Host-directed combinatorial RNAi improves inhibition of diverse strains of influenza A virus in human respiratory epithelial cells.

Influenza A virus infections are important causes of morbidity and mortality worldwide, and currently available prevention and treatment methods are suboptimal. In recent years, genome-wide investigations have revealed numerous host factors that are required for influenza to successfully complete its life cycle. However, only a select, small number of influenza strains were evaluated using this platform, and there was considerable variation in the genes identified across different investigations. In an effort to develop a universally efficacious therapeutic strategy with limited potential for the emergence of resistance, this study was performed to investigate the effect of combinatorial RNA interference (RNAi) on inhibiting the replication of diverse influenza A virus subtypes and strains. Candidate genes were selected for targeting based on the results of multiple previous independent genome-wide studies. The effect of single and combinatorial RNAi on the replication of 12 diverse influenza A viruses, including three strains isolated from birds and one strain isolated from seals, was then evaluated in primary normal human bronchial epithelial cells. After excluding overly toxic siRNA, two siRNA combinations were identified that reduced mean viral replication by greater than 79 percent in all mammalian strains, and greater than 68 percent in all avian strains. Host-directed combinatorial RNAi effectively prevents growth of a broad range of influenza virus strains in vitro, and is a potential therapeutic candidate for further development and future in vivo studies.

Disseminated intravascular coagulation in cats.

The purpose of this study was to describe the clinical characteristics of cats with disseminated intravascular coagulation (DIC), including associated diseases and hemostatic abnormalities, and to identify risk factors for death and treatments that potentially altered outcome. Medical records for cats with DIC from 1990-2004 were evaluated retrospectively. Inclusion criteria were the presence of an underlying disorder associated with DIC and either postmortem examination findings of intravascular fibrin deposition or thrombosis, or both of 2 or more organs or coagulation profiles that meet 3 of 5 criteria: prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), presence of fibrin degradation products (FDP), low plasma fibrinogen (FIB) concentration, and thrombocytopenia (<160,000 platelets/microL). Signalment, historical data, clinical findings, clinicopathologic data, underlying disorders, management, and outcome were recorded. Forty-six cats fulfilled the criteria for DIC. Cats ranged in age from 7 weeks to 17 years (median, 9 years). Hemorrhage was noted in 7 of 46 cats (15%). Three of 46 cats (7%) survived, whereas 43 of 46 (93%) died or were euthanized. The most common underlying disorders were lymphoma, other forms of neoplasia, pancreatitis, and sepsis. There was no association detected between outcome and signalment; underlying disease; hemorrhage; abnormalities in aPTT, FIB, FDPs, platelet count; transfusion of blood products; and heparin therapy. However, the median PT of nonsurvivors was more prolonged than in survivors (P < .005). DIC in cats can result from a variety of neoplastic, infectious, and inflammatory disorders, and is associated with a high case fatality rate.