Application of iterative suboptimal strategies for improving adaptation transients in adaptive systems

Some solutions which involve iterative optimization techniques are given to improve adaptation transients in adaptive systems. Two suboptimal controllers are developed and applied to an equivalent discrete-time system valid for describing the behaviour of a recent adaptive control scheme when one of the (time-varying) parameters entering the adaptation algorithm varies within a closed domain admissible from a convergence point of view. The resulting suboptimal control strategies are translated into corrections of this parameter in order to recompute the adaptation algorithm over a finite horizon. Some numerical simulations illustrate the usefulness of the proposed scheme.     

The CTFA Evaluation of Alternatives Program: an evaluation of in vitro alternatives to the Draize primary eye irritation test. (Phase III) surfactant-based formulations

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.     

Cardiovascular effects of microinjections of opioid agonists into the ''Depressor Region'' of the ventrolateral periaqueductal gray region

Differentiating the binding properties of applied lectins should facilitate the selection of lectins for characterization of glycoreceptors on the cell surface. Based on the binding specificities studied by inhibition assays of lectin-glycan interactions, over twenty Gal and/or GalNAc specific lectins have been divided into eight groups according to their specificity for structural units (lectin determinants), which are the disaccharide as all or part of the determinants and of GalNAc alpha 1-->Ser (Thr) of the peptide chain. A scheme of codes for lectin determinants is illustrated as follows: (1) F (GalNAc alpha 1-->3GalNAc), Forssman specific disaccharide--Dolichos biflorus (DBL), Helix pomatia (HPL) and Wistaria floribunda (WFL) lectins. (2) A (GalNAc alpha 1-->3 Gal), blood group A specific disaccharide--Codium fragile subspecies tomentosoides (CFT), Soy bean (SBL), Vicia villosa-A4 (VVL-A4), and Wistaria floribunda (WFL) lectins. (3) Tn (GalNAc alpha 1-->Ser (Thr) of the protein core)--Vicia villosa B4 (VVL-B4), Salvia sclarea (SSL), Maclura pomifera (MPL), Bauhinia purpurea alba (BPL) and Artocarpus integrifolia (Jacalin, AIL). (4) T (Gal beta 1-->3GalNAc), the mucin type sugar sequences on the human erythrocyte membrane(T alpha), T antigen or the disaccharides at the terminal nonreducing end of gangliosides (T beta)--Peanut (PNA), Bauhinia purpurea alba (BPL), Maclura pomifera (MPL), Sophora japonica (SJL), Artocarpus lakoocha (Artocarpin) lectins and Abrus precatorius agglutinin (APA).(5) I and II (Gal beta 1-->3(4)GlcNAc)--the disaccharide residue at the nonreducing end of the carbohydrate chains derived from either N- or O-glycosidic linkage--Ricinus communis agglutinin (RCA1), Datura stramonium (TAL, Thorn apple), Erythrina cristagalli (ECL, Coral tree), and Geodia cydonium (GCL). (6) B (Gal alpha 1-->3Gal), human blood group B specific disaccharide--Griffonia(Banderiaea) simplicifolia B4 (GSI-B4). (7) E (Gal alpha 1-->4Gal), receptors for pathogenic E. coli agglutinin, Shiga toxin and Mistletoe toxic lectin-I (ML-I) and abrin-a.     

The effect of dark and equiluminant occlusion on the interocular transfer of visual aftereffects

Because changes in intracellular Ca2+ affect progression through the mitotic cell cycle, we investigated the role of Ca2+-binding proteins in regulating cell cycle progression. Evidence was found demonstrating that the activation of Ca2+/calmodulin-dependent protein kinase (CaM kinase) inhibits cell cycle progression in small cell lung carcinoma (SCLC) cells. We also demonstrated that SCLC cells express both CaM kinase type II (CaMKII) and CaM kinase type IV (CaMKIV). Five independent SCLC cell lines expressed proteins reactive with antibody to the CaMKII beta subunit, but none expressed detectable proteins reactive with antibody to the CaMKII alpha subunit. All SCLC cell lines tested expressed both the alpha and beta isoforms of CaMKIV. Immunoprecipitation of CaMKII from SCLC cells yielded multiple proteins that autophosphorylated in the presence of Ca2+ / calmodulin. Autophosphorylation was inhibited by the CaMKII(281-302) peptide, which corresponds to the CaMKII autoinhibitory domain, and by 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine (KN-62), a specific CaM kinase antagonist. Influx of Ca2+ through voltage-gated Ca2+ channels stimulated phosphorylation of CaMKII in SCLC cells, and this was inhibited by KN-62. Incubation of SCLC cells of KN-62 potently inhibited DNA synthesis, and slowed progression through S phase. Similar anti-proliferative effects of KN-62 occurred in SK-N-SH human neuroblastoma cells, which express both CaMKII and CaMKIV, and in K562 human chronic myelogenous leukemia cells, which express CaMKII but not CaMKIV. The expression of both CaMKII and CaMKIV by SCLC cells, and the sensitivity of these cells to the anti-proliferative effects of KN-62, suggest a role for CaM kinase in regulating SCLC proliferation.     

Measurement of Nanometer Aerosols

This paper is a review of my work during the past 18 years on nanometer, i.e., submicrometer, aerosols. These aerosols scatter negligible light so they are difficult to study and must be observed by indirect methods such as diffusion batteries and condensation nucleus counters. Several diffusion batteries are described: “cluster tube” batteries, 5.5 km of 1-mm-diam. straight tubing mounted in clusters; collimated holes structures containing 5.1 km of holes, 1/4 mm in diameter; honeycomb structures containing 3.5 km of holes 1/3 mm in diameter; screen batteries containing 55 stainless steel screens in 10 sections; reticulated vitreous carbon batteries containing 60 k interconnected pores per cm5. From theory, the diffusion battery is shown to be only slowly discriminating, so a series of batteries and measurements is required for particle size analysis. Measurements were made with a continuous flow condensation nucleus counter developed to provide the steady flow required by diffusion battery theory. The measurements were found to agree with those made with an electrical aerosol generator. Particle size was analyzed by a “graphical stripping” method developed in this laboratory and by two computer programs described in the literature. Standard sampling methods such as the thermal precipitator and the electrostatic precipitator were tried but found to be inadequate. An induction furnace and a tube furnace were used to generate silver and gold, as well as NaCl aerosol. The furnaces were found to be superior to the more common hot-wire or exploding-wire methods, and heating the dry NaCl was preferred to spray-drying a suspension. Carbon aerosols of a large range of particle size and concentration were conveniently generated by the incomplete combustion of methane. A tube bridge, following Pollak's design, was built and used to test the “intrinsic” calibration of his counter. Good agreement was found with his calibration table up to a concentration of 300 k/cm³. Above that value, however, the tube bridge showed a progressive undercount so that the maximum value of 641 k given in Pollak's table was, according to our measurements, about 1200 k. The temperature drop during adiabatic expansion in the Pollak counter was measured with the aid of a resistance wire 12.7 um in diameter mounted along the axis of the fog tube. It was found both theoretically and experimentally that the dry adiabatic temperature drop is about 16 °C, in agreement with the literature. However, we found that the wet temperature drop is about 8°C, both experimentally and theoretically. It is frequently stated in the literature that the wet and adiabatic temperature drops are the same. The use of the above-described diffusion batteries in the laboratory and field is described. The collimated holes and honeycomb structures are suitable for aerosols of high concentration in the laboratory and uranium mine atmospheres. The carbon batteries are more suitable for radioactive aerosols of low concentration since their flow rate is 280 liters/min.     

Morphine enhancement of sucrose palatability: analysis by the taste reactivity test

The ability of morphine to modify sucrose palatability was assessed by the taste reactivity test. In Experiment 1, rats were injected with morphine (0.0, 0.5, 2.0, and 10.0 mg/kg, subcutaneously), 30 min before receiving a 10-min intraoral infusion of 2% or 20% sucrose solution. A dose of 2.0 mg/kg morphine enhanced ingestive reactions elicited by both concentrations of sucrose solution. In Experiment 2, the interval between morphine pretreatment and the taste reactivity test was manipulated. Rats given 2.0 mg/kg morphine 30 or 120 min before testing displayed enhanced ingestive reactions elicited by 20% sucrose solution during the first 5 min of a 10-min test. The results support the hypothesis that morphine enhances the hedonic assessment of sucrose solution.     

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.