Differences in Balance Ability and Motor Control between Dancers and Non-Dancers with Varying Foot Positions.

The purpose of this study was to investigate balance and motor control in dancers and non-dancers with different foot positions. Physically active female dancers (n = 11) and non-dancers (n = 9) randomly completed two balance tests in a single visit: 1) Y-balance test (YBT), and 2) motor control test (MCT). Each test was completed with two different foot positions: 1) first ballet position in which heels were touching and feet were externally rotated to 140 degrees, and 2) sixth ballet position in which heels were spaced 10 cm apart and forward parallel. For the YBT, participants completed three attempts at anterior, posteromedial, and posterolateral reaches, which were averaged and standardized to limb length for a composite score. For the MCT, participants completed a multi-directional target test on a Biosway balance system, and accuracy and time to completion were analyzed. Findings revealed no differences in YBT score (p = 0.255), MCT score (p = 0.383), or MCT time (p = 0.306) between groups in the sixth position. However, dancers displayed better YBT scores (p = 0.036), MCT scores (p = 0.020), and faster MCT times (p = 0.009) in the first position. Results suggest that superior balance and motor control in dancers may be limited to less innate dance-specific foot positions.

Duration and mutual entrainment of changes in parenting practices engendered by behavioral parent training targeting recently separated mothers.

Parent management training (PMT) has beneficial effects on child and parent adjustment that last for 5 to 10 years. Short-term changes in parenting practices have been shown to mediate these effects, but the manner in which changes in specific components of parenting are sequenced and become reciprocally reinforcing (or mutually entrained) to engender and sustain the cascade of long-term beneficial effects resulting from PMT has received modest empirical attention. Long-term changes in parenting resulting from the Oregon model of PMT (PMTO) over a 2-year period were examined using data from the Oregon Divorce Study-II in which 238 recently separated mothers and their 6- to 10-year-old sons were randomly assigned to PMTO or a no treatment control (NTC) group. Multiple indicators of observed parenting practices were used to define constructs for positive parenting, monitoring and discipline at baseline, and at 6-, 12-, 18- and 30-months postbaseline. PMTO relative to NTC resulted in increased positive parenting and prevented deterioration in discipline and monitoring over the 30-month period. There were reliable sequential, transactional relationships among parenting practices; positive parenting supported better subsequent monitoring, and positive parenting and better monitoring supported subsequent effective discipline. Small improvements in parenting resulting from PMTO and small deteriorations in parenting in the NTC group may be sustained and amplified by mutually entrained relationships among parenting practices. These data about the change processes engendered by PMTO may provide information needed to enhance the power, effectiveness, and efficiency of behavioral parent training interventions.

Loxapine P-glycoprotein interactions in vitro.

The antipsychotic drugs risperidone, paliperidone, olanzapine, quetiapine, aripiprazole, clozapine, haloperidol, and chlorpromazine have been reported to have various degrees of interaction (substrate or inhibitor) with the multidrug resistance transporter, P-glycoprotein (P-gp). An interaction of the antipsychotic drug loxapine with P-gp was recently reported, but an IC50 value was not determined. Loxapine (as the succinate salt) was evaluated as a P-gp substrate, and inhibitor of P-gp mediated transport of digoxin in vitro in Caco-2 cells. Loxapine was not a substrate for P-gp but did exhibit weak-to-moderate inhibition (IC50 = 9.1 µM). Since the typical steady state maximal plasma concentrations of loxapine in clinical use have been reported to be in the nanomolar range, pharmacokinetic interactions due to the inhibition of P-gp activity are not expected.

Validation of HPLC-MS/MS methods for analysis of loxapine, amoxapine, 7-OH-loxapine, 8-OH-loxapine and loxapine N-oxide in human plasma.

BACKGROUND: Two ESI-LC-MS/MS methods were validated for the quantitative analysis of loxapine, amoxapine, 7-OH-loxapine, 8-OH-loxapine and loxapine N-oxide in human K(2)EDTA plasma. Cation-exchange solid-phase extraction (SPE) was used to extract loxapine, amoxapine and the two hydroxylated metabolites, and organic precipitation was used to quantify loxapine N-oxide. RESULTS: Both methods were shown to be accurate (±13%), intra-assay precision was less than 15%, and inter-assay precision was less than 10% in all instances across the entire dynamic range of the assays (0.0500-50.0 ng/ml for the SPE method and 0.100-25.0 ng/ml for the precipitation method). CONCLUSION: The validated methods for loxapine, amoxapine, 7-OH-loxapine, 8-OH-loxapine and loxapine N-oxide have been used to successfully support clinical trials.

Do children "DRM" like adults? False memory production in children.

The Deese/Roediger-McDermott (DRM) paradigm was used to investigate developmental trends in accurate and false memory production. In Experiment 1, DRM lists adjusted to be more consistent with children's vocabulary were used with 2nd graders, 8th graders, and college students. Accurate and false recall and recognition increased with age, but semantic information appeared to be available to all age groups. Experiment 2 created a set of child-generated lists based on the free associations by a group of 3rd graders to critical items. The child-generated associates were different from those generated by adults; long and short versions of the child-generated lists were therefore presented to 2nd, 5th, and 8th graders and college students in Experiment 3. Second graders exhibited few false memories, whereas 5th graders were similar to adults in low-demand conditions and more similar to younger children in high-demand conditions. Findings are discussed in terms of developmental changes in automatic and effortful processing and the use of semantic networks.

The development of expert face processing: are infants sensitive to normal differences in second-order relational information?

Sensitivity to second-order relational information (i.e., spatial relations among features such as the distance between eyes) is a vital part of achieving expertise with face processing. Prior research is unclear on whether infants are sensitive to second-order differences seen in typical human populations. In the current experiments, we examined whether infants are sensitive to changes in the space between the eyes and between the nose and the mouth that are within the normal range of variability in Caucasian female faces. In Experiment 1, 7-month-olds detected these changes in second-order relational information. Experiment 2 extended this finding to 5-month-olds and also found that infants detect second-order relations in upright faces but not in inverted faces, thereby exhibiting an inversion effect that has been considered to be a hallmark of second-order relational processing during adulthood. These results suggest that infants as young as 5 months are sensitive to second-order relational changes that are within the normal range of human variability. They also indicate that at least rudimentary aspects of face processing expertise are available early in life.

Infants' perception of information along object boundaries: concavities versus convexities.

Object parts are signaled by concave discontinuities in shape contours. In seven experiments, we examined whether 5- and 6 1/2-month-olds are sensitive to concavities as special aspects of contours. Infants of both ages detected discrepant concave elements amid convex distractors but failed to discriminate convex elements among concave distractors. This discrimination asymmetry is analogous to the finding that concave targets among convex distractors pop out for adults, whereas convex targets among concave distractors do not. Thus, during infancy, as during adulthood, concavities appear to be salient regions of shape contours. The current study also found that infants' detection of concavity is impaired if the contours that define concavity and convexity are not part of closed shapes. Thus, for infants, as for adults, concavities and convexities are defined more readily in the contours of closed shapes. Taken together, the results suggest that some basic aspects of part perception from shape contours are available by at least 5 months of age.

Face processing in infancy: developmental changes in the use of different kinds of relational information.

Adults use both first-order, or categorical, relations among features (e.g., the nose is above the mouth), and second-order, or fine spatial relations (e.g., the space between eyes), to process faces. Adults' expertise in face processing is thought to be based on the use of second-order relations. In the current study, 5-month-olds detected second-order changes, but 3-month-olds failed to detect second-order changes induced by 2 different manipulations. Three-month-olds did detect first-order changes, however. Also, inversion affected 5-month-olds' processing of second-order but not first-order information. These results suggest that, although sensitivity to first-order relations is available by 3 months or earlier, sensitivity to second-order information may not develop until sometime between 3 and 5 months of age.

Inhibition of purified factor Xa amidolytic activity may not be predictive of inhibition of in vivo thrombosis: implications for identification of therapeutically active inhibitors.

OBJECTIVE: In this study we test the hypothesis that blood/plasma-based prothrombinase assays, rather than inhibition of purified factor Xa (fXa), are predictive of in vivo antithrombotic activity. METHODS AND RESULTS: Six fXa inhibitors with equivalent nanomolar Ki were studied in thrombin generation assays using human plasma/blood and endogenous macromolecular substrate. In all assays, benzamidine inhibitors were more potent (100 to 800 nmol/L) than the aminoisoquinolines (5 to 58 micromol/L) or neutral inhibitors (3 to 10 micromol/L). A similar rank order of compound inhibition was also seen in purified prothrombinase assays as well as in a rabbit model of deep vein thrombosis. CONCLUSIONS: Assays using prothrombinase with protein substrates are better predictors of in vivo efficacy than fXa Ki using amidolytic substrates.

Design, synthesis and structure-activity relationships of benzoxazinone-based factor Xa inhibitors.

A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.

Design and synthesis of factor Xa inhibitors and their prodrugs.

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.

Substituted acrylamides as factor Xa inhibitors: improving bioavailability by P1 modification.

To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties.

Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P(1) structure-activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides.

Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability.

Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors.

Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.

Design, synthesis, and SAR of substituted acrylamides as factor Xa inhibitors.

Substituted acrylamides were used as templates that bridge P1 and P4 binding elements, resulting in a series of potent (sub-nanomolar) and selective factor Xa inhibitors. In this template, cis-geometry of P1 and P4 ligands is highly preferred. SAR on the substituting groups, as well as on modification of P1 and P4 moieties is described. Compounds in this series show good in vivo efficacy in animal models.