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Clinical electrophysiology of two rod pathways: normative values and clinical application.

BACKGROUND: The scotopic 15-Hz flicker electroretinogram (ERG) has two limbs (slow and fast ERG rod signals), and these have been attributed to two retinal rod pathways (the ON rod bipolar and AII amacrine pathway and the rodcone gap-junction pathway). The aim of this study was to provide normative values of the scotopic 15-Hz flicker ERG, to estimate the inter-individual variability, and to apply this method to a clinical setting. METHODS: Twenty-two normal subjects, one patient with retinitis pigmentosa (RP), and two patients with Stargardt's mascular dystrophy (SMD) participated in the study. The SMD patients were screened for mutations in the 50 exons of the ABCA4 (formerly ABCR) gene. We measured ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic trolands s at a flicker frequency of 15 Hz. RESULTS: The normal scotopic 15-Hz flicker ERG showed a biphasic amplitude pattern with a minimum at about-1.57 log scotopic trolands s, where there was an abrupt phase shift of about 180 deg. The inter-individual variability in ERG amplitude ranged from 47% to 67% for the slow and from 41% to 64% for the fast rod signal. Both the RP patient and the SMD patients (who were compound heterozygotes for mutations in the ABCA4 gene) showed reduced amplitudes for the two rod ERG pathways. CONCLUSION: The inter-individual variability might be explained by anatomical differences between individual retinae. In the RP patient, the amplitude reductions corresponded well with the standard rod ERG. In the SMD patients, however, the scotopic 15-Hz flicker ERG revealed rod dysfunction, whereas the standard rod ERG was within normal limits. The scotopic 15-Hz flicker method may be more sensitive than the standard rod ERG.

ATP-Binding Cassette Transporters↗

Kinematics of the equine back: flexion-extension movements in sound trotting horses.

This study was undertaken to evaluate the flexion-extension movements of the back in a group of sound trotting horses. Using a 3-D kinematic analysis system, 13 clinically sound horses fitted with 5 skin markers placed on the dorsal midline of their trunk were recorded while trotting on a track in the conditions of the routine lameness examination. These markers were used to calculate 3 back angles (thoracic, thoracolumbar and lumbosacral angle). These back angles were then filtered using Fourier series. To evaluate the repeatability of flexion-extension movements, the intra- and inter-individual variabilities were studied. The angle-time diagrams showed that the equine back extended during the first part of each diagonal stance phase and flexed during the second part of each diagonal stance phase. The ranges of motion were less than 4 degrees for the 3 back angles. The intra- and inter-individual variability values of maximal extension and maximal flexion time points were similar and extremely low. This demonstrates the high repeatability of the temporal pattern of flexion-extension movements of the back. Intra- and inter-individual variabilities of the range of motion showed that the back mobility varies more in-between horses than between trials of the same horse. Compared with electromyographic activities of back muscles reported in the literature, flexion-extension movements described in this study tend to show that, at a slow trot, trunk muscles act mainly to limit flexion-extension movements of the back rather than to induce movements.

Animals↗

Word-list-learning performance in younger and older adults: intra-individual performance variability and false memory.

We investigated the word-list-learning performance of younger and older adults over 4 consecutive days at different times of day to study age-related differences in consistency of performance over time and the influence of circadian variation on performance. Eighteen younger (M age, 23.4 years) and 18 older (M age, 73.3 years) men and women participated. The start time of testing alternated between morning and early evening across the 4 days of testing. On each test day, participants learned a different list of 15 unrelated words over four learning trials. As expected, younger adults performed better than older adults on immediate recall, delayed recall, and recognition. Contrary to our expectations, time of day did not significantly influence recall or recognition performance in either the older or younger adults. Older adults did show a greater incidence of false memory (i.e., previously learned list intrusions in free recall and false alarms in recognition) than younger adults. Older adults also exhibited greater intra-individual performance variability on the measures of false memory across test days. This variability was not related to circadian variation. False memory and variability of performance have both been linked to frontal systems dysfunction. The findings presented here are consistent with the notion that changes in cognition with aging in part reflect age-related decline in frontal lobe function.

Adult↗

Systematic evaluation of sample preparation methods for gel-based human urinary proteomics: quantity, quality, and variability.

We performed systematic evaluation of 38 protocols to concentrate normal human urinary proteins prior to 2D-PAGE analysis. Recovery yield and pattern of resolved protein spots were compared among different methods and intra-/inter-individual variabilities were examined. Precipitation with 90% ethanol provided the greatest protein recovery yield (92.99%), whereas precipitation with 10% acetic acid had the least protein recovery (1.91%). In most of precipitation protocols, the higher percentage of applied organic compounds provided the greater recovery yield. With a fixed concentration at 75%, the urine precipitated with acetonitrile had the greatest number of protein spots visualized in 2D gel, whereas the acetic-precipitated sample had the smallest number of spots. For the intra-individual variability, the first morning urine had the greatest amount of total protein but provided the smallest number of protein spots visualized. Excessive water drinking, not caffeine ingestion, caused alterations in the urinary proteome profile with newly presenting spots and also proteins with decreased excretion levels. As expected, there was a considerable degree of inter-individual variability. Coefficients of variation for albumin and transferrin expression were greatest by inter-individual variables. Male urine had greater amount of total protein but provided smaller number of protein spots compared to female urine. These data offer a wealth of useful information for designing a high-quality, large-scale human urine proteome project.

Albumins↗

Food choices at lunch during the third year of life: high selection of animal and starchy foods but avoidance of vegetables.

AIM: The objective was to show patterns of food selection by 2- to 3-y-old children for a wide variety of foods in a self-service cafeteria and to assess the effect of individual variables (gender, BMI, mode of feeding after birth and rank in sibship). METHODS: In a nursery self-service canteen, food choices at lunch made by children (n=418, 24-36 mo; 109 observations per child on average) were recorded by trained assistants who monitored portion size. An offer of eight dishes (animal products, starchy foods, combination dishes, vegetables and dairy products), excluding dessert-type foods, was proposed. Choice level was calculated for each food. Analysis of variance was used to compare choices for the various foods and to assess the effect of the individual variables. RESULTS: The choice of a food largely depended upon its nature: animal products, starchy foods and their combinations were widely chosen, whereas vegetables were not often selected; the choice for dairy products depended upon the type. The mode of preparation of the food influenced its choice. Segmenting products were identified; however, except for cheeses, a given child did not refuse an entire food category. Children's characteristics did not explain the choice variability. CONCLUSION: At the age of 2 to 3 y, children preferentially choose animal products and starchy foods and avoid vegetables; the high individual variability of their food choices could be related to previous food experiences.

Cheese↗

Strain difference in learning impairment in rats following lead administration during brain development.

High and stable avoidance with low variability (THA) rats and non-select Wistar rats were administered 2 mg/ml lead acetate solution (0.2-0.27 g/Kg/day as lead) up to seven weeks of age; via placenta from the 13th day of gestation and from maternal milk before weaning, and per os after weaning. Results were as follows. 1) Significant differences were not observed between the lead-exposed rats and the controls regarding the developmental landmarks in both the Wistar rats and THA rats. Body weight of the exposed rats, however, were significantly less than that of the controls of the two rat strains. 2) Low rate of avoidance, slow acquisition of learning and large individual variabilities were exhibited in both the controls and the exposed rats of the Wistar strain throughout the test sessions. No significant difference was indicated between the controls and the exposed rats of the Wistar strain. In the control THA rats, avoidance learning was acquired rapidly, and a high level and very small individual variabilities of avoidance were demonstrated during the latter sessions of the test. Meanwhile, in the exposed THA rats, slow learning acquisition and large individual variabilities were displayed. It is thought that the learning impairment appearing in the THA exposed rats was induced primarily by lead.

Animals↗

Significance of time to exhaustion during exercise at the velocity associated with VO2max.

In theory, time to exhaustion at the velocity associated with VO2max (tLIM at vVO2max) together with the anaerobic threshold (AT) should provide information about the anaerobic capacity of an individual. The primary purpose of this study was to test that hypothesis, using oxygen deficit as a criterion for anaerobic capacity. A second purpose was to identify factors that might explain the large inter-individual variability reported in tLIM at vVO2max. Subjects were 13 female track athletes who performed incremental treadmill tests to determine VO2max and AT and constant velocity tests at vVO2max to determine tLIM and oxygen deficit. Correlations between oxygen deficit and tLIM at vVO2max and [(tLIM at vVO2max).(VO2max-AT)], a compound variable derived based on the critical power concept, were 0.51 (p < 0.05, one-tailed) and 0.67 (p < 0.01). To identify factors related to the inter-individual variability in tLIM at vVO2max, correlations between tLIM and AT, oxygen deficit, and [oxygen deficit/(VO2max-AT)] were calculated. Intra-individual differences in AT explained 44% of the variability in tLIM at vVO2max, oxygen deficit explained 26% of the variance, and the compound variable explained only 36%. It was concluded that (a) alone, or in combination with AT, tLIM at vVO2max cannot be used to estimate anaerobic capacity and (b) factors other than anaerobic capacity and AT contribute to the relatively large intra-individual variability in tLIM at vVO2max (CV = 21%). Determinants of tLIM at vVO2max must be elucidated if this measure is to be of use to sport scientists.

Adult↗

Automatic evaluation of the exteroceptive suppression of the temporalis muscle activity.

AIM: To set up a reliable automated method of allowing to identify the ES1 and ES2 periods of exteroceptive suppression of the temporal muscle (EST), thereby reducing their intra- and inter-individual variability. MATERIALS AND METHODS: Analyses were performed in 79 healthy subjects with strict inclusion and exclusion criteria. Each individual underwent two separate examinations 1 week apart. Activity of the left and right temporal muscles was recorded in response to unilateral stimulation of the left and right labial commissures. Wave forms were successively rectified, averaged, and filtered; the intersections of the resulting curve with values corresponding to 50%, 60%, 70%, 75%, and 80% of the control period (20 ms preanalysis time) were automatically determined. RESULTS: All subjects reached a 80% level of attenuation for ES2. The values of ES2 durations were normally distributed. The mean ES1 and ES2 durations didn't vary between the two recording session, and there was a good individual reproducibility from one session to the other. Though relatively high, the inter-individual variability was slightly lower in the second than in the first session. CONCLUSIONS: Computed analysis of EST may contribute to decrease inter- and intra-individual test variability. Letting patient habituate through a first recording session could increase test sensitivity, too. The obtained values for ES2 duration are normally distributed and well-reproducible at both the population and individual level. We suggest taking into account both ES2 duration and level of attenuation.

Adult↗

Urea kinetics in healthy young women: minimal effect of stage of menstrual cycle, contraceptive pill and protein intake.

Urea kinetics were measured using prime/intermittent oral doses of [15N15N]urea, on five separate protocols in thirteen normal young women. Each woman underwent either two or three study protocols. Measurements were made at day 12 and day 22 of the menstrual cycle, whilst consuming their habitual protein intake in seven women not taking the contraceptive pill and in six women taking the contraceptive pill. In three women taking the pill, and three not taking the pill, urea kinetics were measured whilst taking a diet in which the intake was restricted to 55 g protein/d. There was no difference in the rate of urea production, urea excretion or urea hydrolysis between the women taking the pill and those not taking the pill at day 22. In the women not taking the pill there was no difference in any measure between day 12 and day 22. In the women taking the pill there was a significant difference in the disposal of urea N to excretion or hydrolysis on day 12 compared with day 22, with a relative decrease in excretion and enhancement of hydrolysis at day 12 compared with day 22. On the restricted diet, an intake of 55 g protein/d represented 77% of the habitual intake and urea production, excretion and hydrolysis were reduced to about 84% of the rate found on the habitual intake. In paired studies the reduction in urea production was statistically significant, and there was a statistically significant linear relationship between urea production and either intake or the sum of intake plus hydrolysis. The within-individual variability for urea production was about 10%, for excretion 15% and for hydrolysis 44%. The between-individual variability for intake was about 17% on the habitual intake. The variability for production, excretion and hydrolysis (14, 13, 36%) was less in the women not taking the contraceptive pill than in those taking the pill 23, 32, 42% respectively). The variability was reduced on the controlled low intake of 55 g protein compared with the habitual intake. These results confirm the wide variability in aspects of urea kinetics between individuals. In women this variability is not, to any large extent, accounted for by changes associated with the menstrual cycle.

Adult↗

First-pass of GTS-21 on canine gut wall and liver determined by portal-systemic concentration difference.

To clarify the cause of the canine individual variability of plasma concentration after oral administration of GTS-21 [(E)-3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetra-hydro-2,3'-bipyridine dihydrochloride], we evaluated the absorption ratio (F(A)), intestinal availability (F(G)), and hepatic availability (F(H)). The bioavailability (F) was evaluated from the ratio of the area under the plasma concentration versus time curves after oral and intravenous administration. Three isoflurane anaesthetised dogs were fitted with an electromagnetic flow probe attached to the portal vein and cannulated through the portal and the femoral veins. After intraduodenal administration of GTS-21, both plasma concentrations were determined simultaneously. F(A) x F(G) was calculated from the portal-systemic concentration difference taking into consideration the blood-plasma partition ratio. F(A) was calculated from the residual drug contents of the small intestine. F(H) was calculated by dividing F by F(A) x F(G). The F values were 0.072, 0.021, and 0.037, indicating an individual variability of ca. threefold. The F(A) values were close to 1, and the F(G) values ranged from 0.449 to 0.461. Accordingly, the F(H) values were estimated at 0.170, 0.047, and 0.083. GTS-21 was completely absorbed but lost by first-pass effects of passage through the gut wall and liver. The first-pass effect of liver is larger than that of the gut wall, and dominates the individual variability in plasma concentration.

Animals↗

Regional distribution of macroscopic lung disease in cystic fibrosis.

We used macroscopic morphometry and multivariate analysis (Hotelling's T2) to quantitate the extent of chronic lung disease and its regional distribution in formalin-inflated right lungs obtained at autopsy from 17 young adults with cystic fibrosis (CF) and 5 without CF as control subjects. Lungs were point-counted, by lobe, for 6 anatomic variables: parenchyma, nonparenchyma, bronchi, vessels, cysts, and emphysema, and the results were expressed for each as volume proportion (Vv). Considering all 6 variables simultaneously, CF lungs differed significantly from control lungs (p = 0.003). For individual variables, Vv bronchus was significantly elevated and Vv parenchyma was significantly reduced in the CF group. Within the CF lungs, there was a significant difference between upper and lower lobes when all variables were considered together (p = 0.001). For individual variables, Vv parenchyma and Vv vessels were significantly less, and Vv bronchus was significantly greater in the upper compared with the lower lobe. There was no difference in the upper versus lower lobe Vv for any variable in the control group. These results indicate that lung disease and remodeling are irregularly distributed in CF and that the upper lobe is disproportionately severely involved.

Adolescent↗

Cytokine-induced ICAM-1 expression in human keratinocytes is highly variable in keratinocyte strains from different donors.

Induction of intercellular adhesion molecule 1 (ICAM-1) expression in the epidermis is felt to be an important initiator of leukocyte/keratinocyte interactions in many inflammatory skin diseases. The purpose of this project was to determine the individual variability of cytokine-induced ICAM-1 expression in human keratinocytes obtained from different donors. In 55 different keratinocyte strains, there was significant individual variability in ICAM-1 expression by either tumor necrosis factor alpha (TNF-alpha) or interferon-gamma. There was no correlation (r = 0.266, p = 0.06) in response of the same strain to either TNF-alpha or interferon-gamma. Multiple (n = 22) keratinocyte strains showed no significant induction of ICAM-1 expression to IL-1. The level of ICAM-1 expression in response to TNF-alpha and ultraviolet radiation (UVR) in individual strains was highly correlated in three different comparisons: level of stimulated response versus baseline (TNF-alpha and UVR both p < 0.0001); stimulation index TNF-alpha versus UVR (p = 0.00947); and variability of stimulated response versus variability of baseline (TNF p < 0.001; UVR p = 0.002). UVR-induced release of TNF from keratinocytes also showed variability among different keratinocyte strains. The UVR-induced ICAM-1 response in human keratinocytes and transformed epithelial cell was variably blocked with anti-TNF antibodies. The release of TNF from keratinocytes by UVR and the individually variable but linked characteristics of UVR and TNF-alpha stimulated ICAM-1 expression support the hypothesis that TNF-alpha is a major mediator of UVR-induced ICAM-1 expression.

Cells, Cultured↗

An analysis program MULTI(ELS) based on extended nonlinear least squares method for microcomputers.

An analysis program MULTI(ELS) was developed for population pharmacokinetics on a microcomputer. The program based on the extended least squares (ELS) is written in the Microsoft minimum BASIC command alone. ELS simultaneously estimates not only the population pharmacokinetic parameters but also the variances of inter-individual variabilities around the population parameters and of intra-individual variabilities for the plural time courses, whereas the ordinary least squares estimates the pharmacokinetic parameters of each time course. Two least squares algorithms (i.e. quasi-Newton and simplex methods) are provided in MULTI(ELS). MULTI(ELS) was compared with NONMEM (Version I, Level 3) developed by Sheiner and Beal for several time course data. It was shown that MULTI(ELS) gave the same results as NONMEM. MULTI(ELS) calculates the Akaike's information criterion (AIC) for the extended least squares. It was also shown that the AIC is effective in comparing the population characteristics of time courses in a group with those in another group and in verifying the model structures of population means, inter-individual variations and intra-individual variations.

Computers↗

Computation of individual latent variable scores from data with multiple missingness patterns.

Latent variable models are used in biological and social sciences to investigate characteristics that are not directly measurable. The generation of individual scores of latent variables can simplify subsequent analyses. However, missing measurements in real data complicate the calculation of scores. Missing observations also result in different latent variable scores having different degrees of accuracy which should be taken into account in subsequent analyses. This manuscript presents a publicly available software tool that addresses both these problems, using as an example a dataset consisting of multiple ratings for ADHD symptomatology in children. The program computes latent variable scores with accompanying accuracy indices, under a 'user-specified' structural equation model, in data with missing data patterns. Since structural equation models encompass factor models, it can also be used for calculating factor scores. The program, documentation and a tutorial, containing worked examples and specimen input and output files, is available at http://statgen.iop.kcl.ac.uk/lsc .

Attention Deficit Disorder with Hyperactivity↗

Tolerability and pharmacokinetics of remoxipride after intramuscular administration.

A study was undertaken in seven schizophrenic patients to evaluate the tolerability and examine the pharmacokinetics of intramuscularly administered remoxipride after a single 200 mg dose and at steady state following repeated doses of 200 mg twice daily for one week. Comparisons of AUC, t1/2 and tmax using the Wilcoxon's signed rank test showed no significant difference between single dose and steady state indicating that the pharmacokinetics of intramuscular remoxipride were linear. The steady-state Cmax was found to be significantly larger than that after single dose and the increase was accounted for by the predicted accumulation factor, assuming linear kinetics. Although the inter-individual variability in plasma concentrations was large, the intra-individual variability was low as shown by the reproducibility of the single-dose and steady-state plasma curves. Remoxipride, administered intramuscularly, was well tolerated.

Adolescent↗

Individual variation of adipose gene expression and identification of covariated genes by cDNA microarrays.

Gene expression profiling through the application of microarrays provides comprehensive assessment of gene expression levels in a given tissue or cell population, as well as information on changes of gene expression in altered physiological or pathological situations. Microarrays are particularly suited to study interactions in the regulation of large numbers of different genes, since their expression is analyzed simultaneously. For improved understanding of the physiology of adipose tissue, and consequently obesity and diabetes, identification of covariability in gene expression was attempted by analysis of the individual variability of gene expression in subcutaneous white and brown fat of the Siberian dwarf hamster using microarrays containing approximately 300 cDNA fragments of adipose genes. No sex-dependant variability in gene expression could be found, and overall individual variability was rather low, with more than 80% of clones showing a coefficient of variation lower than 30%. Uncoupling protein 1 (UCP1) displayed a high variability of gene expression in brown fat, which was negatively correlated with the gene expression of complement factor B (FactB), implying a possible functional relationship.

Adipocytes↗

Electrocardiographic evidence of myocardial salvage after thrombolysis in acute myocardial infarction.

There is a need for a simple clinical measurement that will indicate the extent of myocardial salvage after successful thrombolysis. This study examined whether coronary artery reperfusion reduced the infarct size as assessed electrocardiographically after thrombolytic treatment. The sum of the (sigma) ST segment area in leads showing ST segment elevation in the 12 lead electrocardiogram at presentation was used as an index of potential myocardial injury (initial ischaemic index). The evolved infarct size at 48 h was assessed by a QRS scoring system. Two groups of patients, both admitted with anterior myocardial infarction within 6 h of onset, were studied. Group 1 (n = 35) received analgesia only and group 2 (n = 33) received thrombolytic treatment either by the intracoronary (streptokinase, n = 13) or intravenous route (anistreplase, n = 20). Reperfusion was assessed angiographically. The mean (SD) potential infarct size assessed by the initial ischaemic index was similar in both groups (group 1, sigma ST area = 115 (60) mm2 and group 2 = 126 (77 mm2). The QRS score representing evolved infarct size was significantly lower in the treated group (4.1 (2.5] than in group 1 (7.8 (2.6]. The 95% confidence intervals for QRS scores based on the admission sigma ST area from patients with successful reperfusion were applied to a third set of patients (n = 22) to test the ability of the admission ST area (myocardial injury) to predict the QRS score accurately. While patients with successful reperfusion had significantly lower QRS scores than those who did not (4.5 (3.1) versus 9.3 (3.4)), the wide confidence intervals caused by inter-individual variability precluded an accurate prediction of the QRS score in an individual from the sigma ST area at time of presentation. There was no difference in infarct size in patients treated early (</= 3 h) (QRS score 4.2(2.8)) or later (3-6 h) (4.1(2.1)). This study provides evidence that sequential electrocardiographic changes are reduced in patients with anterior infarction who achieve reperfusion after thrombolytic treatment and that this benefit is shown with treatment given up to six hours after infarct onset. None the less, the relation between the initial ischaemic index and the evolved QRS score has wide confidence intervals, reflecting inter-individual variability, and does not allow the prediction of a QRS score in an individual patient.

Acute Disease↗

Factors that predict individual vulnerability to amphetamine self-administration.

Clinical observations show that there is considerable individual variability in the response to the addictive properties of drugs. This individual variability needs to be taken into account in animal models of addiction. Like humans, only some rats readily self-administer low doses of psychostimulants. The individual animals at risk can be identified on the basis of their response to environmental or pharmacological challenges. This predisposition to develop self-administration can be induced by repeated treatment with amphetamine. These results may help elucidate the neurobiological basis of addiction liability observed in both rats and humans.

Animals↗