A total of 12 horses of different breeds and ages were infected with West Nile virus (WNV) via the bites of infected Aedes albopictus mosquitoes. Half the horses were infected with a viral isolate from the brain of a horse (BC787), and half were infected with an isolate from crow brain (NY99-6625); both were NY99 isolates. Postinfection, uninfected female Ae. albopictus fed on eight of the infected horses. In the first trial, Nt antibody titers reached >1:320, 1:20, 1:160, and 1:80 for horses 1 to 4, respectively. In the second trial, the seven horses with subclinical infections developed Nt antibody titers >1:10 between days 7 and 11 post infection. The highest viremia level in horses fed upon by the recipient mosquitoes was approximately 460 Vero cell PFU/mL. All mosquitoes that fed upon viremic horses were negative for the virus. Horses infected with the NY99 strain of WNV develop low viremia levels of short duration; therefore, infected horses are unlikely to serve as important amplifying hosts for WNV in nature.

Pulmonary thromboembolism (PTE) occurs as a complication to a number of commonly encountered clinical diseases. Antemortem recognition of this life-threatening disorder is hampered by nonspecificity of clinical signs. This retrospective study was performed to analyze clinical features, laboratory findings, imaging abnormalities, and concurrent postmortem diagnoses in 29 dogs with confirmed pulmonary embolism. A variety of clinicopathologic and radiographic abnormalities were noted but there were no pathognomonic findings for PTE. Arterial blood gas analyses were performed in 15 (52%) of 29 dogs; 12 (80%) of 15 exhibited hypoxemia and 15 (100%) of 15 had increased alveolar-arterial oxygen gradients. Response to supplemental O2 was variable and did not correlate with the presence or absence of additional pulmonary pathology on postmortem. At postmortem, 25 (86%) of 29 dogs had grossly visible emboli, 17 (59%) of 29 dogs had multiple disease processes, and 16 (55%) of 29 dogs had additional pulmonary pathology. PTE was suspected antemortem in 11 (38%) of 29 dogs. In dogs with respiratory signs consistent with PTE, the condition was a differential diagnosis in 11 of 17 animals; all had diseases previously reported to be associated with PTE. Neoplasia, systemic bacterial disease, and immune-mediated hemolytic anemia were diagnosed most frequently.

Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC 50 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC 50 0.27 and 0.28 M, respectively) and Fc receptor 1-mediated basophil degranulation (IC 50 0.15 M). Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC 50 0.32 M). Syk-independent signaling and activation were unaffected at much higher concentrations, demonstrating the specificity of kinase inhibition in cellular systems. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. Statistically significant efficacy was observed at concentrations that specifically suppressed Syk activity by ϳ67%. Thus specific Syk inhibition can mimic Syk genetic deficiency to modulate immune function, providing a therapeutic strategy in P505-15 for the treatment of human diseases.

Pulmonary thromboembolism (PTE) occurs as a complication to a number of commonly encountered clinical diseases. Antemortem recognition of this life-threatening disorder is hampered by nonspecificity of clinical signs. This retrospective study was performed to analyze clinical features, laboratory findings, imaging abnormalities, and concurrent postmortem diagnoses in 29 dogs with confirmed pulmonary embolism. A variety of clinicopathologic and radiographic abnormalities were noted but there were no pathognomonic findings for PTE. Arterial blood gas analyses were performed in 15 (52%) of 29 dogs; 12 (80%) of 15 exhibited hypoxemia and 15 (100%) of 15 had increased alveolar-arterial oxygen gradients. Response to supplemental O2 was variable and did not correlate with the presence or absence of additional pulmonary pathology on postmortem. At postmortem, 25 (86%) of 29 dogs had grossly visible emboli, 17 (59%) of 29 dogs had multiple disease processes, and 16 (55%) of 29 dogs had additional pulmonary pathology. PTE was suspected antemortem in 11 (38%) of 29 dogs. In dogs with respiratory signs consistent with PTE, the condition was a differential diagnosis in 11 of 17 animals; all had diseases previously reported to be associated with PTE. Neoplasia, systemic bacterial disease, and immune-mediated hemolytic anemia were diagnosed most frequently.