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Deposition patterns are described of a nasal spray formulation for a novel rhinovirus protease inhibitor. These patterns, which were generated from different nasal spray pumps, were characterized using a multisectional nasal airway model. A human nasal replica was made from an in vivo magnetic resonance imaging (MRI) scan of an adult male human. The nasal replica consisted of 77 acrylic plastic sections, 1.5-mm thick. Our data showed that the aerosols were deposited mainly in the anterior and turbinate regions with little passing beyond the nasopharyngeal region. Detailed deposition information from the turbinate region indicated that deposition was high toward the anterior portion where most deposition was concentrated on the inferior meatus. Spray droplets were also deposited in spots of the middle and posterior portions of the turbinate region, and this nonuniform deposition pattern may be correlated with the flow pattern. The spray angle and droplet size of the nasal spray were found to be important in influencing the deposition pattern in the nasal airway. The droplet size was determined by a laser-diffraction technique and the spray angle by high-speed photography. Larger droplets and a wider spray angle increased deposition in the anterior region of the nasal airway, which prevented more material from depositing in the turbinate region.

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Cesium-137 is a fission product of uranium and plutonium in nuclear reactors and is released in large quantities during nuclear explosions or detonation of an improvised device containing this isotope. This environmentally persistent radionuclide undergoes radioactive decay with the emission of beta particles as well as gamma radiation. Exposure to 137Cs at high doses can cause acute radiation sickness and increase risk for cancer and death. The serious health risks associated with 137Cs exposure makes it critical to understand how it affects human metabolism and whether minimally invasive and easily accessible samples such as urine and serum can be used to triage patients in case of a nuclear disaster or a radiologic event. In this study, we have focused on establishing a time-dependent metabolomic profile for urine collected from mice injected with 137CsCl. The samples were collected from control and exposed mice on days 2, 5, 20 and 30 after injection. The samples were then analyzed by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC/TOFMS) and processed by an array of informatics and statistical tools. A total of 1,412 features were identified in ESI+ and ESI− modes from which 200 were determined to contribute significantly to the separation of metabolomic profiles of controls from those of the different treatment time points. The results of this study highlight the ease of use of the UPLC/TOFMS platform in finding urinary biomarkers for 137Cs exposure. Pathway analysis of the statistically significant metabolites suggests perturbations in several amino acid and fatty acid metabolism pathways. The results also indicate that 137Cs exposure causes: similar changes in the urinary excretion levels of taurine and citrate as seen with external-beam gamma radiation; causes no attenuation in the levels of hexanoylglycine and N-acetylspermidine; and has unique effects on the levels of isovalerylglycine and tiglylglycine.

In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues. We compared the tissue reactions in rats to the carcinogenicity of a tantalum metal (Ta), as a negative foreign-body control, and to a colloidal suspension of radioactive thorium dioxide ((232)Th), Thorotrast, as a positive radioactive control. DU was surgically implanted in the thigh muscles of male Wistar rats as four squares (2.5 x 2.5 x 1.5 mm or 5.0 x 5.0 x 1.5 mm) or four pellets (2.0 x 1.0 mm diameter) per rat. Ta was similarly implanted as four squares (5.0 x 5.0 x 1.1 mm) per rat. Thorotrast was injected at two sites in the thigh muscles of each rat. Control rats had only a surgical implantation procedure. Each treatment group included 50 rats. A connective tissue capsule formed around the metal implants, but not around the Thorotrast. Radiographs demonstrated corrosion of the DU implants shortly after implantation. At later times, rarifactions in the radiographic profiles correlated with proliferative tissue responses. After lifetime observation, the incidence of soft tissue sarcomas increased significantly around the 5.0 x 5.0 mm squares of DU and the positive control, Thorotrast. A slightly increased incidence occurred in rats implanted with the 2.5 x 2.5 mm DU squares and with 5.0 x 5.0 mm squares of Ta. No tumors were seen in rats with 2.0 x 1.0 mm diameter DU pellets or in the surgical controls. These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats.

In this study ultra performance liquid chromatography (UPLC) coupled to time-of-flight mass spectrometry in the MSE mode was used for rapid and comprehensive analysis of metabolites in the serum of mice exposed to internal exposure by Cesium-137 (137Cs). The effects of exposure to 137Cs were studied at several time points after injection of 137CsCl in mice. Over 1800 spectral features were detected in the serum of mice in positive and negative electrospray ionization modes combined. Detailed statistical analysis revealed that several metabolites associated with amino acid metabolism, fatty acid metabolism, and the TCA cycle were significantly perturbed in the serum of 137Cs-exposed mice compared with that of control mice. While metabolites associated with the TCA cycle and glycolysis increased in their serum abundances, fatty acids such as linoleic acid and palmitic acid were detected at lower levels in serum after 137Cs exposure. Furthermore, phosphatidylcholines (PCs) were among the most perturbed ions in the serum of 137Cs-exposed mice. This is the first study on the effects of exposure by an internal emitter in serum using a UPLC–MSE approach. The results have put forth a panel of metabolites, which may serve as potential serum markers to 137Cs exposure.

ABSTRACT. Very large and very small particles most often deposit in the nasal airways. Human volunteers have often been used in deposition studies using particles > 0.5 pm, whereas physical airway models have been used in studies of ultrafine particle deposition. Studies in airway models provide large data sets with which to evaluate the deposition mechanism, while in vivo deposition data are needed to validate results obtained with nasal models. Four adult male, nonsmoking, healthy human volunteers (ages 36-57 yr) participated in this study. Deposition was measured in each subject at constant flow rates of 4, 7.5, 10, and 20 L min-'. Monodisperse silver particles (5, 8, and 20 nm) and polystyrene latex particles (50 and 100 nm) were used. Each subject held his breath for 30-60 sec, during which time, the aerosol was drawn through the nasal airway and exhausted through a mouth tube. Aerosol concentrations in the intake and exhaust air were measured by an ultrafine condensation particle counter. The deposition efficiency in the nasal airway was calculated taking into account particle losses in the mask, mouth tube, and transport lines. Our results were consistent with the turbulent diffusional deposition model previously established from studies using nasal airway casts. However, nasal deposition varied widely among the four subjects. From magnetic resonance imaging data of in vivo nasal airway dimensions for the subjects in this study, we calculated the mean cross-sectional area (A,), mean perimeter (pr), and total surface area (A,) of the individual nasal passages. The turbulent diffusional deposition model was extended to provide a relationship between deposition efficiency and nasal airway dimensions. Our results suggested that deposition can be correlated using the parameter of (~, /~, )~~~~(~r )~~~~.This information indicates a higher nasal deposition for a person with a smaller cross-sectional area, larger