BackgroundTuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.Methods and FindingsHere we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006–0.024 μg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 μg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 μg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.ConclusionsWe concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.

The IP-CHA spacer contributed to high bone fusion rates of the spacers and hinges of the laminae, and there were no complications associated with their use. Cervical laminoplasty with the IP-CHA spacers is a safe and simple method that yields sufficient fixation strength and provides sufficient bone bonding within a short period of time after operation.

SUMMARY This paper explores the potential of orbital angular momentum (OAM) multiplexing as a means to enable high-speed wireless transmission. OAM is a physical property of electro-magnetic waves that are characterized by a helical phase front in the propagation direction. Since the characteristic can be used to create multiple orthogonal channels, wireless transmission using OAM can enhance the wireless transmission rate. Comparisons with other wireless transmission technologies clarify that OAM multiplexing is particularly promising for point-to-point wireless transmission. We also clarify three major issues in OAM multiplexing: beam divergence, mode-dependent performance degradation, and reception (Rx) signal-to-noise-ratio (SNR) reduction. To mitigate mode-dependent performance degradation we first present a simple but practical Rx antenna design method. Exploiting the fact that there are specific location sets with phase differences of 90 or 180 degrees, the method allows each OAM mode to be received at its high SNR region. We also introduce two methods to address the Rx SNR reduction issue by exploiting the property of a Gaussian beam generated by multiple uniform circular arrays and by using a dielectric lens antenna. We confirm the feasibility of OAM multiplexing in a proof of concept experiment at 5.2 GHz. The effectiveness of the proposed Rx antenna design method is validated by computer simulations that use experimentally measured values. The two new Rx SNR enhancement methods are validated by computer simulations using wireless transmission at 60 GHz.

The challenges in preventing and controlling tuberculosis are further complicated by the deadly rise of multi-drug-resistant tuberculosis (MDR-TB). Recognizing the seriousness of the situation, we initiated a program to screen new agents that would satisfy these unmet needs and have a favorable safety profile. Mycobacteria are well known for their lipid-rich properties. In Mycobacterium tuberculosis, mycolic acid in particular has been established the wall component related to the pathogenesis in the host. There are approximately 250 identified genes related to biosynthesis of the lipid turnover that contain InhA, the main target of isoniazid. Thus, the logical approach for developing a chemotherapy agent against tubercle bacilli included screening compounds that could inhibit the biosyntheses of mycolic acid and that had a novel chemical structure to ensure improved efficacy against MDR-TB. Some of the screening systems established for those purposes and some of the candidates are outlined.