The roles of interleukin (IL)-6 and IL-8 in mediating the symptoms and signs of influenza A infection were examined. Adults were intranasally inoculated with a rimantadine-sensitive strain of influenza A HlNl virus and treated with rimantadine or placebo. Viral shedding, secretion weights, symptom scores, and concentrations of IL-6 and IL-8 in nasal lavage fluids were compared between treatment groups. Viral shedding was associated with increases in local and systemic symptoms, in expelled secretion weights, and in levels of IL-6 and IL-8. Compared with placebo, rimantadine treatment reduced viral shedding, systemic symptoms, and levels of IL-8. Days of viral shedding and IL-6 but not IL-8 concentrations were significantly correlated with the other measures of symptoms and signs. These data support a causal relationship between viral replication, cytokine production, and symptom expression, and they suggest that IL-6 may have a role in mediating symptom and sign expression during influenza A infection.

To investigate further the antiangiogenic potential of sunitinib for renal cell carcinoma (RCC) treatment, its effects on tumor vasculature were monitored by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using an orthotopic KCI-18 model of human RCC xenografts in nude mice. Tumor-bearing mice were treated with various doses of sunitinib, and vascular changes were assessed by DCE-MRI and histologic studies. Sunitinib induced dose-dependent vascular changes, which were observed both in kidney tumors and in normal kidneys by DCE-MRI. A dosage of 10 mg/kg per day caused mild changes in Gd uptake and clearance kinetics in kidney tumors. A dosage of 40 mg/kg per day induced increased vascular tumor permeability with Gd retention, probably resulting from the destruction of tumor vasculature, and also caused vascular alterations of normal vessels. However, sunitinib at 20 mg/kg per day caused increased tumor perfusion and decreased vascular permeability associated with thinning and regularization of tumor vessels while mildly affecting normal vessels as confirmed by histologic diagnosis. Alterations in tumor vasculature resulted in a significant inhibition of KCI-18 RCC tumor growth at sunitinib dosages of 20 and 40 mg/kg per day. Sunitinib also exerted a direct cytotoxic effect in KCI-18 cells in vitro. KCI-18 cells and tumors expressed vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor beta molecular targets of sunitinib that were modulated by the drug treatment. These data suggest that a sunitinib dosage of 20 mg/kg per day, which inhibits RCC tumor growth and regularizes tumor vessels with milder effects on normal vessels, could be used to improve blood flow for combination with chemotherapy. These studies emphasize the clinical potential of DCE-MRI in selecting the dose and schedule of antiangiogenic compounds.

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Posterior tibial slope should be measured on a long lateral or an expanded lateral radiograph. Posterior tibial slope decreases the quadriceps force needed to exert knee extension moment. Posterior tibial slope parallel to natural tibial slope minimizes tibial component subsidence. Posterior tibial slope should be increased rather than releasing the posterior cruciate ligament (PCL) to restore normal kinematics in a knee that is tight in flexion. Larger tibial slope widens the flexion gap in posterior stabilized total knee replacement.