticospinal tracts, bundles of axons relevant for the execution of voluntary movements, and the right superior longitudinal fasciculus, a tract important for audio-motor transformations. These results suggest that the speed with which novel complex audio-motor skills can be acquired may be determined by variability in structural properties of white matter fiber tracts connecting brain areas functionally relevant for audio-motor learning. Copyright © 2013 Wiley Periodicals, Inc.

Differences in kinetic asymmetry between injured and noninjured novice runners: a prospective cohort study.

PubMed

Bredeweg, S W; Buist, I; Kluitenberg, B

2013-09-01

The purpose of this prospective study was to describe natural levels of asymmetry in running, compare levels of asymmetry between injured and noninjured novice runners and compare kinetic variables between the injured and noninjured lower limb within the novice runners with an injury. At baseline vertical ground reaction forces and symmetry angles (SA) were assessed with an instrumented treadmill equipped with three force measuring transducers. Female participants ran at 8 and 9 km h(-1) and male runners ran at 9 and 10 km h(-1). Participants were novice female and male recreational runners and were followed during a 9-week running program. Two hundred and ten novice runners enrolled this study, 133 (63.3%) female and 77 (36.7%) male runners. Thirty-four runners reported an RRI. At baseline SA values varied widely for all spatio-temporal and kinetic variables. The inter-individual differences in SA were also high. No significant differences in SA were found between female and male runners running at 9 km h(-1). In injured runners the SA of the impact peak was significantly lower compared to noninjured runners. Natural levels of asymmetry in running were high. The SA of impact peak in injured runners was lower compared to noninjured runners and no differences were seen between the injured and noninjured lower limbs. Copyright © 2013 Elsevier B.V. All rights reserved.

Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies.

PubMed

Smith, Jennifer A; Zhao, Wei; Yasutake, Kalyn; August, Carmella; Ratliff, Scott M; Faul, Jessica D; Boerwinkle, Eric; Chakravarti, Aravinda; Diez Roux, Ana V; Gao, Yan; Griswold, Michael E; Heiss, Gerardo; Kardia, Sharon L R; Morrison, Alanna C; Musani, Solomon K; Mwasongwe, Stanford; North, Kari E; Rose, Kathryn M; Sims, Mario; Sun, Yan V; Weir, David R; Needham, Belinda L

2017-12-18

Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region ( p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region ( p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors.

Mixed Effects Modeling Using Stochastic Differential Equations: Illustrated by Pharmacokinetic Data of Nicotinic Acid in Obese Zucker Rats.

PubMed

Leander, Jacob; Almquist, Joachim; Ahlström, Christine; Gabrielsson, Johan; Jirstrand, Mats

2015-05-01

Inclusion of stochastic differential equations in mixed effects models provides means to quantify and distinguish three sources of variability in data. In addition to the two commonly encountered sources, measurement error and interindividual variability, we also consider uncertainty in the dynamical model itself. To this end, we extend the ordinary differential equation setting used in nonlinear mixed effects models to include stochastic differential equations. The approximate population likelihood is derived using the first-order conditional estimation with interaction method and extended Kalman filtering. To illustrate the application of the stochastic differential mixed effects model, two pharmacokinetic models are considered. First, we use a stochastic one-compartmental model with first-order input and nonlinear elimination to generate synthetic data in a simulated study. We show that by using the proposed method, the three sources of variability can be successfully separated. If the stochastic part is neglected, the parameter estimates become biased, and the measurement error variance is significantly overestimated. Second, we consider an extension to a stochastic pharmacokinetic model in a preclinical study of nicotinic acid kinetics in obese Zucker rats. The parameter estimates are compared between a deterministic and a stochastic NiAc disposition model, respectively. Discrepancies between model predictions and observations, previously described as measurement noise only, are now separated into a comparatively lower level of measurement noise and a significant uncertainty in model dynamics. These examples demonstrate that stochastic differential mixed effects models are useful tools for identifying incomplete or inaccurate model dynamics and for reducing potential bias in parameter estimates due to such model deficiencies.

MODELING OF HUMAN EXPOSURE TO IN-VEHICLE PM2.5 FROM ENVIRONMENTAL TOBACCO SMOKE

PubMed Central

Cao, Ye; Frey, H. Christopher

2012-01-01

Environmental tobacco smoke (ETS) is estimated to be a significant contributor to in-vehicle human exposure to fine particulate matter of 2.5 µm or smaller (PM2.5). A critical assessment was conducted of a mass balance model for estimating PM2.5 concentration with smoking in a motor vehicle. Recommendations for the range of inputs to the mass-balance model are given based on literature review. Sensitivity analysis was used to determine which inputs should be prioritized for data collection. Air exchange rate (ACH) and the deposition rate have wider relative ranges of variation than other inputs, representing inter-individual variability in operations, and inter-vehicle variability in performance, respectively. Cigarette smoking and emission rates, and vehicle interior volume, are also key inputs. The in-vehicle ETS mass balance model was incorporated into the Stochastic Human Exposure and Dose Simulation for Particulate Matter (SHEDS-PM) model to quantify the potential magnitude and variability of in-vehicle exposures to ETS. The in-vehicle exposure also takes into account near-road incremental PM2.5 concentration from on-road emissions. Results of probabilistic study indicate that ETS is a key contributor to the in-vehicle average and high-end exposure. Factors that mitigate in-vehicle ambient PM2.5 exposure lead to higher in-vehicle ETS exposure, and vice versa. PMID:23060732

[Personalized drug therapy-directed clinical pharmacology research based on genetic polymorphisms and pharmacokinetics analysis].

PubMed

Hayashi, Hideki

2013-01-01

In this decade, the field of pharmacogenomics (PGx), which is related to pharmacokinetics (PK) or pharmacodynamics (PD), has attracted much attention because it may provide a possible explanation for individual differences in the clinical efficacy of drugs. For the development of personalized drug therapy, it is important to accumulate evidence from PK/PD/PGx analysis in clinical trials. Warfarin (WF) is one of the most widely prescribed anticoagulants for the prevention and treatment of venous and arterial thromboembolism. However, large interindividual and interethnic differences have been observed in the WF dose required to elicit the anticoagulant effect. We investigated the factors influencing the WF maintenance dose in Japanese patients. Our study confirmed a large interindividual variability in the WF maintenance dose that was due to a VKORC1 1639 G>A polymorphism and differences in body weight, age, and serum albumin. In addition, we found that the CYP4F2 genotype affects the plasma concentration of menaquinone-4, and that this finding was correlated with the WF sensitivity index in Japanese pediatric patients. Methotrexate (MTX) is an antifolate that is widely used to treat rheumatoid arthritis (RA) and cancer. The response to low-dose MTX demonstrated wide interpatient variability; however, the contributing factors remain unclear. We found that the frequency of the RFC1 80A allele was higher in RA patients treated with MTX alone compared with patients who received biological disease-modifying antirheumatic drugs (bDMARDs). This finding may support the combined use of bDMARDs and MTX. Further large-scale prospective clinical trials are required to confirm these findings.

Effects of Handling and Vehicle Injections on Adrenocorticotropic and Corticosterone Concentrations in Sprague–Dawley Compared with Lewis Rats

PubMed Central

Deutsch-Feldman, Molly; Picetti, Roberto; Seip-Cammack, Katharine; Zhou, Yan; Kreek, Mary Jeanne

2015-01-01

The hypothalamic–pituitary–adrenal (HPA) axis is a key factor in the trajectory of the addiction-like cycle (a pattern of behavior characterized by escalating drug use, withdrawal, and relapse) in preclinical and clinical studies. Concentrations of HPA hormones change in laboratory animals in response to standard experimental procedures, including handling and vehicle injections. We compared HPA activity in adult male Lewis (inbred) and Sprague–Dawley (outbred) rats, 2 common strains in rodent models of addiction, after different schedules of handling and saline injections, to explore the extent to which HPA responses differ by strain and whether interindividual differences underlie addiction vulnerability. The 4 treatment conditions were no, short, or long handling and saline injections. In handled groups, rats were handled for 1 to 2 min for 3 times daily and were euthanized after 7 d (short handling) or 14 d (long handling). The injection schedule in the saline injection group mimicked that in a model of binge-like cocaine exposure. Across all treatment groups, concentrations of adrenocorticotropic hormone were higher in Sprague–Dawley than in Lewis rats. In Sprague–Dawley rats, corticosterone concentrations decreased after continued handling but remained constant in Lewis rats. Interindividual variability in hormone levels was greater in Sprague–Dawley than Lewis rats, although corticosterone variability decreased after continued handling. Prolactin did not differ between groups of either Sprague–Dawley and Lewis rats before or after handling. This study underscores the importance of prolonged handling before experimenter-provided drug-administration paradigms and of strain-associated differences that may affect study outcomes. PMID:25651089

Predictors and Trajectories of Morning Fatigue Are Distinct from Evening Fatigue

PubMed Central

Wright, Fay; Melkus, Gail D’Eramo; Hammer, Marilyn; Schmidt, Brian L.; Knobf, M. Tish; Paul, Steven M.; Cartwright, Frances; Mastick, Judy; Cooper, Bruce A.; Chen, Lee-May; Melisko, Michelle; Levine, Jon D.; Kober, Kord; Aouizerat, Bradley E.; Miaskowski, Christine

2015-01-01

Context Fatigue is the most common symptom in oncology patients during chemotherapy (CTX). Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients. Objectives An evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue. Methods A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. Results A large amount of interindividual variability was found in the morning fatigue trajectories. A piecewise model fit the data best. Patients with higher body mass index (BMI), who did not exercise regularly, with a lower functional status, and who had higher levels of state anxiety, sleep disturbance and depressive symptoms, reported higher levels of morning fatigue at enrollment. Variations in the trajectories of morning fatigue were predicted by the patients’ ethnicity and younger age. Conclusion The modifiable risk factors that were associated with only morning fatigue were BMI, exercise, and state anxiety. Modifiable risk factors that were associated with both morning and evening fatigue included functional status, depressive symptoms, and sleep disturbance. Using this information, clinicians can identify patients at higher risk for more severe morning fatigue and evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors. PMID:25828559

Nonlinear mixed effects modeling of the diurnal blood pressure profile in a multiracial population.

PubMed

van Rijn-Bikker, Petra C; Snelder, Nelleke; Ackaert, Oliver; van Hest, Reinier M; Ploeger, Bart A; van Montfrans, Gert A; Koopmans, Richard P; Mathôt, Ron A

2013-09-01

Cardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime and nighttime BP, nocturnal dip (ND), and morning surge (MS)). This investigation aimed to characterize 24-hour diurnal systolic BP (SBP) with parameters that correlate directly with daytime and nighttime SBP, ND, and MS using nonlinear mixed effects modeling. Ambulatory 24-hour SBP measurements (ABPM) of 196 nontreated subjects from three ethnic groups were available. A population model was parameterized in NONMEM to estimate and evaluate the parameters baseline SBP (BSL), nadir (minimum SBP during the night), and change (SBP difference between day and night). Associations were tested between these parameters and patient-related factors to explain interindividual variability. The diurnal SBP profile was adequately described as the sum of 2 cosine functions. The following typical values (interindividual variability) were found: BSL = 139 mm Hg (11%); nadir = 122 mm Hg (14%); change = 25 mm Hg (52%), and residual error = 12 mm Hg. The model parameters correlate well with daytime and nighttime SBP, ND, and MS (R (2) = 0.50-0.92). During covariate analysis, ethnicity was found to be associated with change; change was 40% higher in white Dutch subjects and 26.8% higher in South Asians than in blacks. The developed population model allows simultaneous estimation of BSL, nadir, and change for all individuals in the investigated population, regardless of individual number of SBP measurements. Ethnicity was associated with change. The model provides a tool to evaluate and optimize the sampling frequency for 24-hour ABPM.

Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability.

PubMed

Ring, Caroline L; Pearce, Robert G; Setzer, R Woodrow; Wetmore, Barbara A; Wambaugh, John F

2017-09-01

The thousands of chemicals present in the environment (USGAO, 2013) must be triaged to identify priority chemicals for human health risk research. Most chemicals have little of the toxicokinetic (TK) data that are necessary for relating exposures to tissue concentrations that are believed to be toxic. Ongoing efforts have collected limited, in vitro TK data for a few hundred chemicals. These data have been combined with biomonitoring data to estimate an approximate margin between potential hazard and exposure. The most "at risk" 95th percentile of adults have been identified from simulated populations that are generated either using standard "average" adult human parameters or very specific cohorts such as Northern Europeans. To better reflect the modern U.S. population, we developed a population simulation using physiologies based on distributions of demographic and anthropometric quantities from the most recent U.S. Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES) data. This allowed incorporation of inter-individual variability, including variability across relevant demographic subgroups. Variability was analyzed with a Monte Carlo approach that accounted for the correlation structure in physiological parameters. To identify portions of the U.S. population that are more at risk for specific chemicals, physiologic variability was incorporated within an open-source high-throughput (HT) TK modeling framework. We prioritized 50 chemicals based on estimates of both potential hazard and exposure. Potential hazard was estimated from in vitro HT screening assays (i.e., the Tox21 and ToxCast programs). Bioactive in vitro concentrations were extrapolated to doses that produce equivalent concentrations in body tissues using a reverse dosimetry approach in which generic TK models are parameterized with: 1) chemical-specific parameters derived from in vitro measurements and predicted from chemical structure; and 2) with physiological parameters for a virtual population. For risk-based prioritization of chemicals, predicted bioactive equivalent doses were compared to demographic-specific inferences of exposure rates that were based on NHANES urinary analyte biomonitoring data. The inclusion of NHANES-derived inter-individual variability decreased predicted bioactive equivalent doses by 12% on average for the total population when compared to previous methods. However, for some combinations of chemical and demographic groups the margin was reduced by as much as three quarters. This TK modeling framework allows targeted risk prioritization of chemicals for demographic groups of interest, including potentially sensitive life stages and subpopulations. Published by Elsevier Ltd.

Accountability Accentuates Interindividual-Intergroup Discontinuity by Enforcing Parochialism

PubMed Central

Wildschut, Tim; van Horen, Femke; Hart, Claire

2015-01-01

Interindividual-intergroup discontinuity is the tendency for relations between groups to be more competitive than relations between individuals. We examined whether the discontinuity effect arises in part because group members experience normative pressure to favor the ingroup (parochialism). Building on the notion that accountability enhances normative pressure, we hypothesized that the discontinuity effect would be larger when accountability is present (compared to absent). A prisoner’s dilemma game experiment supported this prediction. Specifically, intergroup (compared to interindividual) interaction activated an injunctive ingroup-favoring norm, and accountability enhanced the influence of this norm on competitive behavior. PMID:26635691

Variability in Humoral Immunity to Measles Vaccine: New Developments

PubMed Central

Haralambieva, Iana H.; Kennedy, Richard B.; Ovsyannikova, Inna G.; Whitaker, Jennifer A.; Poland, Gregory A.

2015-01-01

Despite the existence of an effective measles vaccine, resurgence in measles cases in the United States and across Europe has occurred, including in individuals vaccinated with two doses of the vaccine. Host genetic factors result in inter-individual variation in measles vaccine-induced antibodies, and play a role in vaccine failure. Studies have identified HLA and non-HLA genetic influences that individually or jointly contribute to the observed variability in the humoral response to vaccination among healthy individuals. In this exciting era, new high-dimensional approaches and techniques including vaccinomics, systems biology, GWAS, epitope prediction and sophisticated bioinformatics/statistical algorithms, provide powerful tools to investigate immune response mechanisms to the measles vaccine. These might predict, on an individual basis, outcomes of acquired immunity post measles vaccination. PMID:26602762

The cognitive-behavioral system of leadership: cognitive antecedents of active and passive leadership behaviors

PubMed Central

Dóci, Edina; Stouten, Jeroen; Hofmans, Joeri

2015-01-01

In the present paper, we propose a cognitive-behavioral understanding of active and passive leadership. Building on core evaluations theory, we offer a model that explains the emergence of leaders’ active and passive behaviors, thereby predicting stable, inter-individual, as well as variable, intra-individual differences in both types of leadership behavior. We explain leaders’ stable behavioral tendencies by their fundamental beliefs about themselves, others, and the world (core evaluations), while their variable, momentary behaviors are explained by the leaders’ momentary appraisals of themselves, others, and the world (specific evaluations). By introducing interactions between the situation the leader enters, the leader’s beliefs, appraisals, and behavior, we propose a comprehensive system of cognitive mechanisms that underlie active and passive leadership behavior. PMID:26441721

Physiologically Based Pharmacokinetic (PBPK) Modeling of ...

EPA Pesticide Factsheets

Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, inter-individual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.Objectives: To evaluate the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study. Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and one hybrid mouse strains to calibrate and extend existing physiologically-based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). A Bayesian population analysis of inter-strain variability was used to quantify variability in TCE metabolism. Results: Concentration-time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation was less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production was less variable (2-fold range) than DCA production (5-fold range), although uncertainty bounds for DCA exceeded the predicted variability. Conclusions:

INTERINDIVIDUAL VARIATION IN THE METABOLISM OF ARSENIC IN CULTURED PRIMARY HUMAN HEPATOCYTES

EPA Science Inventory

Liver is a prime site for conversion of inorganic arsenic (iAs) to methylated metabolites, including methylarsenicals (MAs) and dimethylarsenicals (DMAs). To assess interindividual variation in the capacity of liver to metabolize iAs, we examined the metabolic fate of arsenite (...

On the implications of the classical ergodic theorems: analysis of developmental processes has to focus on intra-individual variation.

PubMed

Molenaar, Peter C M

2008-01-01

It is argued that general mathematical-statistical theorems imply that standard statistical analysis techniques of inter-individual variation are invalid to investigate developmental processes. Developmental processes have to be analyzed at the level of individual subjects, using time series data characterizing the patterns of intra-individual variation. It is shown that standard statistical techniques based on the analysis of inter-individual variation appear to be insensitive to the presence of arbitrary large degrees of inter-individual heterogeneity in the population. An important class of nonlinear epigenetic models of neural growth is described which can explain the occurrence of such heterogeneity in brain structures and behavior. Links with models of developmental instability are discussed. A simulation study based on a chaotic growth model illustrates the invalidity of standard analysis of inter-individual variation, whereas time series analysis of intra-individual variation is able to recover the true state of affairs. (c) 2007 Wiley Periodicals, Inc.

Potential antiproliferative activity of polyphenol metabolites against human breast cancer cells and their urine excretion pattern in healthy subjects following acute intake of a polyphenol-rich juice of grumixama (Eugenia brasiliensis Lam.).

PubMed

Teixeira, L L; Costa, G R; Dörr, F A; Ong, T P; Pinto, E; Lajolo, F M; Hassimotto, N M A

2017-06-21

The bioavailability and metabolism of anthocyanins and ellagitannins following acute intake of grumixama fruit, native Brazilian cherry, by humans, and its in vitro antiproliferative activity against breast cancer cells (MDA-MB-231) were investigated. A single dose of grumixama juice was administered to healthy women (n = 10) and polyphenol metabolites were analyzed in urine and plasma samples collected over 24 h. The majority of the metabolites circulating and excreted in urine were phenolic acids and urolithin conjugates, the gut microbiota catabolites of both classes of polyphenols, respectively. According to pharmacokinetic parameters, the subjects were divided into two distinct groups, high and low urinary metabolite excretors. The pool of polyphenol metabolites found in urine samples showed a significant inhibition of cell proliferation and G2/M cell cycle arrest in MDA-MB-231 cells. Our findings demonstrate the large interindividual variability concerning the polyphenol metabolism, which possibly could reflect in health promotion.

Twin studies advance the understanding of gene-environment interplay in human nutrigenomics.

PubMed

Pallister, Tess; Spector, Tim D; Menni, Cristina

2014-12-01

Investigations into the genetic architecture of diet-disease relationships are particularly relevant today with the global epidemic of obesity and chronic disease. Twin studies have demonstrated that genetic makeup plays a significant role in a multitude of dietary phenotypes such as energy and macronutrient intakes, dietary patterns, and specific food group intakes. Besides estimating heritability of dietary assessment, twins provide a naturally unique, case-control experiment. Due to their shared upbringing, matched genes and sex (in the case of monozygotic (MZ) twin pairs), and age, twins provide many advantages over classic epidemiological approaches. Future genetic epidemiological studies could benefit from the twin approach particularly where defining what is 'normal' is problematic due to the high inter-individual variability underlying metabolism. Here, we discuss the use of twins to generate heritability estimates of food intake phenotypes. We then highlight the value of discordant MZ pairs to further nutrition research through discovery and validation of biomarkers of intake and health status in collaboration with cutting-edge omics technologies.

Chromosomal Radiosensitivity in Lymphocytes of Cervix Cancer Patients—Correlation with Side Effect after Radiotherapy

NASA Astrophysics Data System (ADS)

Wegierek-Ciuk, Aneta; Lankoff, Anna; Lisowska, Halina; Banasik-Nowak, Anna; Arabski, Michał; Kedzierawski, Piotr; Florek, Agnieszka; Wojcik, Andrzej

2010-01-01

It is well known that cancer patients receiving similar radiotherapy treatments differ widely in normal tissue reactions ranging from undetectable to unacceptably severe levels. Therefore, an important goal of radiobiological research is to establish a test which would allow identifying individual radiosensitivity of patients prior to radiotherapy. The aim of the presented study is to assess the relationship between lymphocyte intrinsic radiosensitivity in vitro and early reaction of normal tissue in cervix cancer patients treated by radiotherapy. The following endpoints are analyzed in vitro: frequency of micronuclei, the kinetics of DNA repair and apoptosis. Acute normal tissue reaction to radiotherapy in the skin, bladder and rectum are scored according to the EORTC/RTOG scale. Our results show a wide inter-individual variability in chromosomal radiosensitivity in vitro. The majority of patients show a Grade 0, 1 or 2 reaction for all organs studied. No statistically significant correlation has been observed between the in vitro results in lymphocytes and the degree of early normal tissue and organ reaction.

Brain composition and olfactory learning in honey bees

PubMed Central

Gronenberg, Wulfila; Couvillon, Margaret J.

2015-01-01

Correlations between brain or brain component size and behavioral measures are frequently studied by comparing different animal species, which sometimes introduces variables that complicate interpretation in terms of brain function. Here, we have analyzed the brain composition of honey bees (Apis mellifera) that have been individually tested in an olfactory learning paradigm. We found that the total brain size correlated with the bees’ learning performance. Among different brain components, only the mushroom body, a structure known to be involved in learning and memory, showed a positive correlation with learning performance. In contrast, visual neuropils were relatively smaller in bees that performed better in the olfactory learning task, suggesting modality-specific behavioral specialization of individual bees. This idea is also supported by inter-individual differences in brain composition. Some slight yet statistically significant differences in the brain composition of European and Africanized honey bees are reported. Larger bees had larger brains, and by comparing brains of different sizes, we report isometric correlations for all brain components except for a small structure, the central body. PMID:20060918

Retinotopic Maps, Spatial Tuning, and Locations of Human Visual Areas in Surface Coordinates Characterized with Multifocal and Blocked fMRI Designs

PubMed Central

Henriksson, Linda; Karvonen, Juha; Salminen-Vaparanta, Niina; Railo, Henry; Vanni, Simo

2012-01-01

The localization of visual areas in the human cortex is typically based on mapping the retinotopic organization with functional magnetic resonance imaging (fMRI). The most common approach is to encode the response phase for a slowly moving visual stimulus and to present the result on an individual's reconstructed cortical surface. The main aims of this study were to develop complementary general linear model (GLM)-based retinotopic mapping methods and to characterize the inter-individual variability of the visual area positions on the cortical surface. We studied 15 subjects with two methods: a 24-region multifocal checkerboard stimulus and a blocked presentation of object stimuli at different visual field locations. The retinotopic maps were based on weighted averaging of the GLM parameter estimates for the stimulus regions. In addition to localizing visual areas, both methods could be used to localize multiple retinotopic regions-of-interest. The two methods yielded consistent retinotopic maps in the visual areas V1, V2, V3, hV4, and V3AB. In the higher-level areas IPS0, VO1, LO1, LO2, TO1, and TO2, retinotopy could only be mapped with the blocked stimulus presentation. The gradual widening of spatial tuning and an increase in the responses to stimuli in the ipsilateral visual field along the hierarchy of visual areas likely reflected the increase in the average receptive field size. Finally, after registration to Freesurfer's surface-based atlas of the human cerebral cortex, we calculated the mean and variability of the visual area positions in the spherical surface-based coordinate system and generated probability maps of the visual areas on the average cortical surface. The inter-individual variability in the area locations decreased when the midpoints were calculated along the spherical cortical surface compared with volumetric coordinates. These results can facilitate both analysis of individual functional anatomy and comparisons of visual cortex topology across studies. PMID:22590626

Working memory in children predicts performance on a gambling task.

PubMed

Audusseau, Jean; Juhel, Jacques

2015-01-01

The authors investigated whether working memory (WM) plays a significant role in the development of decision making in children, operationalized by the Children's Gambling Task (CGT). A total of 105 children aged 6-7, 8-9, and 10-11 years old carried out the CGT. Children aged 6-7 years old were found to have a lower performance than older children, which shows that the CGT is sensitive to participant's age. The hypothesis that WM plays a significant role in decision making was then tested following two approaches: (a) an experimental approach, comparing between groups the performance on the CGT in a control condition (the CGT only was administered) to that in a double task condition (participants had to carry out a recall task in addition to the CGT); (b) an interindividual approach, probing the relationship between CGT performance and performance on tasks measuring WM efficiency. The between-groups approach evidenced a better performance in the control group. Moreover, the interindividual approach showed that the higher the participants' WM efficiency was, the higher their performance in the CGT was. Taken together, these two approaches yield converging results that support the hypothesis that WM plays a significant role in decision making in children.

Telomere length in the two extremes of abnormal fetal growth and the programming effect of maternal arterial hypertension.

PubMed

Tellechea, Mariana; Gianotti, Tomas Fernandéz; Alvariñas, Jorge; González, Claudio D; Sookoian, Silvia; Pirola, Carlos J

2015-01-19

We tested the hypothesis that leukocyte telomere length (LTL) is associated with birth weight in both extremes of abnormal fetal growth: small (SGA) and large for gestational age newborns (LGA). Clinical and laboratory variables of the mothers and the neonates were explored; 45 newborns with appropriate weight for gestational age (AGA), 12 SGA and 12 LGA were included. Whether the differences might be explained by variation in OBFC1 (rs9419958) and CTC1 (rs3027234) genes associated with LTL was determined. A significant association between birth weight and LTL was observed; LTL was significantly shorter in LGA newborns (1.01 ± 0.12) compared with SGA (1.73 ± 0.19) p < 0.005, mean ± SE. Maternal (Spearman R = -0.6, p = 0.03) and neonatal LTL (R = -0.25, p = 0.03) were significantly and inversely correlated with maternal history of arterial hypertension in previous gestations. Neonatal LTL was not significantly associated with either rs9419950 or rs3027234, suggesting that the association between neonatal LTL and birth weight is not influenced by genetic variation in genes that modify the interindividual LTL. In conclusion, telomere biology seems to be modulated by abnormal fetal growth; modifications in telomere length might be programmed by an adverse environment in utero.

Inter-individual Differences in the Effects of Aircraft Noise on Sleep Fragmentation

PubMed Central

McGuire, Sarah; Müller, Uwe; Elmenhorst, Eva-Maria; Basner, Mathias

2016-01-01

Study Objectives: Environmental noise exposure disturbs sleep and impairs recuperation, and may contribute to the increased risk for (cardiovascular) disease. Noise policy and regulation are usually based on average responses despite potentially large inter-individual differences in the effects of traffic noise on sleep. In this analysis, we investigated what percentage of the total variance in noise-induced awakening reactions can be explained by stable inter-individual differences. Methods: We investigated 69 healthy subjects polysomnographically (mean ± standard deviation 40 ± 13 years, range 18–68 years, 32 male) in this randomized, balanced, double-blind, repeated measures laboratory study. This study included one adaptation night, 9 nights with exposure to 40, 80, or 120 road, rail, and/or air traffic noise events (including one noise-free control night), and one recovery night. Results: Mixed-effects models of variance controlling for reaction probability in noise-free control nights, age, sex, number of noise events, and study night showed that 40.5% of the total variance in awakening probability and 52.0% of the total variance in EEG arousal probability were explained by inter-individual differences. If the data set was restricted to nights (4 exposure nights with 80 noise events per night), 46.7% of the total variance in awakening probability and 57.9% of the total variance in EEG arousal probability were explained by inter-individual differences. The results thus demonstrate that, even in this relatively homogeneous, healthy, adult study population, a considerable amount of the variance observed in noise-induced sleep disturbance can be explained by inter-individual differences that cannot be explained by age, gender, or specific study design aspects. Conclusions: It will be important to identify those at higher risk for noise induced sleep disturbance. Furthermore, the custom to base noise policy and legislation on average responses should be re-assessed based on these findings. Citation: McGuire S, Müller U, Elmenhorst EM, Basner M. Inter-individual differences in the effects of aircraft noise on sleep fragmentation. SLEEP 2016;39(5):1107–1110. PMID:26856901

Pharmacogenetics and forensic toxicology.

PubMed

Musshoff, Frank; Stamer, Ulrike M; Madea, Burkhard

2010-12-15

Large inter-individual variability in drug response and toxicity, as well as in drug concentrations after application of the same dosage, can be of genetic, physiological, pathophysiological, or environmental origin. Absorption, distribution and metabolism of a drug and interactions with its target often are determined by genetic differences. Pharmacokinetic and pharmacodynamic variations can appear at the level of drug metabolizing enzymes (e.g., the cytochrome P450 system), drug transporters, drug targets or other biomarker genes. Pharmacogenetics or toxicogenetics can therefore be relevant in forensic toxicology. This review presents relevant aspects together with some examples from daily routines. Copyright © 2010. Published by Elsevier Ireland Ltd.

Use of Markov Chain Monte Carlo analysis with a physiologically-based pharmacokinetic model of methylmercury to estimate exposures in US women of childbearing age.

PubMed

Allen, Bruce C; Hack, C Eric; Clewell, Harvey J

2007-08-01

A Bayesian approach, implemented using Markov Chain Monte Carlo (MCMC) analysis, was applied with a physiologically-based pharmacokinetic (PBPK) model of methylmercury (MeHg) to evaluate the variability of MeHg exposure in women of childbearing age in the U.S. population. The analysis made use of the newly available National Health and Nutrition Survey (NHANES) blood and hair mercury concentration data for women of age 16-49 years (sample size, 1,582). Bayesian analysis was performed to estimate the population variability in MeHg exposure (daily ingestion rate) implied by the variation in blood and hair concentrations of mercury in the NHANES database. The measured variability in the NHANES blood and hair data represents the result of a process that includes interindividual variation in exposure to MeHg and interindividual variation in the pharmacokinetics (distribution, clearance) of MeHg. The PBPK model includes a number of pharmacokinetic parameters (e.g., tissue volumes, partition coefficients, rate constants for metabolism and elimination) that can vary from individual to individual within the subpopulation of interest. Using MCMC analysis, it was possible to combine prior distributions of the PBPK model parameters with the NHANES blood and hair data, as well as with kinetic data from controlled human exposures to MeHg, to derive posterior distributions that refine the estimates of both the population exposure distribution and the pharmacokinetic parameters. In general, based on the populations surveyed by NHANES, the results of the MCMC analysis indicate that a small fraction, less than 1%, of the U.S. population of women of childbearing age may have mercury exposures greater than the EPA RfD for MeHg of 0.1 microg/kg/day, and that there are few, if any, exposures greater than the ATSDR MRL of 0.3 microg/kg/day. The analysis also indicates that typical exposures may be greater than previously estimated from food consumption surveys, but that the variability in exposure within the population of U.S. women of childbearing age may be less than previously assumed.

Effects of gonadectomy and serotonin depletion on inter-individual differences in anxiety-like behaviour in male Wistar rats.

PubMed

Näslund, Jakob; Studer, Erik; Johansson, Elin; Eriksson, Elias

2016-07-15

Previous studies in Wistar rats suggest inter-individual differences in anxiety-like behaviour as assessed using the elevated plus maze (EPM), both between sexes and among males, to be abolished by serotonin depletion. To shed further light on the influence of sex steroids and serotonin - and on the interplay between the two - on proneness for EPM-assessed anxiety in males, outbred Wistar rats were divided into those with high and low anxiety, respectively, and exposed to gonadectomy or sham operation followed by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine, or saline. Whereas gonadectomy enhanced anxiety-like behaviour in low anxiety rats so that these no longer differed in this regard from the high anxiety group, serotonin depletion reversed this effect, and also reduced anxiety in the low anxiety group regardless of gonadal state. A previously observed association between high anxiety-like behaviour and high expression of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 (Tph2) in the raphe was confirmed in sham-operated animals but absent in gonadectomised rats, an ANCOVA revealing a significant interactive effect of baseline anxiety and gonadal state on Tph2 expression. It is suggested that androgens may contribute to upholding inter-individual differences in anxiety-like behaviour in male rats by interacting with serotonergic neurotransmission. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Stereotactic probability and variability of speech arrest and anomia sites during stimulation mapping of the language dominant hemisphere.

PubMed

Chang, Edward F; Breshears, Jonathan D; Raygor, Kunal P; Lau, Darryl; Molinaro, Annette M; Berger, Mitchel S

2017-01-01

OBJECTIVE Functional mapping using direct cortical stimulation is the gold standard for the prevention of postoperative morbidity during resective surgery in dominant-hemisphere perisylvian regions. Its role is necessitated by the significant interindividual variability that has been observed for essential language sites. The aim in this study was to determine the statistical probability distribution of eliciting aphasic errors for any given stereotactically based cortical position in a patient cohort and to quantify the variability at each cortical site. METHODS Patients undergoing awake craniotomy for dominant-hemisphere primary brain tumor resection between 1999 and 2014 at the authors' institution were included in this study, which included counting and picture-naming tasks during dense speech mapping via cortical stimulation. Positive and negative stimulation sites were collected using an intraoperative frameless stereotactic neuronavigation system and were converted to Montreal Neurological Institute coordinates. Data were iteratively resampled to create mean and standard deviation probability maps for speech arrest and anomia. Patients were divided into groups with a "classic" or an "atypical" location of speech function, based on the resultant probability maps. Patient and clinical factors were then assessed for their association with an atypical location of speech sites by univariate and multivariate analysis. RESULTS Across 102 patients undergoing speech mapping, the overall probabilities of speech arrest and anomia were 0.51 and 0.33, respectively. Speech arrest was most likely to occur with stimulation of the posterior inferior frontal gyrus (maximum probability from individual bin = 0.025), and variance was highest in the dorsal premotor cortex and the posterior superior temporal gyrus. In contrast, stimulation within the posterior perisylvian cortex resulted in the maximum mean probability of anomia (maximum probability = 0.012), with large variance in the regions surrounding the posterior superior temporal gyrus, including the posterior middle temporal, angular, and supramarginal gyri. Patients with atypical speech localization were far more likely to have tumors in canonical Broca's or Wernicke's areas (OR 7.21, 95% CI 1.67-31.09, p < 0.01) or to have multilobar tumors (OR 12.58, 95% CI 2.22-71.42, p < 0.01), than were patients with classic speech localization. CONCLUSIONS This study provides statistical probability distribution maps for aphasic errors during cortical stimulation mapping in a patient cohort. Thus, the authors provide an expected probability of inducing speech arrest and anomia from specific 10-mm 2 cortical bins in an individual patient. In addition, they highlight key regions of interindividual mapping variability that should be considered preoperatively. They believe these results will aid surgeons in their preoperative planning of eloquent cortex resection.

Individual musical tempo preference correlates with EEG beta rhythm.

PubMed

Bauer, Anna-Katharina R; Kreutz, Gunter; Herrmann, Christoph S

2015-04-01

Every individual has a preferred musical tempo, which peaks slightly above 120 beats per minute and is subject to interindividual variation. The preferred tempo is believed to be associated with rhythmic body movements as well as motor cortex activity. However, a long-standing question is whether preferred tempo is determined biologically. To uncover the neural correlates of preferred tempo, we first determined an individual's preferred tempo using a multistep procedure. Subsequently, we correlated the preferred tempo with a general EEG timing parameter as well as perceptual and motor EEG correlates-namely, individual alpha frequency, auditory evoked gamma band response, and motor beta activity. Results showed a significant relation between preferred tempo and the frequency of motor beta activity. These findings suggest that individual tempo preferences result from neural activity in the motor cortex, explaining the interindividual variation. Copyright © 2014 Society for Psychophysiological Research.

Prenatal Arsenic Exposure and Shifts in the Newborn Proteome: Interindividual Differences in Tumor Necrosis Factor (TNF)-Responsive Signaling

PubMed Central

Bailey, Kathryn A.; Laine, Jessica; Rager, Julia E.; Sebastian, Elizabeth; Olshan, Andrew; Smeester, Lisa; Drobná, Zuzana; Stýblo, Miroslav; Rubio-Andrade, Marisela; García-Vargas, Gonzalo; Fry, Rebecca C.

2014-01-01

Exposure to inorganic arsenic (iAs) early in life is associated with adverse health effects in infants, children, and adults, and yet the biological mechanisms that underlie these effects are understudied. The objective of this research was to examine the proteomic shifts associated with prenatal iAs exposure using cord blood samples isolated from 50 newborns from Gómez Palacio, Mexico. Levels of iAs in maternal drinking water (DW-iAs) and the sum of iAs and iAs metabolites in maternal urine (U-tAs) were determined. Cord blood samples representing varying iAs exposure levels during the prenatal period (DW-iAs ranging from <1 to 236 μg As/l) were analyzed for altered expression of proteins associated with U-tAs using a high throughput, antibody-based method. A total of 111 proteins were identified that had a significant association between protein level in newborn cord blood and maternal U-tAs. Many of these proteins are regulated by tumor necrosis factor and are enriched in functionality related to immune/inflammatory response and cellular development/proliferation. Interindividual differences in proteomic response were observed in which 30 newborns were “activators,” displaying a positive relationship between protein expression and maternal U-tAs. For 20 “repressor” newborns, a negative relationship between protein expression level and maternal U-tAs was observed. The activator/repressor status was significantly associated with maternal U-tAs and head circumference in newborn males. These results may provide a critical groundwork for understanding the diverse health effects associated with prenatal arsenic exposure and highlight interindividual responses to arsenic that likely influence differential susceptibility to adverse health outcomes. PMID:24675094

Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity

USDA-ARS?s Scientific Manuscript database

The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritabilit...

INTERINDIVIDUAL VARIATION IN THE METABOLISM OF ARSENIC IN HUMAN HEPATOCYTES

EPA Science Inventory

The liver is the major site for the enzymatic methylation of inorganic arsenic (iAs) in humans. Primary cultures of normal human hepatocytes isolated from tissue obtained at surgery or from donor livers have been used to study interindividual variation in the capacity of live...

Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences

PubMed Central

Mohan, S; Baylink, D J

2010-01-01

Although it is well established that there is considerable inter-individual variation in the circulating levels of IGF-I in normal, healthy individuals and that a genetic component contributes substantially to this variation, the direct evidence that inter-individual variation in IGF-I contributes to differences in peak bone mineral density (BMD) is lacking. To examine if differences in IGF-I expression could contribute to peak BMD differences, we measured skeletal changes at days 23 (prepubertal), 31 (pubertal) and 56 (postpubertal) in mice with haploinsufficiency of IGF-I (+/−) and corresponding control mice (+/+). Mice (MF1/DBA) heterozygous for the IGF-I knockout allele were bred to generate +/+ and +/− mice (n=18–20 per group). Serum IGF-I was decreased by 23% (P<0·001) in mice with IGF-I haploinsufficiency (+/−) group at day 56 compared with the control (+/+) group. Femoral bone mineral content and BMD, as determined by dual energy X-ray absorptiometry, were reduced by 20% (P<0·001) and 12% respectively in the IGF-I (+/−) group at day 56 compared with the control group. The peripheral quantitative computed tomography measurements at the femoral mid-diaphysis revealed that periosteal circumference (7%, P<0·01) and total volumetric BMD (5%, P<0·05) were decreased significantly in the +/− group compared with the +/+ group. Furthermore, serum IGF-I showed significant positive correlations with both areal BMD (r=0·55) and periosteal circumference (r=0·66) in the pooled data from the +/+ and +/− groups. Our findings that haploinsufficiency of IGF-I caused significant reductions in serum IGF-I level, BMD and bone size, together with the previous findings, are consistent with the notion that genetic variations in IGF-I expression could, in part, contribute to inter-individual differences in peak BMD among a normal population. PMID:15930167

Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

PubMed

Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M; Largiadèr, Carlo R; Mohacsi, Paul; Sistonen, Johanna

2015-12-01

Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients. Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts. While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction. Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The key kinematic determinants of undulatory underwater swimming at maximal velocity.

PubMed

Connaboy, Chris; Naemi, Roozbeh; Brown, Susan; Psycharakis, Stelios; McCabe, Carla; Coleman, Simon; Sanders, Ross

2016-01-01

The optimisation of undulatory underwater swimming is highly important in competitive swimming performance. Nineteen kinematic variables were identified from previous research undertaken to assess undulatory underwater swimming performance. The purpose of the present study was to determine which kinematic variables were key to the production of maximal undulatory underwater swimming velocity. Kinematic data at maximal undulatory underwater swimming velocity were collected from 17 skilled swimmers. A series of separate backward-elimination analysis of covariance models was produced with cycle frequency and cycle length as dependent variables (DVs) and participant as a fixed factor, as including cycle frequency and cycle length would explain 100% of the maximal swimming velocity variance. The covariates identified in the cycle-frequency and cycle-length models were used to form the saturated model for maximal swimming velocity. The final parsimonious model identified three covariates (maximal knee joint angular velocity, maximal ankle angular velocity and knee range of movement) as determinants of the variance in maximal swimming velocity (adjusted-r2 = 0.929). However, when participant was removed as a fixed factor there was a large reduction in explained variance (adjusted r2 = 0.397) and only maximal knee joint angular velocity continued to contribute significantly, highlighting its importance to the production of maximal swimming velocity. The reduction in explained variance suggests an emphasis on inter-individual differences in undulatory underwater swimming technique and/or anthropometry. Future research should examine the efficacy of other anthropometric, kinematic and coordination variables to better understand the production of maximal swimming velocity and consider the importance of individual undulatory underwater swimming techniques when interpreting the data.

Decision making in healthy participants on the Iowa Gambling Task: new insights from an operant approach.

PubMed

Bull, Peter N; Tippett, Lynette J; Addis, Donna Rose

2015-01-01

The Iowa Gambling Task (IGT) has contributed greatly to the study of affective decision making. However, researchers have observed high inter-study and inter-individual variability in IGT performance in healthy participants, and many are classified as impaired using standard criteria. Additionally, while decision-making deficits are often attributed to atypical sensitivity to reward and/or punishment, the IGT lacks an integrated sensitivity measure. Adopting an operant perspective, two experiments were conducted to explore these issues. In Experiment 1, 50 healthy participants completed a 200-trial version of the IGT which otherwise closely emulated Bechara et al.'s (1999) original computer task. Group data for Trials 1-100 closely replicated Bechara et al.'s original findings of high net scores and preferences for advantageous decks, suggesting that implementations that depart significantly from Bechara's standard IGT contribute to inter-study variability. During Trials 101-200, mean net scores improved significantly and the percentage of participants meeting the "impaired" criterion was halved. An operant-style stability criterion applied to individual data revealed this was likely related to individual differences in learning rate. Experiment 2 used a novel operant card task-the Auckland Card Task (ACT)-to derive quantitative estimates of sensitivity using the generalized matching law. Relative to individuals who mastered the IGT, persistent poor performers on the IGT exhibited significantly lower sensitivity to magnitudes (but not frequencies) of rewards and punishers on the ACT. Overall, our findings demonstrate the utility of operant-style analysis of IGT data and the potential of applying operant concurrent-schedule procedures to the study of human decision making.

The Role of Catechol-O-Methyl Transferase Val(108/158)Met Polymorphism (rs4680) in the Effect of Green Tea on Resting Energy Expenditure and Fat Oxidation: A Pilot Study

PubMed Central

Hursel, Rick; Janssens, Pilou L. H. R.; Bouwman, Freek G.; Mariman, Edwin C.; Westerterp-Plantenga, Margriet S.

2014-01-01

Introduction Green tea(GT) is able to increase energy expenditure(EE) and fat oxidation(FATox) via inhibition of catechol-O-methyl transferase(COMT) by catechins. However, this does not always appear unanimously because of large inter-individual variability. This may be explained by different alleles of the functional COMT Val108/158Met polymorphism that are associated with COMT enzyme activity; high-activity enzyme, COMTH(Val/Val genotype), and low-activity COMTL(Met/Met genotype). Methods Fourteen Caucasian subjects (BMI: 22.2±2.3 kg/m2, age: 21.4±2.2 years) of whom 7 with the COMTH-genotype and 7 with the COMTL-genotype were included in a randomized, cross-over study in which EE and substrate oxidation were measured with a ventilated-hood system after decaffeinated GT and placebo(PL) consumption. Results At baseline, EE, RQ, FATox and carbohydrate oxidation(CHOox) did not differ between groups. Significant interactions were observed between COMT genotypes and treatment for RQ, FATox and CHOox (p<0.05). After GT vs. PL, EE(GT: 62.2 vs. PL: 35.4 kJ.3.5 hrs; p<0.01), RQ(GT: 0.80 vs. PL: 0.83; p<0.01), FATox(GT: 18.3 vs. PL: 15.3 g/d; p<0.001) and CHOox(GT: 18.5 vs. PL: 24.3 g/d; p<0.001) were significantly different for subjects carrying the COMTH genotype, but not for subjects carrying the COMTL genotype (EE, GT: 60.3 vs. PL: 51.7 kJ.3.5 hrs; NS), (RQ, GT: 0.81 vs. PL: 0.81; NS), (FATox, GT: 17.3 vs. PL: 17.0 g/d; NS), (CHOox, GT: 22.1 vs. PL: 21.4 g/d; NS). Conclusion Subjects carrying the COMTH genotype increased energy expenditure and fat-oxidation upon ingestion of green tea catechins vs, placebo, whereas COMTL genotype carriers reacted similarly to GT and PL ingestion. The differences in responses were due to the different responses on PL ingestion, but similar responses to GT ingestion, pointing to different mechanisms. The different alleles of the functional COMT Val108/158Met polymorphism appear to play a role in the inter-individual variability for EE and FATox after GT treatment. Trial Registration Nederlands Trial register NTR1918 PMID:25238062

Global Proteomic Analysis of Human Liver Microsomes: Rapid Characterization and Quantification of Hepatic Drug-Metabolizing Enzymes.

PubMed

Achour, Brahim; Al Feteisi, Hajar; Lanucara, Francesco; Rostami-Hodjegan, Amin; Barber, Jill

2017-06-01

Many genetic and environmental factors lead to interindividual variations in the metabolism and transport of drugs, profoundly affecting efficacy and toxicity. Precision dosing, that is, targeting drug dose to a well characterized subpopulation, is dependent on quantitative models of the profiles of drug-metabolizing enzymes (DMEs) and transporters within that subpopulation, informed by quantitative proteomics. We report the first use of ion mobility-mass spectrometry for this purpose, allowing rapid, robust, label-free quantification of human liver microsomal (HLM) proteins from distinct individuals. Approximately 1000 proteins were identified and quantified in four samples, including an average of 70 DMEs. Technical and biological variabilities were distinguishable, with technical variability accounting for about 10% of total variability. The biological variation between patients was clearly identified, with samples showing a range of expression profiles for cytochrome P450 and uridine 5'-diphosphoglucuronosyltransferase enzymes. Our results showed excellent agreement with previous data from targeted methods. The label-free method, however, allowed a fuller characterization of the in vitro system, showing, for the first time, that HLMs are significantly heterogeneous. Further, the traditional units of measurement of DMEs (pmol mg -1 HLM protein) are shown to introduce error arising from variability in unrelated, highly abundant proteins. Simulations of this variability suggest that up to 1.7-fold variation in apparent CYP3A4 abundance is artifactual, as are background positive correlations of up to 0.2 (Spearman correlation coefficient) between the abundances of DMEs. We suggest that protein concentrations used in pharmacokinetic predictions and scaling to in vivo clinical situations (physiologically based pharmacokinetics and in vitro-in vivo extrapolation) should be referenced instead to tissue mass. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Response variability of different anodal transcranial direct current stimulation intensities across multiple sessions.

PubMed

Ammann, Claudia; Lindquist, Martin A; Celnik, Pablo A

It is well known that transcranial direct current stimulation (tDCS) is capable of modulating corticomotor excitability. However, a source of growing concern has been the observed inter- and intra-individual variability of tDCS-responses. Recent studies have assessed whether individuals respond in a predictable manner across repeated sessions of anodal tDCS (atDCS). The findings of these investigations have been inconsistent, and their methods have some limitations (i.e. lack of sham condition or testing only one tDCS intensity). To study inter- and intra-individual variability of atDCS effects at two different intensities on primary motor cortex (M1) excitability. Twelve subjects participated in a crossover study testing 7-min atDCS over M1 in three separate conditions (2 mA, 1 mA, sham) each repeated three times separated by 48 h. Motor evoked potentials were recorded before and after stimulation (up to 30min). Time of testing was maintained consistent within participants. To estimate the reliability of tDCS effects across sessions, we calculated the Intra-class Correlation Coefficient (ICC). AtDCS at 2 mA, but not 1 mA, significantly increased cortical excitability at the group level in all sessions. The overall ICC revealed fair to high reliability of tDCS effects for multiple sessions. Given that the distribution of responses showed important variability in the sham condition, we established a Sham Variability-Based Threshold to classify responses and to track individual changes across sessions. Using this threshold an intra-individual consistent response pattern was then observed only for the 2 mA condition. 2 mA anodal tDCS results in consistent intra- and inter-individual increases of M1 excitability. Copyright © 2017 Elsevier Inc. All rights reserved.

A link between individual differences in multisensory speech perception and eye movements

PubMed Central

Gurler, Demet; Doyle, Nathan; Walker, Edgar; Magnotti, John; Beauchamp, Michael

2015-01-01

The McGurk effect is an illusion in which visual speech information dramatically alters the perception of auditory speech. However, there is a high degree of individual variability in how frequently the illusion is perceived: some individuals almost always perceive the McGurk effect, while others rarely do. Another axis of individual variability is the pattern of eye movements make while viewing a talking face: some individuals often fixate the mouth of the talker, while others rarely do. Since the talker's mouth carries the visual speech necessary information to induce the McGurk effect, we hypothesized that individuals who frequently perceive the McGurk effect should spend more time fixating the talker's mouth. We used infrared eye tracking to study eye movements as 40 participants viewed audiovisual speech. Frequent perceivers of the McGurk effect were more likely to fixate the mouth of the talker, and there was a significant correlation between McGurk frequency and mouth looking time. The noisy encoding of disparity model of McGurk perception showed that individuals who frequently fixated the mouth had lower sensory noise and higher disparity thresholds than those who rarely fixated the mouth. Differences in eye movements when viewing the talker's face may be an important contributor to interindividual differences in multisensory speech perception. PMID:25810157

The Importance of Patient-Specific Factors for Hepatic Drug Response and Toxicity

PubMed Central

Lauschke, Volker M.; Ingelman-Sundberg, Magnus

2016-01-01

Responses to drugs and pharmacological treatments differ considerably between individuals. Importantly, only 50%–75% of patients have been shown to react adequately to pharmacological interventions, whereas the others experience either a lack of efficacy or suffer from adverse events. The liver is of central importance in the metabolism of most drugs. Because of this exposed status, hepatotoxicity is amongst the most common adverse drug reactions and hepatic liabilities are the most prevalent reason for the termination of development programs of novel drug candidates. In recent years, more and more factors were unveiled that shape hepatic drug responses and thus underlie the observed inter-individual variability. In this review, we provide a comprehensive overview of different principle mechanisms of drug hepatotoxicity and illustrate how patient-specific factors, such as genetic, physiological and environmental factors, can shape drug responses. Furthermore, we highlight other parameters, such as concomitantly prescribed medications or liver diseases and how they modulate drug toxicity, pharmacokinetics and dynamics. Finally, we discuss recent progress in the field of in vitro toxicity models and evaluate their utility in reflecting patient-specific factors to study inter-individual differences in drug response and toxicity, as this understanding is necessary to pave the way for a patient-adjusted medicine. PMID:27754327

Modelling personality, plasticity and predictability in shelter dogs

PubMed Central

2017-01-01

Behavioural assessments of shelter dogs (Canis lupus familiaris) typically comprise standardized test batteries conducted at one time point, but test batteries have shown inconsistent predictive validity. Longitudinal behavioural assessments offer an alternative. We modelled longitudinal observational data on shelter dog behaviour using the framework of behavioural reaction norms, partitioning variance into personality (i.e. inter-individual differences in behaviour), plasticity (i.e. inter-individual differences in average behaviour) and predictability (i.e. individual differences in residual intra-individual variation). We analysed data on interactions of 3263 dogs (n = 19 281) with unfamiliar people during their first month after arrival at the shelter. Accounting for personality, plasticity (linear and quadratic trends) and predictability improved the predictive accuracy of the analyses compared to models quantifying personality and/or plasticity only. While dogs were, on average, highly sociable with unfamiliar people and sociability increased over days since arrival, group averages were unrepresentative of all dogs and predictions made at the individual level entailed considerable uncertainty. Effects of demographic variables (e.g. age) on personality, plasticity and predictability were observed. Behavioural repeatability was higher one week after arrival compared to arrival day. Our results highlight the value of longitudinal assessments on shelter dogs and identify measures that could improve the predictive validity of behavioural assessments in shelters. PMID:28989764

Inter-subject variability modulates phonological advance planning in the production of adjective-noun phrases.

PubMed

Michel Lange, Violaine; Laganaro, Marina

2014-01-01

The literature on advance phonological planning in adjective-noun phrases (NPs) presents diverging results: while many experimental studies suggest that the entire NP is encoded before articulation, other results favor a span of encoding limited to the first word. Although cross-linguistic differences in the structure of adjective-NPs may account for some of these contrasting results, divergences have been reported even among similar languages and syntactic structures. Here we examined whether inter-individual differences account for variability in the span of phonological planning in the production of French NPs, where previous results indicated encoding limited to the first word. The span of phonological encoding is tested with the picture-word interference (PWI) paradigm using phonological distractors related to the noun or to the adjective of the NPs. In Experiment 1, phonological priming effects were limited to the first word in adjective NPs whichever the position of the adjective (pre-nominal or post-nominal). Crucially, phonological priming effects on the second word interacted with speakers' production speed suggesting different encoding strategies for participants. In Experiment 2, we tested this hypothesis further with a larger group of participants. Results clearly showed that slow and fast initializing participants presented different phonological priming patterns on the last element of adjective-NPs: while the first word was primed by a distractor for all speakers, only the slow speaker group presented a priming effect on the second element of the NP. These results show that the span of phonological encoding is modulated by inter-individual strategies: in experimental paradigms some speakers plan word by word whereas others encode beyond the initial word. We suggest that the diverging results reported in the literature on advance phonological planning may partly be reconciled in light of the present results.

Phase I dose-escalation study of vinflunine hard capsules administered twice a day for 2 consecutive days every week in patients with advanced/metastatic solid tumors.

PubMed

Calvo, E; Vermorken, J B; Hiret, S; Rodon, J; Cortes, J; Senellart, H; Van den Brande, J; Dyck, J; Pétain, A; Ferre, P; Bennouna, J

2012-06-01

Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe. In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations. Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%. Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.

Sleep Consolidates Motor Learning of Complex Movement Sequences in Mice.

PubMed

Nagai, Hirotaka; de Vivo, Luisa; Bellesi, Michele; Ghilardi, Maria Felice; Tononi, Giulio; Cirelli, Chiara

2017-02-01

Sleep-dependent consolidation of motor learning has been extensively studied in humans, but it remains unclear why some, but not all, learned skills benefit from sleep. Here, we compared 2 different motor tasks, both requiring the mice to run on an accelerating device. In the rotarod task, mice learn to maintain balance while running on a small rod, while in the complex wheel task, mice run on an accelerating wheel with an irregular rung pattern. In the rotarod task, performance improved to the same extent after sleep or after sleep deprivation (SD). Overall, using 7 different experimental protocols (41 sleep deprived mice, 26 sleeping controls), we found large interindividual differences in the learning and consolidation of the rotarod task, but sleep before/after training did not account for this variability. By contrast, using the complex wheel, we found that sleep after training, relative to SD, led to better performance from the beginning of the retest session, and longer sleep was correlated with greater subsequent performance. As in humans, the effects of sleep showed large interindividual variability and varied between fast and slow learners, with sleep favoring the preservation of learned skills in fast learners and leading to a net offline gain in the performance in slow learners. Using Fos expression as a proxy for neuronal activation, we also found that complex wheel training engaged motor cortex and hippocampus more than the rotarod training. Sleep specifically consolidates a motor skill that requires complex movement sequences and strongly engages both motor cortex and hippocampus. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation.

PubMed

Jullien, Vincent; Azoulay, Elie; Schwebel, Carole; Le Saux, Thomas; Charles, Pierre Emmanuel; Cornet, Muriel; Souweine, Bertrand; Klouche, Kadda; Jaber, Samir; Trouillet, Jean-Louis; Bruneel, Fabrice; Cour, Martin; Cousson, Joel; Meziani, Ferhat; Gruson, Didier; Paris, Adeline; Darmon, Michael; Garrouste-Orgeas, Maité; Navellou, Jean-Christophe; Foucrier, Arnaud; Allaouchiche, Bernard; Das, Vincent; Gangneux, Jean-Pierre; Ruckly, Stéphane; Wolff, Michel; Timsit, Jean-François

2017-01-01

To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L. A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex

PubMed Central

Pinto, Joshua G. A.; Jones, David G.; Williams, C. Kate; Murphy, Kathryn M.

2015-01-01

Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life. A multidimensional analysis (principle component analysis) showed that most of the variance was captured by the sum of the four synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic. PMID:25729353

Clustering according to urolithin metabotype explains the interindividual variability in the improvement of cardiovascular risk biomarkers in overweight-obese individuals consuming pomegranate: A randomized clinical trial.

PubMed

González-Sarrías, Antonio; García-Villalba, Rocío; Romo-Vaquero, María; Alasalvar, Cesarettin; Örem, Asim; Zafrilla, Pilar; Tomás-Barberán, Francisco A; Selma, María V; Espín, Juan Carlos

2017-05-01

The pomegranate lipid-lowering properties remain controversial, probably due to the interindividual variability in polyphenol (ellagitannins) metabolism. We aimed at investigating whether the microbially derived ellagitannin-metabolizing phenotypes, i.e. urolithin metabotypes A, (UM-A), B (UM-B), and 0 (UM-0), influence the effects of pomegranate extract (PE) consumption on 18 cardiovascular risk biomarkers in healthy overweight-obese individuals. A double-blind, crossover, dose-response, randomized, placebo-controlled trial was conducted. The study (POMEcardio) consisted of two test phases (dose-1 and dose-2, lasting 3 weeks each) and a 3-week washout period between each phase. Forty-nine participants (BMI > 27 kg/m 2 ) daily consumed one (dose-1, 160 mg phenolics/day) or four (dose-2, 640 mg phenolics/day) PE or placebo capsules. Notably, UM-B individuals showed the highest baseline cardiovascular risk. After dose-2, total cholesterol (-15.5 ± 3.7%), LDL-cholesterol (-14.9 ± 2.1%), small LDL-cholesterol (-47 ± 7%), non-HDL-cholesterol (-11.3 ± 2.5%), apolipoprotein-B (-12 ± 2.2%), and oxidized LDL-cholesterol -24 ± 2.5%) dose dependently decreased (P < 0.05) but only in UM-B subjects. These effects were partially correlated with urolithin production and the increase in Gordonibacter levels. Three (50%) nonproducers (UM-0) became producers following PE consumption. UM clustering suggests a personalized effect of ellagitannin-containing foods and could explain the controversial pomegranate benefits. Research on the specific role of urolithins and the microbiota associated with each UM is warranted. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs.

PubMed

De Jaeghere, F; Allémann, E; Cerny, R; Galli, B; Steulet, A F; Müller, I; Schütz, H; Doelker, E; Gurny, R

2001-01-01

RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n = 6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC0-48h of 6.5 microg x h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0-48h of 27.1 microg x h/mL versus 17.7 microg x h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.

Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent

PubMed Central

Follis, Jack L.; Dashti, Hassan S.; Tanaka, Toshiko; Graff, Mariaelisa; Fretts, Amanda M.; Kilpeläinen, Tuomas O.; Wojczynski, Mary K.; Richardson, Kris; Nalls, Mike A.; Schulz, Christina-Alexandra; Liu, Yongmei; Frazier-Wood, Alexis C.; van Eekelen, Esther; Wang, Carol; de Vries, Paul S.; Mikkilä, Vera; Rohde, Rebecca; Psaty, Bruce M.; Hansen, Torben; Feitosa, Mary F.; Lai, Chao-Qiang; Houston, Denise K.; Ferruci, Luigi; Ericson, Ulrika; Wang, Zhe; de Mutsert, Renée; Oddy, Wendy H.; de Jonge, Ester A. L.; Seppälä, Ilkka; Justice, Anne E.; Lemaitre, Rozenn N.; Sørensen, Thorkild I. A.; Province, Michael A.; Parnell, Laurence D.; Garcia, Melissa E.; Bandinelli, Stefania; Orho-Melander, Marju; Rich, Stephen S.; Rosendaal, Frits R.; Pennell, Craig E.; Kiefte-de Jong, Jessica C.; Kähönen, Mika; Young, Kristin L.; Pedersen, Oluf; Aslibekyan, Stella; Rotter, Jerome I.; Mook-Kanamori, Dennis O.; Zillikens, M. Carola; Raitakari, Olli T.; North, Kari E.; Overvad, Kim; Arnett, Donna K.; Hofman, Albert; Lehtimäki, Terho; Tjønneland, Anne; Uitterlinden, André G.; Rivadeneira, Fernando; Franco, Oscar H.; German, J. Bruce; Siscovick, David S.; Cupples, L. Adrienne; Ordovás, José M.

2017-01-01

Scope Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. Methods and results A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction<10−7), and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3′ of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10−8) such that each serving of low-fat dairy was associated with 0.225 kg m−2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure. Conclusion Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight. PMID:28941034

Individual Differences in Pain: Understanding the Mosaic that Makes Pain Personal

PubMed Central

Fillingim, Roger B.

2016-01-01

The experience of pain is characterized by tremendous inter-individual variability. Multiple biological and psychosocial variables contribute to these individual differences in pain, including demographic variables, genetic factors, and psychosocial processes. For example, sex, age and ethnic group differences in the prevalence of chronic pain conditions have been widely reported. Moreover, these demographic factors have been associated with responses to experimentally-induced pain. Similarly, both genetic and psychosocial factors contribute to clinical and experimental pain responses. Importantly, these different biopsychosocial influences interact with each other in complex ways to sculpt the experience of pain. Some genetic associations with pain have been found to vary across sex and ethnic group. Moreover, genetic factors also interact with psychosocial factors, including stress and pain catastrophizing, to influence pain. The individual and combined influences of these biological and psychosocial variables results in a unique mosaic of factors that contributes pain in each individual. Understanding these mosaics is critically important in order to provide optimal pain treatment, and future research to further elucidate the nature of these biopsychosocial interactions is needed in order to provide more informed and personalized pain care. PMID:27902569

Small RNA sequencing in cells and exosomes identifies eQTLs and 14q32 as a region of active export

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsang, Emily K.; Abell, Nathan S.; Li, Xin

Exosomes are small extracellular vesicles that carry heterogeneous cargo, including RNA, between cells. Increasing evidence suggests that exosomes are important mediators of intercellular communication and biomarkers of disease. Despite this, the variability of exosomal RNA between individuals has not been well quantified. To assess this variability, we sequenced the small RNA of cells and exosomes from a 17-member family. Across individuals, we show that selective export of miRNAs occurs not only at the level of specific transcripts, but that a cluster of 74 mature miRNAs on chromosome 14q32 is massively exported in exosomes while mostly absent from cells. We alsomore » observe more interindividual variability between exosomal samples than between cellular ones and identify four miRNA expression quantitative trait loci shared between cells and exosomes. Lastly, our findings indicate that genomically colocated miRNAs can be exported together and highlight the variability in exosomal miRNA levels between individuals as relevant for exosome use as diagnostics.« less

Small RNA sequencing in cells and exosomes identifies eQTLs and 14q32 as a region of active export

DOE PAGES

Tsang, Emily K.; Abell, Nathan S.; Li, Xin; ...

2016-10-31

Exosomes are small extracellular vesicles that carry heterogeneous cargo, including RNA, between cells. Increasing evidence suggests that exosomes are important mediators of intercellular communication and biomarkers of disease. Despite this, the variability of exosomal RNA between individuals has not been well quantified. To assess this variability, we sequenced the small RNA of cells and exosomes from a 17-member family. Across individuals, we show that selective export of miRNAs occurs not only at the level of specific transcripts, but that a cluster of 74 mature miRNAs on chromosome 14q32 is massively exported in exosomes while mostly absent from cells. We alsomore » observe more interindividual variability between exosomal samples than between cellular ones and identify four miRNA expression quantitative trait loci shared between cells and exosomes. Lastly, our findings indicate that genomically colocated miRNAs can be exported together and highlight the variability in exosomal miRNA levels between individuals as relevant for exosome use as diagnostics.« less

Statistical Modeling of the Individual: Rationale and Application of Multivariate Stationary Time Series Analysis

ERIC Educational Resources Information Center

Hamaker, Ellen L.; Dolan, Conor V.; Molenaar, Peter C. M.

2005-01-01

Results obtained with interindividual techniques in a representative sample of a population are not necessarily generalizable to the individual members of this population. In this article the specific condition is presented that must be satisfied to generalize from the interindividual level to the intraindividual level. A way to investigate…

The influence of salivary variables on fluoride retention in dental plaque exposed to a mineral-enriching solution.

PubMed

Kato, K; Nakagaki, H; Arai, K; Pearce, E I F

2002-01-01

This study was carried out to examine interindividual differences in salivary variables related to plaque accumulation and to estimate their influence on the fluoride retention in plaque in vivo by a mineral-enriching solution. Two saliva samples were taken from 10 subjects, once after brushing and once after 24 h without brushing. Calcium, phosphate and monofluorophosphatase (MFPase) activity in the saliva samples were determined. The salivary flow rate and the debris index were also recorded. After plaque had formed over 3 days within in situ plaque-generating devices, subjects were instructed to rinse with a mineral-enriching mouthrinse three times a day on 4 consecutive days. Plaque exposed to distilled water plus flavoring agents served as a control. Fluoride-free dentifrice was used during the experimental period. Twenty-four hours after the last rinsing, the samples were removed from the mouth, and fluoride and mineral distributions in plaque analyzed using a method previously reported by the authors. Salivary flow, MFPase activity and calcium concentration in saliva were significantly higher after 24 h of plaque accumulation. Rinsing with the mineral-enriching solution produced retention of fluoride and phosphate in the outer and middle layers of plaque. Salivary calcium concentration had a direct effect on fluoride uptake in plaque, but no obvious relationship was found between other salivary variables and the plaque fluoride retention. The salivary calcium effect may be due to enhanced bacterial cell wall binding of fluoride via calcium bridging. Copyright 2002 S. Karger AG, Basel

Genetic variants of age at menopause are not related to timing of ovarian failure in breast cancer survivors

PubMed Central

Homer, Michael V.; Charo, Lindsey M.; Natarajan, Loki; Haunschild, Carolyn; Chung, Karine; Mao, Jun J.; DeMichele, Angela M.; Su, H. Irene

2016-01-01

Objective To determine if inter-individual genetic variation in single nucleotide polymorphisms related to age at natural menopause are associated with risk of ovarian failure in breast cancer survivors. Methods A prospective cohort of 169 premenopausal breast cancer survivors recruited at diagnosis with Stages 0 to III disease were followed longitudinally for menstrual pattern via self-reported daily menstrual diaries. Participants were genotyped for 13 single nucleotide polymorphisms (SNPs) previously found to be associated with age at natural menopause: EXO1, TLK1, HELQ, UIMC1, PRIM1, POLG, TMEM224, BRSK1, and MCM8. A risk variable summed the total number of risk alleles in each participant. The association between individual genotypes, as well as the risk variable, and time to ovarian failure (> 12 months of amenorrhea) was tested using time-to-event methods. Results Median age at enrollment was 40.5 years old (range 20.6–46.1). The majority of participants were white (69%) and underwent chemotherapy (76%). Thirty-eight participants (22%) experienced ovarian failure. None of the candidate SNPs or the summary risk variable were significantly associated with time to ovarian failure. Sensitivity analysis restricted to whites or only to participants receiving chemotherapy yielded similar findings. Older age, chemotherapy exposure and lower BMI were related to shorter time to ovarian failure. Conclusions Thirteen previously identified genetic variants associated with time to natural menopause were not related to timing of ovarian failure in breast cancer survivors. PMID:28118297

Genetic variants of age at menopause are not related to timing of ovarian failure in breast cancer survivors.

PubMed

Homer, Michael V; Charo, Lindsey M; Natarajan, Loki; Haunschild, Carolyn; Chung, Karine; Mao, Jun J; DeMichele, Angela M; Su, H Irene

2017-06-01

To determine if interindividual genetic variation in single-nucleotide polymorphisms (SNPs) related to age at natural menopause is associated with risk of ovarian failure in breast cancer survivors. A prospective cohort of 169 premenopausal breast cancer survivors recruited at diagnosis with stages 0 to III disease were followed longitudinally for menstrual pattern via self-reported daily menstrual diaries. Participants were genotyped for 13 SNPs previously found to be associated with age at natural menopause: EXO1, TLK1, HELQ, UIMC1, PRIM1, POLG, TMEM224, BRSK1, and MCM8. A risk variable summed the total number of risk alleles in each participant. The association between individual genotypes, and also the risk variable, and time to ovarian failure (>12 months of amenorrhea) was tested using time-to-event methods. Median age at enrollment was 40.5 years (range 20.6-46.1). The majority of participants were white (69%) and underwent chemotherapy (76%). Thirty-eight participants (22%) experienced ovarian failure. None of the candidate SNPs or the summary risk variable was significantly associated with time to ovarian failure. Sensitivity analysis restricted to whites or only to participants receiving chemotherapy yielded similar findings. Older age, chemotherapy exposure, and lower body mass index were related to shorter time to ovarian failure. Thirteen previously identified genetic variants associated with time to natural menopause were not related to timing of ovarian failure in breast cancer survivors.

Phenotypic Variability in a Family with Acrodysostosis Type 2 Caused by a Novel PDE4D Mutation Affecting the Serine Target of Protein Kinase-A Phosphorylation

PubMed Central

Hoppmann, Julia; Gesing, Julia; Silve, Caroline; Leroy, Chrystel; Bertsche, Astrid; Hirsch, Franz Wolfgang; Kiess, Wieland; Pfäffle, Roland; Schuster, Volker

2017-01-01

Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in protein kinase type 1-α regulatory subunit and acrodysostosis type 2 caused by mutations in phosphodiesterase 4D (PDE4D). Most cases are sporadic. We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation. A 3.5-year-old boy presented with short stature, midfacial hypoplasia, severe brachydactyly, developmental delay, and behavioural problems. Laboratory investigations revealed mild thyrotropin resistance. His mother shared some characteristic features, such as midfacial hypoplasia and severe brachydactyly, but did not show short stature, intellectual disability or hormonal resistance. Genetic analysis identified the identical, novel heterozygous missense mutation of the PDE4D gene c.569C>T (p.Ser190Phe) in both patients. This case illustrates the significant phenotypic variability of acrodysostosis even within one family with identical mutations. Hence, a specific clinical diagnosis of acrodysostosis remains challenging because of great interindividual variability and a substantial overlap of the two subtypes as well as with other related Gsα-cAMP-signalling-linked disorders. PMID:28515031

Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain.

PubMed

Olofsen, Erik; Romberg, Raymonda; Bijl, Hans; Mooren, René; Engbers, Frank; Kest, Benjamin; Dahan, Albert

2005-07-01

To assess whether patient sex contributes to the interindividual variability in alfentanil analgesic sensitivity, the authors compared male and female subjects for pain sensitivity after alfentanil using a pharmacokinetic-pharmacodynamic modeling approach. Healthy volunteers received a 30-min alfentanil or placebo infusion on two occasions. Analgesia was measured during the subsequent 6 h by assaying tolerance to transcutaneous electrical stimulation (eight men and eight women) of increasing intensity or using visual analog scale scores during treatment with noxious thermal heat (five men and five women). Sedation was concomitantly measured. Population pharmacokinetic-pharmacodynamic models were applied to the analgesia and sedation data using NONMEM. For electrical pain, the placebo and alfentanil models were combined post hoc. Alfentanil and placebo analgesic responses did not differ between sexes. The placebo effect was successfully incorporated into the alfentanil pharmacokinetic-pharmacodynamic model and was responsible for 20% of the potency of alfentanil. However, the placebo effect did not contribute to the analgesic response variability. The pharmacokinetic-pharmacodynamic analysis of the electrical and heat pain data yielded similar values for the potency parameter, but the blood-effect site equilibration half-life was significantly longer for electrical pain (7-9 min) than for heat pain (0.2 min) or sedation (2 min). In contrast to the ample literature demonstrating sex differences in morphine analgesia, neither sex nor subject expectation (i.e., placebo) contributes to the large between-subject response variability with alfentanil analgesia. The difference in alfentanil analgesia onset and offset between pain tests is discussed.

Inter-individual Differences in the Effects of Aircraft Noise on Sleep Fragmentation.

PubMed

McGuire, Sarah; Müller, Uwe; Elmenhorst, Eva-Maria; Basner, Mathias

2016-05-01

Environmental noise exposure disturbs sleep and impairs recuperation, and may contribute to the increased risk for (cardiovascular) disease. Noise policy and regulation are usually based on average responses despite potentially large inter-individual differences in the effects of traffic noise on sleep. In this analysis, we investigated what percentage of the total variance in noise-induced awakening reactions can be explained by stable inter-individual differences. We investigated 69 healthy subjects polysomnographically (mean ± standard deviation 40 ± 13 years, range 18-68 years, 32 male) in this randomized, balanced, double-blind, repeated measures laboratory study. This study included one adaptation night, 9 nights with exposure to 40, 80, or 120 road, rail, and/or air traffic noise events (including one noise-free control night), and one recovery night. Mixed-effects models of variance controlling for reaction probability in noise-free control nights, age, sex, number of noise events, and study night showed that 40.5% of the total variance in awakening probability and 52.0% of the total variance in EEG arousal probability were explained by inter-individual differences. If the data set was restricted to nights (4 exposure nights with 80 noise events per night), 46.7% of the total variance in awakening probability and 57.9% of the total variance in EEG arousal probability were explained by inter-individual differences. The results thus demonstrate that, even in this relatively homogeneous, healthy, adult study population, a considerable amount of the variance observed in noise-induced sleep disturbance can be explained by inter-individual differences that cannot be explained by age, gender, or specific study design aspects. It will be important to identify those at higher risk for noise induced sleep disturbance. Furthermore, the custom to base noise policy and legislation on average responses should be re-assessed based on these findings. © 2016 Associated Professional Sleep Societies, LLC.

The role of pelvis-thorax coupling in controlling within-golf club swing speed.

PubMed

Lamb, Peter F; Pataky, Todd C

2018-02-23

Pelvis-thorax coordination has been recognised to be associated with swing speed. Increasing angular separation between the pelvis and thorax has been thought to initiate the stretch shortening cycle and lead to increased clubhead speed. The purpose of this study was to determine whether pelvis-thorax coupling played a significant role in regulating clubhead speed, in a group of low-handicap golfers (mean handicap = 4.1). Sixteen participants played shots to target distances determined based on their typical 5- and 6-iron shot distances. Half the difference between median 5- and 6-iron distance for each participant was used to create three swing effort conditions: "minus", "norm", and "plus". Ten shots were played under each swing effort condition using both the 5-iron and 6-iron, resulting in six shot categories and 60 shots per participant. No significant differences were found for X-factor for club or swing effort. X-factor stretch showed significant differences for club and swing effort. Continuous relative phase (CRP) results mainly showed evidence of the stretch shortening cycle in the downswing and that it was more pronounced late in the downswing as swing effort increased. Substantial inter-individual CRP variability demonstrated the need for individual analyses when investigating coordination in the golf swing.

Mapping the structure of perceptual and visual-motor abilities in healthy young adults.

PubMed

Wang, Lingling; Krasich, Kristina; Bel-Bahar, Tarik; Hughes, Lauren; Mitroff, Stephen R; Appelbaum, L Gregory

2015-05-01

The ability to quickly detect and respond to visual stimuli in the environment is critical to many human activities. While such perceptual and visual-motor skills are important in a myriad of contexts, considerable variability exists between individuals in these abilities. To better understand the sources of this variability, we assessed perceptual and visual-motor skills in a large sample of 230 healthy individuals via the Nike SPARQ Sensory Station, and compared variability in their behavioral performance to demographic, state, sleep and consumption characteristics. Dimension reduction and regression analyses indicated three underlying factors: Visual-Motor Control, Visual Sensitivity, and Eye Quickness, which accounted for roughly half of the overall population variance in performance on this battery. Inter-individual variability in Visual-Motor Control was correlated with gender and circadian patters such that performance on this factor was better for males and for those who had been awake for a longer period of time before assessment. The current findings indicate that abilities involving coordinated hand movements in response to stimuli are subject to greater individual variability, while visual sensitivity and occulomotor control are largely stable across individuals. Copyright © 2015 Elsevier B.V. All rights reserved.

Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk (Final Report)

EPA Science Inventory

EPA announced the availability of the final report, Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk Final Report for Cooperative Agreement. Th...

The role of interindividual variation in human carcinogenesis.

PubMed

Lai, C; Shields, P G

1999-02-01

The process of chemical carcinogenesis is a complex multistage process initiated by DNA damage in growth control genes. Carcinogens enter the body from a variety of sources, but most require metabolic activation before they can damage DNA. There are multiple protective processes that include detoxification and conjugation, DNA repair and programmed cell death. Most of these functions exhibit wide interindividual variation in the population and thus are thought to affect cancer risk. The role of gene-environment interactions is being explored, and current data indicate that genetic susceptibilities can modify carcinogen exposures from the diet and tobacco smoking, although much more data exist for the latter. This review addresses the relationships of human carcinogenesis to these interindividual differences of phase I, phase II and DNA repair enzymes.

Antifungal Therapy in Birds: Old Drugs in a New Jacket.

PubMed

Antonissen, Gunther; Martel, An

2018-05-01

The use of antifungals in birds is characterized by interspecies and interindividual variability in the pharmacokinetics, affecting drug safety and efficacy. Oral antifungal drug absorption is a complex process affected by drug formulation characteristics, gastrointestinal anatomy, and physiology. New antifungal drug delivery systems can enhance drug stability, reduce off-target side effects, prolong residence time in the blood, and improve efficacy. Topical administration of antifungals through nebulization shows promising results. However, therapeutic output is highly influenced by drug formulation and type of nebulizer, indicating these factors should be taken into account when selecting this medication route. Copyright © 2018 Elsevier Inc. All rights reserved.

Subjective Technology Adaptivity Predicts Technology Use in Old Age.

PubMed

Kamin, Stefan T; Lang, Frieder R; Beyer, Anja

2017-01-01

To date, not much is known about the psychological and motivational factors underlying technology use in late life. What are the interindividual determinants that lead older adults to invest in using technological innovations despite the age-related physiological changes that impose challenges on behavioral plasticity in everyday life? This research explores interindividual differences in subjective technology adaptivity - a general technology-related motivational resource that accounts for technology use in late life. More specifically, we investigate the influence of this factor relative to demographic characteristics, personality traits, and functional limitations in a longitudinal sample of community-dwelling older adults. We report results from a paper-and-pencil survey with 136 older adults between 59 and 92 years of age (mean = 71.4, SD = 7.4). Of those participants, 77 participated in a 2-year follow-up. We assessed self-reports of technology use, subjective technology adaptivity, functional limitations, and the personality traits openness to new experiences and neuroticism. Higher levels of subjective technology adaptivity were associated with technology use at the first measurement as well as increased use over the course of 2 years. Subjective technology adaptivity is a significant predictor of technology use in old age. Our findings contribute to improving the understanding of interindividual differences when using technological innovation in late life. Moreover, our findings have implications in the context of user involvement and may contribute to the successful development of innovative technology for older adults. © 2017 S. Karger AG, Basel.

Fragile and Enduring Positive Affect: Implications for Adaptive Aging.

PubMed

Ong, Anthony D; Ram, Nilam

2017-01-01

There is robust evidence linking interindividual differences in positive affect (PA) with adaptive psychological and physical health outcomes. However, recent research has suggested that intraindividual variability or fluctuations in PA states over time may also be an important predictor of individual health outcomes. Here, we report on research that focuses on PA level and various forms of PA dynamics (variability, instability, inertia, and reactivity) in relation to health. PA level refers to the average level of positive feelings. In contrast, PA dynamics refer to short-term changes in PA that unfold over time. We discuss how consideration of both PA level and PA dynamics can provide a framework for reconciling when high PA is conducive or detrimental to health. We conclude that more work on PA dynamics is needed, especially in combination with PA level, and suggest productive questions for future inquiry in this area. © 2016 S. Karger AG, Basel.

A Case for Pharmacogenomics in Management of Cardiac Arrhythmias

PubMed Central

Kandoi, Gaurav; Nanda, Anjali; Scaria, Vinod; Sivasubbu, Sridhar

2012-01-01

Disorders of the cardiac rhythm are quite prevalent in clinical practice. Though the variability in drug response between individuals has been extensively studied, this information has not been widely used in clinical practice. Rapid advances in the field of pharmacogenomics have provided us with crucial insights on inter-individual genetic variability and its impact on drug metabolism and action. Technologies for faster and cheaper genetic testing and even personal genome sequencing would enable clinicians to optimize prescription based on the genetic makeup of the individual, which would open up new avenues in the area of personalized medicine. We have systematically looked at literature evidence on pharmacogenomics markers for anti-arrhythmic agents from the OpenPGx consortium collection and reason the applicability of genetics in the management of arrhythmia. We also discuss potential issues that need to be resolved before personalized pharmacogenomics becomes a reality in regular clinical practice. PMID:22557843

Influence of XRCC1 Genetic Polymorphisms on Ionizing Radiation-Induced DNA Damage and Repair.

PubMed

Sterpone, Silvia; Cozzi, Renata

2010-07-25

It is well known that ionizing radiation (IR) can damage DNA through a direct action, producing single- and double-strand breaks on DNA double helix, as well as an indirect effect by generating oxygen reactive species in the cells. Mammals have evolved several and distinct DNA repair pathways in order to maintain genomic stability and avoid tumour cell transformation. This review reports important data showing a huge interindividual variability on sensitivity to IR and in susceptibility to developing cancer; this variability is principally represented by genetic polymorphisms, that is, DNA repair gene polymorphisms. In particular we have focussed on single nucleotide polymorphisms (SNPs) of XRCC1, a gene that encodes for a scaffold protein involved basically in Base Excision Repair (BER). In this paper we have reported and presented recent studies that show an influence of XRCC1 variants on DNA repair capacity and susceptibility to breast cancer.

Psychophysiological arousal and inter‐ and intraindividual differences in risk‐sensitive decision making

PubMed Central

Scheibehenne, Benjamin; Clark, Luke

2016-01-01

Abstract The current study assessed peripheral responses during decision making under explicit risk, and tested whether intraindividual variability in choice behavior can be explained by fluctuations in peripheral arousal. Electrodermal activity (EDA) and heart rate (HR) were monitored in healthy volunteers (N = 68) during the Roulette Betting Task. In this task, participants were presented with risky gambles to bet on, with the chances of winning varying across trials. Hierarchical Bayesian analyses demonstrated that EDA and HR acceleration responses during the decision phase were sensitive to the chances of winning. Interindividual differences in this peripheral reactivity during risky decision making were related to trait sensitivity to punishment and trait sensitivity to reward. Moreover, trial‐by‐trial variation in EDA and HR acceleration responses predicted a small portion of intraindividual variability in betting choices. Our results show that psychophysiological responses are sensitive to explicit risk and can help explain intraindividual heterogeneity in choice behavior. PMID:26927730

Warfarin therapy: in need of improvement after all these years

PubMed Central

Kimmel, Stephen E

2010-01-01

Background Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal. Objective To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy. Results Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions. Conclusion Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes. PMID:18345947

A Developmental Perspective on Alcohol and Other Drug Use during Adolescence and the Transition to Young Adulthood. Monitoring the Future Occasional Paper.

ERIC Educational Resources Information Center

Schulenberg, John; Maggs, Jennifer L.

This paper offers a developmental perspective on college drinking by focusing on broad developmental themes during adolescence and the transition to young adulthood. Heavy drinking increases during the transition to college, with significant interindividual variation in the course and consequences. The majority of young people make it through…

Comparison of total energy expenditure assessed by two devices in controlled and free-living conditions.

PubMed

Rousset, Sylvie; Fardet, Anthony; Lacomme, Philippe; Normand, Sylvie; Montaurier, Christophe; Boirie, Yves; Morio, Béatrice

2015-01-01

The objective of this study was to evaluate the validity of total energy expenditure (TEE) provided by Actiheart and Armband. Normal-weight adult volunteers wore both devices either for 17 hours in a calorimetric chamber (CC, n = 49) or for 10 days in free-living conditions (FLC) outside the laboratory (n = 41). The two devices and indirect calorimetry or doubly labelled water, respectively, were used to estimate TEE in the CC group and FLC group. In the CC, the relative value of TEE error was not significant (p > 0.05) for Actiheart but significantly different from zero for Armband, showing TEE underestimation (-4.9%, p < 0.0001). However, the mean absolute values of errors were significantly different between Actiheart and Armband: 8.6% and 6.7%, respectively (p = 0.05). Armband was more accurate for estimating TEE during sleeping, rest, recovery periods and sitting-standing. Actiheart provided better estimation during step and walking. In FLC, no significant error in relative value was detected. Nevertheless, Armband produced smaller errors in absolute value than Actiheart (8.6% vs. 12.8%). The distributions of differences were more scattered around the means, suggesting a higher inter-individual variability in TEE estimated by Actiheart than by Armband. Our results show that both monitors are appropriate for estimating TEE. Armband is more effective than Actiheart at the individual level for daily light-intensity activities.

Ability-Based Pairing Strategies in the Team-Based Training of a Complex Skill: Does the Intelligence of Your Training Partner Matter?

ERIC Educational Resources Information Center

Day, Eric Anthony; Arthur, Winfred Jr.; Bell, Suzanne T.; Edwards, Bryan D.; Bennett, Winston Jr.; Mendoza, Jorge L.; Tubre, Travis C.

2005-01-01

Intelligence researchers traditionally focus their attention on the individual level and overlook the role of intelligence at the interindividual level. This research investigated the interplay of the effects of intelligence at the individual and interindividual levels by manipulating the intelligence-based composition of dyadic training teams.…

The Development of Interindividual Sharing of Knowledge and Beliefs in 5- to 9-Year-Old Children

ERIC Educational Resources Information Center

Bradmetz, Joel; Gauthier, Cecile

2005-01-01

The authors studied the evolution of interindividual intentionality in children and showed that the sharing of knowledge and beliefs requires more complex operations than those involved in usual false-belief tasks. The authors conducted 3 experiments on 380 children (aged 5 years, 0 months to 9 years, 6 months). They assessed the children's…

Generalisation within specialization: inter-individual diet variation in the only specialized salamander in the world

PubMed Central

Costa, Andrea; Salvidio, Sebastiano; Posillico, Mario; Matteucci, Giorgio; De Cinti, Bruno; Romano, Antonio

2015-01-01

Specialization is typically inferred at population and species level but in the last decade many authors highlighted this trait at the individual level, finding that generalist populations can be composed by both generalist and specialist individual. Despite hundreds of reported cases of individual specialization there is a complete lack of information on inter-individual diet variation in specialist species. We studied the diet of the Italian endemic Spectacled Salamander (Salamandrina perspicillata), in a temperate forest ecosystem, to disclose the realised trophic niche, prey selection strategy in function of phenotypic variation and inter-individual diet variation. Our results showed that Salamandrina is highly specialized on Collembola and the more specialized individuals are the better performing ones. Analyses of inter-individual diet variation showed that a subset of animals exhibited a broader trophic niche, adopting different foraging strategies. Our findings reflects the optimal foraging theory both at population and individual level, since animals in better physiological conditions are able to exploit the most profitable prey, suggesting that the two coexisting strategies are not equivalent. At last this species, feeding on decomposers of litter detritus, could play a key role determining litter retention rate, nutrient cycle and carbon sequestration. PMID:26292804

Intra-individual and inter-individual variations in sperm aneuploidy frequencies in normal men.

PubMed

Tempest, Helen G; Ko, Evelyn; Rademaker, Alfred; Chan, Peter; Robaire, Bernard; Martin, Renée H

2009-01-01

To investigate whether there are intra-individual and/or inter-individual variations in sperm aneuploidy frequencies within the normal male population, and, if this is the case, whether they are sporadic or time-stable variants. Prospective study. University research laboratory. Ten men aged 18-32 years. None. Fluorescence in situ hybridization was used to investigate sperm aneuploidy frequencies for chromosomes X, Y, 13, and 21 in serial semen samples collected over a period of 12-18 months. Intra-individual and inter-individual variations were investigated by comparing serial samples from the same donor and by comparing the donors with each other, respectively. Intra-individual variations were found in all 10 donors for at least one investigated chromosome; variations tended to be sporadic events affecting only one time point. Inter-individual variations were found for all chromosomes (except XX and YY disomy and disomy 21), with three men identified as stable variants, consistently producing higher levels of aneuploidy for at least one of the following aneuploidies: sex chromosome nullisomy; disomy 13, or diploidy. These results suggest that there are a number of factors and mechanisms that have the potential to sporadically or consistently affect sperm aneuploidy.

Long-Term Species, Sexual and Individual Variations in Foraging Strategies of Fur Seals Revealed by Stable Isotopes in Whiskers

PubMed Central

Kernaléguen, Laëtitia; Cazelles, Bernard; Arnould, John P. Y.; Richard, Pierre; Guinet, Christophe; Cherel, Yves

2012-01-01

Background Individual variations in the use of the species niche are an important component of diversity in trophic interactions. A challenge in testing consistency of individual foraging strategy is the repeated collection of information on the same individuals. Methodology/Principal Findings The foraging strategies of sympatric fur seals (Arctocephalus gazella and A. tropicalis) were examined using the stable isotope signature of serially sampled whiskers. Most whiskers exhibited synchronous δ13C and δ15N oscillations that correspond to the seal annual movements over the long term (up to 8 years). δ13C and δ15N values were spread over large ranges, with differences between species, sexes and individuals. The main segregating mechanism operates at the spatial scale. Most seals favored foraging in subantarctic waters (where the Crozet Islands are located) where they fed on myctophids. However, A. gazella dispersed in the Antarctic Zone and A. tropicalis more in the subtropics. Gender differences in annual time budget shape the seal movements. Males that do not perform any parental care exhibited large isotopic oscillations reflecting broad annual migrations, while isotopic values of females confined to a limited foraging range during lactation exhibited smaller changes. Limited inter-individual isotopic variations occurred in female seals and in male A. tropicalis. In contrast, male A. gazella showed large inter-individual variations, with some males migrating repeatedly to high-Antarctic waters where they fed on krill, thus meaning that individual specialization occurred over years. Conclusions/Significance Whisker isotopic signature yields unique long-term information on individual behaviour that integrates the spatial, trophic and temporal dimensions of the ecological niche. The method allows depicting the entire realized niche of the species, including some of its less well-known components such as age-, sex-, individual- and migration-related changes. It highlights intrapopulation heterogeneity in foraging strategies that could have important implications for likely demographic responses to environmental variability. PMID:22431988

The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

PubMed

Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

2014-09-01

Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids

PubMed Central

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-01-01

Objectives: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Methods: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). Results: The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini–Hochberg criterion for a 10% false discovery rate. Conclusions: Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment. PMID:26087058

Polymorphisms in CYP1A1 and CYP3A5 Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting.

PubMed

Bustos, Martha L; Zhao, Yang; Chen, Huijun; Caritis, Steve N; Venkataramanan, Raman

2016-12-01

Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large interindividual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1, and ABCB1 can alter drug metabolism. This study evaluated the influence of polymorphisms in CYP3A4, CYP3A5, CYP1A1, and ABCB1 on the pharmacokinetic properties of granisetron in pregnant women. The study enrolled 16 pregnant women (gestational age of 12-19 wks). All patients had nausea and vomiting and were treated with granisetron 1 mg. Granisetron plasma concentrations were determined using liquid chromatography tandem-mass spectrometry. The patients' genotype was determined using TaqMan SNP Genotyping Assays. The Hardy-Weinberg equilibrium was assessed by comparing observed and expected genotype frequencies, using the exact test. Intravenous granisetron clearance was used as the dependent variable for analysis of associations. Of 16 patients, 25% were homozygous for the allele variant CYP3A5*3 and had a significantly lower granisetron clearance and increased area under the plasma concentration-versus-time curve (AUC) compared with nonhomozygous patients. Approximately one-third of patients (n=5) were carriers for the allele variant CYP1A1*2A and had a significantly higher granisetron clearance and decreased AUC. We did not find significant differences in the AUC or clearance for any SNPs in CYP3A4 and ABCB1 genes. Polymorphisms in CYP3A5 and CYP1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women. © 2016 Pharmacotherapy Publications, Inc.

Dopamine response to psychosocial stress in humans and its relationship to individual differences in personality traits.

PubMed

Suridjan, Ivonne; Boileau, Isabelle; Bagby, Michael; Rusjan, Pablo M; Wilson, Alan A; Houle, Sylvain; Mizrahi, Romina

2012-07-01

Previous studies have reported inter-individual variability in the dopamine (DA) response to stress. This variability might be related to individual differences in the vulnerability to experience the negative effect of stress. To investigate whether personality traits as measured by the revised NEO personality inventory explain variability in DA response to a psychosocial stress task. Eleven healthy adults, mean age of 26 ± 3.87 underwent two positron emission tomography (PET) scans using the dopamine D(2/3) agonist, [11C]-(+)-PHNO under a control and stress condition. The simplified reference tissue model (SRTM) was used to obtain [11C]-(+)-PHNO binding potential (BP(ND)). Stress-induced DA response was indexed as a percent change in [11C]-(+)-PHNO BP(ND) between control and stress conditions. The regions of interest were defined into D2-rich regions, which included the Associative and Sensorimotor Striatum (AST and SMST); D(2/3) mixed regions, which included the limbic striatum (LST) and globus pallidus (GP); and D3-rich region, which included the Substantia Nigra (SN). Several personality traits within the Neuroticism and Openness to Experience domain were significantly correlated with blunted DA response to stress. Specifically, the Angry-Hostility, Vulnerability, and Depression trait were associated with blunted DA stress response in the AST (r = -0.645, p = 0.032), LST (r = -0.677, p = 0.022) and GP (r = -0.736, p = 0.010), respectively. The Openness to Values was correlated with a decreased DA release in the SN (r = -0.706, p = 0.015). Variability in DA stress response might be related to individual differences in personality. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients

PubMed Central

de Winter, Brenda C. M.; Masman, Anniek D.; van Dijk, Monique; Baar, Frans P. M.; Tibboel, Dick; Koch, Birgit C. P.; van Gelder, Teun; Mathot, Ron A. A.

2017-01-01

Aims Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response. Method A population PD analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check. Results The effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and interindividual variability on the overall effect. The EC50 value was 68.7 μg l–1 for a Ramsay score of 3–5 and 117.1 μg l–1 for a Ramsay score of 6. Comedication with haloperidol was the only significant covariate. The visual predictive check of the final model showed good model predictability. Conclusion We were able to describe the clinical response to midazolam accurately. As expected, there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication, as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure. PMID:28960387

Decision making in healthy participants on the Iowa Gambling Task: new insights from an operant approach

PubMed Central

Bull, Peter N.; Tippett, Lynette J.; Addis, Donna Rose

2015-01-01

The Iowa Gambling Task (IGT) has contributed greatly to the study of affective decision making. However, researchers have observed high inter-study and inter-individual variability in IGT performance in healthy participants, and many are classified as impaired using standard criteria. Additionally, while decision-making deficits are often attributed to atypical sensitivity to reward and/or punishment, the IGT lacks an integrated sensitivity measure. Adopting an operant perspective, two experiments were conducted to explore these issues. In Experiment 1, 50 healthy participants completed a 200-trial version of the IGT which otherwise closely emulated Bechara et al.'s (1999) original computer task. Group data for Trials 1–100 closely replicated Bechara et al.'s original findings of high net scores and preferences for advantageous decks, suggesting that implementations that depart significantly from Bechara's standard IGT contribute to inter-study variability. During Trials 101–200, mean net scores improved significantly and the percentage of participants meeting the “impaired” criterion was halved. An operant-style stability criterion applied to individual data revealed this was likely related to individual differences in learning rate. Experiment 2 used a novel operant card task—the Auckland Card Task (ACT)—to derive quantitative estimates of sensitivity using the generalized matching law. Relative to individuals who mastered the IGT, persistent poor performers on the IGT exhibited significantly lower sensitivity to magnitudes (but not frequencies) of rewards and punishers on the ACT. Overall, our findings demonstrate the utility of operant-style analysis of IGT data and the potential of applying operant concurrent-schedule procedures to the study of human decision making. PMID:25904884

Metabolomic phenotyping of a cloned pig model

PubMed Central

2011-01-01

Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal outbred pigs. Results The metabolic phenotype of cloned pigs (n = 5) was for the first time elucidated by nuclear magnetic resonance (NMR)-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n = 6) by multivariate data analysis, which revealed differences in the metabolic phenotypes. Plasma lactate was higher for cloned vs control pigs, while multiple metabolites were altered in the bile. However a lower inter-individual variability for cloned pigs compared with control pigs could not be established. Conclusions From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals. PMID:21859467

Clinical vision characteristics of the congenital achromatopsias. II. Color vision.

PubMed

Haegerstrom-Portnoy, G; Schneck, M E; Verdon, W A; Hewlett, S E

1996-07-01

Twelve X-linked (XL) achromats and 43 autosomal recessive (AR) achromats were tested using the Farnsworth D-15, Nagel anomaloscope, Sloan achromatopsia test, and Berson test using standard procedures. All of the tests identify achromatopsia, but very few differentially diagnose the various types. AR achromats were subclassified as complete (rods only) or incomplete (residual cone function present) by additional psychophysical testing. Complete and incomplete ARs do not perform differently on any clinical color vision measure, indicating that (1) rods predominantly mediate vision in both groups and (2) these tests are not useful for distinguishing between the groups. Both groups show considerable interindividual variation on all measures. Only one of the measures, the Berson test, designed to distinguish XLs from ARs, does so reliably. XLs and ARs do not differ significantly on the Nagel anomaloscope or most of the Sloan plates. The confusion angles of the D-15 do differ for the two groups, but the variability in each group makes the measure unreliable for classifying individuals. The Berson test is recommended to distinguish the XL from AR achromats.

Comparison of genetic variations of the SLCO1B1, SLCO1B3, and SLCO2B1 genes among five ethnic groups.

PubMed

Namgoong, Suhg; Cheong, Hyun Sub; Kim, Ji On; Kim, Lyoung Hyo; Na, Han Sung; Koh, In Song; Chung, Myeon Woo; Shin, Hyoung Doo

2015-11-01

Organic anion-transporting polypeptide (OATP; gene symbol, SLCO) transporters are generally involved in the uptake of multiple drugs and their metabolites at most epithelial barriers. The pattern of single-nucleotide polymorphisms (SNPs) in these transporters may be determinants of interindividual variability in drug disposition and response. The objective of this study was to define the distribution of SNPs of three SLCO genes, SLCO1B1, SLCO1B3, and SLCO2B1, in a Korean population and other ethnic groups. The study was screened using the Illumina GoldenGate assay for genomic DNA from 450 interethnic subjects, including 11 pharmacogenetic core variants and 76 HapMap tagging SNPs. The genotype distribution of the Korean population was similar to East Asian populations, but significantly different from African American and European American cohorts. These interethnic differences will be useful information for prospective studies, including genetic association and pharmacogenetic studies of drug metabolism by SLCO families. Copyright © 2015 Elsevier B.V. All rights reserved.

The expression of the skeletal muscle force-length relationship in vivo: a simulation study.

PubMed

Winter, Samantha L; Challis, John H

2010-02-21

The force-length relationship is one of the most important mechanical characteristics of skeletal muscle in humans and animals. For a physiologically realistic joint range of motion and therefore range of muscle fibre lengths only part of the force-length curve may be used in vivo, i.e. only a section of the force-length curve is expressed. A generalised model of a mono-articular muscle-tendon complex was used to examine the effect of various muscle architecture parameters on the expressed section of the force-length relationship for a 90 degrees joint range of motion. The parameters investigated were: the ratio of tendon resting length to muscle fibre optimum length (L(TR):L(F.OPT)) (varied from 0.5 to 11.5), the ratio of muscle fibre optimum length to average moment arm (L(F.OPT):r) (varied from 0.5 to 5), the normalised tendon strain at maximum isometric force (c) (varied from 0 to 0.08), the muscle fibre pennation angle (theta) (varied from 0 degrees to 45 degrees) and the joint angle at which the optimum muscle fibre length occurred (phi). The range of values chosen for each parameter was based on values reported in the literature for five human mono-articular muscles with different functional roles. The ratios L(TR):L(F.OPT) and L(F.OPT):r were important in determining the amount of variability in the expressed section of the force-length relationship. The modelled muscle operated over only one limb at intermediate values of these two ratios (L(TR):L(F.OPT)=5; L(F.OPT):r=3), whether this was the ascending or descending limb was determined by the precise values of the other parameters. It was concluded that inter-individual variability in the expressed section of the force-length relationship is possible, particularly for muscles with intermediate values of L(TR):L(F.OPT) and L(F.OPT):r such as the brachialis and vastus lateralis. Understanding the potential for inter-individual variability in the expressed section is important when using muscle models to simulate movement. (c) 2009 Elsevier Ltd. All rights reserved.

Expression of human oxoguanine glycosylase 1 or formamidopyrimidine glycosylase in human embryonic kidney 293 cells exacerbates methylmercury toxicity in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ondovcik, Stephanie L.; Preston, Thomas J.; McCallum, Gordon P.

Exposure to methylmercury (MeHg) acutely at high levels, or via chronic low-level dietary exposure from daily fish consumption, can lead to adverse neurological effects in both the adult and developing conceptus. To determine the impact of variable DNA repair capacity, and the role of reactive oxygen species (ROS) and oxidatively damaged DNA in the mechanism of toxicity, transgenic human embryonic kidney (HEK) 293 cells that stably express either human oxoguanine glycosylase 1 (hOgg1) or its bacterial homolog, formamidopyrimidine glycosylase (Fpg), which primarily repair the oxidative lesion 8-oxo-2′-deoxyguanosine (8-oxodG), were used to assess the in vitro effects of MeHg. Western blottingmore » confirmed the expression of hOgg1 or Fpg in both the nuclear and mitochondrial compartments of their respective cell lines. Following acute (1–2 h) incubations with 0–10 μM MeHg, concentration-dependent decreases in clonogenic survival and cell growth accompanied concentration-dependent increases in lactate dehydrogenase (LDH) release, ROS formation, 8-oxodG levels and apurinic/apyrimidinic (AP) sites, consistent with the onset of cytotoxicity. Paradoxically, hOgg1- and Fpg-expressing HEK 293 cells were more sensitive than wild-type cells stably transfected with the empty vector control to MeHg across all cellular and biochemical parameters, exhibiting reduced clonogenic survival and cell growth, and increased LDH release and DNA damage. Accordingly, upregulation of specific components of the base excision repair (BER) pathway may prove deleterious potentially due to the absence of compensatory enhancement of downstream processes to repair toxic intermediary abasic sites. Thus, interindividual variability in DNA repair activity may constitute an important risk factor for environmentally-initiated, oxidatively damaged DNA and its pathological consequences. - Highlights: • hOgg1 and Fpg repair oxidatively damaged DNA. • hOgg1- and Fpg-expressing cells are more sensitive to MeHg toxicity. • Enhanced sensitivity is likely due to an accumulation of toxic repair intermediates. • Interindividual variability in DNA repair activity may modulate toxicological risk.« less

Fecal concentrations of bacterially derived vitamin K forms are associated with gut microbiota composition but not plasma or fecal cytokine concentrations in healthy adults.

PubMed

Karl, J Philip; Meydani, Mohsen; Barnett, Junaidah B; Vanegas, Sally M; Barger, Kathryn; Fu, Xueyan; Goldin, Barry; Kane, Anne; Rasmussen, Helen; Vangay, Pajau; Knights, Dan; Jonnalagadda, Satya S; Saltzman, Edward; Roberts, Susan B; Meydani, Simin N; Booth, Sarah L

2017-10-01

Background: Emerging evidence suggests novel roles for bacterially derived vitamin K forms known as menaquinones in health and disease, which may be attributable in part to anti-inflammatory effects. However, the relevance of menaquinones produced by gut bacteria to vitamin K requirements and inflammation is undetermined. Objective: This study aimed to quantify fecal menaquinone concentrations and identify associations between fecal menaquinone concentrations and serum vitamin K concentrations, gut microbiota composition, and inflammation. Design: Fecal and serum menaquinone concentrations, fecal microbiota composition, and plasma and fecal cytokine concentrations were measured in 80 men and postmenopausal women (48 men, 32 women, age 40-65 y) enrolled in a randomized, parallel-arm, provided-food trial. After consuming a run-in diet for 2 wk, participants were randomly assigned to consume a whole grain-rich (WG) or a refined grain-based (RG) diet for 6 wk. Outcomes were measured at weeks 2 and 8. Results: The median total daily excretion of menaquinones in feces was 850 nmol/d but was highly variable (range: 64-5358 nmol/d). The total median (IQR) fecal concentrations of menaquinones decreased in the WG diet compared with the RG diet [-6.8 nmol/g (13.0 nmol/g) dry weight for WG compared with 1.8 nmol/g (12.3 nmol/g) dry weight for RG; P < 0.01)]. However, interindividual variability in fecal menaquinone concentrations partitioned individuals into 2 distinct groups based on interindividual differences in concentrations of different menaquinone forms rather than the diet group or the time point. The relative abundances of several gut bacteria taxa, Bacteroides and Prevotella in particular, differed between these groups, and 42% of identified genera were associated with ≥1 menaquinone form. Menaquinones were not detected in serum, and neither fecal concentrations of individual menaquinones nor the menaquinone group was associated with any marker of inflammation. Conclusion: Menaquinone concentrations in the human gut appear highly variable and are associated with gut microbiota composition. However, the health implications remain unclear. This trial was registered at clinicaltrials.gov as NCT01902394. © 2017 American Society for Nutrition.

A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours

PubMed Central

Undevia, Samir D.; Innocenti, Federico; Ramirez, Jacqueline; House, Larry; Desai, Apurva A.; Skoog, Linda A.; Singh, Deepti A.; Karrison, Theodore; Kindler, Hedy L.; Ratain, Mark J.

2009-01-01

Purpose To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose. Methods R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1–5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmaco-kinetic studies. Results Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma. Conclusions The recommended phase II doses are 850–1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes. PMID:18650079

Inter-individual and intragenomic variations in the ITS region of Clonorchis sinensis (Trematoda: Opisthorchiidae) from Russia and Vietnam.

PubMed

Tatonova, Yulia V; Chelomina, Galina N; Nguyen, Hung Manh

2017-11-01

Here we examined the intraspecific genetic variability of Clonorchis sinensis from Russia and Vietnam using nuclear DNA sequences (the 5.8S gene and two internal transcribed spacers of the ribosomal cluster). Despite the low level of variability in the ITS1 region, this marker has revealed some features of C. sinensis across multiple geographic regions. The genetic diversity levels for the Russian and Vietnamese populations were similar (0.1 and 0.09%, respectively) but were significantly lower than the C. sinensis from China (0.31%). About half of the sequences of the Chinese (53%) and Korean (47%) populations and about a tenth of the Vietnamese (12%) and Russian (8%) sequences included a 5bp insertion. No sequences with nucleotide substitutions both upstream and downstream of the 5bp insertion were found within the whole data set. The population of northern China had both sequence variants (with substitutions either upstream or downstream of the insertion), while only one of these variants was presented at the other localities. The Vietnamese population had a higher frequency of intragenomic polymorphism than the Russian population (69% vs. 46% and 23% vs. 3% at the 114bp and 339bp positions, respectively). These data are discussed in connection with parasite origin and adaptation, and also its invasive capacity and drug-resistance. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacogenetics of CYP1A2 activity and inducibility in smokers and exsmokers.

PubMed

Dobrinas, Maria; Cornuz, Jacques; Eap, Chin B

2013-05-01

There is a high interindividual variability in cytochrome P4501A2 (CYP1A2) activity and in its inducibility by smoking, only poorly explained by known CYP1A2 polymorphisms. We aimed to study the contribution of other regulatory pathways, including transcription factors and nuclear receptors, toward this variability. CYP1A2 activity was determined by the paraxanthine/caffeine ratio in 184 smokers and in 113 of them who were abstinent for 4 weeks. Participants were genotyped for 22 polymorphisms in 12 genes. A significant influence on CYP1A2 inducibility was observed for the NR1I3 rs2502815 (P=0.0026), rs4073054 (P=0.029), NR2B1 rs3818740 (P=0.0045), rs3132297 (P=0.036), AhR rs2282885 (P=0.040), rs2066853 (P=0.019), NR1I1 rs2228570 (P=0.037), and NR1I2 rs1523130 (P=0.044) polymorphisms. Among these, the NR1I3 rs2502815 (P=0.0045), rs4073054 (P=0.048), and NR2B1 rs3818740 (P=0.031) also influenced CYP1A2 basal activity. This is the first in-vivo demonstration of the influence of genes involved in CYP1A2 regulatory pathways on its basal activity and inducibility by smoking. These results need to be confirmed by other studies.

A Comparative Magnetic Resonance Imaging Study of the Anatomy, Variability, and Asymmetry of Broca's Area in the Human and Chimpanzee Brain

PubMed Central

Keller, Simon S.; Roberts, Neil; Hopkins, William

2009-01-01

The frontal operculum—classically considered to be Broca's area—has special significance and interest in clinical, cognitive, and comparative neuroscience given its role in spoken language and the long-held assumption that structural asymmetry of this region of cortex may be related to functional lateralization of human language. We performed a detailed morphological and morphometric analysis of this area of the brain in humans and chimpanzees using identical image acquisition parameters, image analysis techniques, and consistent anatomical boundaries in both species. We report great inter-individual variability of the sulcal contours defining the operculum in both species, particularly discontinuity of the inferior frontal sulcus in humans and bifurcation of the inferior precentral sulcus in chimpanzees. There was no evidence of population-based asymmetry of the frontal opercular gray matter in humans or chimpanzees. The diagonal sulcus was only identified in humans, and its presence was significantly (F = 12.782, p < 0.001) associated with total volume of the ipsilateral operculum. The findings presented here suggest that there is no population-based interhemispheric macroscopic asymmetry of Broca's area in humans or Broca's area homolog in chimpanzees. However, given that previous studies have reported asymmetry in the cytoarchitectonic fields considered to represent Broca's area—which is important given that cytoarchitectonic boundaries are more closely related to the regional functional properties of cortex relative to sulcal landmarks—it may be that the gross morphology of the frontal operculum is not a reliable indicator of Broca's area per se. PMID:19923293

Steroid profiles of professional soccer players: an international comparative study.

PubMed

Strahm, E; Sottas, P-E; Schweizer, C; Saugy, M; Dvorak, J; Saudan, C

2009-12-01

Urinary steroid profiling is used in doping controls to detect testosterone abuse. A testosterone over epitestosterone (T/E) ratio exceeding 4.0 is considered as suspicious of testosterone administration, irrespectively of individual heterogeneous factors such as the athlete's ethnicity. A deletion polymorphism in the UGT2B17 gene was demonstrated to account for a significant part of the interindividual variability in the T/E between Caucasians and Asians. Here, the variability of urinary steroid profiles was examined in a widely heterogeneous cohort of professional soccer players. The steroid profile of 57 Africans, 32 Asians, 50 Caucasians and 32 Hispanics was determined by gas chromatography-mass spectrometry. Significant differences have been observed between all ethnic groups. After estimation of the prevalence of the UGT2B17 deletion/deletion genotype (African: 22%; Asian: 81%; Caucasian: 10%; Hispanic: 7%), ethnic-specific thresholds were developed for a specificity of 99% for the T/E (African: 5.6; Asian: 3.8; Caucasian: 5.7; Hispanic: 5.8). Finally, another polymorphism could be hypothesised in Asians based on specific concentration ratio of 5alpha-/5beta-androstane-3alpha,17beta-diol in urine. These results demonstrate that a unique and non-specific threshold to evidence testosterone misuse is not fit for purpose. An athlete's endocrinological passport consisting of a longitudinal follow-up together with the ethnicity and/or the genotype would strongly enhance the detection of testosterone abuse. Finally, additional genotyping studies should be undertaken to determine whether the remaining unexplained disparities have an environmental or a genetic origin.

Intra-lesional spatial correlation of static and dynamic FET-PET parameters with MRI-based cerebral blood volume in patients with untreated glioma.

PubMed

Göttler, Jens; Lukas, Mathias; Kluge, Anne; Kaczmarz, Stephan; Gempt, Jens; Ringel, Florian; Mustafa, Mona; Meyer, Bernhard; Zimmer, Claus; Schwaiger, Markus; Förster, Stefan; Preibisch, Christine; Pyka, Thomas

2017-03-01

18 F-fluorethyltyrosine-(FET)-PET and MRI-based relative cerebral blood volume (rCBV) have both been used to characterize gliomas. Recently, inter-individual correlations between peak static FET-uptake and rCBV have been reported. Herein, we assess the local intra-lesional relation between FET-PET parameters and rCBV. Thirty untreated glioma patients (27 high-grade) underwent simultaneous PET/MRI on a 3 T hybrid scanner obtaining structural and dynamic susceptibility contrast sequences. Static FET-uptake and dynamic FET-slope were correlated with rCBV within tumour hotspots across patients and intra-lesionally using a mixed-effects model to account for inter-individual variation. Furthermore, maximal congruency of tumour volumes defined by FET-uptake and rCBV was determined. While the inter-individual relationship between peak static FET-uptake and rCBV could be confirmed, our intra-lesional, voxel-wise analysis revealed significant positive correlations (median r = 0.374, p < 0.0001). Similarly, significant inter- and intra-individual correlations were observed between FET-slope and rCBV. However, rCBV explained only 12% of the static and 5% of the dynamic FET-PET variance and maximal overlap of respective tumour volumes was 37% on average. Our results show that the relation between peak values of MR-based rCBV and static FET-uptake can also be observed intra-individually on a voxel basis and also applies to a dynamic FET parameter, possibly determining hotspots of higher biological malignancy. However, just a small part of the FET-PET signal variance is explained by rCBV and tumour volumes determined by the two modalities showed only moderate overlap. These findings indicate that FET-PET and MR-based rCBV provide both congruent and complimentary information on glioma biology.

Proactive vs. reactive car driving: EEG evidence for different driving strategies of older drivers

PubMed Central

Wascher, Edmund; Getzmann, Stephan

2018-01-01

Aging is associated with a large heterogeneity in the extent of age-related changes in sensory, motor, and cognitive functions. All these functions can influence the performance in complex tasks like car driving. The present study aims to identify potential differences in underlying cognitive processes that may explain inter-individual variability in driving performance. Younger and older participants performed a one-hour monotonous driving task in a driving simulator under varying crosswind conditions, while behavioral and electrophysiological data were recorded. Overall, younger and older drivers showed comparable driving performance (lane keeping). However, there was a large difference in driving lane variability within the older group. Dividing the older group in two subgroups with low vs. high driving lane variability revealed differences between the two groups in electrophysiological correlates of mental workload, consumption of mental resources, and activation and sustaining of attention: Older drivers with high driving lane variability showed higher frontal Alpha and Theta activity than older drivers with low driving lane variability and—with increasing crosswind—a more pronounced decrease in Beta activity. These results suggest differences in driving strategies of older and younger drivers, with the older drivers using either a rather proactive and alert driving strategy (indicated by low driving lane variability and lower Alpha and Beta activity), or a rather reactive strategy (indicated by high driving lane variability and higher Alpha activity). PMID:29352314

Development and Validation of a Short-Form Adaptation of the Age-Related Vision Loss Scale: The AVL12

ERIC Educational Resources Information Center

Horowitz, Amy; Reinhardt, Joann P.; Raykov, Tenko

2007-01-01

This article describes the development and evaluation of a short form of the 24-item Adaptation to Age-Related Vision Loss (AVL) scale. The evaluation provided evidence of the reliability and validity of the short form (the AVL12), for significant interindividual differences at the baseline and for individual-level change in AVL scores over time.…

Inter- and Intra-individual variability following intermittent theta burst stimulation: implications for rehabilitation and recovery.

PubMed

Hinder, Mark R; Goss, Emily L; Fujiyama, Hakuei; Canty, Alison J; Garry, Michael I; Rodger, Jennifer; Summers, Jeffery J

2014-01-01

The continued refinement of non-invasive brain stimulation (NBS) techniques is indicative of promising clinical and rehabilitative interventions that are able to modulate cortical excitability. Intermittent theta burst stimulation (iTBS) is one such technique that can increase cortical excitability, purportedly via LTP-like mechanisms. While iTBS may have the capacity to promote recovery after neurological injury, and to combat cognitive and motor decline, recent reports observed highly variable effects across individuals, questioning the efficacy of iTBS as a clinical tool. The aim of this study was to examine intra-individual reliability and inter-individual variability in responses to iTBS. Thirty healthy participants completed two experimental sessions of the iTBS protocol 1-3 weeks apart. Motor evoked potentials in response to single pulse TMS were used to assess corticospinal excitability prior to, and up to 36 min following, iTBS. At the group level, iTBS evoked statistically significant increases in motor cortical excitability across both sessions (P < 0.001), with 22 out of 30 participants exhibiting increases in excitability in both sessions. A strong intraclass correlation demonstrated that both the direction, and magnitude of the plastic changes were reliable at the individual level. Overall, our results suggest that iTBS is capable of inducing relatively robust and consistent effects within and between young individuals. As such, the capacity for iTBS to be exploited in clinical and rehabilitative interventions should continue to be explored. Copyright © 2014 Elsevier Inc. All rights reserved.

Normative Measurements of Grip and Pinch Strengths of 21st Century Korean Population

PubMed Central

Shim, Jin Hee; Kim, Jin Soo; Lee, Dong Chul; Ki, Sae Hwi; Yang, Jae Won; Jeon, Man Kyung; Lee, Sang Myung

2013-01-01

Background Measuring grip and pinch strength is an important part of hand injury evaluation. Currently, there are no standardized values of normal grip and pinch strength among the Korean population, and lack of such data prevents objective evaluation of post-surgical recovery in strength. This study was designed to establish the normal values of grip and pinch strength among the healthy Korean population and to identify any dependent variables affecting grip and pinch strength. Methods A cross-sectional study was carried out. The inclusion criterion was being a healthy Korean person without a previous history of hand trauma. The grip strength was measured using a Jamar dynamometer. Pulp and key pinch strength were measured with a hydraulic pinch gauge. Intra-individual and inter-individual variations in these variables were analyzed in a standardized statistical manner. Results There were a total of 336 healthy participants between 13 and 77 years of age. As would be expected in any given population, the mean grip and pinch strength was greater in the right hand than the left. Male participants (137) showed mean strengths greater than female participants (199) when adjusted for age. Among the male participants, anthropometric variables correlated positively with grip strength, but no such correlations were identifiable in female participants in a statistically significant way. Conclusions Objective measurements of hand strength are an important component of hand injury evaluation, and population-specific normative data are essential for clinical and research purposes. This study reports updated normative hand strengths of the South Korean population in the 21st century. PMID:23362480

Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.

PubMed

Nader, Ahmed; Zahran, Noran; Alshammaa, Aya; Altaweel, Heba; Kassem, Nancy; Wilby, Kyle John

2017-04-01

Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice. A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII ® . A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics. Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c ) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively). Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

A physiome interoperability roadmap for personalized drug development

PubMed Central

2016-01-01

The goal of developing therapies and dosage regimes for characterized subgroups of the general population can be facilitated by the use of simulation models able to incorporate information about inter-individual variability in drug disposition (pharmacokinetics), toxicity and response effect (pharmacodynamics). Such observed variability can have multiple causes at various scales, ranging from gross anatomical differences to differences in genome sequence. Relevant data for many of these aspects, particularly related to molecular assays (known as ‘-omics’), are available in online resources, but identification and assignment to appropriate model variables and parameters is a significant bottleneck in the model development process. Through its efforts to standardize annotation with consequent increase in data usability, the human physiome project has a vital role in improving productivity in model development and, thus, the development of personalized therapy regimes. Here, we review the current status of personalized medicine in clinical practice, outline some of the challenges that must be overcome in order to expand its applicability, and discuss the relevance of personalized medicine to the more widespread challenges being faced in drug discovery and development. We then review some of (i) the key data resources available for use in model development and (ii) the potential areas where advances made within the physiome modelling community could contribute to physiologically based pharmacokinetic and physiologically based pharmacokinetic/pharmacodynamic modelling in support of personalized drug development. We conclude by proposing a roadmap to further guide the physiome community in its on-going efforts to improve data usability, and integration with modelling efforts in the support of personalized medicine development. PMID:27051513

Calcium and nitrogen balance, experiment M007

NASA Technical Reports Server (NTRS)

Whedon, G. D.; Lutwak, L.; Neuman, W. F.; Lachance, P. A.

1971-01-01

The collection of data on the response of the skeletal and muscular systems to 14-day space flights was evaluated for loss of calcium, nitrogen, and other metabolically related elements. Considerable interindividual variability was demonstrated in all experimental factors that were measured. Calcium balance became less positive and urinary phosphate excretion increased substantially in flight despite a reduction in phosphate intake. Patterns of excretion of magnesium, sodium, potassium, and chloride were different for each subject, and, in part, could be correlated with changes in adrenocortical steroid production. The principal hormonal change was a striking decrease during flight in the urinary excretion of 17-hydroxycortocosteroids. Dermal losses of calcium, magnesium, sulfate, and phosphate were insignificant during all three phases.

Endocrine responses in long-duration manned space flight

NASA Technical Reports Server (NTRS)

Leach, C. S.; Rambaut, P. C.

1975-01-01

Endocrine measurements to assess the physiological cost of the combined stresses of space flight are considered from two aspects. First, fluid and electrolyte balance are correlated with weight loss, changes in the excretion of aldosterone and vasopressin and fluid compartments. The second area involves estimation of the physiological cost of maintaining a given level of performance during space flight by analysis of urinary catecholamines and cortisol. Inter-individual variability is demonstrated for most experimental indices measured. The measured changes are consistent with the hypothesis that a relative increase in thoracic blood volume upon transition to the zero-gravity environment can be interpreted as a true volume expansion resulting in an osmotic diuresis.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

PubMed Central

Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Eline Slagboom, P.; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O’Brien, Eoin; Shaw-Hawkins, Sue; Ida Chen, Y.-D.; Nickerson, Deborah A.; Smith, Joshua D.; Pierre Dubé, Marie; Matthijs Boekholdt, S.; Kees Hovingh, G.; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O’Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; MacFadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Adrienne Cupples, L.; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Wouter Jukema, J; Caulfield, Mark J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; McCarthy, Mark I.; Spencer, Chris C. A.

2014-01-01

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response. PMID:25350695

Measurement of temperature induced in bone during drilling in minimally invasive foot surgery.

PubMed

Omar, Noor Azzizah; McKinley, John C

2018-02-19

There has been growing interest in minimally invasive foot surgery due to the benefits it delivers in post-operative outcomes in comparison to conventional open methods of surgery. One of the major factors determining the protocol in minimally invasive surgery is to prevent iatrogenic thermal osteonecrosis. The aim of the study is to look at various drilling parameters in a minimally invasive surgery setting that would reduce the risk of iatrogenic thermal osteonecrosis. Sixteen fresh-frozen tarsal bones and two metatarsal bones were retrieved from three individuals and drilled using various settings. The parameters considered were drilling speed, drill diameter, and inter-individual cortical variability. Temperature measurements of heat generated at the drilling site were collected using two methods; thermocouple probe and infrared thermography. The data obtained were quantitatively analysed. There was a significant difference in the temperatures generated with different drilling speeds (p<0.05). However, there was no significant difference in temperatures recorded between the bones of different individuals and in bones drilled using different drill diameters. Thermocouple showed significantly more sensitive tool in measuring temperature compared to infrared thermography. Drilling at an optimal speed significantly reduced the risk of iatrogenic thermal osteonecrosis by maintaining temperature below the threshold level. Although different drilling diameters did not produce significant differences in temperature generation, there is a need for further study on the mechanical impact of using different drill diameters. Copyright © 2018 Elsevier Ltd. All rights reserved.

Integrating Genomic Based Information into Clinical Warfarin (Coumadin®) Management: An Illustrative Case Report

PubMed Central

LaSala, Anthony; Bower, Bruce; Windemuth, Andreas; White, C. Michael; Kocherla, Mohan; Seip, Richard; Duconge, Jorge; Ruaño, Gualberto

2013-01-01

Warfarin is a well established oral anticoagulant for the treatment of thromboembolic disorders. Warfarin therapy is complicated by a narrow therapeutic index and marked inter-individual dose variability with therapeutic doses ranging from 1 mg to 10 mg/day.1 Recently genetic variation and resultant drug metabolizing polymorphisms have been found to contribute to warfarin dose variability with resultant hemorrhagic or thromboembolic complications. Cytochrome P450 2C9 alters the rate of warfarin metabolism and clearance. A second enzyme, vitamin K epoxide reductase comple (VKOR) binds and reduces vitamin K which is necessary for activation of clotting Factors II, VII, IX and X. The VKORC1 gene encodes for vitamin K epoxide reductase complex subunit 1, a key component of VKOR. The combination of physiologic factors (30%), CYP2C9 variations (20%) and VKORC1 variants (25%) accounts for approximately 75% of warfarin dose variability. This illustrative case report demonstrates the clinical importance of this new information. Clinicians need to incorporate these new genomic findings into appropriate management of warfarin dose anticoagulation. PMID:18763667

The Importance of Encoding-Related Neural Dynamics in the Prediction of Inter-Individual Differences in Verbal Working Memory Performance

PubMed Central

Majerus, Steve; Salmon, Eric; Attout, Lucie

2013-01-01

Studies of brain-behaviour interactions in the field of working memory (WM) have associated WM success with activation of a fronto-parietal network during the maintenance stage, and this mainly for visuo-spatial WM. Using an inter-individual differences approach, we demonstrate here the equal importance of neural dynamics during the encoding stage, and this in the context of verbal WM tasks which are characterized by encoding phases of long duration and sustained attentional demands. Participants encoded and maintained 5-word lists, half of them containing an unexpected word intended to disturb WM encoding and associated task-related attention processes. We observed that inter-individual differences in WM performance for lists containing disturbing stimuli were related to activation levels in a region previously associated with task-related attentional processing, the left intraparietal sulcus (IPS), and this during stimulus encoding but not maintenance; functional connectivity strength between the left IPS and lateral prefrontal cortex (PFC) further predicted WM performance. This study highlights the critical role, during WM encoding, of neural substrates involved in task-related attentional processes for predicting inter-individual differences in verbal WM performance, and, more generally, provides support for attention-based models of WM. PMID:23874935

Development from childhood to adulthood increases morphological and functional inter-individual variability in the right superior temporal cortex.

PubMed

Bonte, Milene; Frost, Martin A; Rutten, Sanne; Ley, Anke; Formisano, Elia; Goebel, Rainer

2013-12-01

We study the developmental trajectory of morphology and function of the superior temporal cortex (STC) in children (8-9 years), adolescents (14-15 years) and young adults. We analyze cortical surface landmarks and functional MRI (fMRI) responses to voices, other natural categories and tones and examine how hemispheric asymmetry and inter-subject variability change across age. Our results show stable morphological asymmetries across age groups, including a larger left planum temporale and a deeper right superior temporal sulcus. fMRI analyses show that a rightward lateralization for voice-selective responses is present in all groups but decreases with age. Furthermore, STC responses to voices change from being less selective and more spatially diffuse in children to highly selective and focal in adults. Interestingly, the analysis of morphological landmarks reveals that inter-subject variability increases during development in the right--but not in the left--STC. Similarly, inter-subject variability of cortically-realigned functional responses to voices, other categories and tones increases with age in the right STC. Our findings reveal asymmetric developmental changes in brain regions crucial for auditory and voice perception. The age-related increase of inter-subject variability in right STC suggests that anatomy and function of this region are shaped by unique individual developmental experiences. © 2013.

Spectral Remittance and Transmittance of Visible and Infrared-A Radiation in Human Skin-Comparison Between in vivo Measurements and Model Calculations.

PubMed

Piazena, Helmut; Meffert, Hans; Uebelhack, Ralf

2017-11-01

The aim of the study was to assess the interindividual variability of spectral remittance and spectral transmittance of visible and infrared-A radiations interacting with human skin and subcutaneous tissue, and direct measurements were taken in vivo using healthy persons of different skin color types. Up to wavelengths of about 900 nm, both spectral remittance and spectral transmittance depended significantly on the individual contents of melanin and hemoglobin in the skin, whereas the contents of water and lipids mainly determined spectral slopes of both characteristics of interaction for wavelengths above about 900 nm. In vivo measured data of spectral transmittance showed approximately similar decreases with tissue thickness between about 900 nm and 1100 nm as compared with model data which were calculated using spectral absorption and scattering coefficients of skin samples in vitro published by different authors. In addition, in vivo measured data and in vitro-based model calculations of spectral remittance were approximately comparable in this wavelength range. In contrast, systematic but individually varying differences between both methods were found for both spectral remittance and spectral transmittance at wavelengths below about 900 nm, where interaction of radiation was significantly affected by both melanin and hemoglobin. © 2017 The American Society of Photobiology.

PILOT RESULTS ON FORWARD COLLISION WARNING SYSTEM EFFECTIVENESS IN OLDER DRIVERS

PubMed Central

Lester, Benjamin D.; Sager, Lauren N.; Dawson, Jeffrey; Hacker, Sarah D.; Aksan, Nazan; Rizzo, Matthew; Kitazaki, Satoshi

2016-01-01

Summary Advanced Driver Assistance Systems (ADAS) have largely been developed with a “one-size-fits-all” approach. This approach neglects the large inter-individual variability in perceptual and cognitive abilities that affect aging ADAS users. We investigated the effectiveness of a forward collision warning (FCW) with fixed response parameters in young and older drivers with differing levels of cognitive functioning. Drivers responded to a pedestrian stepping into the driver’s path on a simulated urban road. Behavioral metrics included response times (RT) for pedal controls and two indices of risk penetration (e.g., maximum deceleration and minimum time-to-collision (TTC)). Older drivers showed significantly slower responses at several time points compared to younger drivers. The FCW facilitated response times (RTs) for older and younger drivers. However, older drivers still showed smaller safety gains compared to younger drivers at accelerator pedal release and initial brake application when the FCW was active. No significant differences in risk metrics were observed within the condition studied. The results demonstrate older drivers likely differ from younger drivers using a FCW with a fixed parameter set. Finally, we briefly discuss how future research should examine predictive relationships between domains of cognitive functioning and ADAS responses to develop parameter sets to fit the individual. PMID:27135061

Detecting components of hearing aid fitting using a self-assessment-inventory.

PubMed

Meister, Hartmut; Lausberg, Isabel; Kiessling, Juergen; von Wedel, Hasso; Walger, Martin

2005-07-01

The evaluation of hearing-aid fitting includes numerous assessments such as electro- and psychoacoustic tests. The subjective estimation of the hearing aid user can be elicited with self-assessment inventories encompassing various parameters, e.g., benefit, satisfaction and usage. A questionnaire comprising 11 domains (disability, handicap, frequency and significance of the listening situation, importance of the hearing aid, expectation, demand, aided performance, benefit, satisfaction and usage) within three different conditions (speech in quiet and in noise and listening to sounds) was used to detect components underlying hearing aid fitting. The data show a three-factor structure (situation-, restriction- and aid-related variables) independent from the conditions. Usage depends on all of the three factors. Disability and handicap reveal the highest values for speech in noise, whereas the aid-related factor shows the lowest values for this condition. Global satisfaction with the hearing aid is significantly correlated with the aid-related factor, but independent from the restriction of hearing. The aid-related factor is positively influenced by the amount of social activity because more active persons report higher benefit and satisfaction for all listening conditions. Age does not exhibit a significant relationship to one of the components. Basically, all correlation coefficients are only intermediate, revealing that inter-individual differences of the patients are rather high. The data indicate that extra-audiological factors might also play an important role in the success of hearing aid fitting.

Effects of Interaction Between DRD4 Methylation and Prenatal Maternal Stress on Methylphenidate-Induced Changes in Continuous Performance Test Performance in Youth with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kim, Johanna Inhyang; Kim, Jae-Won; Shin, Inkyung; Kim, Bung-Nyun

2018-06-15

Environmental factors may interact with genetic factors via the epigenetic process, and this interaction can contribute to inter-individual variability in the treatment response. The purpose of this study was to investigate the interaction effects between dopamine receptor D4 (DRD4) methylation and prenatal maternal stress on the methylphenidate (MPH) response of youth with attention-deficit/hyperactivity disorder (ADHD). This study was an 8-week open-label trial of MPH that included 74 ADHD youth. We investigated the associations between MPH treatment response, which was defined as a score ≤2 on the Clinical Global Impressions-Improvement (CGI-I) scale, and the methylation of 28 cytosine-guanine dinucleotide (CpG) sites of DRD4. Additionally, the interaction effects between DRD4 methylation and prenatal maternal stress on changes in Continuous Performance Test (CPT) scores after MPH treatment were investigated. Although there were no significant sites that showed significant association with treatment response, there was a significant interaction effect of the methylation of CpG7 and prenatal maternal stress on changes in omission errors of the CPT following treatment (p = 0.0001). The present findings indicate that the interaction between methylation of CpG7 of DRD4 and prenatal maternal stress may be predictive of the treatment response to MPH in youth with ADHD.

Dose-response effects of aerobic exercise on energy compensation in postmenopausal women: combined results from two randomized controlled trials.

PubMed

McNeil, J; Brenner, D R; Courneya, K S; Friedenreich, C M

2017-08-01

Despite the clear health benefits of exercise, exercised-induced weight loss is often less than expected. The term 'exercise energy compensation' is used to define the amount of weight loss below what is expected for the amount of exercise energy expenditure. We examined the dose-response effects of exercise volume on energy compensation in postmenopausal women. Data from Alberta Physical Activity and Breast Cancer Prevention (ALPHA) and Breast Cancer and Exercise Trial in Alberta (BETA) were combined for the present analysis. The ALPHA and BETA trials were two-centred, two-armed, 12-month randomized controlled trials. The ALPHA trial included 160 participants randomized to 225 min per week of aerobic exercise, and the BETA trial randomized 200 participants to each 150 and 300 min per week of aerobic exercise. All participants were aged 50-74 years, moderately inactive (<90 min per week of exercise), had no previous cancer diagnosis and a body mass index between 22 and 40 kg m -2 . Energy compensation was based on changes in body composition (dual-energy X-ray absorptiometry scan) and estimated exercise energy expenditure from completed exercise volume. Associations between Δenergy intake, ΔVO 2peak and Δphysical activity time with energy compensation were assessed. No differences in energy compensation were noted between interventions. However, there were large inter-individual differences in energy compensation between participants; 9.4% experienced body composition changes that were greater than expected based on exercise energy expenditure, 64% experienced some degree of energy compensation and 26.6% experienced weight gain based on exercise energy expenditure. Increases in VO 2peak were associated with reductions in energy compensation (β=-3.44 ml kg -1  min -1 , 95% confidence interval for β=-4.71 to -2.17 ml kg -1  min -1 ; P=0.0001). Large inter-individual differences in energy compensation were noted, despite no differences between activity doses. In addition, increases in VO 2peak were associated with lower energy compensation. Future studies are needed to identify behavioral and metabolic factors that may contribute to this large inter-individual variability in energy compensation.

Total energy expenditure in adults with cerebral palsy as assessed by doubly labeled water.

PubMed

Johnson, R K; Hildreth, H G; Contompasis, S H; Goran, M I

1997-09-01

To characterize total energy expenditure (TEE) in free-living adults with cerebral palsy (CP) using the doubly labeled water technique, and to determine those physiologic variables and characteristics of CP that were markers of TEE in adults with CP. TEE was measured using the doubly labeled water technique in 30 free-living adults with CP (12 women, 18 men). To determine the best markers of TEE, the following factors were examined: CP status, resting metabolic rate (RMR), anthropometric characteristics and body composition by means of dual-energy x-ray absorptiometry (DXA) and skinfold thickness measurements, energy cost of leisure-time activities, and oral-motor impairment. Means +/- standard deviations, t tests, Pearson product-moment correlation coefficients, Spearman rank correlation coefficients, chi 2, stepwise multiple-correlation regression analysis, and analysis of covariance were used to examine the relationships among variables of interest. TEE was highly variable in the sample (mean = 2,455 +/- 622 kcal/day for men and 1,986 +/- 363 kcal/day for women). Stepwise regression analysis showed that TEE was best predicted in the sample by RMR, percentage body fat determined by DXA, ambulation status, and sex (multiple R = .68, P = .003). When practical, easily measured variables were used, TEE was best predicted by height, ambulation status, percentage body fat by skinfold thickness measurements, and sex (multiple R = .61, P. = 018). The contribution of energy expended in physical activity to TEE was significantly higher in the ambulatory subjects than the nonambulatory subjects (25% vs 16%, respectively; P = .009). The high degree of variability in TEE, largely attributable to high interindividual variation in energy expended in physical activity, makes it difficult to provide general guidelines for energy requirements for adults with CP. Because ambulation status was an important predictor of TEE, it must be accounted for in estimating energy requirements in this population.

Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers.

PubMed

Hamitouche, Noureddine; Comets, Emmanuelle; Ribot, Mégane; Alvarez, Jean-Claude; Bellissant, Eric; Laviolle, Bruno

2017-05-01

This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC 50 ) was about 200 times lower for fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered.

Examination of emotion-induced changes in eating: A latent profile analysis of the Emotional Appetite Questionnaire.

PubMed

Bourdier, L; Morvan, Y; Kotbagi, G; Kern, L; Romo, L; Berthoz, S

2018-04-01

It is now recognized that emotions can influence food intake. While some people report eating less when distressed, others report either no change of eating or eating more in the same condition. The question whether this interindividual variability also occurs in response to positive emotions has been overlooked in most studies on Emotional Eating (EE). Using the Emotional Appetite Questionnaire (EMAQ) and Latent Profile Analysis, this study aimed to examine the existence of latent emotion-induced changes in eating profiles, and explore how these profiles differ by testing their relations with 1) age and sex, 2) BMI and risk for eating disorders (ED) and 3) factors that are known to be associated with EE such as perceived positive/negative feelings, depression, anxiety, stress symptoms and impulsivity. Among 401 university students (245 females) who completed the EMAQ, 3 profiles emerged (P1:11.2%, P2:60.1%, P3:28.7%), with distinct patterns of eating behaviors in response to negative emotions and situations but few differences regarding positive ones. Negative emotional overeaters (P1) and negative emotional undereaters (P3) reported similar levels of emotional distress and positive feelings, and were at greater risk for ED. However, the people in the former profile i) reported decreasing their food intake in a positive context, ii) were in majority females, iii) had higher BMI and iv) were more prone to report acting rashly when experiencing negative emotions. Our findings suggest that a person-centred analysis of the EMAQ scores offers a promising way to capture the inter-individual variability of emotionally-driven eating behaviors. These observations also add to the growing literature underscoring the importance of further investigating the role of different facets of impulsivity in triggering overeating and to develop more targeted interventions of EE. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

PubMed

Wiebe, Sabrina; Schnell, David; Külzer, Raimund; Gansser, Dietmar; Weber, Anne; Wallenstein, Gudrun; Halabi, Atef; Conrad, Anja; Wind, Sven

2017-06-01

Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30-59 mL/min/1.73 m 2 and 15-29 mL/min/1.73 m 2 , respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC last ) and maximum plasma concentration (C max ) between subjects with renal impairment and healthy matched controls. Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUC last and C max , was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUC last for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3-213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28-39 % for moderate impairment, 34-42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

Antisperm contraceptive vaccines: where we are and where we are going?

PubMed

Naz, Rajesh K

2011-07-01

This is a review of current status and future perspectives on the development of antisperm contraceptive vaccines (CV) and immunocontraceptives. The development of antisperm CV is an exciting proposition. There is a strong rationale and recent data indicating that this proposition can translate into reality. The search for novel sperm-specific antigens/genes, that can be used for CV, continues using various recent developing technologies. Various approaches of proteomics, genomics, reproductive biology, mucosal immunity and vaccinology and several novel technologies such as gene knockout technology, phage display technology, antibody engineering, differential display technique, subtractive hybridization, and hybridoma technology are being used to delineate sperm-specific antigens and construct CV. Various sperm antigens/genes have been delineated, cloned, and sequenced from various laboratories. Vaccination with these sperm antigens (recombinant/synthetic peptide/DNA) causes a reversible contraceptive effect in females and males of various animal species, by inducing a systemic and local antisperm antibody response. The efficacy is enhanced by combination vaccination, including peptides based on various sperm antigens. Several human novel scFv antibodies with unique complementarity-determining regions (CDRs), that react with specific well-defined fertility-related sperm antigens, have been synthesized. These human infertility-related antibodies may find application in the development of novel immunocontraceptives. Besides finding the novel sperm antigens, the present and future focus is on enhancing the immunogenicity, bioefficacy, and on obliterating the inter-individual variability of the immune response, and proceeding for primate and human clinical trials. Multi-epitope vaccines combining sperm proteins involved in various steps of fertilization cascade have been found to enhance the immunogenicity and bioefficacy of the contraceptive effect. The in vitro synthesis of infertility-related human scFv antibodies may provide unique once-a-month immunocontraceptives, the first of its kind, for human use. The multi-epitope CV and preformed engineered human antibodies of defined specificity may obliterate the concern related to inter-individual variability of the immune response. © 2011 John Wiley & Sons A/S.

Population-Based in Vitro Hazard and Concentration–Response Assessment of Chemicals: The 1000 Genomes High-Throughput Screening Study

PubMed Central

Abdo, Nour; Xia, Menghang; Brown, Chad C.; Kosyk, Oksana; Huang, Ruili; Sakamuru, Srilatha; Zhou, Yi-Hui; Jack, John R.; Gallins, Paul; Xia, Kai; Li, Yun; Chiu, Weihsueh A.; Motsinger-Reif, Alison A.; Austin, Christopher P.; Tice, Raymond R.

2015-01-01

Background: Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations. Objectives: We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability. Methods: We used 1,086 lymphoblastoid cell lines from the 1000 Genomes Project, representing nine populations from five continents, to assess variation in cytotoxic response to 179 chemicals. Analysis included assessments of population variation and heritability, and genome-wide association mapping, with attention to phenotypic relevance to human exposures. Results: For about half the tested compounds, cytotoxic response in the 1% most “sensitive” individual occurred at concentrations within a factor of 10½ (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was > 10. Genetic mapping suggested important roles for variation in membrane and transmembrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance. Conclusions: This experimental approach fills critical gaps unaddressed by recent large-scale toxicity testing programs, providing quantitative, experimentally based estimates of human toxicodynamic variability, and also testable hypotheses about mechanisms contributing to interindividual variation. Citation: Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. 2015. Population-based in vitro hazard and concentration–response assessment of chemicals: the 1000 Genomes high-throughput screening study. Environ Health Perspect 123:458–466; http://dx.doi.org/10.1289/ehp.1408775 PMID:25622337

Effect of food on the pharmacokinetics of dronabinol oral solution versus dronabinol capsules in healthy volunteers

PubMed Central

Oh, D Alexander; Parikh, Neha; Khurana, Varun; Cognata Smith, Christina; Vetticaden, Santosh

2017-01-01

Dronabinol is a pharmaceutical tetrahydrocannabinol originally developed as an oral capsule. A dronabinol oral solution was recently approved, and the effects of food on absorption and bioavailability of the oral solution versus capsules were compared in an open-label, single-dose, 3-period crossover study. Healthy volunteers were randomized to either dronabinol oral solution 4.25 mg (fed) or dronabinol capsule 5 mg (fed or fasted). Dosing was separated by a 7-day washout period. Plasma pharmacokinetics were evaluated for dronabinol and its major metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-Δ9-THC). Pharmacokinetic data were available for analysis in 54 volunteers. In the fed state, initial dronabinol absorption was faster with oral solution versus capsule (mean time to the first measurable concentration, 0.15 vs 2.02 hours, respectively), with 100% and 15% of volunteers, respectively, having detectable plasma dronabinol levels 30 minutes postdose. There was less interindividual variability in plasma dronabinol concentration during early absorption with oral solution versus capsule. Compared with the fasted state, mean area under the plasma concentration–time curve from time zero to the last measurable concentration (AUC0−t) increased by 2.1- and 2.4-fold for dronabinol oral solution and capsule, respectively, when taken with food. Mean time to maximum plasma concentration was similarly delayed for dronabinol oral solution with food (7.7 hours) and capsule with food (5.6 hours) versus capsule with fasting (1.7 hours). Under fed conditions, AUC0−t and area under the plasma concentration–time curve from time zero to infinity were similar for the oral solution versus capsule based on 11-OH-Δ9-THC levels. An appreciable food effect was observed for dronabinol oral solution and capsules. Dronabinol oral solution may offer therapeutic benefit to patients, given its rapid and lower interindividual absorption variability versus dronabinol capsule. PMID:28138268

Pharmacogenetic screening for polymorphisms in drug-metabolizing enzymes and drug transporters in a Dutch population.

PubMed

Bosch, T M; Doodeman, V D; Smits, P H M; Meijerman, I; Schellens, J H M; Beijnen, J H

2006-01-01

A possible explanation for the wide interindividual variability in toxicity and efficacy of drug therapy is variation in genes encoding drug-metabolizing enzymes and drug transporters. The allelic frequency of these genetic variants, linkage disequilibrium (LD), and haplotype of these polymorphisms are important parameters in determining the genetic differences between patients. The aim of this study was to explore the frequencies of polymorphisms in drug-metabolizing enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1, GSTT1) and drug transporters (ABCB1[MDR1] and ABCC2[MRP2]), and to investigate the LD and perform haplotype analysis of these polymorphisms in a Dutch population. Blood samples were obtained from 100 healthy volunteers and genomic DNA was isolated and amplified by PCR. The amplification products were sequenced and analyzed for the presence of polymorphisms by sequence alignment. In the study population, we identified 13 new single nucleotide polymorphisms (SNPs) in Caucasians and three new SNPs in non-Caucasians, in addition to previously recognized SNPs. Three of the new SNPs were found within exons, of which two resulted in amino acid changes (A428T in CYP2C9 resulting in the amino acid substitution D143V; and C4461T in ABCC2 in a non-Caucasian producing the amino acid change T1476M). Several LDs and haplotypes were found in the Caucasian individuals. In this Dutch population, the frequencies of 16 new SNPs and those of previously recognized SNPs were determined in genes coding for drug-metabolizing enzymes and drug transporters. Several LDs and haplotypes were also inferred. These data are important for further research to help explain the interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

Polymorphisms of pesticide-metabolizing genes in children living in intensive farming communities.

PubMed

Gómez-Martín, Antonio; Hernández, Antonio F; Martínez-González, Luis Javier; González-Alzaga, Beatriz; Rodríguez-Barranco, Miguel; López-Flores, Inmaculada; Aguilar-Garduno, Clemente; Lacasana, Marina

2015-11-01

Polymorphisms in genes encoding xenobiotic-metabolizing enzymes (XME) are important parameters accounting for the wide inter-individual variability to environmental exposures. Paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and Cytochrome-P450 constitute major classes of XME involved in the detoxification of pesticide chemicals, in particular organophosphates. This study explored the allelic frequency, linkage disequilibrium and haplotype analysis of ten common polymorphic variants of seven key genes involved in organophosphate metabolism (BCHE-K, BCHE-A, PON1 Q192R, PON1 L55M, PON1 -108C/T, CYP2C19 G681A, CYP2D6 G1846A, CYP3AP1 -44G/A, GSTM1∗0 and GSTT1∗0) in a children population living near an intensive agriculture area in Spain. It was hypothesized that individuals with unfavorable combinations of gene variants will be more susceptible to adverse effects from organophosphate exposure. Genomic DNA from 496 healthy children was isolated and amplified by PCR. Hydrolysis probes were used for the detection of eight specific SNPs and two copy number variants (CNVs) by using TaqMan® Assay-based real-time PCR. Frequencies of SNPs and CNVs in the target genes were in Hardy-Weinberg equilibrium and broadly consistent with European populations. Linkage disequilibrium was found between the three PON1 genetic polymorphisms studied and between BCHE-K and BCHE-A. The adverse genotype combination (unusual BCHE variants, PON1 55MM/-108TT and null genotype for both GSTM1 and GSTT1) potentially conferring a greater genetic risk from exposure to organophosphates was observed in 0.2% of our study population. This information allows broadening our knowledge about differential susceptibility toward environmental toxicants and may be helpful for further research to understand the inter-individual toxicokinetic variability in response to organophosphate pesticides exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prevalence of Non-responders for Glucose Control Markers after 10 Weeks of High-Intensity Interval Training in Adult Women with Higher and Lower Insulin Resistance.

PubMed

Álvarez, Cristian; Ramírez-Campillo, Rodrigo; Ramírez-Vélez, Robinson; Izquierdo, Mikel

2017-01-01

Background: Exercise training improves performance and biochemical parameters on average, but wide interindividual variability exists, with individuals classified as responders (R) or non-responders (NRs), especially between populations with higher or lower levels of insulin resistance. This study assessed the effects of high-intensity interval training (HIIT) and the prevalence of NRs in adult women with higher and lower levels of insulin resistance. Methods: Forty adult women were assigned to a HIIT program, and after training were analyzed in two groups; a group with higher insulin resistance (H-IR, 40 ± 6 years; BMI: 29.5 ± 3.7 kg/m 2 ; n = 20) and a group with lower insulin resistance (L-IR, 35 ± 9 years; 27.8 ± 2.8 kg/m 2 ; n = 20). Anthropometric, cardiovascular, metabolic, and performance variables were measured at baseline and after 10 weeks of training. Results: There were significant training-induced changes [delta percent (Δ%)] in fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) scores in the H-IR group (-8.8, -26.5, -32.1%, p < 0.0001), whereas no significant changes were observed in the L-IR. Both groups showed significant pre-post changes in other anthropometric variables [waist circumference (-5.2, p < 0.010, and -3.8%, p = 0.046) and tricipital (-13.3, p < 0.010, and -13.6%, p < 0.0001), supra-iliac (-19.4, p < 0.0001, and -13.6%, p < 0.0001), and abdominal (-18.2, p < 0.0001, and -15.6%, p < 0.010) skinfold measurements]. Systolic blood pressure decreased significantly only in the L-IR group (-3.2%, p < 0.010). Both groups showed significant increases in 1RM LE (+12.9, p < 0.010, and +14.7%, p = 0.045). There were significant differences in the prevalence of NRs between the H-IR and L-IR groups for fasting glucose (25 vs. 95%, p < 0.0001) and fasting insulin ( p = 0.025) but not for HOMA-IR (25 vs. 45%, p = 0.185). Conclusion: Independent of the "magnitude" of the cardiometabolic disease (i.e., higher vs. lower insulin resistance), no differences were observed in the NRs prevalence with regard to improved HOMA-IR or to anthropometric, cardiovascular, and muscle performance co-variables after 10 weeks of HIIT in sedentary adult women. This research demonstrates the protective effect of HIIT against cardiometabolic disease progression in a sedentary population.

Prevalence of Non-responders for Glucose Control Markers after 10 Weeks of High-Intensity Interval Training in Adult Women with Higher and Lower Insulin Resistance

PubMed Central

Álvarez, Cristian; Ramírez-Campillo, Rodrigo; Ramírez-Vélez, Robinson; Izquierdo, Mikel

2017-01-01

Background: Exercise training improves performance and biochemical parameters on average, but wide interindividual variability exists, with individuals classified as responders (R) or non-responders (NRs), especially between populations with higher or lower levels of insulin resistance. This study assessed the effects of high-intensity interval training (HIIT) and the prevalence of NRs in adult women with higher and lower levels of insulin resistance. Methods: Forty adult women were assigned to a HIIT program, and after training were analyzed in two groups; a group with higher insulin resistance (H-IR, 40 ± 6 years; BMI: 29.5 ± 3.7 kg/m2; n = 20) and a group with lower insulin resistance (L-IR, 35 ± 9 years; 27.8 ± 2.8 kg/m2; n = 20). Anthropometric, cardiovascular, metabolic, and performance variables were measured at baseline and after 10 weeks of training. Results: There were significant training-induced changes [delta percent (Δ%)] in fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) scores in the H-IR group (−8.8, −26.5, −32.1%, p < 0.0001), whereas no significant changes were observed in the L-IR. Both groups showed significant pre-post changes in other anthropometric variables [waist circumference (−5.2, p < 0.010, and −3.8%, p = 0.046) and tricipital (−13.3, p < 0.010, and −13.6%, p < 0.0001), supra-iliac (−19.4, p < 0.0001, and −13.6%, p < 0.0001), and abdominal (−18.2, p < 0.0001, and −15.6%, p < 0.010) skinfold measurements]. Systolic blood pressure decreased significantly only in the L-IR group (−3.2%, p < 0.010). Both groups showed significant increases in 1RMLE (+12.9, p < 0.010, and +14.7%, p = 0.045). There were significant differences in the prevalence of NRs between the H-IR and L-IR groups for fasting glucose (25 vs. 95%, p < 0.0001) and fasting insulin (p = 0.025) but not for HOMA-IR (25 vs. 45%, p = 0.185). Conclusion: Independent of the “magnitude” of the cardiometabolic disease (i.e., higher vs. lower insulin resistance), no differences were observed in the NRs prevalence with regard to improved HOMA-IR or to anthropometric, cardiovascular, and muscle performance co-variables after 10 weeks of HIIT in sedentary adult women. This research demonstrates the protective effect of HIIT against cardiometabolic disease progression in a sedentary population. PMID:28729841

Inter-individual differences in the impulsive/compulsive dimension: deciphering related dopaminergic and serotonergic metabolisms at rest.

PubMed

Dellu-Hagedorn, Françoise; Rivalan, Marion; Fitoussi, Aurélie; De Deurwaerdère, Philippe

2018-04-19

Several impulse control disorders such as ADHD, mania, personality disorders or substance abuse share common behavioural traits, like impulsiveness, risk-taking or inflexible behaviour. These disorders are treated with drugs targeting dopamine (DA) and/or serotonin (5-HT). However, the patient's monoamine imbalance that these neurotransmitters compensate is unclear. This study aims to investigate the patterns of DA and 5-HT metabolisms at rest within selected brain regions related to inter-individual variability in six main components of impulsivity/compulsivity (anticipatory hyperactivity, premature responses, delay discounting, risk-taking, perseveration, flexibility). Rats with adaptive and highly inadaptive behaviours were identified in each task and a sensitive biochemical approach allowed mapping of post-mortem endogenous monoamine tissue content in 20 brain areas. Distinct patterns of 5-HT and DA metabolisms were revealed according to the behavioural traits. Except for hyperactive responses, lower control of actions was mainly associated with a lower DA or 5-HT metabolism in prefrontal and/or subcortical areas (i.e. in orbitofrontal cortex (DA), amygdala and anterior cingulate cortex (5-HT) for inflexible and risk-prone rats). Our results reveal the complex nature of behavioural traits related to impulse control disorders through their associated monoaminergic networks at rest, paving the way for understanding the link between mental disorders and drug therapeutic actions.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. © 2018 The Author(s).

Evaluation of Interindividual Human Variation in Bioactivation and DNA Adduct Formation of Estragole in Liver Predicted by Physiologically Based Kinetic/Dynamic and Monte Carlo Modeling.

PubMed

Punt, Ans; Paini, Alicia; Spenkelink, Albertus; Scholz, Gabriele; Schilter, Benoit; van Bladeren, Peter J; Rietjens, Ivonne M C M

2016-04-18

Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA adduct formation for the related alkenylbenzene methyleugenol. Adequate model predictions could be made, with the predicted DNA adduct levels at the estimated daily intake of estragole of 0.01 mg/kg bw ranging between 1.6 and 8.8 adducts in 10(8) nucleotides (nts) (50th and 99th percentiles, respectively). This is somewhat lower than values reported in the literature for the related alkenylbenzene methyleugenol in surgical human liver samples. The predicted levels seem to be below DNA adduct levels that are linked with tumor formation by alkenylbenzenes in rodents, which were estimated to amount to 188-500 adducts per 10(8) nts at the BMD10 values of estragole and methyleugenol. Although this does not seem to point to a significant health concern for human dietary exposure, drawing firm conclusions may have to await further validation of the model's predictions.

No Associations between Interindividual Differences in Sleep Parameters and Episodic Memory Consolidation

PubMed Central

Ackermann, Sandra; Hartmann, Francina; Papassotiropoulos, Andreas; de Quervain, Dominique J.F.; Rasch, Björn

2015-01-01

Study Objectives: Sleep and memory are stable and heritable traits that strongly differ between individuals. Sleep benefits memory consolidation, and the amount of slow wave sleep, sleep spindles, and rapid eye movement sleep have been repeatedly identified as reliable predictors for the amount of declarative and/or emotional memories retrieved after a consolidation period filled with sleep. These studies typically encompass small sample sizes, increasing the probability of overestimating the real association strength. In a large sample we tested whether individual differences in sleep are predictive for individual differences in memory for emotional and neutral pictures. Design: Between-subject design. Setting: Cognitive testing took place at the University of Basel, Switzerland. Sleep was recorded at participants' homes, using portable electroencephalograph-recording devices. Participants: Nine hundred-twenty-nine healthy young participants (mean age 22.48 ± 3.60 y standard deviation). Interventions: None. Measurements and results: In striking contrast to our expectations as well as numerous previous findings, we did not find any significant correlations between sleep and memory consolidation for pictorial stimuli. Conclusions: Our results indicate that individual differences in sleep are much less predictive for pictorial memory processes than previously assumed and suggest that previous studies using small sample sizes might have overestimated the association strength between sleep stage duration and pictorial memory performance. Future studies need to determine whether intraindividual differences rather than interindividual differences in sleep stage duration might be more predictive for the consolidation of emotional and neutral pictures during sleep. Citation: Ackermann S, Hartmann F, Papassotiropoulos A, de Quervain DJF, Rasch B. No associations between interindividual differences in sleep parameters and episodic memory consolidation. SLEEP 2015;38(6):951–959. PMID:25325488

Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin

PubMed Central

Soeria-Atmadja, Sandra; Österberg, Emma; Gustafsson, Lars L.; Dahl, Marja-Liisa; Eriksen, Jaran; Rubin, Johanna

2017-01-01

Background Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults. Aim To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight. Method EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records. Results Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85–19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55–13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level). Conclusion Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children. PMID:28886044