Influenza A virus is an important human pathogen causing significant morbidity and mortality every year and threatening the human population with epidemics and pandemics. Therefore, it is important to understand the biology of this virus to develop strategies to control its pathogenicity. Here we demonstrate that live influenza A virus infection causes accumulation of autophagosomes by blocking their fusion with lysosomes. Matrix protein 2 is sufficient and necessary for this inhibition of autophagosome degradation. Macroautophagy inhibition compromises cell survival of influenza virus infected cells, but does not influence viral replication. We propose that influenza A virus, which also encodes pro-apoptotic proteins, is able to determine the death of its host cell by inducing apoptosis and blocking macroautophagy.

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SummarySox17 and β-catenin cooperate to regulate the transcription of endodermal genes

Activin receptor-like kinase 1 (ALK1) is an endothelial serine–threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.

CONTEXT: Computerized physician order entry (CPOE) with clinical decision support (CDS) has been promoted as an effective strategy to prevent the development of a drug injury defined as an adverse drug event (ADE). OBJECTIVE:To systematically review studies evaluating the effects of CPOE with CDS on the development of an ADE as an outcome measure.DATA SOURCES: PUBMED versions of MEDLINE (from inception through March 2007) were searched to identify relevant studies. Reference lists of included studies were also searched. METHODS:We searched for original investigations, randomized and nonrandomized clinical trials, and observational studies that evaluated the effect of CPOE with CDS on the rates of ADEs. The studies identified were assessed to determine the type of computer system used, drug categories being evaluated, types of ADEs measured, and clinical outcomes assessed. RESULTS:Of the 543 citations identified, 10 studies met our inclusion criteria. These studies were grouped into categories based on their setting: hospital or ambulatory; no studies related to the long-term care setting were identified. CPOE with CDS contributed to a statistically significant (P≤.05) decrease in ADEs in 5 (50.0%) of the 10 studies. Four studies (40.0%) reported a nonstatistically significant reduction in ADE rates, and 1 study (10.0%) demonstrated no change in ADE rates.CONCLUSIONS: Few studies have measured the effect of CPOE with CDS on the rates of ADEs, and none were randomized controlled trials. Further research is needed to evaluate the efficacy of CPOE with CDS across the various clinical settings.KEY WORDS: computerized physician order entry; clinical decision support; adverse drug event.

Disclosure of a dementia diagnosis does not prompt a catastrophic emotional reaction in most people, even those who are only mildly impaired, and may provide some relief once an explanation for symptoms is known and a treatment plan is developed.

Computerized provider order entry with decision support did not reduce the adverse drug event rate or preventable adverse drug event rate in the long-term care setting. Alert burden, limited scope of the alerts, and a need to more fully integrate clinical and laboratory information may have affected efficacy.

Aims: Pannexins (Panx) form ATP release channels and it has been proposed that they play an important role in the regulation of vascular tone. However, distribution of Panx across the arterial vasculature is not documented. Methods: We tested antibodies against Panx1, Panx2 and Panx3 on human embryonic kidney cells (which do not endogenously express Panx proteins) transfected with plasmids encoding each Panx isoform and Panx1^–/– mice. Each of the Panx antibodies was found to be specific and was tested on isolated arteries using immunocytochemistry. Results: We demonstrated that Panx1 is the primary isoform detected in the arterial network. In large arteries, Panx1 is primarily in endothelial cells, whereas in small arteries and arterioles it localizes primarily to the smooth muscle cells. Panx1 was the predominant isoform expressed in coronary arteries, except in arteries less than 100 µm where Panx3 became detectable. Only Panx3 was expressed in the juxtaglomerular apparatus and cortical arterioles. The pulmonary artery and alveoli had expression of all 3 Panx isoforms. No Panx isoforms were detected at the myoendothelial junctions. Conclusion: We conclude that the specific localized expression of Panx channels throughout the vasculature points towards an important role for these channels in regulating the release of ATP throughout the arterial network.