Biomedical subjects
Publications and source records attributed to N Matthews.
We report the case of a 65-year-old patient who had complete excision of an atrial myxoma and subsequently presented to our unit with recurrent cerebral metastasis. The case demonstrates that cardiac myxoma despite benign histological appearance is capable of metastatic spread.
OBJECTIVE: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). METHODS: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). RESULTS: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. CONCLUSIONS: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.
OBJECTIVE: To establish the validity of a 15 m multistage shuttle run test (MSRT) as a predictor of anaerobic capacity (expressed as mean power output (MPO) from the 30 second Wingate anaerobic test (WAnT)) in female university standard games players. METHODS: Data came from three phases using a total of 72 players (mean (SD) age 20.3 (1.5) years, body mass 64.9 (8.8) kg, and stature 1.67 (0.04) m). The repeatability of the MSRT was assessed in phase 1 by applying 95% limits of agreement (LoA) to the test and retest results from a random sample of 20 players. In phase 2, linear relations between MPO and performance on the MSRT were investigated in a random sample of 36 players. As a result, a calibration model (Y = a + bX) was developed and cross validated in phase 3, in which the remaining 36 players performed both the WAnT and the MSRT. Time (seconds) to volitional exhaustion/disqualification from the MSRT was substituted into the calibration model from which MPO was predicted. The agreement between MPO predicted and MPO measured from the WAnT was quantified using LoA. RESULTS: Insignificant bias between repeat applications of the MSRT (mean(diff) (SD(diff)) = 1.0 (3.5) seconds (4 (14) m), t = 1.23, p = 0.230) was found from phase 1. Data were homoscedastic (r = 0.061, p = 0.799) with LoA +/- 6.9 seconds (+/- 27 m). In phase 2 the strongest correlation was between MPO (W/kg(0.67)) and time to volitional exhaustion/disqualification on the MSRT; r = 0.715 (r(2) = 51.1%, p = 0.0005). As a result, the calibration model developed was: MPO (W/kg(0.67)) = 12.5 + (0.2 x time (seconds)) with a standard error of prediction of 2.1 W/kg(0.67). The cross validation in phase 3 showed insignificant bias between measured and predicted MPO (mean(diff) (SD(diff)) = 0.3 (2.8) W/kg(0.67), t = 0.75, p = 0.460). Data were homoscedastic (r = 0.05, p = 0.774) with LoA +/- 5.5 W/kg(0.67). CONCLUSIONS: The MSRT requires minimal equipment and training of assessors, and it is easy to perform. In the population studied, it provides scores that are repeatable, and anaerobic capacity (MPO) can be successfully predicted from its performance. It would seem therefore to be a useful field based test for use by female games players, their coaches, and support scientists.
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This study was conducted to determine whether humans' judgments about the speed and direction of moving stimuli was differentially affected by transcranial magnetic stimulation (TMS). Subjects viewed two successively presented moving stimuli that differed from each other both in speed and direction of motion. Single-pulse TMS was applied either medially (approximately 2 cm above the inion) or laterally (approximately 5 cm lateral to and 4 cm above the inion), while subjects judged the speed and direction differences. The physical stimulation (visual and TMS) was identical on the two tasks, as was discriminability (d') when TMS was not applied. We found significant criterion (beta) shifts on the speed discrimination task at both stimulation sites. Specifically, on TMS trials the proportion of "slower" judgments increased significantly, consistent with subjective reports that stimuli often appeared to slow when TMS was applied. The subjective reports indicated no corresponding change in perceived direction. We also found that speed discriminability was impaired significantly more than direction discriminability, but only when TMS was applied medially. Indeed, after controlling for TMS-related changes in reaction time, speed discriminability was impaired significantly, while direction discriminability remained largely intact. This dissociation suggests that the sensory response constraining speed discrimination is at least partially independent from the sensory response constraining direction discrimination. Combined with previous psychophysical data, the present data suggest a double dissociation between speed and direction discrimination in humans.
Regan and Beverley [Regan, D., & Beverley, K. I. (1985). Postadaptation orientation discrimination. Journal of the Optical Society of America A, 2(2), 147-155] previously demonstrated that adapting to an oriented visual stimulus improves sensitivity to subtle orientation differences while impairing contrast sensitivity. Here, we investigated whether practice-based improvements in orientation sensitivity would, like adaptation, impair contrast sensitivity. To the contrary, we found that contrast sensitivity actually improved significantly after observers demonstrated practice-based increases in orientation sensitivity. Therefore, while orientation sensitivity can be enhanced either by orientation-discrimination training or by adapting to visual stimuli, these two procedures have opposite effects on contrast sensitivity. This difference suggests that adaptation and perceptual learning on orientation discrimination cannot be explained sufficiently by a shared underlying cause, such as a reduction in neural activity.
In their classic study on motion repulsion, Marshak and Sekuler (Science 205 (1979) 1399) reported a repulsion of up to 10 degrees when two different directions of motion were presented dichoptically. However, subjects in that study did not experience binocular rivalry, presumably because of the brief presentation time. In the present study, we measured repulsion during binocular rivalry by requiring subjects to dichoptically view the stimuli until one direction of motion appeared to exclusively dominate the other (Blake, Yu, Lokey, & Norman (1998). J. Cogn. Neurosci., 10, 46-60). We found that motion repulsion was significantly reduced during exclusive dominance. Indeed, after controlling for reference repulsion--the misjudgment of a single direction of motion (Rauber & Treue (1998). Perception, 27, 393-402)--we found no significant motion repulsion during exclusive dominance. These data suggest that motion repulsion may require the perception, rather than merely the physical presence, of multiple directions.
We investigated the extent to which motion repulsion and binocular motion rivalry depend on the distance between moving elements. The stimuli consisted of two sets of spatially intermingled, finite-life random dots that moved across each other. The distance between the dots moving in different directions was manipulated by spatially pairing the dot trajectories with various precisions. Data from experiment 1 indicated that motion repulsion occurred reliably only when the average distance between orthogonally moving elements was at least 21.0 arc min. When the dots were precisely paired, a single global direction intermediate to the two actual directions was perceived. This result suggests that, at a relatively small spatial scale, interaction between different directions favors motion attraction or coherence, while interaction at a somewhat larger scale generates motion repulsion. Similarly, data from experiment 2 indicated that binocular motion rivalry was significantly diminished by spatially pairing the dots, which moved in opposite directions in the two eyes. This supports the recent proposal that rivalry occurs at or after the stage of binocular convergence, since monocular cells could not have directly responded to our interocular pairing manipulation. Together, these findings suggest that the neural mechanisms underlying motion perception are highly sensitive to the fine spatial relationship between moving elements.
Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism. To test this hypothesis we performed an association study on the collection of families from the International Molecular Genetic Study of Autism (IMGSA) Consortium, using the transmission disequilibrium test. Two polymorphisms in the 5-HTT gene (a functional insertion-deletion polymorphism in the promoter and a variable number tandem repeat in the second intron) were examined in 90 families comprising 174 affected individuals. Furthermore, seven microsatellite markers spanning the 15q11-q13 region were studied in 94 families with 182 affected individuals. No significant evidence of association or linkage was found at any of the markers tested, indicating that the 5-HTT and the GABRB3 genes are unlikely to play a major role in the aetiology of autism in our family data set.
Several members of the ABC family of proteins have been implicated in multidrug resistance associated with cancer therapies. A novel member of this gene family, designated pABC11, has been identified using degenerate polymerase chain reaction. The full-length cDNA spans 5881 base pairs and encodes an open reading frame of 1437 amino acids predicted to contain two sets of transmembrane domains and two nucleotide binding domains characteristic of ABC proteins. The nucleotide sequence described herein extends that of three recently reported sequences, MRP5 (Kool, M., de Haas, M., Scheffer, G., Scheper, R., van Eijk, M., Juijn, J., Baas, F., and Borst, P. (1997) Cancer Res. 57, 3537-3547), SMRP (Suzuki, T., Nishio, K., Sasaki, H., Kurokawa, H., Saito-Ohara, F., Ikeuchi, T., Tanabe, S., Terada, M., and Saijo, N. (1997) Biochem. Biophys. Res. Commun. 238, 790-794), and MOAT-C (Belinsky, M., Bain, L., Balsara, B., Testa, J., and Kruh, G. (1998) J. Natl. Cancer Inst. 90, 1735-1741), in the 5' direction. Northern blot analysis detected five transcripts that were differentially expressed in several tissue types, and the gene encoding pABC11 was mapped to chromosome 3. Confocal imaging of HEK293 cells expressing a green fluorescent protein-pABC11 construct confirmed plasma membrane localization of the fusion protein. Overexpression of pABC11 resulted in reduced labeling with the fluorochromes 5-chloromethylfluorescein diacetate, fluorescein diacetate, and 2',7'-bis-(2-carboxyethyl)-5 (and-6)-carboxyfluorescein acetoxymethyl ester but not with calcein or rhodamine derivatives, consistent with pABC11 being an anion transporter. Fluorochrome export was ATP-dependent but glutathione-independent. We also show that this export pump does not confer resistance to various classes of cytotoxic drugs but does provide small but significant resistance to CdCl(2) and potassium antimonyl tartrate.
We describe a procedure for the measurement of pyridoxal 5'-phosphate and of 4-pyridoxic acid in human plasma samples. It is based on the conversion of pyridoxal 5'-phosphate to 4-pyridoxic acid 5'-phosphate by cyanide in alkaline medium, followed by a high pressure liquid chromatographic separation, with fluorescence detection at acid pH. The assay is robust, sensitive, linear over a wide range, reproducible, and simple to perform. Samples stored at -80 degrees C are stable. Satisfactory agreement was obtained with results from the tyrosine decarboxylase-based assay for pyridoxal 5'-phosphate, in two other laboratories. Plasma samples from a National Survey of older British people were analyzed, and reference intervals for plasma pyridoxal 5'-phosphate intervals were derived. From the lower 2.5 percentile of the reference group, taken as the lower cut-off of the normal range, ca. 20% of elderly men and 11% of elderly women in the UK showed evidence of biochemical deficiency.
The motion of an object can be described by a single velocity vector, or equivalently, by direction and speed separately. Similarly, our ability to see subtle differences in the motion of two objects could be constrained by either a velocity-based sensory response, or separate sensory responses to direction and speed. To distinguish between these possibilities we investigated whether direction discrimination and speed discrimination were differentially affected by changes in the axis-of-motion. Psychophysical data from 12 naive observers indicated that direction discrimination depended on axis-of-motion, but speed discrimination did not. The difference suggests that a velocity-based sensory response is not the limiting factor on the two tasks. Instead, the results imply that the sensory response which constrains speed discrimination is at least partially independent from the sensory response which constrains direction discrimination.
Two experiments were conducted to determine the extent to which perceptual learning transfers between orientation and direction discrimination. Naive observers were trained to discriminate orientation differences between two single-line stimuli, and direction differences between two single-moving-dot stimuli. In the first experiment, observers practiced the orientation and direction tasks along orthogonal axes in the fronto-parallel plane. In the second experiment, a different group of observers practiced both tasks along a single axis. Perceptual learning was observed on both tasks in both experiments. Under the same-axis condition, the observers' orientation sensitivity was found to be significantly elevated after the direction training, indicating a transfer of learning from direction to orientation. There was no evidence of transfer in any other cases tested. In addition, the rate of learning on the orientation task was much higher than the rate on the direction task. The implications of these findings on the neural mechanisms subserving orientation and direction discrimination are discussed.
Understanding the physiological regulation of fetal growth is important, as normal variations in size at birth relate to differences in neonatal and adult health. Although fetal growth directly reflects net placental transfer, little is known about how normal fetal growth relates to the transfer capabilities of the placental epithelium, the syncytiotrophoblast. The Na(+)-dependent and Na(+)-independent uptakes of methylaminoisobutyric acid (MeAIB) by vesicles prepared from the syncytiotrophoblast microvillous plasma membrane give measurements of system A neutral amino acid transporter activity and diffusive permeability, respectively. In 62 normal pregnancies, we related vesicle MeAIB uptakes to neonatal anthropometry. Smaller babies with a lower abdominal circumference had higher placental system A activity per mg membrane protein (P = 0.004); activity rose from 0.020 to 0.043 nmol/30 sec/mg protein as abdominal circumference fell from 34.6 cm or more to 32.0 cm or less. Within the normal range of fetal and placental size, this may reflect a tendency toward compensatory up-regulation of the placental system A transporter in smaller babies. Babies with a lower abdominal circumference also had higher Na(+)-independent MeAIB uptakes (P = 0.0005); this could reflect important compositional changes in the microvillous plasma membrane, leading in vivo to increased back-diffusion of amino acids out of the syncytiotrophoblast.
We report our experience with 11 children treated by continuous veno-venous hemodiafiltration. The median age was 5.0 years (range 3 days to 14 years). Access was via dual-lumen subclavian or femoral vein catheters. Hemofilters were chosen on the basis of patient size and dialysis requirements. Bicarbonate-buffered dialysis solution was prepared shortly before use by supplementation of a specially prepared base solution with commercially available electrolyte solutions. The mean ultrafiltration rate was 37.4 +/- 27 ml/kg body weight per hour. Urea and creatinine clearances were 15.1 +/- 6.4 ml/kg body weight per min and 16.4 +/- 8.4 ml/kg body weight per min, respectively. Metabolic acidosis was readily controlled in all patients. Of the 11 patients, 7 ultimately recovered normal renal function.
A study designed to determine how inducer-surround contrast and inducer polarity affect the contour clarity and the lightness of illusory figures is reported. Using magnitude estimation procedures, ten naive subjects rated both the contour clarity and the lightness of Kanizsa squares. The magnitude of the inducer-surround contrast and the inducer polarity (all-black, all-white, or black-and-white) were varied randomly on each trial. The data indicate that contour clarity increases with contrast at the same rate across polarity conditions but that contour clarity at any given contrast level depends significantly on polarity. Contour clarity judgments were significantly lower when the inducers were all-white than when the inducers were all-black or black-and-white, and significantly greater in the 'mixed' polarity case (black-and-white inducers) than in the 'same' polarity case (the average of the all-black and all-white inducer conditions). Inducer contrast and polarity significantly affected the lightness of the illusory figure in a manner consistent with simultaneous spatial contrast. Also, for a given increment in contrast, contour clarity altered significantly more than surface lightness, regardless of inducer polarity. The findings suggest that the mechanism which mediates boundary formation is sensitive to the direction of contrast, and that the boundary formation mechanism is more sensitive than the surface lightness mechanism to changes in contrast magnitude. The results are considered within the context of neural network models of form perception.
Thirty-six Brown University students participated in three experiments designed to address perceptual learning. In each experiment, visual discrimination thresholds were tracked over 4,200 trials. Results from Experiment 1 suggest that the pattern of threshold reduction on a single-dot motion-direction discrimination task was stimulus direction specific and matched (in a velocity-dependent manner) the threshold reduction pattern previously reported for a line-orientation discrimination task. In Experiment 2, it was determined that the stationary-line-orientation-specific practice effects originally reported by Vogels and Orban (1985) could be replicated but were contingent on line length. Similarly, the results from Experiment 3 suggest that practice effects originally reported by Ball and Sekuler (1987) could be replicated but were contingent on stimulus velocity. Implications for the mechanisms underlying direction and orientation discrimination are considered.
Lymphocyte migration into inflammatory sites involves a change from a spherical, non-motile phenotype to an irregular, constantly shape-changing, motile phenotype. We have previously shown that lymphocytes are maintained in the non-motile state by the constitutive activity of protein kinase C (PKC). In this paper we have attempted to identify the PKC isotype which regulates these morphological changes by three different approaches. (a) Motile and non-motile T-cell lines were compared for expression of the alpha, beta I, beta II, gamma, delta, epsilon, eta, zeta and theta isotypes by Western blotting. There was no obvious correlation of isotype expression with motility. (b) Two different PKC inhibitors, one specific for classical isotypes, Go6976 and the other GF109203X, which inhibits both classical and non-classical isotypes were compared for induction of motility in non-motile lymphocytes. Only GF109203X induced motility implying that a non-classical isotype is involved. (c) Non-motile lymphocytes were chronically treated with the PKC activator bryostatin and the time courses of induction of motility and downregulation of PKC isotypes were compared. Induction of motility correlated better with downregulation of epsilon, eta and theta than with alpha or beta. It is concluded that the data fit best with the involvement of a non-classical PKC isotype in regulating lymphocyte motility although no association with a particular isotype was found.