Function of the Loading Module in CorI and of the O-Methyltransferase CorH in Vinyl Carbamate Biosynthesis of the Antibiotic Corallopyronin A

Corallopyronin A is a promising in vivo active antibiotic, currently undergoing preclinical evaluation. This myxobacterial compound interferes with a newly identified drug target site, i.e., the switch region of the bacterial DNA-dependent RNA-polymerase (RNAP). Since this target site differs from that of known RNAP inhibitors such as the rifamycins, corallopyronin A shows no cross-resistance with other antibacterial agents. Corallopyronin A is a polyketide synthase- and nonribosomal peptide synthetase-derived molecule whose structure and biosynthesis is distinguished by several peculiarities, such as the unusual vinyl carbamate functionality whose formation involves carbonic acid as an unprecedented C1-starter unit. Using in vitro experiments the nature of this starter molecule was revealed to be the methyl ester of carbonic acid. Biochemical investigations showed that methylation of carbonic acid is performed by the O-methyltransferase CorH. These experiments shed light on the biosynthesis of the Eastern chain of α-pyrone antibiotics such as corallopyronin A.     

Clinical outcomes of laparo-endoscopic single-site surgery radical nephrectomy

Introduction

The conventional laparoscopic surgery is now paving way to the new technologies including robotic and laparoscopic single-site surgery (LESS). We present our updated experience on LESS radical nephrectomy (LESS–RN).

Patients and methods

The data from patients undergoing LESS–RN in our two institutions were reviewed along with various clinical and pathological parameters.

Results

Between 2008 and 2011, 42 LESS–RN were performed (right?=?22, left?=?20) with mean (range) age and BMI of 63.7 (33–86) years and 25.1 (18–38.6)?kg/m², respectively. In addition to the instruments in the single port, one extra 3-mm needlescopic instrument was required in 19 patients (right?=?17, left?=?2). In three patients, two additional 5-mm trocars and instruments were required. None required open conversion. The recorded adverse events include one bowel injury (intraoperative closure without the need for stoma), one postoperative bleeding requiring blood transfusion, one prolonged ileus, and one deep venous thrombosis. The resected specimens revealed pT1a (n?=?3), pT1b (n?=?33), pT2a (n?=?4), and pT3b (n?=?2) tumors. The finding of pT3b was incidental rather than planned procedure. None of the patients had positive margins.

Conclusion

LESS–RN has proven to be feasible and safe. Beyond cosmesis, further advantages of this approach need to be addressed by randomized trials.     

Assessing the population health impact of market interventions to improve access to antiretroviral treatment

Despite extraordinary global progress in increasing coverage of antiretroviral treatment (ART), the majority of people needing ART currently are not receiving treatment. Both the number of people needing ART and the average ART price per patient-year are expected to increase in coming years, which will dramatically raise funding needs for ART. Several international organizations are using interventions in ART markets to decrease ART price or to improve ART quality, delivery and innovation, with the ultimate goal of improving population health. These organizations need to select those market interventions that are most likely to substantially affect population health outcomes (ex ante assessment) and to evaluate whether implemented interventions have improved health outcomes (ex post assessment). We develop a framework to structure ex ante and ex post assessment of the population health impact of market interventions, which is transmitted through effects in markets and health systems. Ex ante assessment should include evaluation of the safety and efficacy of the ART products whose markets will be affected by the intervention; theoretical consideration of the mechanisms through which the intervention will affect population health; and predictive modelling to estimate the potential population health impact of the intervention. For ex post assessment, analysts need to consider which outcomes to estimate empirically and which to model based on empirical findings and understanding of the economic and biological mechanisms along the causal pathway from market intervention to population health. We discuss methods for ex post assessment and analyse assessment issues (unintended intervention effects, interaction effects between different interventions, and assessment impartiality and cost). We offer seven recommendations for ex ante and ex post assessment of population health impact of market interventions.     

Characterisation of vaccine-induced, broadly cross-reactive IFN-γ secreting T cell responses that correlate with rapid protection against classical swine fever virus

Live attenuated C-strain classical swine fever viruses (CSFV) provide a rapid onset of protection, but the lack of a serological test that can differentiate vaccinated from infected animals limits their application in CSF outbreaks. Since immunity may precede antibody responses, we examined the kinetics and specificity of peripheral blood T cell responses from pigs vaccinated with a C-strain vaccine and challenged after five days with a genotypically divergent CSFV isolate. Vaccinated animals displayed virus-specific IFN-γ responses from day 3 post-challenge, whereas, unvaccinated challenge control animals failed to mount a detectable response. Both CD4(+) and cytotoxic CD8(+) T cells were identified as the cellular source of IFN-γ. IFN-γ responses showed extensive cross-reactivity when T cells were stimulated with CSFV isolates spanning the major genotypes. To determine the specificity of these responses, T cells were stimulated with recombinant CSFV proteins and a proteome-wide peptide library from a related virus, BVDV. Major cross-reactive peptides were mapped on the E2 and NS3 proteins. Finally, IFN-γ was shown to exert potent antiviral effects on CSFV in vitro. These data support the involvement of broadly cross-reactive T cell IFN-γ responses in the rapid protection conferred by the C-strain vaccine and this information should aid the development of the next generation of CSFV vaccines.     

An integrated approach to data management, risk assessment, and decision making

This paper describes a methodology called Risk Analysis, Communication, Evaluation, and Reduction (RACER) that converts environmental data directly to human health risk to enhance decision making and communication. The methodology was developed and implemented following the Cerro Grande fire in New Mexico that burned approximately 7,500 acres of Los Alamos National Laboratory in May 2000. The absence of a coordinated and comprehensive approach to managing and understanding environmental data was a major weakness in the responding agencies' ability to make and communicate decisions. RACER consists of three basic elements: managing information, converting information to knowledge, and communicating knowledge to decision makers and stakeholders. Data are maintained in a web-accessible database that accepts data as they are validated and uploaded. The user can select data for evaluation and convert them to knowledge using human health risk as a benchmark for ranking radionuclides, chemicals, pathways, or other criteria needed to make decisions. Knowledge about risk is communicated using graphic and tabular formats. The process is transparent, flexible, and rapid, which enhances credibility and trust among decision makers and stakeholders. The fundamental principles used in RACER can be applied anywhere radionuclides or chemicals are present in the environment.