Quality of return to work in patients with mild traumatic brain injury: a prospective investigation of associations among post-concussion symptoms, neuropsychological functions, working status and stability.

PRIMARY OBJECTIVE: Although 'return to work' (RTW) has been always emphasized for patients with mild traumatic brain injury (MTBI), methodological drawbacks weakened its representativeness. This study thus aims to evaluate the 'work quality' (WQ) which originated from 'working status' and 'working stability' simultaneously, and to further explore the associations among post-concussion symptoms (PCS), neuropsychological functions and WQ. METHODS AND PROCEDURES: A total of 179 participants, which included 132 patients with MTBI and 47 healthy participants, were prospectively recruited. The work quality index (WQI) was developed to evaluate WQ. All patients were evaluated for their PCS, neuropsychological functions and WQ at two weeks post-injury (T1), while PCS and WQ were recorded by one month post-injury (T2). RESULTS: More than half of the patients were not able to retain their pre-injury jobs at T1, while 26% of the patients still failed to regain previous works at T2. Interestingly, WQ was significantly associated with educational levels and physical PCS, such as headache and dizziness. CONCLUSIONS: Simultaneously considering working status and stability to reveal the quality of RTW is merited. A higher educational level might be a protective factor for successful RTW, and ameliorating physical symptoms is also necessary to get favourable WQ by one month after MTBI.

E339...R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors.

The nucleoprotein (NP) of the influenza virus exists as trimers, and its tail-loop binding pocket has been suggested as a potential target for antiinfluenza therapeutics. The possibility of NP as a drug target was validated by the recent reports that nucleozin and its analogs can inhibit viral replication by inducing aggregation of NP trimers. However, these inhibitors were identified by random screening, and the binding site and inhibition mechanism are unclear. We report a rational approach to target influenza virus with a new mechanism--disruption of NP-NP interaction. Consistent with recent work, E339A, R416A, and deletion mutant Δ402-428 were unable to support viral replication in the absence of WT NP. However, only E339A and R416A could form hetero complex with WT NP, but the complex was unable to bind the RNA polymerase, leading to inhibition of viral replication. These results demonstrate the importance of the E339…R416 salt bridge in viral survival and establish the salt bridge as a sensitive antiinfluenza target. To provide further support, we showed that peptides encompassing R416 can disrupt NP-NP interaction and inhibit viral replication. Finally we performed virtual screening to target E339…R416, and some small molecules identified were shown to disrupt the formation of NP trimers and inhibit replication of WT and nucleozin-resistant strains. This work provides a new approach to design antiinfluenza drugs.

High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity.

As influenza viruses have developed resistance towards current drugs, new inhibitors that prevent viral replication through different inhibitory mechanisms are useful. In this study, we developed a screening procedure to search for new antiinfluenza inhibitors from 1,200,000 compounds and identified previously reported as well as new antiinfluenza compounds. Several antiinfluenza compounds were inhibitory to the influenza RNA-dependent RNA polymerase (RdRP), including nucleozin and its analogs. The most potent nucleozin analog, 3061 (FA-2), inhibited the replication of the influenza A/WSN/33 (H1N1) virus in MDCK cells at submicromolar concentrations and protected the lethal H1N1 infection of mice. Influenza variants resistant to 3061 (FA-2) were isolated and shown to have the mutation on nucleoprotein (NP) that is distinct from the recently reported resistant mutation of Y289H [Kao R, et al. (2010) Nat Biotechnol 28:600]. Recombinant influenza carrying the Y52H NP is also resistant to 3061 (FA-2), and NP aggregation induced by 3061 (FA-2) was identified as the most likely cause for inhibition. In addition, we identified another antiinfluenza RdRP inhibitor 367 which targets PB1 protein but not NP. A mutant resistant to 367 has H456P mutation at the PB1 protein and both the recombinant influenza and the RdRP expressing the PB1 H456P mutation have elevated resistance to 367. Our high-throughput screening (HTS) campaign thus resulted in the identification of antiinfluenza compounds targeting RdRP activity.

In vivo protection provided by a synthetic new alpha-galactosyl ceramide analog against bacterial and viral infections in murine models.

Alpha-galactosyl ceramide (α-GalCer) has been known to bind to the CD1d receptor on dendritic cells and activate invariant natural killer T (iNKT) cells, which subsequently secrete T-helper-cell 1 (Th1) and Th2 cytokines, which correlate with anti-infection activity and the prevention of autoimmune diseases, respectively. α-GalCer elicits the secretion of these two cytokines nonselectively, and thus, its effectiveness is limited by the opposing effects of the Th1 and Th2 cytokines. Reported here is the synthesis of a new α-GalCer analog (compound C34), based on the structure of CD1d, with a 4-(4-fluorophenoxy) phenyl undecanoyl modification of the N-acyl moiety of α-GalCer. Using several murine bacterial and viral infection models, we demonstrated that C34 has superior antibacterial and antiviral activities in comparison with those of several other Th1-selective glycolipids and that it is most effective by administering it to mice in a prophylactic manner before or shortly after infection.