Patients with paroxysmal nocturnal hemoglobinuria demonstrate a prothrombotic clotting phenotype which is improved by complement inhibition with eculizumab

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement‐mediated intravascular hemolysis and thrombosis. The increased incidence of PNH‐driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement‐mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to significantly reduce the number of thromboembolic events in these patients. Based on previously described links between changes in fibrin clot structure and thrombosis in other disorders, our aim was to investigate clot structure as a possible mechanism of thrombosis in patients with PNH and the anti‐thrombotic effects of eculizumab treatment on clot structure. Clot structure, fibrinogen levels and thrombin generation were examined in plasma samples from 82 patients from the National PNH Service in Leeds, UK. Untreated PNH patients were found to have increased levels of fibrinogen and thrombin generation, with subsequent prothrombotic changes in clot structure. No link was found between increasing disease severity and fibrinogen levels, thrombin generation, clot formation or structure. However, eculizumab treated patients showed decreased fibrinogen levels, thrombin generation and clot density, with increasing time spent on treatment augmenting these antithrombotic effects. These data suggest that PNH patients have a prothrombotic clot phenotype due to increased fibrinogen levels and thrombin generation, and that the antithrombotic effects of eculizumab are, in‐part, due to reductions in fibrinogen and thrombin generation with downstream effects on clot structure

Next generation spindles for micromilling.

There exists a wide variety of important applications for micro- and meso-scale mechanical systems in the commercial and defense sectors, which require high-strength materials and complex geometries that cannot be produced using current MEMS fabrication technologies. Micromilling has great potential to fill this void in MEMS technology by adding the capability of free form machining of complex 3D shapes from a wide variety and combination of traditional, well-understood engineering alloys, glasses and ceramics. Inefficiencies in micromilling result from the relationships between a cutting tool's breaking strength, the applied cutting force, and the metal removal rate. Because machining times in mesofeatures scale inversely to the part size, a feature 1/10th as large will take 10 times as long to machine. Also, required chip sizes of 1 m or less are cut with tools having edge radius of 2-3 m, the cutting edge effectively has a highly negative rake angle, cutting forces are increased significantly causing chip loads to be further reduced and the machining takes even longer than predicted above. However, cutting forces do not increase with cutting speed, so faster spindles with reduced tool runout are the path to achieve efficient mesoscale milling. This research explored the development of new ultra-high speed micromilling spindles. A novel air-bearing spindle design is discussed that will run at very high speeds (450,000 rpm) and provide very minimal runout allowing the best use of micromilling cutters and reducing overall machining time drastically. Two generations of this spindle design were completed; one with an air bearing supported tool shaft and one with a novel rolling element bearing supported tool shaft. Both designs utilized friction-drive systems that relied on diameter differences between the drive wheel (operating at speeds up to 90,000 rpm) and the tool shaft to achieve high rotational tool speeds. Runout, stiffness, and machining tests were conducted with the spindle designs and though they both showed promise for ultra-high speed machining, runout issues in the friction drive and in the stock tools kept the system from achieving sustained machining capability

Systematic review of mass media interventions designed to improve public recognition of stroke symptoms, emergency response and early treatment

<p>Abstract</p> <p>Background</p> <p>Mass media interventions have been implemented to improve emergency response to stroke given the emergence of effective acute treatments, but their impact is unclear.</p> <p>Methods</p> <p>Systematic review of mass media interventions aimed at improving emergency response to stroke, with narrative synthesis and review of intervention development.</p> <p>Results</p> <p>Ten studies were included (six targeted the public, four both public and professionals) published between 1992 and 2010. Only three were controlled before and after studies, and only one had reported how the intervention was developed. Campaigns aimed only at the public reported significant increase in awareness of symptoms/signs, but little impact on awareness of need for emergency response. Of the two controlled before and after studies, one reported no impact on those over 65 years, the age group at increased risk of stroke and most likely to witness a stroke, and the other found a significant increase in awareness of two or more warning signs of stroke in the same group post-intervention. One campaign targeted at public and professionals did not reduce time to presentation at hospital to within two hours, but increased and sustained thrombolysis rates. This suggests the campaign had a primary impact on professionals and improved the way that services for stroke were organised.</p> <p>Conclusions</p> <p>Campaigns aimed at the public may raise awareness of symptoms/signs of stroke, but have limited impact on behaviour. Campaigns aimed at both public and professionals may have more impact on professionals than the public. New campaigns should follow the principles of good design and be robustly evaluated.</p

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

The molecular basis of polysaccharide cleavage by lytic polysaccharide monooxygenases.

Lytic polysaccharide monooxygenases (LPMOs) are copper-containing enzymes that oxidatively break down recalcitrant polysaccharides such as cellulose and chitin. Since their discovery, LPMOs have become integral factors in the industrial utilization of biomass, especially in the sustainable generation of cellulosic bioethanol. We report here a structural determination of an LPMO-oligosaccharide complex, yielding detailed insights into the mechanism of action of these enzymes. Using a combination of structure and electron paramagnetic resonance spectroscopy, we reveal the means by which LPMOs interact with saccharide substrates. We further uncover electronic and structural features of the enzyme active site, showing how LPMOs orchestrate the reaction of oxygen with polysaccharide chains.We thank K. Rasmussen and R.M. Borup for experimental assistance, and MAXLAB, Sweden and the European Synchrotron Radiation Facility (ESRF), France, for synchrotron beam time and assistance. This work was supported by the UK Biotechnology and Biological Sciences Research Council (grant numbers BB/L000423 to P.D., G.J.D. and P.H.W., and BB/L021633/1 to G.J.D. and P.H.W.), Agence Française de l'Environnement et de la Maîtrise de l'Energie (grant number 1201C102 to B.H.), the Danish Council for Strategic Research (grant numbers 12-134923 to L.L.L. and 12-134922 to K.S.J.). Travel to synchrotrons was supported by the Danish Ministry of Higher Education and Science through the Instrument Center DANSCATT and the European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement 283570). L.M., S.F., S.C. and H.D. were supported by Institut de Chimie Moléculaire de Grenoble FR 2607, LabEx ARCANE (ANR-11-LABX-0003-01), the PolyNat Carnot Institute and the French Agence Nationale de la Recherche (PNRB2005-11).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nchembio.202

Equity in healthcare for coronary heart disease, Wales (UK) 2004–2010: A population-based electronic cohort study

Despite substantial falls in coronary heart disease (CHD) mortality in the United Kingdom (UK), marked socioeconomic inequalities in CHD risk factors and CHD mortality persist. We investigated whether inequity in CHD healthcare in Wales (UK) could contribute to the observed social gradient in CHD mortality. Linking data from primary and secondary care we constructed an electronic cohort of individuals (n = 1199342) with six year follow-up, 2004–2010. We identified indications for recommended CHD interventions, measured time to their delivery, and estimated risk of receiving the interventions for each of five ordered deprivation groups using a time-to-event approach with Cox regression frailty models. Interventions in primary and secondary prevention included risk-factor measurement, smoking management, statins and antihypertensive therapy, and in established CHD included medication and revascularization. For primary prevention, five of the 11 models favoured the more deprived and one favoured the less deprived. For medication in secondary prevention and established CHD, one of the 15 models favoured the more deprived and one the less deprived. In relation to revascularization, six of the 12 models favoured the less deprived and none favoured the more deprived–this evidence of inequity exemplified by a hazard ratio for revascularization in stable angina of 0.79 (95% confidence interval 0.68, 0.92). The main study limitation is the possibility of under-ascertainment or misclassification of clinical indications and treatment from variability in coding. Primary care components of CHD healthcare were equitably delivered. Evidence of inequity was found for revascularization procedures, although this inequity is likely to have only a modest effect on social gradients in CHD mortality. Policymakers should focus on reducing inequalities in CHD risk factors, particularly smoking, as these, rather than inequity in healthcare, are likely to be key drivers of inequalities in CHD mortality

Mass extinctions drove increased global faunal cosmopolitanism on the supercontinent Pangaea

Mass extinctions have profoundly impacted the evolution of life through not only reducing taxonomic diversity but also reshaping ecosystems and biogeographic patterns. In particular, they are considered to have driven increased biogeographic cosmopolitanism, but quantitative tests of this hypothesis are rare and have not explicitly incorporated information on evolutionary relationships. Here we quantify faunal cosmopolitanism using a phylogenetic network approach for 891 terrestrial vertebrate species spanning the late Permian through Early Jurassic. This key interval witnessed the Permian–Triassic and Triassic–Jurassic mass extinctions, the onset of fragmentation of the supercontinent Pangaea, and the origins of dinosaurs and many modern vertebrate groups. Our results recover significant increases in global faunal cosmopolitanism following both mass extinctions, driven mainly by new, widespread taxa, leading to homogenous ‘disaster faunas’. Cosmopolitanism subsequently declines in post-recovery communities. These shared patterns in both biotic crises suggest that mass extinctions have predictable influences on animal distribution and may shed light on biodiversity loss in extant ecosystems

Efficacy of AZM therapy in patients with gingival overgrowth induced by Cyclosporine A: a systematic review

<p>Abstract</p> <p>Background</p> <p>In daily clinical practice of a dental department it's common to find gingival overgrowth (GO) in periodontal patients under treatment with Cyclosporine A (CsA). The pathogenesis of GO and the mechanism of action of Azithromycin (AZM) are unclear. A systematic review was conducted in order to evaluate the efficacy of Azithromycin in patients with gingival overgrowth induced by assumption of Cyclosporine A.</p> <p>Methods</p> <p>A bibliographic search was performed using the online databases MEDLINE, EMBASE and Cochrane Central of Register Controlled Trials (CENTRAL) in the time period between 1966 and September 2008.</p> <p>Results</p> <p>The literature search retrieved 24 articles; only 5 were Randomised Controlled Trials (RCTs), published in English, fulfilled the inclusion criteria. A great heterogeneity between proposed treatments and outcomes was found, and this did not allow to conduct a quantitative meta-analysis. The systematic review revealed that a 5-day course of Azithromycin with Scaling and Root Planing reduces the degree of gingival overgrowth, while a 7-day course of metronidazole is only effective on concomitant bacterial over-infection.</p> <p>Conclusion</p> <p>Few RCTs on the efficacy of systemic antibiotic therapy in case of GO were found in the literature review. A systemic antibiotic therapy without plaque and calculus removal is not able to reduce gingival overgrowth. The great heterogeneity of diagnostic data and outcomes is due to the lack of precise diagnostic methods and protocols about GO. Future studies need to improve both diagnostic methods and tools and adequate classification aimed to determine a correct prognosis and an appropriate therapy for gingival overgrowth.</p