Virulence in Toxoplasma gondii is strongly influenced by the genotype of the parasite. Type I strains uniformly cause rapid death in mice regardless of the host genotype or the challenge dose. In contrast, the outcome of infections with type II strains is highly dependent on the challenge dose and the genotype of the host. To understand the basis of acute virulence in toxoplasmosis, we compared low and high doses of the RH strain (type I) and the ME49/PTG strain (type II) of T. gondii in outbred mice. Differences in virulence were reflected in only modestly different growth rates in vivo, and both strains disseminated widely to different tissues. The key difference in the virulent RH strain was the ability to reach high tissue burdens rapidly following a low dose challenge. Lethal infections caused by type I (RH) or type II (PTG) strain infections were accompanied by extremely elevated levels of Th1 cytokines in the serum, including IFN-γ, TNF-α, IL-12, and IL-18. Extensive liver damage and lymphoid degeneration accompanied the elevated levels of cytokines produced during lethal infection. Increased time of survival following lethal infection with the RH strain was provided by neutralization of IL-18, but not TNF-α or IFN-γ. Nonlethal infections with a low dose of type II PTG strain parasites were characterized by a modest induction of Th1 cytokines that led to control of infection and minimal damage to host tissues. Our findings establish that overstimulation of immune responses that are normally necessary for protection is an important feature of acute toxoplasmosis.

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Hyperlipidemia promotes the chronic inflammatory disease atherosclerosis through poorly understood mechanisms. Atherogenic lipoproteins activate platelets, but it is unknown whether platelets contribute to early inflammatory atherosclerotic lesions. To address the role of platelet aggregation in diet-induced vascular disease, we studied ␤3 integrin-deficient mice (lacking platelet integrin ␣IIb␤3 and the widely expressed nonplatelet integrin ␣v␤3) in two models of atherosclerosis, apolipoprotein E (apoE)-null and low-density lipoprotein receptor (LDLR)-null mice. Unexpectedly, a high-fat, Western-type (but not a low-fat) diet caused death in two-thirds of the ␤3 ؊/؊ apoE ؊/؊ and half of the ␤3 ؊/؊ LDLR ؊/؊ mice due to noninfectious pneumonitis. In animals from both models surviving high-fat feeding, pneumonitis was absent, but aortic atherosclerosis was 2-to 6-fold greater in ␤3 ؊/؊ compared with ␤ ؉/؉ littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of ␤3 ؊/؊ LDLR ؊/؊ mice. Each was also increased in smooth muscle cells cultured from ␤3-deficient mice and suppressed by retroviral reconstitution of ␤3. These data show that the platelet defect caused by ␣IIb␤3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that ␣v␤3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.

This study was designed to determine whether chronic exposure to radiofrequency (RF) radiation from cellular phones increased the incidence of spontaneous tumors in F344 rats. Eighty male and 80 female rats were randomly placed in each of three irradiation groups. The sham group received no irradiation; the Frequency Division Multiple Access (FDMA) group was exposed to 835.62 MHz FDMA RF radiation; and the Code Division Multiple Access (CDMA) group was exposed to 847.74 MHz CDMA RF radiation. Rats were irradiated 4 h per day, 5 days per week over 2 years. The nominal time-averaged specific absorption rate (SAR) in the brain for the irradiated animals was 0.85 +/- 0.34 W/kg (mean +/- SD) per time-averaged watt of antenna power. Antennas were driven with a time-averaged power of 1.50 +/- 0.25 W (range). That is, the nominal time-averaged brain SAR was 1.3 +/- 0.5 W/kg (mean +/- SD). This number was an average from several measurement locations inside the brain, and it takes into account changes in animal weight and head position during irradiation. All major organs were evaluated grossly and histologically. The number of tumors, tumor types and incidence of hyperplasia for each organ were recorded. There were no significant differences among final body weights or survival days for either males or females in any group. No significant differences were found between treated and sham-exposed animals for any tumor in any organ. We conclude that chronic exposure to 835.62 MHz FDMA or 847.74 MHz CDMA RF radiation had no significant effect on the incidence of spontaneous tumors in F344 rats.

The antitumor activity and potential toxicity of a clinical-grade keyhole limpet hemocyanin preparation (KLH-Immune Activator; KLH-IA) were determined in the MB-49 intravesical murine bladder tumor model. Mice were immunized subcutaneously with KLH-IA two weeks prior to intravesical implantation of MB-49 tumor cells. Treatment consisted of intravesical KLH-IA (10 or 100 micrograms.) 1, 4, 7, 14 and 21 days after implantation. Control animals either were not immunized prior to tumor implantation and KLH-IA treatment, or were immunized with KLH-IA and treated with the vehicle. By 4 weeks after implantation tumor outgrowth in the treated groups was significantly decreased (p < 0.01, Fisher's Exact) relative to the control groups. Prior subcutaneous immunization was required to elicit antitumor activity of KLH-IA; thus, the mechanism of action is immune-mediated and not due to spurious interference with tumor implantation by intravesical instillations. Animals treated with a dissociated form of KLH exhibited decreased tumor outgrowth approaching, but not attaining, significance (p < 0.09, Fisher's Exact). A separate toxicity study in which KLH-IA was given subcutaneously (4 mg./kg.), intraperitoneally (40 mg./kg.), or intravesically (40 mg./kg.) disclosed no significant gross or histopathologic abnormalities except for mild-to-moderate papillary hyperplasia in all catheterized animals. These results establish the efficacy and safety of KLH-IA in mice and suggest that clinical trials for intravesical treatment of superficial bladder cancer may be warranted.