Simultaneous determination of plasma levels of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric method is presented which allows the simultaneous determination of the plasma concentrations of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine after derivatization with the chiral reagent, (S)-(-)-N-trifluoroacetylprolyl chloride. No interference was observed from endogenous compounds following the extraction of plasma samples from six different human subjects. The standard curves were linear over a working range of 10 to 750 ng/ml for racemic fluoxetine and norfluoxetine and of 50 to 500 ng/ml for fluvoxamine. Recoveries ranged from 50 to 66% for the three compounds. Intra- and inter-day coefficients of variation ranged from 4 to 10% for fluvoxamine and from 4 to 13% for fluoxetine and norfluoxetine. The limits of quantitation of the method were found to be 2 ng/ml for fluvoxamine and 1 ng/ml for the (R)- and (S)-enantiomers of fluoxetine and norfluoxetine, hence allowing its use for single dose pharmacokinetics. Finally, by using a steeper gradient of temperature, much shorter analysis times are obtained if one is interested in the concentrations of fluvoxamine alone.

Examining the Agreement of Structural Loss Measured With Heidelberg Retinal Tomograhy and Functional Loss With Standard Automated Perimetry (SAP; Octopus), Pulsar Perimetry (PP), and Moorfields Motion Displacement Test (MDT) Perimetry

Purpose: To examine the relationship of functional measurements with structural measures. Methods: 146 eyes of 83 test subjects underwent Heidelberg Retinal Tomography (HRTIII) (disc area<2.43, mphsd<40), and perimetry testing with Octopus (SAP; Dynamic), Pulsar (PP; TOP) and Moorfields MDT (ESTA). Glaucoma was defined as progressive structural or functional loss (20 eyes). Perimetry test points were grouped into 6 sectors based on the estimated optic nerve head angle into which the associated nerve fiber bundle enters (Garway-Heath map). Perimetry summary measures (PSM) (MD SAP/ MD PP/ PTD MDT) were calculated from the average total deviation of each measured threshold from the normal for each sector. We calculated the 95% significance level of the sectorial PSM from the respective normative data. We calculated the percentage agreement with group1 (G1), healthy on HRT and within normal perimetric limits, and group 2 (G2), abnormal on HRT and outside normal perimetric limits. We also examined the relationship of PSM and rim area (RA) in those sectors classified as abnormal by MRA (Moorfields Regression Analysis) of HRT. Results: The mean age was 65 (range= [37, 89]). The global sensitivity versus specificity of each instrument in detecting glaucomatous eyes was: MDT 80% vs. 88%, SAP 80% vs. 80%, PP 70% vs. 89% and HRT 80% vs. 79%. Highest percentage agreement of HRT (respectively G1, G2, sector) with PSM were MDT (89%, 57%, nasal superior), SAP (83%, 74%, temporal superior), PP (74%, 63%, nasal superior). Globally percentage agreement (respectively G1, G2) was MDT (92%, 28%), SAP (87%, 40%) and PP (77%, 49%). Linear regression showed there was no significant trend globally associating RA and PSM. However, sectorally the supero-nasal sector had a statistically significant (p<0.001) trend with each instrument, the associated r2 coefficients are (MDT 0.38 SAP 0.56 and PP 0.39). Conclusions: There were no significant differences in global sensitivity or specificity between instruments. Structure-function relationships varied significantly between instruments and were consistently strongest supero-nasally. Further studies are required to investigate these relationships in detail.

A new approach to accurate measurement of uniaxial joint angles based on a combination of accelerometers and gyroscopes.

A new method of measuring joint angle using a combination of accelerometers and gyroscopes is presented. The method proposes a minimal sensor configuration with one sensor module mounted on each segment. The model is based on estimating the acceleration of the joint center of rotation by placing a pair of virtual sensors on the adjacent segments at the center of rotation. In the proposed technique, joint angles are found without the need for integration, so absolute angles can be obtained which are free from any source of drift. The model considers anatomical aspects and is personalized for each subject prior to each measurement. The method was validated by measuring knee flexion-extension angles of eight subjects, walking at three different speeds, and comparing the results with a reference motion measurement system. The results are very close to those of the reference system presenting very small errors (rms = 1.3, mean = 0.2, SD = 1.1 deg) and excellent correlation coefficients (0.997). The algorithm is able to provide joint angles in real-time, and ready for use in gait analysis. Technically, the system is portable, easily mountable, and can be used for long term monitoring without hindrance to natural activities.

Testing Spatial Autocorrelation in Weighted Networks : the Modes Permutation Test

In a weighted spatial network, as specified by an exchange matrix, the variances of the spatial values are inversely proportional to the size of the regions. Spatial values are no more exchangeable under independence, thus weakening the rationale for ordinary permutation and bootstrap tests of spatial autocorrelation. We propose an alternative permutation test for spatial autocorrelation, based upon exchangeable spatial modes, constructed as linear orthogonal combinations of spatial values. The coefficients obtain as eigenvectors of the standardised exchange matrix appearing in spectral clustering, and generalise to the weighted case the concept of spatial filtering for connectivity matrices. Also, two proposals aimed at transforming an acessibility matrix into a exchange matrix with with a priori fixed margins are presented. Two examples (inter-regional migratory flows and binary adjacency networks) illustrate the formalism, rooted in the theory of spectral decomposition for reversible Markov chains.

Relative and absolute reliability of the clinical version of the Narrow Path Walking Test (NPWT) under single and dual task conditions.

Decline in gait stability has been associated with increased fall risk in older adults. Reliable and clinically feasible methods of gait instability assessment are needed. This study evaluated the relative and absolute reliability and concurrent validity of the testing procedure of the clinical version of the Narrow Path Walking Test (NPWT) under single task (ST) and dual task (DT) conditions. Thirty independent community-dwelling older adults (65-87 years) were tested twice. Participants were instructed to walk within the 6-m narrow path without stepping out. Trial time, number of steps, trial velocity, number of step errors, and number of cognitive task errors were determined. Intraclass correlation coefficients (ICCs) were calculated as indices of agreement, and a graphic approach called "mountain plot" was applied to help interpret the direction and magnitude of disagreements between testing procedures. Smallest detectable change and smallest real difference (SRD) were computed to determine clinically relevant improvement at group and individual levels, respectively. Concurrent validity was assessed using Performance Oriented Mobility Assessment Tool (POMA) and the Short Physical Performance Battery (SPPB). Test-retest agreement (ICC1,2) varied from 0.77 to 0.92 in ST and from 0.78 to 0.92 in DT conditions, with no apparent systematic differences between testing procedures demonstrated by the mountain plot graphs. Smallest detectable change and smallest real change were small for motor task performance and larger for cognitive errors. Significant correlations were observed for trial velocity and trial time with POMA and SPPB. The present results indicate that the NPWT testing procedure is highly reliable and reproducible.

25-hydroxyvitamin D concentration is inversely associated with serum MMP-9 in a cross-sectional study of African American ESRD patients.

BACKGROUND: Circulating 25-hydroxyvitamin D [25(OH)D] concentration is inversely associated with peripheral arterial disease and hypertension. Vascular remodeling may play a role in this association, however, data relating vitamin D level to specific remodeling biomarkers among ESRD patients is sparse. We tested whether 25(OH)D concentration is associated with markers of vascular remodeling and inflammation in African American ESRD patients.METHODS: We conducted a cross-sectional study among ESRD patients receiving maintenance hemodialysis within Emory University-affiliated outpatient hemodialysis units. Demographic, clinical and dialysis treatment data were collected via direct patient interview and review of patients records at the time of enrollment, and each patient gave blood samples. Associations between 25(OH)D and biomarker concentrations were estimated in univariate analyses using Pearson's correlation coefficients and in multivariate analyses using linear regression models. 25(OH) D concentration was entered in multivariate linear regression models as a continuous variable and binary variable (<15 ng/ml and =15 ng/ml). Adjusted estimate concentrations of biomarkers were compared between 25(OH) D groups using analysis of variance (ANOVA). Finally, results were stratified by vascular access type.RESULTS: Among 91 patients, mean (standard deviation) 25(OH)D concentration was 18.8 (9.6) ng/ml, and was low (<15 ng/ml) in 43% of patients. In univariate analyses, low 25(OH) D was associated with lower serum calcium, higher serum phosphorus, and higher LDL concentrations. 25(OH) D concentration was inversely correlated with MMP-9 concentration (r = -0.29, p = 0.004). In multivariate analyses, MMP-9 concentration remained negatively associated with 25(OH) D concentration (P = 0.03) and anti-inflammatory IL-10 concentration positively correlated with 25(OH) D concentration (P = 0.04).CONCLUSIONS: Plasma MMP-9 and circulating 25(OH) D concentrations are significantly and inversely associated among ESRD patients. This finding may suggest a potential mechanism by which low circulating 25(OH) D functions as a cardiovascular risk factor.

Robust response transformations based on optimal prediction

Nonlinear regression problems can often be reduced to linearity by transforming the response variable (e.g., using the Box-Cox family of transformations). The classic estimates of the parameter defining the transformation as well as of the regression coefficients are based on the maximum likelihood criterion, assuming homoscedastic normal errors for the transformed response. These estimates are nonrobust in the presence of outliers and can be inconsistent when the errors are nonnormal or heteroscedastic. This article proposes new robust estimates that are consistent and asymptotically normal for any unimodal and homoscedastic error distribution. For this purpose, a robust version of conditional expectation is introduced for which the prediction mean squared error is replaced with an M scale. This concept is then used to develop a nonparametric criterion to estimate the transformation parameter as well as the regression coefficients. A finite sample estimate of this criterion based on a robust version of smearing is also proposed. Monte Carlo experiments show that the new estimates compare favorably with respect to the available competitors.

Analysis of the enantiomers of citalopram and its demethylated metabolites using chiral liquid chromatography.

A procedure using a chirobiotic V column is presented which allows separation of the enantiomers of citalopram and its two N-demethylated metabolites, and of the internal standard, alprenolol, in human plasma. Citalopram, demethylcitalopram and didemethylcitalopram, as well as the internal standard, were recovered from plasma by liquid-liquid extraction. The limits of quantification were found to be 5 ng/ml for each enantiomer of citalopram and demethylcitalopram, and 7.5 ng/ml for each enantiomer of didemethylcitalopram. Inter- and intra-day coefficients of variation varied from 2.4% to 8.6% for S- and R-citalopram, from 2.9% to 7.4% for S- and R-demethylcitalopram, and from 5.6% to 12.4% for S- and R- didemethylcitalopram. No interference was observed from endogenous compounds following the extraction of plasma samples from 10 different patients treated with citalopram. This method allows accurate quantification for each enantiomer and is, therefore, well suited for pharmacokinetic and drug interaction investigations. The presented method replaces a previously described highly sensitive and selective high-performance liquid chromatography procedure using an acetylated 3-cyclobond column which, because of manufactural problems, is no longer usable for the separation of the enantiomers of citalopram and its demethylated metabolites.

A new alternative method for testing skin irritation using a human skin model: a pilot study.

Studies assessing skin irritation to chemicals have traditionally used laboratory animals; however, such methods are questionable regarding their relevance for humans. New in vitro methods have been validated, such as the reconstructed human epidermis (RHE) model (Episkin®, Epiderm®). The comparison (accuracy) with in vivo results such as the 4-h human patch test (HPT) is 76% at best (Epiderm®). There is a need to develop an in vitro method that better simulates the anatomo-pathological changes encountered in vivo. To develop an in vitro method to determine skin irritation using human viable skin through histopathology, and compare the results of 4 tested substances to the main in vitro methods and in vivo animal method (Draize test). Human skin removed during surgery was dermatomed and mounted on an in vitro flow-through diffusion cell system. Ten chemicals with known non-irritant (heptylbutyrate, hexylsalicylate, butylmethacrylate, isoproturon, bentazon, DEHP and methylisothiazolinone (MI)) and irritant properties (folpet, 1-bromohexane and methylchloroisothiazolinone (MCI/MI)), a negative control (sodiumchloride) and a positive control (sodiumlaurylsulphate) were applied. The skin was exposed at least for 4h. Histopathology was performed to investigate irritation signs (spongiosis, necrosis, vacuolization). We obtained 100% accuracy with the HPT model; 75% with the RHE models and 50% with the Draize test for 4 tested substances. The coefficients of variation (CV) between our three test batches were <0.1, showing good reproducibility. Furthermore, we reported objectively histopathological irritation signs (irritation scale): strong (folpet), significant (1-bromohexane), slight (MCI/MI at 750/250ppm) and none (isoproturon, bentazon, DEHP and MI). This new in vitro test method presented effective results for the tested chemicals. It should be further validated using a greater number of substances; and tested in different laboratories in order to suitably evaluate reproducibility.

Intra-individual stability of neuromotor tasks from 6 to 18 years: a longitudinal study.

This study investigates the intra-individual stability of the speed of several motor tasks and the intensity of associated movements in 256 children (131 girls, 125 boys) from the Zurich generational study using the Zurich neuromotor assessment battery (ZNA) over a 12-year period from the age of 6 to 18 years. The stability was assessed by correlograms of standard deviation scores calculated from age- and gender-adjusted normative values and compared with standing height and full scale intelligence quotient (IQ). While motor tasks of hand, finger and foot (HFT) and contralateral associated movements (CAM) exhibited a moderate stability (summary measure as correlation coefficients between two measurements made 4 years apart: .61 and .60), other tasks (dynamic balance, static balance and pegboard) were only weakly stable (.46, .47 and .49). IQ and height were more stable than neuromotor components (.72 and .86). We conclude that the moderately stable HFT and CAM may reflect "motor traits", while the stability of the pegboard and balance tasks is weaker because these skills are more experience related and state-dependent.

Random measurement error and regression dilution bias.

Summary points: - The bias introduced by random measurement error will be different depending on whether the error is in an exposure variable (risk factor) or outcome variable (disease) - Random measurement error in an exposure variable will bias the estimates of regression slope coefficients towards the null - Random measurement error in an outcome variable will instead increase the standard error of the estimates and widen the corresponding confidence intervals, making results less likely to be statistically significant - Increasing sample size will help minimise the impact of measurement error in an outcome variable but will only make estimates more precisely wrong when the error is in an exposure variable

Statistical discrimination of black gel pen inks analysed by laser desorption/ionization mass spectrometry

Pearson correlation coefficients were applied for the objective comparison of 30 black gel pen inks analysed by laser desorption ionization mass spectrometry (LDI-MS). The mass spectra were obtained for ink lines directly on paper using positive and negative ion modes at several laser intensities. This methodology has the advantage of taking into account the reproducibility of the results as well as the variability between spectra of different pens. A differentiation threshold could thus be selected in order to avoid the risk of false differentiation. Combining results from positive and negative mode yielded a discriminating power up to 85%, which was better than the one obtained previously with other optical comparison methodologies. The technique also allowed discriminating between pens from the same brand.

Mise au point et validation d'un fantôme spécifique pour asssurer le suivi des mesures quantitatives en tomographie par émission de positons.

L'index de consommation du glucose, SUV pour standardized uptake value, est largement utilisé en tomographie par émission de positons (TEP) pour quantifier la concentration relative de [18F]2-fluoro-2-désoxy-D-glucose (18F-FDG) dans les tissus. Cependant, cet indice dépend de nombreux facteurs méthodologiques et biologiques et son utilisation fait débat. Il est donc primordial d'instaurer un contrôle qualité régulier permettant d'assurer la stabilité de la mesure des indices quantitatifs. Dans cette optique, un fantôme spécifique avec inserts cylindriques de différentes tailles a été développé. L'objectif de cette étude est de montrer la sensibilité et l'intérêt de ce fantôme. Méthodes. - La sensibilité du fantôme a été étudiée à travers la mesure des SUV et des coefficients de recouvrement (RC). Plusieurs méthodes de mesure ont été utilisées. Les données ont été reconstruites en utilisant les algorithmes de routine clinique. Nous avons étudié la variation des RC en fonction de la taille des cylindres et le changement relatif de fixation, en utilisant des activités différentes. Le fantôme a ensuite été testé sur l'appareil d'un autre centre. Résultats. - Pour toutes les méthodes de mesure, une forte variation des RC avec la taille des cylindres, de l'ordre de 50 %, a été obtenue. Ce fantôme a également permis de mesurer un changement relatif de fixation qui s'est révélé être indépendant de la méthode de mesure. Malgré un étalonnage des deux systèmes TEP/TDM, des différences de quantification d'environ 20 % ont subsisté. Conclusion. - Les résultats obtenus montrent l'intérêt de ce fantôme dans le cadre du suivi des mesures quantitatives.

Comparison of the polynomial model against explicit measurements of noise components for different mammography systems.

Given the adverse impact of image noise on the perception of important clinical details in digital mammography, routine quality control measurements should include an evaluation of noise. The European Guidelines, for example, employ a second-order polynomial fit of pixel variance as a function of detector air kerma (DAK) to decompose noise into quantum, electronic and fixed pattern (FP) components and assess the DAK range where quantum noise dominates. This work examines the robustness of the polynomial method against an explicit noise decomposition method. The two methods were applied to variance and noise power spectrum (NPS) data from six digital mammography units. Twenty homogeneously exposed images were acquired with PMMA blocks for target DAKs ranging from 6.25 to 1600 µGy. Both methods were explored for the effects of data weighting and squared fit coefficients during the curve fitting, the influence of the additional filter material (2 mm Al versus 40 mm PMMA) and noise de-trending. Finally, spatial stationarity of noise was assessed.Data weighting improved noise model fitting over large DAK ranges, especially at low detector exposures. The polynomial and explicit decompositions generally agreed for quantum and electronic noise but FP noise fraction was consistently underestimated by the polynomial method. Noise decomposition as a function of position in the image showed limited noise stationarity, especially for FP noise; thus the position of the region of interest (ROI) used for noise decomposition may influence fractional noise composition. The ROI area and position used in the Guidelines offer an acceptable estimation of noise components. While there are limitations to the polynomial model, when used with care and with appropriate data weighting, the method offers a simple and robust means of examining the detector noise components as a function of detector exposure.

Chemical labelling of oyster shells used for time-calibrated high-resolution Mg/Ca ratios: A tool for estimation of past seasonal temperature variations

The geochemical compositions of biogenic carbonates are increasingly used for palaeoenvironmental reconstructions. The skeletal delta O-18 temperature relationship is dependent on water salinity, so many recent studies have focused on the Mg/Ca and Sr/Ca ratios because those ratios in water do not change significantly on short time scales. Thus, those elemental ratios are considered to be good palaeotemperature proxies in many biominerals, although their use remains ambiguous in bivalve shells. Here, we present the high-resolution Mg/Ca ratios of two modern species of juvenile and adult oyster shells, Crassostrea gigas and Ostrea edulis. These specimens were grown in controlled conditions for over one year in two different locations. In situ monthly Mn-marking of the shells has been used for day calibration. The daily Mg/Ca.ratios in the shell have been measured with an electron microprobe. The high frequency Mg/Ca variation of all specimens displays good synchronism with lunar cycles, suggesting that tides strongly influence the incorporation of Mg/Ca into the shells. Highly significant correlation coefficients (0.70<R<0.83, p<0.0001) between the Mg/Ca ratios and the seawater temperature are obtained only for juvenile C. gigas samples, while metabolic control of Mg/Ca incorporation and lower shell growth rates preclude the use of the Mg/Ca ratio in adult shells as a palaeothermometer. Data from three juvenile C. gigas shells from the two study sites are selected to establish a relationship: T = 3.77Mg/Ca + 1.88, where T is in degrees C and Mg/Ca in mmol/mol. (c) 2012 Elsevier B.V. All rights reserved.