Exchange anisotropy pinning of a standing spin wave mode

Standing spin waves in a thin film are used as sensitive probes of interface pinning induced by an antiferromagnet through exchange anisotropy. Using coplanar waveguide ferromagnetic resonance, pinning of the lowest energy spin wave thickness mode in Ni(80)Fe(20)/Ir(25)Mn(75) exchange biased bilayers was studied for a range of IrMn thicknesses. We show that pinning of the standing mode can be used to amplify, relative to the fundamental resonance, frequency shifts associated with exchange bias. The shifts provide a unique `fingerprint' of the exchange bias and can be interpreted in terms of an effective ferromagnetic film thickness and ferromagnet/antiferromagnet interface anisotropy. Thermal effects are studied for ultra-thin antiferromagnetic Ir(25)Mn(75) thicknesses, and the onset of bias is correlated with changes in the pinning fields. The pinning strength magnitude is found to grow with cooling of the sample, while the effective ferromagnetic film thickness simultaneously decreases. These results suggest that exchange bias involves some deformation of magnetic order in the interface region.Comment: 7 pages, 7 figure

Citizens who inject drugs: the 'Fitpack' study

Most injecting drug users have never been in drug treatment yet much research is done on samples with high treatment rates drawn from agency and peer recruited populations. This study accessed drug injectors with little or no prior drug treatment, described their characteristics, BBVI risk behaviours and feedback on services. Its results challenge some stereotypes about citizens who inject drugs. A sample of 511 'hidden' drug injectors, of whom only 28.7% had any specialist drug treatment agency contact, completed a questionnaire which was distributed with 'Fitpack' needle packs sold through community pharmacies in WA. The mean age of respondents was 26.2 years, 43.4% were women, 44.3% were living with their sexual partner, 41.7% were parents, and 46.4% were employed, mostly in full time work. In the previous month 61.2% had injected less frequently than daily. The study accessed a diverse group of drug injectors not typically seen in agency and peer recruited research. They provided useful feedback about how harm reduction strategies among injectors can be improved. However, they also reported higher rates of injecting and sharing than previously found in traditionally recruited samples of injectors which suggests there is no room for complacency regarding the potential for BBVI transmission in this grou

Advances in Alzheimer therapy: understanding pharmacological approaches to the disease

Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy"

The effectiveness of multifactorial and multicomponent interventions for the prevention of falls for adults in hospital settings: a systematic review and meta-analysis.

The objective of this systematic review and meta-analysis was to evaluate the effectiveness of multicomponent and multifactorial interventions for reducing falls in adult in-patients. Falls are the most common cause of accidental injury in hospitals worldwide, resulting in high human and economic costs. In attempts to reduce the number of falls, a wide range of interventions have been employed, often in combination, either as a package (multicomponent) or tailored to the individual (multifactorial). There is a need to synthesise the findings from primary studies and assess which approach may be more effective. The systematic review included studies comprising adult inpatients aged 18 years and over from any hospital setting including elective, non-elective, day-case and secondary care. Randomized controlled trials (RCT), cluster-randomised trials, quasi-experimental controlled trials and historical controlled trials were included that presented sufficient information regarding the rate or number of falls. This effectiveness review was conducted in accordance with JBI methodology and was guided by an a priori protocol. A comprehensive 3-step search strategy was employed across 14 databases. Screening was conducted by two independent reviewers, and data was extracted using a bespoke data extraction tool designed for this review. Methodological quality was assessed using adapted versions of JBI critical appraisal checklists. Meta-analyses were conducted within a Bayesian framework to interpret results probabilistically and account for covariance in multiple sets of falls data reported in the same study. Effect sizes were calculated by comparing the rate or number of falls in the intervention group compared with usual care. Narrative syntheses were conducted on studies that met the inclusion criteria but did not provide sufficient data for inclusion in meta-analyses. A total of 9,637 records were obtained and following screening 24 studies were included in this review, 21 of which presented sufficient information to be included in meta-analyses. Most studies (n=16) comprised a weaker historical control design with 6 quasi-experimental and only 5 RCT studies. Multifactorial interventions were more common (n=18) than multicomponent (n=6), with the most frequent components including environmental adaptations and assistive aids (75% of studies). Meta-analyses provided evidence that both intervention types were effective at reducing the rate and risk of falls compared to usual care. Evidence was also obtained of greater reductions in rate and risk of falls with multicomponent interventions, however, analyses were potentially confounded by an association between intervention type and study design. Falls interventions routinely employed in hospitals can substantially reduce falls, however, no evidence was obtained in support of tailoring interventions to individual risk factors. Future high-quality RCTs are required that directly compare multicomponent and multifactorial interventions

Lessons from a BACE1 inhibitor trial: off-site but not off base

Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future

Preoperative Kidney Function linked to mortality and readmission outcomes at Day 90 and 30 in Older Emergency Surgical Patients

Grants were received from British Geriatric Society and The Renal Association to support Louis EvansPeer reviewedPublisher PD

The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo