The first small-molecule inhibitors of members of the ribonuclease E family

The Escherichia coli endoribonuclease RNase E is central to the processing and degradation of all types of RNA and as such is a pleotropic regulator of gene expression. It is essential for growth and was one of the first examples of an endonuclease that can recognise the 5′-monophosphorylated ends of RNA thereby increasing the efficiency of many cleavages. Homologues of RNase E can be found in many bacterial families including important pathogens, but no homologues have been identified in humans or animals. RNase E represents a potential target for the development of new antibiotics to combat the growing number of bacteria that are resistant to antibiotics in use currently. Potent small molecule inhibitors that bind the active site of essential enzymes are proving to be a source of potential drug leads and tools to dissect function through chemical genetics. Here we report the use of virtual high-throughput screening to obtain small molecules predicted to bind at sites in the N-terminal catalytic half of RNase E. We show that these compounds are able to bind with specificity and inhibit catalysis of Escherichia coli and Mycobacterium tuberculosis RNase E and also inhibit the activity of RNase G, a paralogue of RNase E

Cosmogenic neutron production at the Sudbury Neutrino Observatory

Neutrons produced in nuclear interactions initiated by cosmic-ray muons present an irreducible background to many rare-event searches, even in detectors located deep underground. Models for the production of these neutrons have been tested against previous experimental data, but the extrapolation to deeper sites is not well understood. Here we report results from an analysis of cosmogenically produced neutrons at the Sudbury Neutrino Observatory. A specific set of observables are presented, which can be used to benchmark the validity of geant4 physics models. In addition, the cosmogenic neutron yield, in units of 10-4 cm2/(g·μ), is measured to be 7.28±0.09(stat)-1.12+1.59(syst) in pure heavy water and 7.30±0.07(stat)-1.02+1.40(syst) in NaCl-loaded heavy water. These results provide unique insights into this potential background source for experiments at SNOLAB

Trends in postpartum hemorrhage in high resource countries: a review and recommendations from the International Postpartum Hemorrhage Collaborative Group

<p>Abstract</p> <p>Background</p> <p>Postpartum hemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Several recent publications have noted an increasing trend in incidence over time. The international PPH collaboration was convened to explore the observed trends and to set out actions to address the factors identified.</p> <p>Methods</p> <p>We reviewed available data sources on the incidence of PPH over time in Australia, Belgium, Canada, France, the United Kingdom and the USA. Where information was available, the incidence of PPH was stratified by cause.</p> <p>Results</p> <p>We observed an increasing trend in PPH, using heterogeneous definitions, in Australia, Canada, the UK and the USA. The observed increase in PPH in Australia, Canada and the USA was limited solely to immediate/atonic PPH. We noted increasing rates of severe adverse outcomes due to hemorrhage in Australia, Canada, the UK and the USA.</p> <p>Conclusion</p> <p><it>Key Recommendations</it></p> <p indent="1">1. Future revisions of the International Classification of Diseases should include separate codes for atonic PPH and PPH immediately following childbirth that is due to other causes. Also, additional codes are required for placenta accreta/percreta/increta.</p> <p indent="1">2. Definitions of PPH should be unified; further research is required to investigate how definitions are applied in practice to the coding of data.</p> <p indent="1">3. Additional improvement in the collection of data concerning PPH is required, specifically including a measure of severity.</p> <p indent="1">4. Further research is required to determine whether an increased rate of reported PPH is also observed in other countries, and to further investigate potential risk factors including increased duration of labor, obesity and changes in second and third stage management practice.</p> <p indent="1">5. Training should be provided to all staff involved in maternity care concerning assessment of blood loss and the monitoring of women after childbirth. This is key to reducing the severity of PPH and preventing any adverse outcomes.</p> <p indent="1">6. Clinicians should be more vigilant given the possibility that the frequency and severity of PPH has in fact increased. This applies particularly to small hospitals with relatively few deliveries where management protocols may not be defined adequately and drugs or equipment may not be on hand to deal with unexpected severe PPH.</p

Analysis of two methods of isometric muscle contractions during the anti-G straining maneuver

This study investigated the difference in Mean Arterial Pressure (MAP) and Cardiac Output (CO) between two methods of isometric muscle contractions during the Anti-G Straining Maneuver (AGSM). 12 subjects (ages 18 to 38 yrs, height 176.8 +/- 7.4 cm, body mass 78.8 +/- 15.6 kg, percent body fat 14.3 +/- 6.6%) participated in the study. The study was a one-way within-subject design with test conditions counterbalanced. Two methods of isometric muscle contractions lasting 30 seconds each were assessed; an isometric push contraction and an isometric muscle tensing contraction. The dependent parameters were MAP and CO. The average MAP during the push contraction was 123 mmHg, SD +/- 11 and for tense was 118 mmHg, SD +/- 8. CO was 7.6 L/min, SD +/- 1.6 for push and 7.9 L/min, SD +/- 2.0 for tense method. Dependent t-tests revealed t(11) = 1.517, p = 0.157 for MAP and t(11) = 0.875, p = 0.400 for CO. This study demonstrated that the two methods of isometric muscle contractions were not statistically different with regards to MAP and CO. Therefore, both forms of isometric contractions may be potentially useful when performing the muscle contraction portion of the AGSM

Innovations in total knee replacement: new trends in operative treatment and changes in peri-operative management

The human knee joint can sustain damage due to injury, or more usually osteoarthritis, to one, two or all three of the knee compartments: the medial femorotibial, the lateral femorotibial and the patellofemoral compartments. When pain associated with this damage is unmanageable using nonsurgical techniques, knee replacement surgery might be the most appropriate course of action. This procedure aims to restore a pain-free, fully functional and durable knee joint. Total knee replacement is a well-established treatment modality, and more recently, partial knee replacement—more commonly known as bi- or unicompartmental knee replacement—has seen resurgence in interest and popularity. Combined with the use of minimally invasive surgery (MIS) techniques, gender-specific prosthetics and computer-assisted navigation systems, orthopaedic surgeons are now able to offer patients knee replacement procedures that are associated with (1) minimal risks during and after surgery by avoiding fat embolism, reducing blood loss and minimising soft tissue disruption; (2) smaller incisions; (3) faster and less painful rehabilitation; (4) reduced hospital stay and faster return to normal activities of daily living; (5) an improved range of motion; (6) less requirement for analgesics; and (7) a durable, well-aligned, highly functional knee. With the ongoing advancements in surgical technique, medical technology and prosthesis design, knee replacement surgery is constantly evolving. This review provides a personal account of the recent innovations that have been made, with a particular emphasis on the potential use of MIS techniques combined with computer-assisted navigation systems to treat younger, more physically active patients with resurfacing partial/total implant knee arthroplasty

Mapping Human Whole-Brain Structural Networks with Diffusion MRI

Understanding the large-scale structural network formed by neurons is a major challenge in system neuroscience. A detailed connectivity map covering the entire brain would therefore be of great value. Based on diffusion MRI, we propose an efficient methodology to generate large, comprehensive and individual white matter connectional datasets of the living or dead, human or animal brain. This non-invasive tool enables us to study the basic and potentially complex network properties of the entire brain. For two human subjects we find that their individual brain networks have an exponential node degree distribution and that their global organization is in the form of a small world