Antithrombotic potency of hirudin is increased in nonhuman primates by fibrin targeting

BACKGROUND: Inhibition of thrombin by either the indirect thrombin inhibitor heparin or by more potent direct thrombin inhibitors such as hirudin reduces thrombus formation after arterial injury. The present study was designed to determine if a fibrin-specific thrombin inhibitor could, by local thrombin inhibition, prevent thrombosis more effectively. METHODS AND RESULTS: We first studied antithrombotic potency in vitro, comparing fibrin-targeted hirudin (recombinant hirudin covalently linked to the Fab' fragment of the anti-fibrin monoclonal antibody 59D8) to recombinant hirudin in baboon plasma. Fibrin-targeted hirudin was nine times more effective than recombinant hirudin in inhibiting fibrin deposition on experimental clot surfaces in baboon plasma (P < .01). The potency of fibrin-targeted hirudin was then compared with that of recombinant hirudin in a baboon model of thrombus formation. 111In-labeled platelet deposition was measured in a synthetic graft segment of an extracorporeal arteriovenous shunt in control animals and in animals receiving either fibrin-targeted hirudin or hirudin. In these experiments, fibrin-targeted hirudin was 10-fold more potent than hirudin in inhibiting platelet deposition and thrombus formation (P < .05). CONCLUSIONS: These data indicate that targeting a thrombin inhibitors such as hirudin to an epitope present in thrombi results in increased antithrombotic potency.     

Variability and misclassification of worker estimated hand force

Ergonomic studies often use worker estimated hand force reproduced on a dynamometer to quantify force exposures but this method has not been well-studied in real work settings. This study evaluated the validity of worker estimates of hand force in a field study and determined the misclassification of worker estimated hand force exposures compared to directly measured forces. Eight experienced sheet metal assemblers completed ¼-inch diameter fastener installations using 6 different pneumatic tools. Grip forces were recorded by a pressure mat and were compared to worker estimated forces demonstrated on a dynamometer. Directly measured and worker estimated readings showed moderate correlations (0.53–0.67) for four installation tools and fair to moderate for two tools. The coefficient for variation of force estimates was 65% within repeated subject trials and 78% between averaged subject trials but 69% between subject trials during actual tool installations. Misclassification of worker estimated exposures varied by two cut-points: 29% using 4.0 kg and 49% using 6.0 kg. The force match procedure may provide adequate differentiation of high and low exposures in some settings, but is likely to result in substantial misclassification in other settings.     

TRADE‐OFF BETWEEN APPROXIMATION ACCURACY AND COMPLEXITY FOR TS FUZZY MODELS

This paper proposes a transformation method that serves the trade‐off between the modelling complexity and accuracy of multi‐variable Takagi‐Sugeno fuzzy inference operator‐based modelling (TS fuzzy modelling). The relation between the number of fuzzy rules and the modelling accuracy is defined in the paper. The proposed transformation method is capable of finding the minimal number of fuzzy rules for a given accuracy of a given TS fuzzy model. A case study, focusing on a benchmark problem of fault diagnosis, developed in the framework of EC‐founded Research Training Network DAMADICS, of an actuator in a sugar factory, is presented to provide feasibility of the proposed method.     

MEMS lubricants based on bound and mobile phases of hydrocarbon compounds: film deposition and performance evaluation

The concept of a thin layer of mobile hydrocarbon-based lubricant providing protection by replenishment to a surface already protected by a chemically bound material has been explored for the first time, for application to silicon-based microelectromechanical (MEMS) systems. Several bound/mobile pairs of lubricants were evaluated to study the effects of bound phase end group and mobile phase chemical functionality on wettability and performance. The bound species studied were derived from 1-decanol and 1,7-heptanediol. Mobile phases investigated were, a pentaerythritol ester, a multiply alkylated cyclopentane, Pennzane, and a polysilane developed for spacecraft application. Hydrocarbon lubricant performance was evaluated using electrostatic motors run in dry air, and was compared with that provided by Fomblin Zdol under identical conditions. Motors with hydrocarbon coatings showed substantial improvement in performance over uncoated motors, and for some bound/mobile pairs, was equal to Zdol within experimental error. We believe that for silicon-based devices, hydrocarbon coatings will be preferable at least for some applications, as the degradation observed due to aging of a fluorinated lubricant in direct contact with a silicon surface is absent.     

Milk secretion at the cellular level: a unique approach to the mechanism of exocytosis.

Drugs which interfere with the mechanism of exocytosis such as colchicine and vincristine, so-called microtubule antagonists, are providing a fruitful approach to the study of milk secretion at the cellular level. Intramammary infusions of a milligram or less of these substances into lactating goats produce dramatic drops in milk yields in 24 to 36 h. These depressions are reversed substantially by 48 h. In vitro experiments and tissue observations confirm that these drugs are blocking secretion at the level of the lactating cell and that secretion of all the major milk components (fat globules, casein micelles, lactose, and water) is restrained. Mammary infusion of the plant lectin concanavalin A, a protein which binds to cell surface receptors, produces similar changes in milk flow to those of the microtubule antagonists. This indicates that cell surface membrane components perturbed by concanavalin also must be involved in the secretory mechanism. One of the known receptors for concanavalin A in the apical (secretory) plasma membrane of the lactating cell is the enzyme 5'nucleotidase. The possibility must be considered that this enzyme (glycoprotein), inactivated by concanavalin A, is involved in milk secretion.     

Mixed time- and frequency-domain robust eigenstructure assignment

This paper considers robust eigenstructure assignment for multivariable systems. The time-domain performance specifications provided by eigenstructure assignment and robust performance specifications in the frequency domain considered by H infinity control are combined to realize joint optimal robust control design. A parametric expression for state-feedback eigenstructure assignment is introduced on the basis of a set of free parameters. The mixed performance index used as the cost function consists of two parts: robustness in the frequency domain; and system eigenstructure constraints in the time domain. The analytical gradient calculation of the cost function with respect to the free parameters is derived for optimal robust eigenstructure assignment using gradientbased optimization. The mixed time- and frequency-domain robust eigenstructure assignment is demonstrated in the design of a mode-decoupled roll-yaw autopilot.     

The combinatorial design approach to automatic test generation

The combinatorial design method substantially reduces testing costs. The authors describe an application in which the method reduced test plan development from one month to less than a week. In several experiments, the method demonstrated good code coverage and fault detection ability     

Robust fault detection using Luenberger-type unknown input observers-a parametric approach

A new parametric observer-based approach for robust fault detection in multivariable linear systems with unknown disturbances is proposed. The residual is generated through utilizing a Luenberger function observer. By using a parametric solution to a class of generalized Sylvester matrix equations, a parametrization is proposed for the residual generator on the basis of a Luenberger function observer. By further properly constraining the design parameters provided in the Luenberger observer design, the effect of the unknown disturbance is decoupled from the residual signal. The proposed approach provides all the degrees of freedom and is demonstrated to be simple and effective.     

Active fault tolerant control for nonlinear systems with simultaneous actuator and sensor faults

The goal of this paper is to describe a novel fault tolerant tracking control (FTTC) strategy based on robust fault estimation and compensation of simultaneous actuator and sensor faults. Within the framework of fault tolerant control (FTC) the challenge is to develop an FTTC design strategy for nonlinear systems to tolerate simultaneous actuator and sensor faults that have bounded first time derivatives. The main contribution of this paper is the proposal of a new architecture based on a combination of actuator and sensor Takagi-Sugeno (T-S) proportional state estimators augmented with proportional and integral feedback (PPI) fault estimators together with a T-S dynamic output feedback control (TSDOFC) capable of time-varying reference tracking. Within this architecture the design freedom for each of the T-S estimators and the control system are available separately with an important consequence on robust L ₂ norm fault estimation and robust L ₂ norm closed-loop tracking performance. The FTTC strategy is illustrated using a nonlinear inverted pendulum example with time-varying tracking of a moving linear position reference.