Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the "synthetic pentasaccharide" (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 +/- 0.3 v 48 +/- 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 +/- 15 anti-factor Xa U/mg v 850 +/- 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti-factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti-factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50 values = 40.0 +/- 3.4 and 105.0 +/- 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti-factor Xa activity. SANORG 34006 enhanced rt-PA-induced thrombolysis and inhibited accretion of 125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.     

Analytical and clinical performance of an automated immunoassay system (Immulite) for estradiol in serum

Mouse strains congenic for individual quantitative trait loci (QTLs) conferring hypnotic sensitivity to ethanol were constructed by backcrossing genotypically selected ILS x ISS N2 individuals to either inbred Long Sleep (ILS) or inbred Short Sleep (ISS) mice. We used a novel "speed congenic" approach in which N2 mice were genotyped for markers flanking each of the five originally identified QTLs. Genotypic selection for ISS regions at four of the five QTLs, and for ILS/ISS at the fifth QTL, allowed rapid fixation of the genetic background. We call this strategy "QTL-Marker-Assisted Counter Selection" or QMACS. By the N4 generation, phenotypic assessments showed that in some sublines the QTL had not been captured; these sublines were discarded and positive lines split to create new replicate sublines. One QTL, on Chromosome (Chr) 8, was not confirmed. At the N8, virtually all sublines on the remaining QTLs retained the phenotypic difference between heterozygotes and ISS homozygotes. Small numbers of interim congenics were produced at the N6 and later generations in which the ILS QTL was made homozygous on the ISS background; as expected, these congenic mice showed an increased sleep time. For later backcrosses (after the N4), the parents were selected on the basis of phenotype as well as genotype. The parent-offspring correlation over all QTLs was significant, supporting the use of phenotypic selection in congenic construction.     

Stray Light Rejection in Rotational Coherent Anti-Stokes Raman Spectroscopy by use of a Sodium-Seeded Flame

A common experimental problem with rotational coherent anti-Stokes Raman spectroscopy (CARS) is undesired spectral interference that is due to stray light from the primary laser beams. Also, for the most developed approach, dual-broadband rotational CARS, practical measurements often suffer from stray light interference from the narrow-band laser, inasmuch as the CARS signal is produced inherently in the spectral vicinity of the narrow-band laser beam. An optical filter does not provide a sufficiently sharp transmission profile, thus leading to signal loss and spectral distortion of the rotational CARS signal. An atomic filter consisting of a sodium-seeded flame is presented here as a solution to the problem, and its usefulness was demonstrated in dual-broadband rotational CARS experiments.     

Response of phase Doppler anemometer systems to nonspherical droplets

The Phase Doppler Anemometer (PDA) technique measures particle diameter assuming sphericity. A means for detecting nonsphericity has usually been implemented in commercial PDA systems to avoid sizing errors if the sphericity assumption is not valid. In the present research the response of standard and planar PDA systems is examined experimentally in more detail by passing nonspherical droplets of known shape through the measurement volume. The effectiveness of nonsphericity detection schemes can be evaluated, and furthermore the influence of the droplet oscillations on the frequency and phase evolution of individual signals can be quantified. The light scattering from such particles has been simulated by using geometric optics, and the computed response of standard and planar PDA systems agrees well with the experimental observations. We conclude with some remarks concerning the possibilities of characterizing the nonsphericity with PDA systems.     

Measurements on a Dynamic A-B Phase Boundary in Superfluid 3He at Very Low Temperatures

We present preliminary measurements of the dynamics of a moving A-B phase interface in superfluid ³ He at temperatures below 0.2T _c We initially stabilise the interface at low temperatures with a shaped magnetic field. We can then move the interface in a controlled manner by applying small additional time-dependent fields. The interface is created inside a quasiparticle radiator consisting of a cylindrical chamber in weak thermal contact with the refrigerant. Vibrating wire resonators inside the radiator allow us to monitor the temperature of the superfluid and to infer the heat generated by the interface motion. When we oscillate the interface at low frequencies, we measure spectacular oscillatory swings of the liquid temperature arising from the enormous change in the low lying density of states as the volume of the A-phase superfluid is alternately compressed and expanded. We have also observed hysteresis in the transition as a function of magnetic field. In particular, we observe a small history-dependent super-magnetisation of the B-phase prior to A-phase nucleation in the experimental chamber. When the system is in the metastable super-magnetised state we are able to observe a higher nucleation probability of the A-phase when the cryostat is exposed to neutrons.     

Heat Capacity of Atomically Layered 3He –4He Mixture Films

We report preliminary results of the first heat capacity measurements on atomically layered ³ He – ⁴ He mixture films adsorbed on the surface of graphite. The ⁴ He film consists of two solid and two superfluid atomic layers. The heat capacity has been investigated over the range 1 – 70mK as a function of the surface density of ³ He atoms added to the film. At coveragesn₃ < 4nm ^–2 , the ³He forms a uniform two dimensional Fermi system. The coverage dependence of the linear coefficient of the heat capacity, , allows a determination of the hydrodynamic effective mass and . At higher coverages a step-like increase in is observed, interpreted as the formation of a second two dimensional Fermi system.     

Universal Features of the Superfluid Transition of a Thin 4He Film on an Atomically Flat Substrate

We analyse recent observations, using a torsional oscillator, of the superfluid transition of a fluid ⁴ He bilayer, within the framework of a modified dynamic theory of the Kosterlitz-Thouless transition. A parametric plot of the real and imaginary parts of the complex superfluid density, determined from the measured period shift and dissipation, achieves a high degree of collapse of the experimental data at different coverages onto a universal curve. This is compared with the result of the recent theory.     

Simultaneous machining of parallel grooves in SnO(2) thin films using a Nd:YAG laser and a kinoform

A kinoform is used to split the beam of a Nd:YAG laser into six beams. The laser beams are, by means of optical fibers and collimating-focusing optics, transferred to the surface to be machined. Thus multiple grooves can be machined simultaneously. For demonstration, 100-μm-wide grooves are simultaneously machined into a SnO(2) thin film deposited on a glass substrate. The resulting grooves are well isolated. This result shows that the technique could be used, for example, in solar cell manufacturing to increase the efficiency of laser scribing.