Pyrrolo[2,3-e]indazole as a novel chemotype for both influenza A virus and pneumococcal neuraminidase inhibitors.

Influenza infections are often exacerbated by secondary bacterial infections, primarily caused by Streptococcus pneumoniae. Both respiratory pathogens have neuraminidases that support infection. Therefore, we hypothesized that dual inhibitors of viral and bacterial neuraminidases might be an advantageous strategy for treating seasonal and pandemic influenza pneumonia complicated by bacterial infections. By screening our in-house chemical library, we discovered a new chemotype that may be of interest for a further campaign to find small molecules against influenza. Our exploration of the pyrrolo[2,3-e]indazole space led to the identification of two hit compounds, 6h and 12. These molecules were well-tolerated by MDCK cells and inhibited the replication of H3N2 and H1N1 influenza A virus strains. Moreover, both compounds suppress viral and pneumococcal neuraminidases indicating their dual activity. Given its antiviral activity, pyrrolo[2,3-e]indazole has been identified as a promising scaffold for the development of novel neuraminidase inhibitors that are active against influenza A virus and S. pneumoniae.

Operation care: a pilot case management intervention for frequent emergency medical system users.

OBJECTIVES: This study aims to determine if a prehospital case management intervention reduces transport and nontransport emergency medical system (EMS) responses to frequent EMS users. METHODS: The 25 most frequent EMS users in a major metropolitan area were identified, and 10 were enrolled in the intervention. These patients received linkage to psychosocial and medical resources through weekly case management visits for 5 to 12 weeks between May and August 2008. Main outcome measures were the number of transport and nontransport EMS responses to patients during the intervention as compared with predicted EMS responses based on each patient's previous year's EMS use. Transport data were available for all patients, but nontransport data were unavailable for 1 patient who was homeless and 6 patients living in apartment buildings. Secondary outcome measures included cost savings to the entire health care system and the Baltimore City Fire Department. RESULTS: Transport responses decreased 32% over the 76 predicted transport responses during the intervention, and nontransport responses decreased 79% over the 24 predicted nontransport responses during the intervention. Including the dedicated case manager's salary, this represented a cost savings to the entire health care system and to the Baltimore City Fire Department of $14 461 and $6311, respectively, over 12 weeks. CONCLUSIONS: Prehospital case management may reduce EMS use in high-frequency EMS users and create significant cost savings to municipalities and the health care system. Additional large-scale studies are needed to validate these findings.

Leaf palmate venation and vascular redundancy confer tolerance of hydraulic disruption.

Leaf venation is a showcase of plant diversity, ranging from the grid-like network in grasses, to a wide variety of dendritic systems in other angiosperms. A principal function of the venation is to deliver water; however, a hydraulic significance has never been demonstrated for contrasting major venation architectures, including the most basic dichotomy, "pinnate" and "palmate" systems. We hypothesized that vascular redundancy confers tolerance of vein breakage such as would occur during mechanical or insect damage. We subjected leaves of woody angiosperms of contrasting venation architecture to severing treatments in vivo, and, after wounds healed, made detailed measurements of physiological performance relative to control leaves. When the midrib was severed near the leaf base, the pinnately veined leaves declined strongly in leaf hydraulic conductance, stomatal conductance, and photosynthetic rate, whereas palmately veined leaves were minimally affected. Across all of the species examined, a higher density of primary veins predicted tolerance of midrib damage. This benefit for palmate venation is consistent with its repeated evolution and its biogeographic and habitat distribution. All leaves tested showed complete tolerance of damage to second- and higher-order veins, demonstrating that the parallel flow paths provided by the redundant, reticulate minor vein network protect the leaf from the impact of hydraulic disruption. These findings point to a hydraulic explanation for the diversification of low-order vein architecture and the commonness of reticulate, hierarchical leaf venation. These structures suggest roles for both economic constraints and risk tolerance in shaping leaf morphology during 130 million years of flowering plant evolution.