Icatibant , the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

INTRODUCTION: HOE-140/ Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency. AREAS COVERED: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin-receptor interactions. EXPERT OPINION: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.

High-temperature induced dehydration, phase transition and exsolution in amicite: A single-crystal X-ray study

Temperature dependent single-crystal X-ray data were collected on amicite K4Na4(Al8Si8O32)·11H2O from Kola Peninsula (Russia) in steps of 25 °C from room temperature to 175 °C and of 50 °C up to 425 °C. At room temperature amicite has space group I2 with a = 10.2112(1), b = 10.4154(1), c = 9.8802(1) Å, β = 88.458(1)°, V = 1050.416(18) Å3. Its crystal structure is based on a Si–Al ordered tetrahedral framework of the GIS type with two systems of eight-membered channels running along the a and c axes. Extraframework K and Na cations are ordered at two fully occupied sites. Above 75 °C amicite was found to partly dehydrate into two separate but coherently intergrown phases, both of space group I2/a, one K-rich ∼K8(Al8Si8O32) ·4H2O (at 75 °C: a = 10.038(2), b = 9.6805(19), c = 9.843(2) Å, β = 89.93(3)°, V = 956.5(3) Å3) and the other Na-rich ∼Na8(Al8Si8O32)·2H2O (at 75 °C: a = 9.759(2), b = 8.9078(18), c = 9.5270(19) Å, β = 89.98(3)°, V = 828.2(3) Å3). Upon further heating above 75 °C the Na- and K-phases lost remaining H2O with only minor influence on the framework structure and became anhydrous at 175 °C and 375 °C, respectively. The two anhydrous phases persisted up to 425 °C. Backscattered electron images of a heated crystal displayed lamellar intergrowth of the K- and Na-rich phases. Exposed to ambient humid conditions K- and Na-rich phases rehydrated and conjoined to the original one phase I2 structure.

New Technologies and Concepts for Rehabilitation in the Acute Phase of Stroke: A Collaborative Matrix

The process of developing a successful stroke rehabilitation methodology requires four key components: a good understanding of the pathophysiological mechanisms underlying this brain disease, clear neuroscientific hypotheses to guide therapy, adequate clinical assessments of its efficacy on multiple timescales, and a systematic approach to the application of modern technologies to assist in the everyday work of therapists. Achieving this goal requires collaboration between neuroscientists, technologists and clinicians to develop well-founded systems and clinical protocols that are able to provide quantitatively validated improvements in patient rehabilitation outcomes. In this article we present three new applications of complementary technologies developed in an interdisciplinary matrix for acute-phase upper limb stroke rehabilitation – functional electrical stimulation, arm robot-assisted therapy and virtual reality-based cognitive therapy. We also outline the neuroscientific basis of our approach, present our detailed clinical assessment protocol and provide preliminary results from patient testing of each of the three systems showing their viability for patient use.

Water–montmorillonite systems: Neutron scattering and tracer throughdiffusion studies

Designs for deep geological respositories of nuclear waste include bentonite as a hydraulic and chemisorption buffer material to protect the biosphere from leakage of radionuclides. Bentonite is chosen because it is a cheap, naturally occurring material with the required properties. It consists essentially of montmorillonite, a swelling clay mineral. Upon contact with groundwater such clays can seal the repository by incorporating water in the interlayers of their crystalline structure. The intercalated water exhibits significantly different properties to bulk water in the surrounding interparticle pores, such as lower diffusion coefficients (González Sánchez et. al. 2008). This doctoral thesis presents water distribution and diffusion behavior on various time and space scales in montmorillonite. Experimental results are presented for Na- and Cs-montmorillonite samples with a range of bulk dry densities (0.8 to 1.7 g/cm3). The experimental methods employed were neutron scattering (backscattering, diffraction, time-of-flight), adsorption measurements (water, nitrogen) and tracer-through diffusion. For the tracer experiments the samples were fully saturated via the liquid phase under volume-constrained conditions. In contrast, for the neutron scattering experiments, the samples were hydrated via the vapor phase and subsequently compacted, leaving a significant fraction of interparticle pores unfilled with water. Owing to these differences in saturation, the water contents of the samples for neutron scattering were characterized by gravimetry whereas those for the tracer experiments were obtained from the bulk dry density. The amount of surface water in interlayer pores could be successfully discriminated from the amount of bulk-like water in interparticle pores in Na- and Csmontmorillonite using neutron spectroscopy. For the first time in the literature, the distribution of water between these two pore environments was deciphered as a function of gravimetric water content. The amount was compared to a geometrical estimation of the amount of interlayer and interparticle water determined by neutron diffraction and adsorption measurements. The relative abundances of the 1 to 4 molecular water layers in the interlayer were determined from the area ratios of the (001)-diffraction peaks. Depending on the characterization method, different fractions of surface water and interlayer water were obtained. Only surface and interlayer water exists in amontmorillonite with water contents up to 0.18 g/g according to spectroscopic measurements and up to 0.32 g/g according to geometrical estimations, respectively. At higher water contents, bulk-like and interparticle water also exists. The amounts increase monotonically, but not linearly, from zero to 0.33 g/g for bulk-like water and to 0.43 g/g for interparticle water. It was found that water most likely redistributes between the surface and interlayer sites during the spectroscopic measurements and therefore the reported fraction is relevant only below about -10 ºC (Anderson, 1967). The redistribution effect can explain the discrepancy in fractions between the methods. In a novel approach the fractions of water in different pore environments were treated as a fixed parameter to derive local diffusion coefficients for water from quasielastic neutron scattering data, in particular for samples with high water contents. Local diffusion coefficients were obtained for the 1 to 4 molecular water layers in the interlayer of 0.5·10–9, 0.9·10–9, 1.5·10–9 and 1.4·10–9 m²/s, respectively, taking account of the different water fractions (molecular water layer, bulk-like water). The diffusive transport of 22Na and HTO through Na-montmorillonite was measured on the laboratory experimental scale (i.e. cm, days) by tracer through-diffusion experiments. We confirmed that diffusion of HTO is independent of the ionic strength of the external solution in contact with the clay sample but dependent on the bulk dry density. In contrast, the diffusion of 22Na was found to depend on both the ionic strength of the pore solution and on the bulk dry density. The ratio of the pore and surface diffusion could be experimentally determined for 22Na from the dependence of the diffusion coefficient on the ionic strength. Activation energies were derived from the temperaturedependent diffusion coefficients via the Arrhenius relation. In samples with high bulk dry density the activation energies are slightly higher than those of bulk water whereas in low density samples they are lower. The activation energies as a function of ionic strengths of the pore solutions are similar for 22Na and HTO. The facts that (i) the slope of the logarithmic effective diffusion coefficients as a function of the logarithmic ionic strength is less than unity for low bulk dry densities and (ii) two water populations can be observed for high gravimetric water contents (low bulk dry densities) support the interlayer and interparticle porosity model proposed by Glaus et al. (2007), Bourg et al. (2006, 2007) and Gimmi and Kosakowski (2011).

Real-time simulation of large open quantum spin systems driven by dissipation

We consider a large quantum system with spins 12 whose dynamics is driven entirely by measurements of the total spin of spin pairs. This gives rise to a dissipative coupling to the environment. When one averages over the measurement results, the corresponding real-time path integral does not suffer from a sign problem. Using an efficient cluster algorithm, we study the real-time evolution from an initial antiferromagnetic state of the two-dimensional Heisenberg model, which is driven to a disordered phase, not by a Hamiltonian, but by sporadic measurements or by continuous Lindblad evolution.

A practical approach to designing syndromic surveillance systems for livestock and poultry

The field of animal syndromic surveillance (SyS) is growing, with many systems being developed worldwide. Now is an appropriate time to share ideas and lessons learned from early SyS design and implementation. Based on our practical experience in animal health SyS, with additions from the public health and animal health SyS literature, we put forward for discussion a 6-step approach to designing SyS systems for livestock and poultry. The first step is to formalise policy and surveillance goals which are considerate of stakeholder expectations and reflect priority issues (1). Next, it is important to find consensus on national priority diseases and identify current surveillance gaps. The geographic, demographic, and temporal coverage of the system must be carefully assessed (2). A minimum dataset for SyS that includes the essential data to achieve all surveillance objectives while minimizing the amount of data collected should be defined. One can then compile an inventory of the data sources available and evaluate each using the criteria developed (3). A list of syndromes should then be produced for all data sources. Cases can be classified into syndrome classes and the data can be converted into time series (4). Based on the characteristics of the syndrome-time series, the length of historic data available and the type of outbreaks the system must detect, different aberration detection algorithms can be tested (5). Finally, it is essential to develop a minimally acceptable response protocol for each statistical signal produced (6). Important outcomes of this pre-operational phase should be building of a national network of experts and collective action and evaluation plans. While some of the more applied steps (4 and 5) are currently receiving consideration, more emphasis should be put on earlier conceptual steps by decision makers and surveillance developers (1-3).

Real-time dynamics of open quantum spin systems driven by dissipative processes

We study the real-time evolution of large open quantum spin systems in two spatial dimensions, whose dynamics is entirely driven by a dissipative coupling to the environment. We consider different dissipative processes and investigate the real-time evolution from an ordered phase of the Heisenberg or XY model towards a disordered phase at late times, disregarding unitary Hamiltonian dynamics. The corresponding Kossakowski-Lindblad equation is solved via an efficient cluster algorithm. We find that the symmetry of the dissipative process determines the time scales, which govern the approach towards a new equilibrium phase at late times. Most notably, we find a slow equilibration if the dissipative process conserves any of the magnetization Fourier modes. In these cases, the dynamics can be interpreted as a diffusion process of the conserved quantity.