The effects of nonionic polymers on human red blood cell (RBC) aggregation were investigated. The hydrodynamic radius (Rh) of individual samples of dextran, polyvinylpyrrolidone, and polyoxyethylene over a range of molecular weights (1,500-2,000,000) were calculated from their intrinsic viscosities using the Einstein viscosity relation and directly measured by quasi-elastic light scattering, and the effect of each polymer sample on RBC aggregation was studied by nephelometry and low-shear viscometry. For all three polymers, despite their different structures, samples with Rh <4 nm were found to inhibit aggregation, whereas those with Rh >4 nm enhanced aggregation. Inhibition increased with Rh and was maximal at approximately 3 nm; above 4 nm the pro-aggregant effect increased with Rh. For comparison, the Rh of 12 plasma proteins were calculated from literature values of intrinsic viscosity or diffusion coefficient. Each protein known to promote RBC aggregation had Rh >4 nm, whereas those with Rh <4 nm either inhibited or had no effect on aggregation. These results suggest that the influence of a nonionic polymer or plasma protein on RBC aggregation is simply a consequence of its size in an aqueous environment, and that the specific type of macromolecule is of minor importance.

BACKGROUND. Rapid clearance of poly(ethylene glycol)‐asparaginase (PEG‐ASNase) has been reported for up to one‐third of patients treated for acute lymphoblastic leukemia (ALL), potentially rendering their treatment ineffective. A 25% occurrence of an antibody against PEG (anti‐PEG) was previously reported in healthy blood donors. The objective of the study was to determine whether anti‐PEG was associated with rapid clearance PEG‐ASNase. METHODS. The investigation reanalyzed stored sera from pediatric patients enrolled in the ALL Berlin‐Frankfurt‐Muenster 2000 studies. Twenty‐eight samples were selected to include 15 subjects with undetectable ASNase activity after receiving PEG‐ASNase. Sixteen subjects treated with unmodified ASNase were also included, 8 with low ASNase activity. Sera were tested for anti‐PEG using 2 techniques: 1) serology, by agglutination of PEG‐coated red blood cells; 2) flow cytometry, by analysis of 10 μm PEG beads stained for bound immunoglobulins. RESULTS. Of the 15 sera from PEG‐ASNase‐treated patients with undetectable ASNase activity, anti‐PEG was detected in 9 by serology and in 12 by flow cytometry. Anti‐PEG was detected in 1 PEG‐ASNase‐treated patient with lower ASNase activity (123 U/L). No relation was observed between anti‐PEG and serum ASNase activity for patients treated with unmodified ASNase. CONCLUSIONS. The presence of anti‐PEG was very closely associated with rapid clearance of PEG‐ASNase. Further comprehensive studies are warranted to fully elucidate the effect of anti‐PEG on PEG‐conjugated agents. Screening and monitoring for anti‐PEG may allow identification of patients for whom a modified dosing strategy or use of a non‐PEGylated drug would be appropriate. Cancer 2007. © 2007 American Cancer Society.

The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here, we show that GLUT1 deficiency in mice overexpressing amyloid β-petpide (Aβ) precursor protein leads to: 1) early cerebral microvascular degeneration, blood flow reductions and dysregulation, and BBB breakdown; and (2) accelerated amyloid β-peptide (Aβ) pathology, reduced Aβ clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function suggesting that GLUT1 may represent a novel therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

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