Analysis Of Inter-individual Differences Research Articles

Inter-individual differences in human brain structure and morphology link to variation in demographics and behavior.

We perform a comprehensive integrative analysis of multiple structural MR-based brain features and find for the first-time strong evidence relating inter-individual brain structural variations to a wide range of demographic and behavioral variates across a large cohort of young healthy human volunteers. Our analyses reveal that a robust 'positive-negative' spectrum of behavioral and demographic variates, recently associated to covariation in brain function, can already be identified using only structural features, highlighting the importance of careful integration of structural features in any analysis of inter-individual differences in functional connectivity and downstream associations with behavioral/demographic variates.

Vitamin D Binding Protein Isoforms and Apolipoprotein E in Cerebrospinal Fluid as Prognostic Biomarkers of Multiple Sclerosis.

BackgroundMultiple sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system with a heterogeneous and unpredictable course. To date there are no prognostic biomarkers even if they would be extremely useful for early patient intervention with personalized therapies. In this context, the analysis of inter-individual differences in cerebrospinal fluid (CSF) proteome may lead to the discovery of biological markers that are able to distinguish the various clinical forms at diagnosis.MethodsTo this aim, a two dimensional electrophoresis (2-DE) study was carried out on individual CSF samples from 24 untreated women who underwent lumbar puncture (LP) for suspected MS. The patients were clinically monitored for 5 years and then classified according to the degree of disease aggressiveness and the disease-modifying therapies prescribed during follow up.ResultsThe hierarchical cluster analysis of 2-DE dataset revealed three protein spots which were identified by means of mass spectrometry as Apolipoprotein E (ApoE) and two isoforms of vitamin D binding protein (DBP). These three protein spots enabled us to subdivide the patients into subgroups correlated with clinical classification (MS aggressive forms identification: 80%). In particular, we observed an opposite trend of values for the two protein spots corresponding to different DBP isoforms suggesting a role of a post-translational modification rather than the total protein content in patient categorization.ConclusionsThese findings proved to be very interesting and innovative and may be developed as new candidate prognostic biomarkers of MS aggressiveness, if confirmed.

Receptor occupancy theory-based analysis of interindividual differences in antiemetic effects of 5-HT3 receptor antagonists

The aim of this study was to estimate interindividual differences in the antiemetic effects of 5-HT(3) receptor antagonists by evaluating the influence of pharmacokinetics on 5-HT(3) receptor occupancies, based on receptor occupancy theory. We analyzed interindividual differences of 5-HT(3) receptor occupancies and antiemetic effects after the oral and/or intravenous administration of standard doses of the following 5-HT(3) receptor antagonists: azasetron, granisetron, indisetron, ondansetron, ramosetron, and tropisetron. The interindividual difference between maximum and minimum 5-HT(3) receptor occupancies after oral administration ranged from 0.6% to 64.0%, and that difference after intravenous administration ranged from 0.6% to 29.6%. Following oral administration, the interindividual difference between maximum and minimum complete vomiting inhibition rates ranged from 0.2% to 16.1%. After intravenous administration, that difference ranged from 0.8% to 52.5%. Interindividual differences in the clinical effects of 5-HT(3) receptor antagonists could be evaluated based on receptor occupancy theory, and the differences varied among drugs. Drug selection considering these individual variations might be useful for the patients who experienced vomiting associated with chemotherapy.

Interindividual differences in muscle sympathetic nerve activity: a key to new insight into cardiovascular regulation?

The paper reviews findings in humans regarding interindividual differences in sympathetic nerve activity. Data come predominantly from microneurographic multi- or single fibre recordings of sympathetic nerve activity in healthy subjects. Findings relate to interindividual differences in muscle sympathetic nerve activity (MSNA) during resting conditions and in response to surprising sensory stimuli. At rest there are marked interindividual differences in the number of multiunit MSNA bursts. At the single fibre level the differences are because of more vasoconstrictor fibres being active in subjects with high than in subjects with low number of bursts. There are inverse relationships between (i) sympathetic burst incidence and cardiac output (CO) and (ii) between sympathetic burst incidence and vascular responsiveness to noradrenaline. Both findings contribute to explaining the absence of correlation between resting levels of MSNA and blood pressure. Surprising visual, somatosensory or auditory stimuli of sufficient strength cause a short lasting inhibition of MSNA in approx. 50-60% of healthy subjects. In subjects who display significant inhibition, the stimulus-induced blood pressure increase is smaller than in subjects without inhibition. The underlying mechanism may be related to fear of blood/injury. It is concluded that analysis of interindividual differences in sympathetic activity improves the understanding of central nervous control of the circulation.

Impact of inter‐individual differences in drug metabolism and pharmacokinetics on safety evaluation

Safety evaluation aims to assess the dose-response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is 'without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 10(0.5) (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment.

Aberrant RNA splicing of the protein C and protein S genes in healthy individuals.

RNA-based studies are an important tool for the identification and functional characterization of mutations underlying inherited disease. These studies could in principle be compromised by 'aberrant splicing' (the generation of alternatively spliced transcripts lacking any obvious function) during normal expression of the genes under investigation. Using a highly sensitive RT-PCR assay, we show here that aberrant splicing is a frequent occurrence during expression of the protein C (PROC) and protein S (PROS) genes. Aberrantly spliced transcripts were present in different cell types including liver, the main expressing tissue for both protein C and protein S. In an attempt to compare individual mRNA splicing patterns, PROC and PROS RNA from easily accessible cells of different healthy control individuals was studied. However, variation between different RT-PCR assays from the same individual precluded both the relative quantitation of the aberrant transcripts and the analysis of interindividual differences. Our findings are consistent with the notion that a low level of aberrantly spliced transcripts are routinely generated during PROC and PROS gene expression. The possibility that these transcripts may complicate the RT-PCR analysis of pathological transcripts must be taken into account when RNA-based strategies of disease analysis are considered.

Adolescent mental health.

Definitions and descriptions of adolescent mental health are beginning to be grounded in psychologists' empirical studies of a wide variety of patterns of adaptation to adolescence. Three major themes guiding current research relevant to mental health in adolescence are discussed in this article: (a) a focus on analysis of interindividual differences to describe variety in adaptation; (b) the integration of biological, psychological, social, and cultural variables in models of adolescence; and (c) an emphasis on the developmental aspects of adolescent mental health. Empirical investigations of adolescent mental health and development within the social context of the family are reviewed.