Back to the Future: Middle Molecules, High Flux Membranes, and Optimal Dialysis

Middle molecules can be defined as compounds with a molecular weight (MW) above 500 Da. An even broader definition includes those molecules that do not cross the membranes of standard low‐flux dialyzers, not only because of molecular weight, but also because of protein binding and/or multicompartmental behavior. Recently, several of these middle molecules have been linked to the increased tendency of uremic patients to develop inflammation, malnutrition, and atheromatosis. Other toxic actions can also be attributed to the middle molecules. In the present publication we will consider whether improved removal of middle molecules by large pore membranes has an impact on clinical conditions related to the uremic syndrome.
The clinical benefits of large pore membranes are reduction of uremia‐related amyloidosis; maintenance of residual renal function; and reduction of inflammation, malnutrition, anemia, dyslipidemia, and mortality. It is concluded that middle molecules play a role in uremic toxicity and especially in the processes related to inflammation, atherogenesis, and malnutrition. Their removal seems to be related to a better outcome, although better biocompatibility of membranes might be a confounding factor.     

An Overview of Uremic Toxicity

About 100 uremic retention solutes have been identified at present, but not all of these compounds are necessarily toxic. They can be defined as uremic toxins if they exert biochemical/biological actions. Based on their physicochemical characteristics, there are three major groups of uremic retention solutes: 1) the small water‐soluble compounds (<500 Da), which are easily removed by standard low‐pore‐size dialyzer membranes; 2) the protein‐bound solutes (also mostly <500 Da), whose dialytic removal is hampered by their protein binding, irrespective of the membrane type; and 3) the so‐called middle molecules (>500 Da), which can be removed only by membranes with a large pore size and/or adsorptive capacity. In the present review, we will summarize the currently known information about the toxicity of the uremic retention solutes. Although removal of small water‐soluble urea has been recognized for many years as a current measure of dialysis adequacy, data on its toxicity are very scanty. Almost 50 other water‐soluble compounds are known to be retained in uremia, but only a few exert biological effects. Most of the toxic water‐soluble moieties, such as the guanidines, phosphate, xanthine, and hypoxanthine show an intra‐dialytic compartmental behavior, which is different from urea. A substantial number of uremic solutes are protein bound, and most of them exert biological action. Among them are the phenols, indoles, homocysteine, and carboxy‐methyl‐propyl‐furanpropionic acid. Recent data suggest that protein binding acts as a buffer against the toxic effects of these compounds, and that hypoalbuminemia increases both their free fraction and their toxicity. In addition, many middle molecules, such as ß₂‐microglobulin, leptin, and advanced glycation end products, have been related to biological/clinical effects. Our current knowledge of the biological impact of the middle molecules is very likely incomplete. It is concluded that many of the water‐soluble compounds exert little or no toxicity, and that urea removal pattern per se is not identical to that of many biologically active molecules. Hence, in dialysis, more than urea removal alone should be pursued.     

Leukocyte CD14 and CD45 expression during hemodialysis: polysulfone versus cuprophane

Four Klebsiella pneumoniae isolates (LB1, LB2, LB3, and LB4) with increased antimicrobial resistance were obtained from the same patient. The four isolates were indistinguishable in biotype, plasmid content, lipopolysaccharide, and DNA analysis by pulse-field gel electrophoresis. Isolate LB1 made TEM-1 and SHV-1 beta-lactamases. Isolates LB2, LB3, and LB4 produced SHV-5 in addition to TEM-1 and SHV-1. MICs of cefoxitin, ceftazidime, and cefotaxime against LB1 were 4, 1, and 0.06 micrograms/ml, respectively. MICs of ceftazidime against K. pneumoniae LB2, LB3, and LB4 were > 256 micrograms/ml, and those of cefotaxime were 2, 4, and 64 micrograms/ml, respectively. MICs of cefoxitin against K. pneumoniae LB2 and LB3 were 4 micrograms/ml, but that against K. pneumoniae LB4 was 128 micrgrams/ml. K. pneumoniae LB4 could transfer resistance to ceftazidime and cefotaxime, but not that to cefoxitin, to Escherichia coli. Isolate LB4 and cefoxitin-resistant laboratory mutants lacked an outer membrane protein of about 35 kDa whose molecular mass, mode of isolation, resistance to proteases, and reaction with a porin-specific antiserum suggested that it was a porin. MICs of cefoxitin and cefotaxime reverted to 4 and 2 micrograms/ml, respectively, when isolate LB4 was transformed with a gene coding for the K. pneumoniae porin OmpK36. We conclude that the increased resistance to cefoxitin and expanded-spectrum cephalosporins of isolate LB4 was due to loss of a porin channel for antibiotic uptake.     

Synthesis and sintering of a monazite–brabantite solid solution ceramics using metaphosphate

In order to improve monazite-based ceramics, to be used as actinides waste-form, a procedure for synthesis and sintering of a monazite–brabantite solid solution (ssMB) using metaphosphate La(PO₃)₃ is described. Using LaPO₄, CeO₂, ThO₂, CaCO₃ and La(PO₃)₃ as precursors, the gaseous emissions are strongly reduced, compared to a process using (NH₄)H₂PO₄. Detailed dilatometric studies show sintering of that product is a two-steps process: coalescence and boundary diffusion. From X-ray diffraction, electron microprobe analyses, SEM observation, dilatometric study and TG–DTA, the reaction scheme is identified and the thermal treatment for synthesis and sintering is optimized to obtain homogeneous, dense, reproducible and well-crystallized pellets of La_0.73Ce_0.09Th_0.09Ca_0.09PO₄ and La_0.91Ce_0.09PO₄.     

Surface Tension of Liquid Alumina from Contactless Techniques

New data for the surface tension of liquid alumina from 2300 to 3200 K are reported. Aerodynamic levitation of CO₂ laser-heated liquid drops allowed contactless measurement of vibration frequencies directly related to surface tension. Consistent data were obtained on drops of different mass ranging from 20 to 160 mg. It was also shown that the oxydo-reducing character of the atmosphere does not modify the results within experimental uncertainty.     

Refractive index variations induced by a microwave field interacting with the active medium of an FIR laser

Double-resonance effects due to irradiation of the active molecules of an FIR laser by a resonant microwave field are demonstrated. In particular, dispersion effects are shown to contribute to both AM and FM of the FIR laser output. By using double resonance in a metallic waveguide laser, amplitude modulation up to 30 percent and FM shift to 40 kHz were obtained with 50mW microwave driving power. Higher modulations could be obtained if stronger microwave power were used.     

Effect of Porosity on Thermal Conductivity of Al–Si–Fe–X Alloy Powder Compacts

The thermal conductivity and thermal diffusivity of hot- and cold-pressed Al–17Si–5Fe–3.5Cu–1.1Mg–0.6Zr (mass%) alloy powder compacts were investigated as a function of the porosity volume fraction. Samples with a very low degree of porosity were produced by hot-pressing air atomized alloy powder with a particle size of 45–100 m. The same powder was used to produce highly porous compacts by cold compaction using a manual press. The thermal diffusivity of the powder compacts was measured using a sinusoidal modulation photopyroelectric technique in a configuration that is similar to the laser flash method. The thermal diffusivity of the material decreases by a factor of about 13 with an increasing porosity of 25 vol% and a factor of about 300 at 60 vol % porosity. Since the calculated specific heat (weighted average of mass specific heat values of major alloy compounds) is much less porosity dependent, the porosity dependence of the thermal conductivity is similar to the thermal diffusivity and decreases exponentially with increasing porosity. Microstructural characterization of high porosity samples prepared by cold compaction indicated that the distribution of pores is not uniform over the cross-section. An interconnecting network of open and closed pores in the form of channels created pockets of porosity,clearpage 2.3pc which are largely responsible for a drastic reduction of thermal conductivity 4pc with increasing porosity.     

Creating & Testing CLARIN Metadata Components

The CLARIN Metadata Infrastructure (CMDI) that is being developed in Common Language Resources and Technology Infrastructure (CLARIN) is a computer-supported framework that combines a flexible component approach with the explicit declaration of semantics. The goal of the Dutch CLARIN project “Creating & Testing CLARIN Metadata Components” was to create metadata components and profiles for a wide variety of existing resources housed at two data centres according to the CMDI specifications. In doing so the principles of the framework were tested. The results of the project are of benefit to other CLARIN-projects that are expected to adhere to the CMDI framework and its accompanying tools.     

Density of Superheated and Undercooled Liquid Alumina by a Contactless Method

The density of liquid alumina drops maintained in levitation with an aerodynamic device and heated with CO₂ lasers is determined by analysis of high-speed video digital images between 2000 and 3100 K in various gases. It is shown that consistent results can be achieved for the lighter drops (m<100 mg) which do not depend on the nature of the gas. Experiments performed with lasers impinging the drop surface or during free cooling of the preheated drop gave similar results. The density is represented by the following expression: d=(2.79±0.01)(l–(T–2500)) g·cm^–3, where =(4.22 ±0.14) × 10^–5K^–1.