Jet injection of a monoclonal antibody: A preliminary study.

Monoclonal antibodies (mAbs) represent a major group of biotherapeutics. The high concentration and volume of drug administered together with a shift to administration via the subcutaneous route have generated interest in alternative delivery technologies. The feasibility of using a novel, highly controllable jet injection technology to deliver a mAb is presented. The effect of delivery parameters on protein structure were evaluated and compared with delivery using a conventional needle and syringe. Injection of mAb into a rat model showed that jet injection using the device resulted in more rapid absorption and longer duration of exposure.

3D-1D threading methods for protein fold recognition.

The threading approach to protein fold recognition attempts to evaluate how well a query sequence fits into an already-solved fold. 3D-1D threaders rely on matching 1-dimensional strings of 3-dimensional information predicted from the query sequence with corresponding features of the target structure. In many cases this is combined with a sequence comparison. The combination of sequence and structure information has been shown to improve the accuracy of fold recognition, relative to the exclusive use of sequence or structure. In this paper, we review progress made since the introduction of threading methods a decade ago, highlighting recent advances. We focus on two emerging methods that are unconventional 3D-1D threaders: proximity correlation matrices and parallel cascade identification.

Induction of labor using high-dose or low-dose prostaglandin vaginal pessaries.

Two hundred women were studied in a randomized controlled trial of induction of labor using high-dose (3 mg) or low-dose (0.5 mg) prostaglandin E2 vaginal pessaries. Induction using 3-mg pessaries was more successful, with a shorter overall induction-delivery interval and less requirement for analgesia, although uterine hyperstimulation occurred in two patients. In contrast, the low-dose regimen did not cause hypertonus and, though less successful in inducing labor, the total dose of prostaglandin E2 used was considerably less than in the 3-mg group. The cesarean section rate when the cervix was initially unfavorable was high in both groups (high dose 18.2%, low dose 16.7%). The response to prostaglandin E2 did not relate closely to the initial cervical state.

Force sensation in isometric contractions: a relative force effect.

A contralateral limb matching paradigm was employed to investigate the perception of isometric forces. Both force and brachial biceps and triceps EMG were recorded from each arm as subjects matched isometric contractions on the basis of equal sensation. It was found that smaller forces were consistently overestimated in magnitude and that the most accurate estimation of force occurred around the middle of the force domain. It is proposed that these results reflect the properties of the biceps muscle which is predominantly involved in gross motor activity.

Respiratory components of human postural sway.

The effects of respiration on postural sway in normal human subjects was studied using averaging and spectral techniques. During voluntarily paced respiration a substantial proportion of sway was found to result from respiratory activity. The magnitude of the respiratory contribution to sway was approximately constant over the normal range of respiratory rates and linearly related to respiration amplitude. Respiration evoked similar changes in reaction torque in seated subjects. These results indicate that body movements associated with paced respiration are an important disturbance to the postural control system. Furthermore, these disturbances are not reduced by compensatory movements of the hip as has been suggested by others.

Parallel cascade identification and its application to protein family prediction.

Parallel cascade identification is a method for modeling dynamic systems with possibly high order nonlinearities and lengthy memory, given only input/output data for the system gathered in an experiment. While the method was originally proposed for nonlinear system identification, two recent papers have illustrated its utility for protein family prediction. One strength of this approach is the capability of training effective parallel cascade classifiers from very little training data. Indeed, when the amount of training exemplars is limited, and when distinctions between a small number of categories suffice, parallel cascade identification can outperform some state-of-the-art techniques. Moreover, the unusual approach taken by this method enables it to be effectively combined with other techniques to significantly improve accuracy. In this paper, parallel cascade identification is first reviewed, and its use in a variety of different fields is surveyed. Then protein family prediction via this method is considered in detail, and some particularly useful applications are pointed out.

Design and characterization of a laser-based instrument with spectroscopic feedback control for treatment of vascular lesions: the "Smart Scalpel".

To improve the effectiveness of microsurgical techniques, we are developing a semi-autonomous robotic surgical tool (called the "Smart Scalpel") as an alternate approach to treatment of vascular lesions. The device employs optical reflectance spectroscopy as part of a line scan imaging system to identify and selectively target blood vessels in a vascular lesion for thermal treatment with a focused laser beam. Our proof-of-concept reported here presents the design and construction of a prototype instrument, initial quantification of imaging system resolution and contrast, and preliminary verification of the imaging and targeting strategies with standard targets and live dermal tissue.

System identification of human joint dynamics.

The dynamics of joint mechanics are a fundamental characteristic of the motor system. They determine the displacements evoked by perturbing forces during postural control and the forces that must be generated to perform a voluntary movement. This article reviews experimental studies of these dynamics, with an emphasis on the behavior of single joints in alert humans. Technical aspects of the experimental and analytic methods that have been used are summarized first. Major results obtained with the different methods are then reviewed, compared, and contrasted. The interpretation of these results in terms of the underlying physiological mechanisms is then considered, with an emphasis on the relative contributions of passive properties of tissue, the mechanical behavior of muscle, and stretch reflexes. Finally, important unanswered questions regarding the dynamics of joint mechanics are reviewed.

An anatomical heart model with applications to myocardial activation and ventricular mechanics.

A three-dimensional finite element model of the mechanical and electrical behavior of the heart is being developed in a collaboration among Auckland University, New Zealand; the University of California at San Diego, U.S.; and McGill University, Canada. The equations of continuum mechanics from the theory of finite deformation elasticity are formulated in a prolate spheroidal coordinate system and solved using a combination of Galerkin and collocation techniques. The finite element basis functions used for the dependent and independent variables range from linear Lagrange to cubic Hermite, depending on the degree of spatial variation and continuity required for each variable. Orthotropic constitutive equations derived from biaxial testing of myocardial sheets are defined with respect to the microstructural axes of the tissue at the Gaussian quadrature points of the model. In particular, we define the muscle fiber orientation and the newly identified myocardial sheet axis orientation throughout the myocardium using finite element fields with nodal parameters fitted by least-squares to comprehensive measurements of these variables. Electrical activation of the model is achieved by solving the FitzHugh-Nagumo equations with collocation at fixed material points of the anatomical finite element model. Electrical propagation relies on an orthotropic conductivity tensor defined with respect to the local material axes. The mechanical constitutive laws for the Galerkin continuum mechanics model are (1) an orthotropic "pole-zero" law for the passive mechanical properties of myocardium and (2) a Wiener cascade model of the active mechanical properties of the muscle fibers. This chapter concentrates on two aspects of the model: first, grid generation, including both the generation of nodal coordinates for the finite element mesh and the generation of orthotropic material axes at each computational point, and, second, the formulation of constitutive laws suitable for numerically intensive finite element computations. Extensions to this model and applications to the mechanical and electrical function of the heart are described in Chapter 16 by McCulloch and co-workers.

Dynamics of human ankle stiffness: variation with mean ankle torque.

The left foot of five human subjects was rotated in a fixed stochastic pattern about a constant ankle angle and the forces opposing these perturbations were measured. The dynamic stiffness transfer functions relating ankle angular position to ankle torque were calculated. Stiffness gain was flat at low frequencies, had a resonant valley at intermediate frequencies and rose at about 40 dB/decade at high frequencies. The low frequency gain and resonant frequency increased progressively with increases in tonic muscular activity. The dynamic stiffness of the ankle was well described by a linear, under-damped, second-order transfer function having inertial, viscous and elastic terms. Estimates of the inertial parameter were independent of the level of muscle activity whereas the viscous and elastic parameters increased with increases in mean torque level.

Dynamics of human ankle stiffness: variation with displacement amplitude.

The left foot of five normal human subjects was rotated in a fixed stochastic pattern about a constant ankle angle and the torques opposing these rotations were measured. The dynamic stiffness transfer functions relating ankle angular position to ankle torque were calculated. Stiffness gain was flat at low frequencies, had a resonant valley at intermediate frequencies, and rose to about 40 dB/decade at high frequencies. The mean ankle torque was held constant and the peak-to-peak amplitude of the displacement was varied. The low frequency gain and resonant frequency decreased progressively with increases in the peak-to-peak amplitude of the displacement. The dynamic stiffness was well described by a linear, second-order transfer function having inertial, viscous and elastic terms. Estimates of the inertial parameter were independent of the displacement amplitude but the viscous and elastic parameters decreased with increases in displacement amplitude.

Invariance of ankle dynamic stiffness during fatiguing muscle contractions.

Our objective was to determine the effect of muscle fatigue on the dynamic stiffness of the human ankle. Four subjects were required to maintain constant-force contractions of tibialis anterior until the required force could no longer be maintained. Repeated pseudo-random displacements of ankle angular position were applied throughout each contraction. The dynamic relation between ankle angular position and ankle torque was identified by determining non-parametric compliance impulse response functions (CIRFs). The CIRFs were redetermined every 2.55S throughout the sustained contractions to provide a quantitative measure of changes in ankle stiffness dynamics. Inspection of these CIRFS revealed little change in shape or magnitude throughout the contractions, despite large increases in tibialis anterior EMG. The dynamics were further quantified by estimating the equivalent joint inertia, viscosity and elasticity associated with each CIRF. As each contraction progressed, the inertial and elastic terms remained constant whereas the viscous term decreased slightly. These findings demonstrate that fatigue of tibialis anterior during sustained constant mean force contractions results in little change in the mechanical dynamics of the human ankle.

Position dependence of ankle joint dynamics--I. Passive mechanics.

System identification techniques were used to examine the position dependence of passive ankle joint mechanics. The relaxed ankle was stochastically perturbed about different angles in the range of motion (ROM). The linear dynamic relation between ankle position and torque was identified and modelled as a second-order underdamped system, having inertial (I), viscous (B) and elastic (K) parameters. Mean joint torque changed as the ankle was rotated through the ROM; it was small at mid-range and became much larger toward either extreme. While I remained constant both B and K changed as a function of ankle angle. At the extremes of the ROM, K was much larger than previously assumed and the relation between stiffness and the passive torque generated when the ankle was placed at different mean positions was linear. These results show that large variations in joint mechanics are possible even in the absence of voluntary muscle contraction. Moreover, these changes appear to be related to the torque generated when passive joint structures are stretched.

Position dependence of ankle joint dynamics--II. Active mechanics.

System identification techniques were used to examine the position dependence of active ankle joint mechanics. Subjects were required to maintain tonic contractions in either the tibialis anterior (TA) or triceps surae (TS) muscles while the ankle was stochastically displaced about different mean angular positions. The dynamic relation between ankle position and torque was determined for each mean position/tonic torque combination; a non-linear minimization technique was used to estimate the three parameters (inertial, viscous and elastic) of a second-order, underdamped system. Whereas the inertial parameter remained essentially invariant across all test conditions, the viscous and elastic (K) parameters became larger as the level of tonic activity increased and as the joint was rotated toward the extremes of the range of motion. The relation between K and torque was linear at all ankle angles. The slope of this relation remained constant at all mean positions during plantarflexor contractions; during dorsiflexor contractions the slope increased as the ankle was rotated from maximum plantarflexion to maximum dorsiflexion. These findings are discussed in terms of: the physiological correlates of ankle mean position, the relative significance of passive and active joint mechanics and contrasts in joint behaviour during active dorsiflexor and plantarflexor contractions.

Human ankle joint stiffness over the full range of muscle activation levels.

System identification techniques have been used to track changes in dynamic stiffness of the human ankle joint over a wide range of muscle contraction levels. Subjects lay supine on an experimental table with their left foot encased in a rigid, low-inertia cast which was fixed to an electro-hydraulic actuator operating as a position servo. Subjects generated tonic plantarflexor or dorsiflexor torques of different magnitudes ranging from rest to maximum voluntary contractions (MVC) during repeated presentations of a stochastic ankle angular position perturbation. Compliance impulse response functions (IRF) were determined from every 2.5 s perturbation sequence. The gain (G), natural frequency (omega n), and damping (zeta) parameters of the second-order model providing the best fit to each IRF were determined and used to compute the corresponding inertial (I), viscous (B) and elastic (K) stiffness parameters. The behaviour of these parameters with mean torque was found to follow two simple rules. First, the elastic parameter (K) increased in proportion to mean ankle torque as it was varied from rest to MVC; these changes were considerable involving increases of more than an order of magnitude. Second, the damping parameter (zeta) remained almost invariant over the entire range of contractions despite the dramatic changes in K.

Identification of time-varying biological systems from ensemble data.

The theory underlying a new method for the identification of time-varying systems is described. The method uses singular value decomposition to obtain least-squares estimates of time-varying impulse response functions from an ensemble of input-output realizations. No a priori assumptions regarding the system structure or form of the time-variation are required and there are few restrictions on the input signal. Simulation studies, using a model of time-varying joint dynamics, show that the method can track rapid changes in system dynamics accurately and is robust in the presence of output noise. An application of the method is demonstrated by using it to track dynamic ankle stiffness during a rapid, voluntary, isometric contraction. During the transient phase of the contraction, low-frequency ankle stiffness gain decreased in a manner which could not be described with the second-order model of joint dynamics often used under stationary conditions.

An airjet actuator system for identification of the human arm joint mechanical properties.

A system is described for determining the mechanical properties of the human arm during unconstrained posture and movement. An airjet perturbation device is attached to the wrist with a special cuff, and provides high-frequency stochastic perturbations in potentially three orthogonal directions. The airjet operates as a fluidic flip-flop utilizing the Coanda effect, and generates binary force sequences with a steady-state thrust of 4 N, a flat frequency response to 75 Hz, usable thrust to 150 Hz, and a rise time of 1 ms, when the static pressure at the nozzle inlet is 5.5 x 10(5) Pa (80 psi). These operating characteristics are adequate to identify the arm's mechanical properties efficiently and robustly.

Performance on variable-interval schedules arranged singly and concurrently.

Extensive parametric data were obtained from pigeons responding on variable-interval schedules arranged on three, two, and one response keys. Number of responses on the keys, the time spent responding on the keys, and the number of reinforcements obtained on the keys were measured. Response rates on each key were an increasing function of the reinforcement rate on that key, and an inverse function of the reinforcement rate on the other keys. In terms of preference, both response and time-allocation ratios undermatched ratios of obtained reinforcements, and the degree of undermatching was consistent both within, and between, two- and three-schedule data. When absolute response-rate data were analyzed according to Herrnstein's (1970) quantitative account, obtained values of assumed constants were not consistent either within or between conditions. However, a power-function modification of Herrnstein's account fitted the data well and provided similar exponent values to those obtained for the undermatching of preference ratios.

Response rate and changeover performance on concurrent variable-interval schedules.

Six pigeons were exposed to variable-interval schedules arranged on one, two, three, and four response keys. The reinforcement rate was also varied across conditions. Numbers of responses, the time spent responding, the number of reinforcements, and the number of changeovers between keys were recorded. Response rates on each key were an increasing function of reinforcement rate on that key and a decreasing function of the reinforcement rate on other keys. Response and time-allocation ratios under-matched ratios of obtained reinforcements. Three sets of equations were developed to express changeover rate as a function of response rate, time allocation, and reinforcement rate respectively. These functions were then applied to a broad range of experiments in the literature in order to test their generality. Further expressions were developed to account for changeover rates reported in experiments where changeover delays were varied.

Concurrent schedules: undermatching and control by previous experimental conditions.

Five pigeons were trained on concurrent variable-interval schedules. A series of conditions in which the ratio of reinforcement rates on two keys was progressively increased and then decreased was arranged twice. The birds were then exposed to an irregular sequence of conditions. Each condition in which reinforcement was available on both keys lasted six sessions. Performance in the first, third, and sixth sessions after a condition change was analyzed. Following a condition change, preference was biased toward the preference in the last condition, but this effect largely disappeared before the sixth session of training. The birds' preferences also appeared less sensitive to reinforcement rates in early sessions after a transition. Preference in a session was a function of both the reinforcements in that session and the reinforcements obtained in as many as four or five previous sessions. The effects of reinforcements in previous sessions could be summarized by the performance in the immediately preceding session, giving a relatively simple relation between present performance and a combination of present reinforcement and prior session performance. While such hysteresis could cause undermatching when only a small number of sessions are arranged in a condition, undermatching in a stable-state performance probably arises elsewhere.