The small quinolone derived compound HT61 enhances the effect of tobramycin against Pseudomonas aeruginosa in vitro and in vivo.

HT61 is a small quinolone-derived compound previously demonstrated to exhibit bactericidal activity against gram-positive bacteria including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). When combined with the classical antibiotics and antiseptics neomycin, gentamicin, mupirocin and chlorhexidine, HT61 demonstrated synergistic bactericidal activity against both MSSA and MRSA infections in vitro. In this study, we investigated the individual antimicrobial activity of HT61 alongside its capability to increase the efficacy of tobramycin against both a tobramycin sensitive laboratory reference strain (PAO1) and tobramycin resistant clinical isolates (RP73, NN2) of the gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa). Using broth microdilution methods, the MICs of HT61 against all strains were assessed, as well as the effect of HT61 in combination with tobramycin using both the chequerboard method and bacterial time-kill assays. A murine model of pulmonary infection was also used to evaluate the combination therapy of tobramycin and HT61 in vivo. In these studies, we demonstrated significant synergism between HT61 and Tobramycin against the tobramycin resistant P. aeruginosa strains RP73 and NN2, whilst an additive/intermediate effect was observed for P. aeruginosa strain PA01 which was further confirmed using bacterial time kill analysis. In addition, the enhancement of tobramycin by HT61 was also evident in in vitro assays of biofilm eradication. Finally, in vivo studies revealed analogous effects to those observed in vitro with HT61 when administered in combination with tobramycin against each of the three P. aeruginosa strains at the highest tested dose (10 mg/kg)

What Courses Should Law Students Take? Harvard’s Largest Employers Weigh In

We report the results of an online survey, conducted on behalf of Harvard Law School, of 124 practicing attorneys at major law firms. The survey had two main objectives: (1) to assist students in selecting courses by providing them with data about the relative importance of courses; and (2) to provide faculty with information about how to improve the curriculum and best advise students. The most salient result is that students were strongly advised to study accounting and financial statement analysis, as well as corporate finance. These subject areas were viewed as particularly valuable, not only for corporate/transactional lawyers, but also for litigators. Intriguingly, non-traditional courses and skills, such as business strategy and teamwork, are seen as more important than many traditional courses and skills

Low-Earth-Orbit (LEO) Life Cycle Evaluation of Nickel-Zinc Batteries

The conclusion of the Low-Earth-Orbit (LEO) life cycle evaluation of nickel-zinc batteries are: that composite nickel electrode provide excellent performance at a reduced weight and lower cost; calcium / zinc electrode minimizes shape change; unioptimized cell designs yield 60 Wh/kg; nickel-zinc delivers 600 cycles at 80% DOD; long cycle life obtainable at low DOD; high rate capability power density; long-term failure mechanism is stack dry; and anomalous overcharge (1120%) greatly affected cell performance but did not induce failure and was recoverable

Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway

Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation

The Labour Government, the Treasury and the £6 pay policy of July 1975

The 1974-79 Labour Government was elected in a climate of opinion that was fiercely opposed to government intervention in the wage determination process, and was committed to the principles of free collective bargaining in its manifestoes. However, by December 1974 the Treasury was advocating a formal incomes policy, and by July 1975 the government had introduced a £6 flat rate pay norm. With reference to archival sources, the paper demonstrates that TUC and Labour Party opposition to incomes policy was reconciled with the Treasury's advocacy by limiting the Bank of England‟s intervention in the foreign exchange market when sterling came under pressure. This both helped to achieve the Treasury's objective of improving the competitiveness of British industry, and acted as a catalyst for the introduction of incomes policy because the slide could be attributed to a lack of market confidence in British counter-inflation policy

Examining the use of telehealth in community nursing: identifying the factors affecting frontline staff acceptance and telehealth adoption

Aims: To examine frontline staff acceptance of telehealth and identify barriers to and enablers of successful adoption of remote monitoring for patients with Chronic Obstructive Pulmonary Disease and Chronic Heart Failure. Background: The use of telehealth in the UK has not developed at the pace and scale anticipated by policy. Many existing studies report frontline staff acceptance as a key barrier, however data are limited and there is little evidence of the adoption of telehealth in routine practice. Design: Case studies of four community health services in England that use telehealth to monitor patients with Chronic Obstructive Pulmonary Disease and Chronic Heart Failure. Methods: Thematic analysis of qualitative interviews with 84 nursing and other frontline staff; and 21 managers and key stakeholders; data collected May 2012-June 2013. Findings: Staff attitudes ranged from resistance to enthusiasm, with varied opinions about the motives for investing in telehealth and the potential impact on nursing roles. Having reliable and flexible technology and dedicated resources for telehealth work were identified as essential in helping to overcome early barriers to acceptance, along with appropriate staff training and a partnership approach to implementation. Early successes were also important, encouraging staff to use telehealth and facilitating clinical learning and increased adoption. Conclusions: The mainstreaming of telehealth hinges on clinical 'buy-in'. Where barriers to successful implementation exist, clinicians can lose faith in using technology to perform tasks traditionally delivered in person. Addressing barriers is therefore crucial if clinicians are to adopt telehealth into routine practice

Inhibition of microbial sulfate reduction in a flow-through column system by (per)chlorate treatment.

Microbial sulfate reduction is a primary cause of oil reservoir souring. Here we show that amendment with chlorate or perchlorate [collectively (per)chlorate] potentially resolves this issue. Triplicate packed columns inoculated with marine sediment were flushed with coastal water amended with yeast extract and one of nitrate, chlorate, or perchlorate. Results showed that although sulfide production was dramatically reduced by all treatments, effluent sulfide was observed in the nitrate (10 mM) treatment after an initial inhibition period. In contrast, no effluent sulfide was observed with (per)chlorate (10 mM). Microbial community analyses indicated temporal community shifts and phylogenetic clustering by treatment. Nitrate addition stimulated Xanthomonadaceae and Rhizobiaceae growth, supporting their role in nitrate metabolism. (Per)chlorate showed distinct effects on microbial community structure compared with nitrate and resulted in a general suppression of the community relative to the untreated control combined with a significant decrease in sulfate reducing species abundance indicating specific toxicity. Furthermore, chlorate stimulated Pseudomonadaceae and Pseudoalteromonadaceae, members of which are known chlorate respirers, suggesting that chlorate may also control sulfidogenesis by biocompetitive exclusion of sulfate-reduction. Perchlorate addition stimulated Desulfobulbaceae and Desulfomonadaceae, which contain sulfide oxidizing and elemental sulfur-reducing species respectively, suggesting that effluent sulfide concentrations may be controlled through sulfur redox cycling in addition to toxicity and biocompetitive exclusion. Sulfur isotope analyses further support sulfur cycling in the columns, even when sulfide is not detected. This study indicates that (per)chlorate show great promise as inhibitors of sulfidogenesis in natural communities and provides insight into which organisms and respiratory processes are involved