The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.

Prolonged inflammation and reactive oxygen species (ROS) generated around an implanted biosensor are the primary causes of the foreign body response, including encapsulation of biosensor membranes. We have previously demonstrated that TiO2 surfaces reduce ROS. Here we investigated the potential of using the anti-inflammatory properties of TiO2 in the design of biosensor membranes with improved long-term in vivo transport properties. Micropatterned Ti films were sputtered onto quartz surfaces in a series of hexagonally distributed dots with identical coverage area of 23% and dot size ranging from 5 to 100 microm. The antioxidant effect of the surfaces was investigated using a cell-free peroxynitrite donor assay and assays of superoxide released from stimulated surface-adhering neutrophils and macrophages. In all three assays, the amount of ROS was monitored using luminol-amplified chemiluminescence. Patterned surfaces in all experimental models significantly decreased ROS compared to the etched surfaces. In the cell-free experiment, the ROS reduction was only dependent on fractional surface coverage. In the cell experiments, however, a dot-size-dependent ROS reduction was seen, with the largest reduction at the smallest dot-size surfaces. These results indicate that micropatterned surfaces with small dots covering only 23% of the surface area exhibit similar antioxidative effect as fully covered surfaces.

While titanium implants are generally recognized as having excellent biocompatibility, the mechanistic basis for this has yet to be established. We previously demonstrated that TiO2, found on surfaces of titanium, has antioxidant properties that degrade the reactive oxygen species (ROS) which mediate the inflammatory response. We hypothesized that the antioxidant mechanism was similar to that known to mediate photocatalysis by titanium oxides. Specifically, we investigated whether the electronic or valence state of the surface titanium atoms mediates the catalytic degradation of ROS. Surface Ti(IV) atoms in TiO2 and SrTiO3 single crystal substrates were converted into Ti(III) while maintaining the bulk crystalline structure by vacuum annealing or Niobium doping. The degradation of both chemically-induced and neutrophil-derived ROS were significantly increased by changing the valence state of surface titanium. These results suggest that titanium-mediated degradation of ROS is through a catalytic mechanism. Furthermore, we describe a series of novel biomaterials that have antioxidant properties superior to those of titanium.

We have investigated transport properties across interfaces between the conducting ferromagnetic oxides SrRuO3, La0.5Sr0.5CoO3, La0.67Sr0.33MnO3, and the metals Nb, Al, Pd, and Au. The interface resistances range from smaller than 10−8 to 102 Ω cm2, depending on the choice of ferromagnetic oxide and metal. The three conducting metal oxides exhibit distinctly different behavior in their interface resistances with metals, which we believe is due to different processes taking place at the interface. By making the metals superconducting at 4.2 K, by proximity effect with a capping Nb layer, we show that the dominant transport mechanism through the resistive interface seems to be elastic tunneling. In the case of La0.67Sr0.33MnO3/Al interfaces, we found a way to control the magnitude of the tunneling resistance by adding a very thin Pd layer.

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