(De)synchronization of advanced visual information and ball flight characteristics constrains emergent information-movement couplings during one-handed catching.

Advance visual information of a projection action and ball flight information is important for organizing dynamic interceptive actions like catching. However, how the central nervous system (CNS) manages the relationship between advance visual information and emerging ball flight information in regulating behavior is less well understood. Here, we sought to examine the extent that advance visual information to the CNS constrains regulation of catching actions by synchronizing and desynchronizing its relationship with ball trajectory characteristics. Novel technology was used to present video footage of an actor throwing a ball at three different speeds, integrated with information from a real ball projected by a machine set to the three speeds. The technology enabled three synchronized and six desynchronized conditions between advance visual information and subsequent ball flight trajectories. Catching performance, kinematic data from the catching hand and gaze behaviors were recorded. Findings revealed that desynchronization of video images of ball projection shaped emergent catching behaviors. Footage of slower throws, paired with faster ball projection speeds, caused catching performance decrements. Timing in early phases of action was organized by the CNS to match the advance visual information presented. In later phases, like the grasp, ball flight information constraints adapted and regulated behaviors. Gaze behaviors showed increased ball projection speed resulted in participants tracking the ball for a smaller percentage of ball flight. Findings highlighted the role of the two visual systems in perception and action, implicating the importance of coupling advanced visual information and ball flight to regulate emergent movement coordination tendencies during interceptive behaviors.

An integrated ball projection technology for the study of dynamic interceptive actions.

Dynamic interceptive actions, such as catching or hitting a ball, are important task vehicles for investigating the complex relationship between cognition, perception, and action in performance environments. Representative experimental designs have become more important recently, highlighting the need for research methods to ensure that the coupling of information and movement is faithfully maintained. However, retaining representative design while ensuring systematic control of experimental variables is challenging, due to the traditional tendency to employ methods that typically involve use of reductionist motor responses such as buttonpressing or micromovements. Here, we outline the methodology behind a custom-built, integrated ball projection technology that allows images of advanced visual information to be synchronized with ball projection. This integrated technology supports the controlled presentation of visual information to participants while they perform dynamic interceptive actions. We discuss theoretical ideas behind the integration of hardware and software, along with practical issues resolved in technological design, and emphasize how the system can be integrated with emerging developments such as mixed reality environments. We conclude by considering future developments and applications of the integrated projection technology for research in human movement behaviors.

The development of evidence-informed physical activity guidelines for adults with spinal cord injury.

OBJECTIVES: To systematically develop evidence-informed physical activity guidelines to improve physical fitness in people with spinal cord injury (SCI). SETTING: This study was conducted in Canada. METHODS: The Appraisal of Guidelines, Research and Evaluation II guideline development protocol was used to develop exercise guidelines to improve physical capacity and muscular strength. The evidence base for the guideline development process consisted of a systematic review and quality appraisal of research examining the effects of exercise on physical fitness among people with SCI. A multidisciplinary expert panel deliberated the evidence and generated the guidelines. Pilot testing led to refinement of the wording and presentation of the guidelines. RESULTS: The expert panel generated the following guidelines: for important fitness benefits, adults with a SCI should engage in (a) at least 20 min of moderate to vigorous intensity aerobic activity two times per week and (b) strength training exercises two times per week, consisting of three sets of 8-10 repetitions of each exercise for each major muscle group. CONCLUSION: People with SCI, clinicians, researchers and fitness programmers are encouraged to adopt these rigorously developed guidelines.

Maximal migration of human smooth muscle cells on fibronectin and type IV collagen occurs at an intermediate attachment strength.

Although a biphasic dependence of cell migration speed on cell-substratum adhesiveness has been predicted theoretically, experimental data directly demonstrating a relationship between these two phenomena have been lacking. To determine whether an optimal strength of cell-substratum adhesive interactions exists for cell migration, we measured quantitatively both the initial attachment strength and migration speed of human smooth muscle cells (HSMCs) on a range of surface concentrations of fibronectin (Fn) and type IV collagen (CnIV). Initial attachment strength was measured in order to characterize short time-scale cell-substratum interactions, which may be representative of dynamic interactions involved in cell migration. The critical fluid shear stress for cell detachment, determined in a radial-flow detachment assay, increased linearly with the surface concentrations of adsorbed Fn and CnIV. The detachment stress required for cells on Fn, 3.6 +/- 0.2 x 10(-3) mu dynes/absorbed molecule, was much greater than that on CnIV, 5.0 +/- 1.4 x 10(-5) mu dynes/absorbed molecule. Time-lapse videomicroscopy of individual cell movement paths showed that the migration behavior of HSMCs on these substrates varied with the absorbed concentration of each matrix protein, exhibiting biphasic dependence. Cell speed reached a maximum at intermediate concentrations of both proteins, with optimal concentrations for migration at 1 x 10(3) molecules/micron2 and 1 x 10(4) molecules/micron2 on Fn and CnIV, respectively. These optimal protein concentrations represent optimal initial attachment strengths corresponding to detachment shear stresses of 3.8 mu dyne/micron2 on Fn and 1.5 mu dyne/micron2 on CnIV. Thus, while the optimal absorbed protein concentrations for migration on Fn and CnIV differed by an order of magnitude, the optimal initial attachment strengths for migration on these two proteins were very similar. Further, the same minimum strength of initial attachment, corresponding to a detachment shear stress of approximately 1 mu dyne/micron2, was required for movement on either protein. These results suggest that initial cell-substratum attachment strength is a central variable governing cell migration speed, able to correlate observations of motility on substrata differing in adhesiveness. They also demonstrate that migration speed depends in biphasic manner on attachment strength, with maximal migration at an intermediate level of cell-substratum adhesiveness.

Quantitative response in ion mobility spectrometry with atmospheric pressure chemical ionization in positive polarity as a function of moisture and temperature.

Response of an ion mobility spectrometer at ambient pressure was quantitatively determined for fourteen chemicals from five chemical families spanning a range of proton affinities and temperature from 30 to 175 °C with moisture from 1 to 1 × 104 ppmv in purified air. Peak intensities, drift times and reduced mobility coefficients were determined for hydrated protons from a63Ni ion source and for protonated monomers and proton bound dimers of alcohols, aldehydes, acetates, ketones, and organophosphates. These measurements permitted the determination of response factors with atmospheric pressure chemical ionization and the influence of moisture and temperature on APCI response with correlation to computational models of hydration values. The formation of protonated monomers and proton bound dimers was described by heats of formation for a displacement reaction of water on H+(H2O)n by an analyte vapor and favorably matched results from density functional theory (DFT) with the 6-311 + G(dp) basis set. Response factors worsened with increased moisture and decreased temperature for compounds of medium, and more so, of low proton affinities. Findings here provide a broad measure and understanding for quantitative response in ion mobility spectrometers for substances for combinations of moisture and temperature.

Differential Mobility Spectrometry of Ketones in Air at Extreme Levels of Moisture.

The performance of a differential mobility spectrometer was characterized at ambient pressure and ten values of water vapor concentration, from 1.0 × 102 to 1.7 × 104 ppm using a homologous series of seven ketones from acetone to 2-dodecanone. Dispersion plots at 30 °C with separation fields from 35 to 123 Td exhibited increased alpha functions for the hydrated proton, protonated monomers, and proton bound dimers with increased moisture levels. Increases in the level of moisture were accompanied by decreased quantitative response with progressive suppression in the formation of the proton bound dimer first and then protonated monomer. Product ions for 2-octanone at 7 ppb were not observed above a moisture level of 4.0 × 103 ppm, establishing a limit for observation of analyte ion formation. The observation limit increased from 1.1 × 103 ppm for acetone to 5.7 × 103 ppm for 2-dodecanone. These findings demonstrate that ketones can be determined with a differential mobility spectrometry (DMS) analyzer near room temperature in the presence of elevated levels of moisture expected with the use of membrane inlets or headspace sampling of surface or ground waters. Moisture levels entering this DMS analyzer employed as an environmental monitor should be kept at 1.0 × 103 ppm or below and quantitative studies for individual ketones should be made at a fixed moisture level.

Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval.

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.

Mobility resolution and mass analysis of ions from ammonia and hydrazine complexes with ketones formed in air at ambient pressure.

Protonated ammonia and hydrazines (MH(+)) form complexes with ketones and the differences in masses and mobilities of the resulting ions, MH(+)(ketone)(n), are sufficient for separation in an ion mobility spectrometer at ambient pressure. The highest mass ion for any of the protonated molecules is obtained when the ketone is present at elevated concentrations in the supporting atmosphere of both the source and drift regions of the spectrometer so that an ion maintains a discrete composition and mobility. The sizes of the ion-molecule complexes were found to depend on the number of H atoms on the protonated nitrogen atom--four for ammonia, three for hydrazine, two for monomethylhydrazine, and one for 1,1-dimethylhydrazine, and the drift times of these ions were proportional to the size of the ion-molecule complex. Unexpected side products, including protonated hydrazones and azines, and associated ketone clusters, were isolated to a single drift tube containing ceramic parts and could not, from CID studies, be attributed to gas-phase ion chemistry. These findings illustrate that mobility resolution of ions in IMS and IMS/MS experiments can be enhanced through chemical modification of the supporting gas atmosphere without changes in the core ion.

Temporal and spatial occlusion of advanced visual information constrains movement (re)organization in one-handed catching behaviors.

Dynamic interceptive actions are performed under severe spatial and temporal constraints. Here, behavioral processes underpinning anticipation in one-handed catching were examined using novel technology to implement a spatial and temporal occlusion design. Video footage of an actor throwing a ball was manipulated to create four temporal and five spatial occlusion conditions. Data from twelve participants' hand kinematics and gaze behaviors were recorded while attempting to catch a projected ball synchronized with the video footage. Catching performance decreased with earlier occlusion of the footage. Movement onset of the catching hand and initiation of visual ball tracking emerged earlier when footage of the thrower was occluded at a later time point in the throwing action. Spatial occlusion did not affect catching success, although movement onset emerged later when increased visual information of the actor was occluded. Later movement onset was countered by greater maximum velocity of the catching hand. Final stages of action (e.g., grasping action of the hand) remained unchanged across both spatial and temporal conditions suggesting that later phases of the action were organized using ball flight information. Findings highlighted the importance of maintaining information-movement coupling during performance of interceptive actions, since movement behaviors were continuously (re)organized using kinematic information from a thrower's actions and ball flight information.

Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors.

Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies. Identified effects of sex, baseline Eastern Cooperative Oncology Group performance status, measures of renal and hepatic function, tumor type and burden, and prior ipilimumab treatment on pembrolizumab exposure were modest and lacked clinical significance. Furthermore, simulations demonstrated the model has robust power to detect clinically relevant covariate effects on clearance. These results support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations.

Population Pharmacokinetic/Pharmacodynamic Modeling of Tumor Size Dynamics in Pembrolizumab-Treated Advanced Melanoma.

Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.

Disease Systems Analysis of Bone Mineral Density and Bone Turnover Markers in Response to Alendronate, Placebo, and Washout in Postmenopausal Women.

A previously established mechanism-based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women (n = 1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone-specific alkaline phosphatase activity (BSAP), urinary N-telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model. The final model gave an accurate description of all four biomarkers for the different treatments. Simulations were used to visualize the dynamics of the underlying network and the natural disease progression upon alendronate treatment and discontinuation. These results complement the previous applications of this mechanism-based disease systems model to data from various treatments for osteoporosis.

Exaggerated respiratory chemosensitivity and association with SaO2 level at 3568 m in obesity.

To investigate whether obesity is associated with alterations in respiratory chemosensitivity, we compared the ventilatory response to hypoxia (HVR) and hypercapnia (HCVR) in 9 obese men (BMI: 37.0+/-4.3 kg m(-2)) and 10 lean men (BMI: 25.8+/-4.8 kg m(-2)). HVR (DeltaVE, L min(-1) per DeltaSaO2, %) was measured by a progressive isocapnic hypoxia technique, and HCVR (DeltaVE/DeltaPETCO2, L min(-1)Torr(-1)) was measured by a progressive hypercapnic method. HCVR, was greater (p<0.001) in the obese men (2.68+/-0.78) than in the lean men (1.4+/-0.45) as was HVR (p<0.05) (1.26+/-0.65 versus 0.71+/-0.43, respectively). The difference (DeltaSaO2, 4.30+/-3.69 and 10.54+/-3.45 in the lean and obese men, respectively, p<0.01) between daytime (86+/-1 and 86+/-1%) and nighttime SaO2 (81+/-3 and 76+/-4%) at a simulated altitude of 3658 m was significantly (p<0.05) correlated with both HVR (r=0.51) and HCVR (r=0.48). These results suggest that chemosensitivity in mildly obese men is increased, not blunted. Furthermore, otherwise healthy, obese individuals have the potential for significant desaturation during sleep at high altitude possibly due to exaggerated sleep-disordered breathing.

Application of a Systems Pharmacology-Based Placebo Population Model to Analyze Long-Term Data of Postmenopausal Osteoporosis.

Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.

a compact high pressure ion source for high and low energy collision-induced dissociation studies of cluster ions on a VG analytical ZAB-2FQ.

A compact, field-free high pressure ion source designed to replace, with minimum disruption, the electron impact/chemical ionization ion source of a VG Analytical ZAB-2FQ hybrid BEqQ mass spectrometer is described. This ion source may be operated at temperatures from ≈40 to 250 °C and at pressures up to 4-5 torr and, thus, is capable of producing proton-bound cluster ions up to hexamers in good yields. Examples of high energy collision-induced dissociation, low energy collision-induced dissociation, and neutralization-reionization studies of proton-bound cluster ions produced in this source are presented.

Unusual cells in lupus erythematosus bullae.

We saw a case of bullous lupus erythematosus (LE) in which there were pre-LE cells and hematoxylin bodies in clear bullous fluid. Pre-LE cells are degenerated leukocytes with pyknotic nuclei. The diagnosis of lupus erythematosus was substantiated by immunofluorescence studies.

Evaluation of CSF leaks: high-resolution CT compared with contrast-enhanced CT and radionuclide cisternography.

BACKGROUND AND PURPOSE: Radiologic evaluation of CSF leaks is a diagnostic challenge that often involves multiple imaging studies with the associated expense and patient discomfort. We evaluated the use of screening noncontrast high-resolution CT in identifying the presence and site of CSF rhinorrhea and otorrhea and compared it with contrast-enhanced CT cisternography and radionuclide cisternography. METHODS: We retrospectively reviewed the imaging studies and medical records of all patients who were evaluated for CSF leak during a 7-year period. Forty-two patients with rhinorrhea and/or otorrhea underwent high-resolution CT of the face or temporal bone and then had CT cisternography and radionuclide cisternography via lumbar puncture. The results of the three studies were compared and correlated with the surgical findings in 21 patients. RESULTS: High-resolution CT showed bone defects in 30 of 42 patients (71%) with CSF leak. High-resolution, radionuclide cisternography and CT cisternography did not show bone defects or CSF leak for 12 patients (29%) who had clinical evidence of CSF leak. Among the 30 patients with bone defects, 20 (66%) had positive results of their radionuclide cisternography and/or CT cisternography. For the 21 patients who underwent surgical exploration and repair, intraoperative findings correlated with the defects revealed by high-resolution CT in all cases. High-resolution CT identified significantly more patients with CSF leak than did radionuclide cisternography and CT cisternography, with a moderate degree of agreement. CONCLUSION: Noncontrast high-resolution CT showed a defect in 70% of the patients with CSF leak. No radionuclide cisternography or CT cisternography study produced positive results without previous visualization of a defect on high-resolution CT. CT cisternography and radionuclide cisternography may be reserved for patients in whom initial high-resolution CT does not identify a bone defect or for patients with multiple fractures or postoperative defects.

Malignant schwannoma of the trigeminal nerve.

SUMMARY: We present the MR imaging, CT, and clinical findings of a patient with malignant schwannoma of the trigeminal nerve. Local tumor recurrence is frequent and may be mistaken for lymphatic spread. In this report, we emphasize the natural history of this rare tumor and discuss the importance of imaging in diagnosis and surveillance.

The choline/creatine ratio in five benign neoplasms: comparison with squamous cell carcinoma by use of in vitro MR spectroscopy.

BACKGROUND AND PURPOSE: The choline (Cho)/creatine (Cr) ratio has been shown to be a reliable proton MR spectroscopy metabolic marker for differentiating squamous cell carcinoma (SCCA) from normal muscle in the upper aerodigestive tract. However, it is unclear whether the Cho/Cr ratio can be used to differentiate a malignant tumor from a benign neoplasm in the extracranial head and neck. Our purpose was to determine whether the Cho/Cr ratio can be used to differentiate benign from malignant tumors in this region. METHODS: In vitro one-dimensional proton MR spectroscopy (2,000/136,272 [TR/TE]) was performed at 11 T on tissue specimens obtained from glomus tumors (n = 3), inverting papilloma (n = 1), and schwannoma (n = 1). Cho/Cr area ratios were calculated and compared with similar, previously reported in vitro (11 T) findings and with samples of SCCA and normal muscle. RESULTS: The Cho/Cr ratio was elevated in relation to muscle in all benign tumors at TE = 136 (glomus tumors = 4.52, inverting papilloma = 3.85, schwannoma = 2.2) and at TE = 272 (glomus tumors = 8.01, inverting papilloma = 2.1, schwannoma = 4.28). The average Cho/Cr ratio for benign lesions was 3.92 (TE = 136) and 6.11 (TE = 272). The Cho/Cr ratio was significantly higher in benign tumors than in both SCCA and muscle. The average Cho/Cr ratio for muscle at TEs of 136 and 272 was 1.16 and 1.31, respectively, whereas for SCCA the average Cho/Cr ratio at TEs of 136 and 272 was 1.67 and 2.45, respectively. CONCLUSION: In our small group, the Cho/Cr ratio was significantly higher in benign tumors than in muscle and SCCA of the extracranial head and neck.

Evaluation of the mass balance assumption with respect to the two-resistance model of intestinal absorption by using in situ single-pass intestinal perfusion of theophylline in rats.

Methods of analyzing drug absorption data from rat intestinal-perfusion experiments are discussed in terms of mass-transfer resistances, or reciprocal permeabilities, and mass balances. Typically, a two-resistance model is used to determine the dimensionless effective permeability (P*eff) by measuring the disappearance of drug from the perfusing solution. Unstated assumptions in two-resistance models are (1) the portal blood is under sink conditions and (2) complete transfer of drug occurs from the intestinal perfusate to the portal vein. The assumption of sink conditions is generally acceptable, because the drug concentration in portal blood is approximately two orders of magnitude less than in the perfusate. Single-pass intestinal-perfusion experiments were performed on rats with theophylline as a model compound. The drug mass leaving the intestinal perfusate was substantially less than the drug mass appearing in the portal plasma; that is, the assumption of complete transfer did not hold for theophylline in this experimental system. These data indicate that models based on the two-resistance theory can lead to overestimation of P*eff by the ratio of the drug mass leaving the perfusate to the drug mass appearing in the plasma. For compounds for which the assumption of complete transfer does not hold, a more accurate estimate of P*eff may be determined by dividing the value derived from perfusate data by the mass balance ratio (i.e., the drug mass leaving the perfusate divided by the drug mass appearing in the plasma).