A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic

Background Understanding how complex antibiotics are synthesised by their producer bacteria is essential for creation of new families of bioactive compounds. Thiomarinols, produced by marine bacteria belonging to the genus Pseudoalteromonas, are hybrids of two independently active species: the pseudomonic acid mixture, mupirocin, which is used clinically against MRSA, and the pyrrothine core of holomycin. Methodology/Principal Findings High throughput DNA sequencing of the complete genome of the producer bacterium revealed a novel 97 kb plasmid, pTML1, consisting almost entirely of two distinct gene clusters. Targeted gene knockouts confirmed the role of these clusters in biosynthesis of the two separate components, pseudomonic acid and the pyrrothine, and identified a putative amide synthetase that joins them together. Feeding mupirocin to a mutant unable to make the endogenous pseudomonic acid created a novel hybrid with the pyrrothine via “mutasynthesis” that allows inhibition of mupirocin-resistant isoleucyl-tRNA synthetase, the mupirocin target. A mutant defective in pyrrothine biosynthesis was also able to incorporate alternative amine substrates. Conclusions/Significance Plasmid pTML1 provides a paradigm for combining independent antibiotic biosynthetic pathways or using mutasynthesis to develop a new family of hybrid derivatives that may extend the effective use of mupirocin against MRSA

Effects of short-term treatment with atorvastatin in smokers with asthma - a randomized controlled trial

<b>Background</b> The immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control in smokers with asthma.<p></p> <b>Methods</b> Seventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 ug per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation.<p></p> <b>Results</b> At 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow [-10.67 L/min, 95% CI -38.70 to 17.37, p=0.449], but there was an improvement with atorvastatin in asthma quality of life score [0.52, 95% CI 0.17 to 0.87 p=0.005]. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks.<p></p> <b>Conclusions</b> Short-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma. Clinicaltrials.gov identifier: NCT0046382

Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study

<p>Background: Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.</p> <p>Methods and Findings: The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p<0.001) than men (2.3: 2.0–2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p<0.001) in men and 2.7 (2.2–3.4, p<0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.</p> <p>Conclusions: Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.</p&gt

Efficient calculation of two-dimensional periodic and waveguide acoustic Green’s functions

New representations and efficient calculation methods are derived for the problem of propagation from an infinite regularly spaced array of coherent line sources above a homogeneous impedance plane, and for the Green's function for sound propagation in the canyon formed by two infinitely high, parallel rigid or sound soft walls and an impedance ground surface. The infinite sum of source contributions is replaced by a finite sum and the remainder is expressed as a Laplace-type integral. A pole subtraction technique is used to remove poles in the integrand which lie near the path of integration, obtaining a smooth integrand, more suitable for numerical integration, and a specific numerical integration method is proposed. Numerical experiments show highly accurate results across the frequency spectrum for a range of ground surface types. It is expected that the methods proposed will prove useful in boundary element modeling of noise propagation in canyon streets and in ducts, and for problems of scattering by periodic surfaces

“Cautiously Optimistic” Older Parent-Carers of Adults with Intellectual Disabilities response to the Care Act 2014

This paper discusses potential opportunities for best practice in the UK that may be brought about by the Care Act (2014). Carers in the UK were given new rights within this legislation with a focus on needs led assessment. The underpinning philosophy of the Care Act is to streamline previous legislation and offer a framework for carers and people in receipt of care, to enable a more personalised approach to care and support

Contemporary Risk of Hip Fracture in Type 1 and Type 2 Diabetes:A National Registry Study From Scotland

The purpose of this study was to compare contemporary risk of hip fracture in type 1 and type 2 diabetes with the nondiabetic population. Using a national diabetes database, we identified those with type 1 and type 2 diabetes who were aged 20 to 84 years and alive anytime from January 1, 2005 to December 31, 2007. All hospitalized events for hip fracture in 2005 to 2007 for diabetes patients were linked and compared with general population counts. Age- and calendar-year-adjusted incidence rate ratios were calculated by diabetes type and sex. One hundred five hip fractures occurred in 21,033 people (59,585 person-years) with type 1 diabetes; 1421 in 180,841 people (462,120 person-years) with type 2 diabetes; and 11,733 hip fractures over 10,980,599 person-years in the nondiabetic population (3.66 million people). Those with type 1 diabetes had substantially elevated risks of hip fracture compared with the general population incidence risk ratio (IRR) of 3.28 (95% confidence interval [CI] 2.52–4.26) in men and 3.54 (CI 2.75–4.57) in women. The IRR was greater at younger ages, but absolute risk difference was greatest at older ages. In type 2 diabetes, there was no elevation in risk among men (IRR 0.97 [CI 0.92–1.02]) and the increase in risk in women was small (IRR 1.05 [CI 1.01–1.10]). There remains a substantial elevation relative risk of hip fracture in people with type 1 diabetes, but the relative risk is much lower than in earlier studies. In contrast, there is currently little elevation in overall hip fracture risk with type 2 diabetes, but this may mask elevations in risk in particular subgroups of type 2 diabetes patients with different body mass indexes, diabetes duration, or drug exposure

Emerging therapies for severe asthma

Many patients with asthma have poorly controlled symptoms, and particularly for those with severe disease, there is a clear need for improved treatments. Two recent therapies licensed for use in asthma are omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, and bronchial thermoplasty, which involves the delivery of radio frequency energy to the airways to reduce airway smooth muscle mass. In addition, there are new therapies under development for asthma that have good potential to reach the clinic in the next five years. These include biological agents targeting pro-inflammatory cytokines such as interleukin-5 and interleukin-13, inhaled ultra long-acting β2-agonists and once daily inhaled corticosteroids. In addition, drugs that block components of the arachidonic acid pathway that targets neutrophilic asthma and CRTH2 receptor antagonists that inhibit the proinflammatory actions of prostaglandin D2 may become available. We review the recent progress made in developing viable therapies for severe asthma and briefly discuss the idea that development of novel therapies for asthma is likely to increasingly involve the assessment of genotypic and/or phenotypic factors