bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of Pulse Repetition Frequency Adjustment for 3‐ and 4‐Dimensional Power Doppler Quantification
Authors: Miyague Andre H. , Pavan Theo Z. , Soares Carlos A. , De Catte Luc , Nastri Carolina O. , Welsh Alec W. , Martins Wellington P.
Published: November 2015

Objectives

To determine the influence of the pulse repetition frequency (PRF) and wall motion filter on the 3‐dimensional (3D) power Doppler vascularization‐flow index (VFI) and volumetric pulsatility index (PI) obtained from spatiotemporal image correlation (STIC) data sets acquired from a common carotid artery of a healthy participant.

Methods

We acquired 11 STIC data sets, 1 for each PRF value ranging from 0.6 to 9.0 kHz. Vascularization‐flow index and volumetric PI values were determined from the 440 static 3D data sets contained in these STIC data sets. Additionally, 3 sets of radio‐frequency data were acquired for offline processing of different wall motion filter values for PRF values of 0.6, 3.3, and 10 kHz.

Results

We constructed VFI curves and observed 2 patterns: a flattened pattern with a low PRF and a triphasic pattern with a high PRF, correlating with the known pulsed wave Doppler profile of this vessel. Volumetric PI values were around 0 for low PRF settings and increased with increasing PRF. Analysis of the radiofrequency data showed that increasing wall motion filter values gradually filtered out the low‐velocity power Doppler signals while retaining the higher‐velocity ones, allowing the distinction of integrated power Doppler signal velocity throughout the cardiac cycle.

Conclusions

We conclude that the PRF and wall motion filter dramatically influence 3D power Doppler indices and the volumetric PI, and the use of PRF values in which minimum VFI values are measured during the diastolic phase in the spectral Doppler wave may validate the use of the volumetric PI.
Sonographic Quantification of Pronator Quadratus Activity During Gripping Effort
Authors: Shin Won-Jeong , Kim Jong-Pil , Kim Jeong-Sang , Park Hee-Jung
Published: November 2015

Objectives

The aim of this study was to obtain quantitative data related to the activity of each head of the pronator quadratus based on dynamic sonographic parameters during gripping effort and to assess their relationships with grip and pronation strengths.

Methods

The forearms of 33 healthy volunteers were evaluated at 5 positions of axial rotation (full supination, 45° supination, neutral, 45° pronation, and full pronation). Echogenic intensity ratios and muscle thicknesses of each head of the pronator quadratus were measured from transverse cross‐sectional sonograms obtained during maximal grip and release. Grip strengths and maximal isokinetic pronation torques at 90°/s and 360°/s were evaluated as strength parameters and correlated with sonographic measures.

Results

Echogenic intensity ratios of both heads significantly decreased during power grip (P≤ .002). Changes in echogenic intensity ratios of the superficial head were greater when the forearm was pronated compared to supination (P< .001), whereas changes in echogenic intensity ratios of the deep head were constant at all forearm positions. Muscle thicknesses of the superficial head maximally increased at the neutral position during power grip (P< .001), whereas muscle thicknesses of the deep head did not change. There were significant negative correlations between grip strength and echogenic intensity ratios of both heads at all respective forearm positions (P ≤ .048). Pronation torque was significantly correlated with echogenic intensity ratios of the superficial head at all forearm positions and the deep head at 45° and full pronation positions (P ≤ .034).

Conclusions

The data revealed that the superficial head of the pronator quadratus more actively contracts when the forearm is in pronation, whereas the deep head constantly contracts at all positions. This study suggests that both heads of the pronator quadratus also play a role in grip strength, but the superficial head contributes more to pronation strength.
Off-label use of mirtazapine for anxiety
Authors: Begert John , Bradley Bridget
Published: November 2015

Introduction

Currently, mirtazapine is only approved for use in patients with major depressive disorder, yet the unique dual mechanism of action for this agent has led many to inquire about potential alternative uses. The purpose of this article is to review the evidence available and evaluate the efficacy and tolerability of mirtazapine for use in patients presenting with various forms of anxiety.

Methods

A search of the medical literature using Ovid Medline and the search terms “mirtazapine” and “anxiety disorders” resulted in the identification of 12 trials and 1 meta-analysis investigating off-label mirtazapine use in various subsets of anxiety.

Results

Upon review of the literature, mirtazapine was found to perform significantly better than placebo at controlling symptoms of anxiety with comorbid depression, post-traumatic stress disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder; and with comparable efficacy, in some cases with significantly better response rates, to more current standard treatments such as tricyclic antidepressants and selective serotonin reuptake inhibitors.

Discussion

The observed efficacy of mirtazapine in these trials for the various forms of anxiety and the relatively small side-effect profile warrant consideration for further research into this alternative indication as another option for the treatment of symptoms of anxiety.
Unusually large tsunamis frequent a currently creeping part of the Aleutian megathrust
Authors: Witter Robert C. , Carver Gary A. , Briggs Richard W. , Gelfenbaum Guy , Koehler Richard D. , La Selle SeanPaul , Bender Adrian M. , Engelhart Simon E. , Hemphill‐Haley Eileen , Hill Troy D.
Published: November 2015

Current models used to assess earthquake and tsunami hazards are inadequate where creep dominates a subduction megathrust. Here we report geological evidence for large tsunamis, occurring on average every 300–340 years, near the source areas of the 1946 and 1957 Aleutian tsunamis. These areas bookend a postulated seismic gap over 200 km long where modern geodetic measurements indicate that the megathrust is currently creeping. At Sedanka Island, evidence for large tsunamis includes six sand sheets that blanket a lowland facing the Pacific Ocean, rise to 15 m above mean sea level, contain marine diatoms, cap terraces, adjoin evidence for scour, and date from the past 1700 years. The youngest sheet and modern drift logs found as far as 800 m inland and >18 m elevation likely record the 1957 tsunami. Previously unrecognized tsunami sources coexist with a presently creeping megathrust along this part of the Aleutian Subduction Zone.
Two possible source regions for central Greenland last glacial dust
Authors: Újvári Gábor , Stevens Thomas , Svensson Anders , Klötzli Urs S. , Manning Christina , Németh Tibor , Kovács János , Sweeney Mark R. , Gocke Martina , Wiesenberg Guido L. B. , Markovic Slobodan B. , Zech Michael
Published: November 2015

Dust in Greenland ice cores is used to reconstruct the activity of dust‐emitting regions and atmospheric circulation. However, the source of dust material to Greenland over the last glacial period is the subject of considerable uncertainty. Here we use new clay mineral and <10 µm Sr–Nd isotopic data from a range of Northern Hemisphere loess deposits in possible source regions alongside existing isotopic data to show that these methods cannot discriminate between two competing hypothetical origins for Greenland dust: an East Asian and/or central European source. In contrast, Hf isotopes (<10 µm fraction) of loess samples show considerable differences between the potential source regions. We attribute this to a first‐order clay mineralogy dependence of Hf isotopic signatures in the finest silt/clay fractions, due to absence of zircons. As zircons would also be absent in Greenland dust, this provides a new way to discriminate between hypotheses for Greenland dust sources.
Obliquity‐driven expansion of North Atlantic sea ice during the last glacial
Authors: Turney Chris S. M. , Thomas Zoë A. , Hutchinson David K. , Bradshaw Corey J. A. , Brook Barry W. , England Matthew H. , Fogwill Christopher J. , Jones Richard T. , Palmer Jonathan , Hughen Konrad A. , Cooper Alan
Published: November 2015

North Atlantic late Pleistocene climate (60,000 to 11,650 years ago) was characterized by abrupt and extreme millennial duration oscillations known as Dansgaard‐Oeschger (D‐O) events. However, during the Last Glacial Maximum (LGM) 23,000 to 19,000 cal years ago (23 to 19 ka), no D‐O events are observed in the Greenland ice cores. Our new analysis of the Greenland δ18O record reveals a switch in the stability of the climate system around 30 ka, suggesting that a critical threshold was passed. Climate system modeling suggests that low axial obliquity at this time caused vastly expanded sea ice in the Labrador Sea, shifting Northern Hemisphere westerly winds south and reducing the strength of meridional overturning circulation. The results suggest that these feedbacks tipped the climate system into full glacial conditions, leading to maximum continental ice growth during the LGM.
Static stress drop in the Mw 9 Tohoku‐oki earthquake: Heterogeneous distribution and low average value
Authors: Brown Lonn , Wang Kelin , Sun Tianhaozhe
Published: November 2015

Static stress drop distribution and its average value over the rupture area contain important information on the mechanics of large earthquakes. Here we derive static stress drop distributions from 40 published rupture models for the 2011 Mw 9 Tohoku‐oki earthquake that are based on various multidisciplinary observations. Average stress drop value over the fault area encompassed by the 5 m coseismic slip contour is not unusually large for each rupture model; the mean for the 40 models is 2.3 ± 1.3 MPa, assuming a uniform rigidity 40 GPa. The value for the entire rupture zone and with a more realistic rigidity structure will be even lower. In the majority of the models, local stress drop in parts of the rupture zone well exceeds 20 MPa. The heterogeneous stress change distribution, with large stress drop being accompanied by large stress increase, leads to the small average for the earthquake.
Deep‐sea coral δ13C: A tool to reconstruct the difference between seawater pH and δ11B‐derived calcifying fluid pH
Authors: Martin Patrick , Goodkin Nathalie F. , Stewart Joseph A. , Foster Gavin L. , Sikes Elisabeth L. , White Helen K. , Hennige Sebastian , Roberts J. Murray
Published: November 2015

The boron isotopic composition (δ11B) of coral skeleton is a proxy for seawater pH. However, δ11B‐based pH estimates must account for the pH difference between seawater and the coral calcifying fluid, ΔpH. We report that skeletal δ11B and ΔpH are related to the skeletal carbon isotopic composition (δ13C) in four genera of deep‐sea corals collected across a natural pH range of 7.89–8.09, with ΔpH related to δ13C by ΔpH = 0.029 × δ13C + 0.929, r2 = 0.717. Seawater pH can be reconstructed by determining ΔpH from δ13C and subtracting it from the δ11B‐derived calcifying fluid pH. The uncertainty for reconstructions is ±0.12 pH units (2 standard deviations) if estimated from regression prediction intervals or between ±0.04 and ±0.06 pH units if estimated from confidence intervals. Our new approach quantifies and corrects for vital effects, offering improved accuracy relative to an existing δ11B versus seawater pH calibration with deep‐sea scleractinian corals.
Mapping geoelectric fields during magnetic storms: Synthetic analysis of empirical United States impedances
Authors: Bedrosian Paul A. , Love Jeffrey J.
Published: November 2015

Empirical impedance tensors obtained from EarthScope magnetotelluric data at sites distributed across the midwestern United States are used to examine the feasibility of mapping magnetic storm induction of geoelectric fields. With these tensors, in order to isolate the effects of Earth conductivity structure, we perform a synthetic analysis—calculating geoelectric field variations induced by a geomagnetic field that is geographically uniform but varying sinusoidally with a chosen set of oscillation frequencies that are characteristic of magnetic storm variations. For north‐south oriented geomagnetic oscillations at a period of T0=100 s, induced geoelectric field vectors show substantial geographically distributed differences in amplitude (approximately a factor of 100), direction (up to 130∘), and phase (over a quarter wavelength). These differences are the result of three‐dimensional Earth conductivity structure, and they highlight a shortcoming of one‐dimensional conductivity models (and other synthetic models not derived from direct geophysical measurement) that are used in the evaluation of storm time geoelectric hazards for the electric power grid industry. A hypothetical extremely intense magnetic storm having 500 nT amplitude at T0=100 s would induce geoelectric fields with an average amplitude across the midwestern United States of about 2.71 V/km, but with a representative site‐to‐site range of 0.15 V/km to 16.77 V/km. Significant improvement in the evaluation of such hazards will require detailed knowledge of the Earth's interior three‐dimensional conductivity structure.
Influence of anthropogenic aerosol deposition on the relationship between oceanic productivity and warming
Authors: Wang Rong , Balkanski Yves , Bopp Laurent , Aumont Olivier , Boucher Olivier , Ciais Philippe , Gehlen Marion , Peñuelas Josep , Ethé Christian , Hauglustaine Didier , Li Bengang , Liu Junfeng , Zhou Feng , Tao Shu
Published: November 2015

Satellite data and models suggest that oceanic productivity is reduced in response to less nutrient supply under warming. In contrast, anthropogenic aerosols provide nutrients and exert a fertilizing effect, but its contribution to evolution of oceanic productivity is unknown. We simulate the response of oceanic biogeochemistry to anthropogenic aerosols deposition under varying climate from 1850 to 2010. We find a positive response of observed chlorophyll to deposition of anthropogenic aerosols. Our results suggest that anthropogenic aerosols reduce the sensitivity of oceanic productivity to warming from −15.2 ± 1.8 to −13.3 ± 1.6 Pg C yr−1 °C−1 in global stratified oceans during 1948–2007. The reducing percentage over the North Atlantic, North Pacific, and Indian Oceans reaches 40, 24, and 25%, respectively. We hypothesize that inevitable reduction of aerosol emissions in response to higher air quality standards in the future might accelerate the decline of oceanic productivity per unit warming.
The hydrological cycle response to cirrus cloud thinning
Authors: Kristjánsson Jón Egill , Muri Helene , Schmidt Hauke
Published: November 2015

Recent multimodel studies have shown that if one attempts to cancel increasing CO2 concentrations by reducing absorbed solar radiation, the hydrological cycle will weaken if global temperature is kept unchanged. Using a global climate model, we investigate the hydrological cycle response to “cirrus cloud thinning (CCT),” which is a proposed climate engineering technique that seeks to enhance outgoing longwave radiation. Investigations of the “fast response” in experiments with fixed sea surface temperatures reveal that CCT causes a significant enhancement of the latent heat flux and precipitation. This is due to enhanced radiative cooling of the troposphere, which is opposite to the effect of increased CO2 concentrations. By combining CCT with CO2 increase in multidecadal simulations with a slab ocean, we demonstrate a systematic enhancement of the hydrological cycle due to CCT. This leads to enhanced moisture availability in low‐latitude land regions and a strengthening of the Indian monsoon.
Convective and stratiform components of the precipitation‐moisture relationship
Authors: Ahmed Fiaz , Schumacher Courtney
Published: November 2015

We reexamine the well known empirical relationship between area‐averaged surface precipitation (P) and the column moisture content (r) using ground radar and satellite observations, with an emphasis on the convective and stratiform rainfall classifications. The rapid rise in P above critical r (rc) or the “pickup” is more pronounced for stratiform rainfall on hourly and less time scales while convective rainfall, displays only a weak pickup above rc. After partitioning the area‐averaged rainfall into conditional rain rates and rain area, we find that the nonlinearity in the P‐r curve can be almost entirely explained by the nonlinear increase in rain area, especially in stratiform regions. These findings have implications for the representation of organized convective cloud systems in global circulation models.
Attachment process in subsequent strokes and residual channel luminosity between strokes of natural lightning
Authors: Tran M. D. , Rakov V. A.
Published: November 2015

We examined high‐speed video and electric field records of 23 subsequent strokes following the previous stroke channel in three natural negative lightning flashes, which were obtained at the Lightning Observatory in Gainesville (LOG), Florida. Five strokes exhibited faintly luminous formations (FLFs) occurring in a single, pre‐return‐stroke frame and ranging from 130 to 908 m in length between the lower end of downward leader and the prospective strike point. The FLFs were inferred to be not streamers (as in first strokes) but manifestations of an increase in conduction current in the defunct channel between the leader and ground in response to the increasing electric field produced by the descending leader. Further, in eight strokes, we observed residual channel luminosity persisting over many frames (for 4.7 to 18 ms), through the pre‐return‐stroke frame. The residual luminosity was apparently associated with a stronger channel heating and a larger channel radius (and hence a lower temperature decay rate), both associated with the relatively long preceding continuing current. Presence of either FLF or residual channel luminosity did not appear to significantly influence the mode and velocity of propagation of the descending leader.
Lateral Wedge Insoles for Reducing Biomechanical Risk Factors for Medial Knee Osteoarthritis Progression: A Systematic Review and Meta‐Analysis
Authors: Arnold John B. , Wong Daniel X. , Jones Richard K. , Hill Catherine L. , Thewlis Dominic
Published: November 2015

Objective

Lateral wedge insoles are intended to reduce biomechanical risk factors of medial knee osteoarthritis (OA) progression, such as increased knee joint load; however, there has been no definitive consensus on this topic. The aim of this systematic review and meta‐analysis was to establish the within‐subject effects of lateral wedge insoles on knee joint load in people with medial knee OA during walking.

Methods

Six databases were searched from inception until February 13, 2015. Included studies reported on the immediate biomechanical effects of lateral wedge insoles during walking in people with medial knee OA. Primary outcomes of interest relating to the biomechanical risk of disease progression were the first and second peak external knee adduction moment (EKAM) and knee adduction angular impulse (KAAI). Eligible studies were pooled using random‐effects meta‐analysis.

Results

Eighteen studies were included with a total of 534 participants. Lateral wedge insoles resulted in a small but statistically significant reduction in the first peak EKAM (standardized mean difference [SMD] −0.19; 95% confidence interval [95% CI] −0.23, −0.15) and second peak EKAM (SMD −0.25; 95% CI −0.32, −0.19) with a low level of heterogeneity (I2 = 5% and 30%, respectively). There was a favorable but small reduction in the KAAI with lateral wedge insoles (SMD −0.14; 95% CI −0.21, −0.07, I2 = 31%). Risk of methodologic bias scores (quality index) ranged from 8 to 13 out of 16.

Conclusion

Lateral wedge insoles cause small reductions in the EKAM and KAAI during walking in people with medial knee OA. Current evidence demonstrates that lateral wedge insoles appear ineffective at attenuating structural changes in people with medial knee OA as a whole and may be better suited to targeted use in biomechanical phenotypes associated with larger reductions in knee load.
Exploring the Potential of Starch/Polycaprolactone Aligned Magnetic Responsive Scaffolds for Tendon Regeneration
Authors: Gonçalves Ana I. , Rodrigues Márcia T. , Carvalho Pedro P. , Bañobre‐López Manuel , Paz Elvira , Freitas Paulo , Gomes Manuela E.
Published: November 2015

The application of magnetic nanoparticles (MNPs) in tissue engineering (TE) approaches opens several new research possibilities in this field, enabling a new generation of multifunctional constructs for tissue regeneration. This study describes the development of sophisticated magnetic polymer scaffolds with aligned structural features aimed at applications in tendon tissue engineering (TTE). Tissue engineering magnetic scaffolds are prepared by incorporating iron oxide MNPs into a 3D structure of aligned SPCL (starch and polycaprolactone) fibers fabricated by rapid prototyping (RP) technology. The 3D architecture, composition, and magnetic properties are characterized. Furthermore, the effect of an externally applied magnetic field is investigated on the tenogenic differentiation of adipose stem cells (ASCs) cultured onto the developed magnetic scaffolds, demonstrating that ASCs undergo tenogenic differentiation synthesizing a Tenascin C and Collagen type I rich matrix under magneto‐stimulation conditions. Finally, the developed magnetic scaffolds were implanted in an ectopic rat model, evidencing good biocompatibility and integration within the surrounding tissues. Together, these results suggest that the effect of the magnetic aligned scaffolds structure combined with magnetic stimulation has a significant potential to impact the field of tendon tissue engineering toward the development of more efficient regeneration therapies.
Rhodium(III)‐Catalyzed Direct CH Olefination of Arenes with Aliphatic Olefins
Authors: Xue Xiao , Xu Jianbin , Zhang Lingjuan , Xu Conghui , Pan Yixiao , Xu Lijin , Li Huanrong , Zhang Weidong
Published: November 2015

A rhodium(III)‐catalyzed direct ortho CH bond olefination of arenes, including but not limited to benzamides, arylpyridines and indoles, with a variety of unactivated aliphatic olefins has been developed. In the presence of catalytic amounts of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer {[Cp*RhCl2]2}, copper(II) acetate monohydrate [Cu(OAc)2⋅H2O] and silver hexafluoroantimonate(V) (AgSbF6), the coupling reaction occurred efficiently to afford the ortho‐olefinated linear products in good to excellent yields with high regio‐ and stereoselectivities, and a range of functional groups in both coupling partners is compatible with the reaction conditions. This protocol relies on the use of directing groups, and the addition of AgSbF6 as additive is crucial for the catalysis. This new method expands the scope of rhodium(III)‐catalyzed direct CH bond olefination of arenes, and provides a rapid access to useful linear arylation products of unactivated olefins.

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Rotational Molding of Poly(lactic acid): Effect of Polymer Grade and Granulometry
Authors: Greco Antonio , Maffezzoli Alfonso
Published: November 2015

This paper is aimed at studying the effect of the grade and the granulometry of poly(lactic acid) (PLA) on its processability by rotational molding. Two PLA grades were considered: a low melt flow rate (MFR), high viscosity, material, characterized by an excellent quenchability, leading to a completely amorphous structure of rotomolded samples; a high MFR, low viscosity, material, characterized by a lower quenchability, leading to a semicrystalline structure of rotomolded samples. Three different granulometries were considered: a coarser one, that is, the pellets as received, intermediate size pellets produced by extrusion followed by pelletizing, and a powder obtained by grinding of as received pellets. Besides the different dimensions, the intermediate size pellets also experienced a supplementary extrusion step, which induced some degradation in the material. For both grades and three granulometries, void‐free prototypes were obtained, which indicate a very efficient sintering process, attributed to the low viscosity of all PLA grades. As a consequence, the modulus of the rotomolded samples was found to be unaffected by the PLA grade or granulometry. In contrast, the strength was shown to be more significantly dependent on quenchability than on the grade. To obtain an adequately high strength, an amorphous structure must be developed during cooling. Finally, the supplementary extrusion step experienced by the intermediate size pellets was shown to significantly decrease the strength of prototypes, as a consequence of the thermal degradation induced by this additional processing step.
Multigenerational autosomal dominant inheritance of 5p chromosomal deletions
Authors: Zhang Bin , Willing Marcia , Grange Dorothy K. , Shinawi Marwan , Manwaring Linda , Vineyard Marisa , Kulkarni Shashikant , Cottrell Catherine E.
Published: November 2015

Deletion of the short arm of chromosome 5 (5p‐) is associated with phenotypic features including a cat‐like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri‐du‐Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat‐like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra‐ and inter‐familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra‐familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype–phenotype correlations. © 2015 Wiley Periodicals, Inc.
Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome
Authors: Kantarci Orhun H. , Lebrun Christine , Siva Aksel , Keegan Mark B. , Azevedo Christina J. , Inglese Matilde , Tintoré Mar , Newton Braeden D. , Durand‐Dubief Francoise , Amato Maria Pia , De Stefano Nicola , Sormani Maria Pia , Pelletier Daniel , Okuda Darin T.
Published: November 2015

Objective

The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS).

Methods

A multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome [CIS] or relapsing‐remitting MS) and were also compared to two other population‐ and clinic‐based PPMS cohorts.

Results

Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow‐up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6–5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p < 0.001) when compared to CIS/MS, independent of follow‐up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow‐up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS.

Interpretation

Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age‐dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum. Ann Neurol 2016;79:288–294
Free fatty acid as an outcome predictor of atrial fibrillation–associated stroke
Authors: Choi Jeong‐Yoon , Jung Jin‐Man , Kwon Do‐Young , Park Moon Ho , Kim Ji Hyun , Oh Kyungmi , Koh Seong‐Beom , Seo Woo‐Keun
Published: November 2015

Objective

We investigated whether baseline plasma free fatty acid (FFA) concentration is associated with any (ischemic/hemorrhagic) stroke, ischemic stroke/systemic embolism (ISSE), or ischemic stroke among stroke survivors with atrial fibrillation (A‐fib). Moreover, we compared the outcome predictability of FFA with previously adopted models, including the CHADS2 and CHA2DS2‐VASc scoring systems.

Methods

We analyzed data from 279 stroke patients with A‐fib and investigated the association between plasma FFA concentration and outcomes using Cox regression models with competing risk analyses.

Results

Median follow‐up period was 17.5 months. During the study period, any stroke, ISSE, and ischemic stroke occurred in 22, 21, and 17 patients, respectively. The cumulative risk for any stroke, ISSE, and ischemic stroke were 5.1%, 4.7%, and 4.2% at the end of the first year and 14.8%, 12.1%, and 10.8% at the end of the third year, respectively. After adjusting covariates (model 1), baseline FFA concentration was associated with recurrence of any stroke (hazard ratio [HR] = 1.774, 95% confidence interval [CI] = 1.124–2.801, per 1mEq/l increment of FFA). FFA showed a trend association with ISSE (HR = 1.569, 95% CI = 0.950–2.592) and ischemic stroke (HR = 1.630, 95% CI = 0.967–2.746). In adjusted models including CHADS2 or CHA2DS2‐VASc score as a covariate, (models 2 and 3) FFA was still shown to be an independent predictor of any stroke and ischemic stroke. There was a significant or trend association between FFA and ISSE.

Interpretation

FFA may be a potential biomarker that predicts outcome events in stroke with A‐fib along with the CHADS2 and CHA2DS2‐VASc scoring systems. Ann Neurol 2016;79:317–325
A Catalyst Designed for the Enantioselective Construction of Methyl‐ and Alkyl‐Substituted Tertiary Stereocenters
Authors: Claraz Aurélie , Sahoo Gokarneswar , Berta Dénes , Madarász Ádám , Pápai Imre , Pihko Petri M.
Published: November 2015

Tertiary methyl‐substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama–Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three‐parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α‐methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4–C13 segment of (−)‐bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.
Enantioselective Synthesis of 3a‐Amino‐Pyrroloindolines by Copper‐Catalyzed Direct Asymmetric Dearomative Amination of Tryptamines
Authors: Liu Chuan , Yi Ji‐Cheng , Zheng Zhong‐Bo , Tang Yong , Dai Li‐Xin , You Shu‐Li
Published: November 2015

A direct asymmetric dearomative amination of tryptamines with O‐(2,4‐dinitrophenyl)hydroxylamine (DPH) was achieved using CuBr‐bisoxazoline complex as a catalyst, affording 3a‐amino‐pyrroloindolines in good to excellent enantioselectivity under mild reaction conditions. Furthermore, the synthetic value of this method was demonstrated in the total synthesis of (−)‐psychotriasine in a highly concise manner.
Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior
Authors: Driscoll Clare , Chanalaris Anastasios , Knights Chancie , Ismail Heba , Sacitharan Pradeep K. , Gentry Clive , Bevan Stuart , Vincent Tonia L.
Published: November 2015

Objective

Pain is the most common symptom of osteoarthritis (OA), yet where it originates in the joint and how it is driven are unknown. The aim of this study was to identify pain‐sensitizing molecules that are regulated in the joint when mice subjected to surgical joint destabilization develop OA‐related pain behavior, the tissues in which these molecules are being regulated, and the factors that control their regulation.

Methods

Ten‐week‐old mice underwent sham surgery, partial meniscectomy, or surgical destabilization of the medial meniscus (DMM). Pain‐related behavior as determined by a variety of methods (testing of responses to von Frey filaments, cold plate testing for cold sensitivity, analgesiometry, incapacitance testing, and forced flexion testing) was assessed weekly. Once pain‐related behavior was established, RNA was extracted from either whole joints or microdissected tissue samples (articular cartilage, meniscus, and bone). Reverse transcription–polymerase chain reaction analysis was performed to analyze the expression of 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature hips from wild‐type or genetically modified mice or by explanting articular cartilage from porcine joints preinjected with pharmacologic inhibitors. Levels of nerve growth factor (NGF) protein were measured by enzyme‐linked immunosorbent assay.

Results

Mice developed pain‐related behavior 8 weeks after undergoing partial meniscectomy or 12 weeks after undergoing DMM. NGF, bradykinin receptors B1 and B2, tachykinin, and tachykinin receptor 1 were significantly regulated in the joints of mice displaying pain‐related behavior. Little regulation of inflammatory cytokines, leukocyte activation markers, or chemokines was observed. When tissue samples from articular cartilage, meniscus, and bone were analyzed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage, although there were some differences between the 2 models. NGF and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a transforming growth factor β–activated kinase 1–, fibroblast growth factor 2–, and Src kinase–dependent manner.

Conclusion

Damaged joint tissues produce proalgesic molecules, including NGF, in murine OA.
RETRACTION: Long noncoding RNA linc‐ITGB1 promotes cell migration and invasion in human breast cancer
Authors: Yan Meidi , Zhang Lina , Li Guoqing , Xiao Shengwen , Dai Ji , Cen Xueying
Published: November 2015

RETRACTION: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer‐related death in women globally. Its high morbidity and mortality, as well as its elevated tendency to metastasize to other organs, warrant the urgency to find new biomarkers for breast cancer diagnosis and treatment. The specific roles of long noncoding RNA linc‐ITGB1 on cell proliferation and metastasis in breast cancer were explored in this study. The expression of linc‐ITGB1 was significantly upregulated in both clinical breast cancer tissues and cultured breast cancer cell lines. The linc‐ITGB1 knockdown with specific short hairpin RNA (shRNA) decreased cell proliferation and colony formation in vitro. Tumor growth in vivo was also inhibited by linc‐ITGB1 depletion. In addition, linc‐ITGB1 depletion caused cell accumulation in the G0/G1 phase. Breast cancer cell lines with linc‐ITGB1 depletion exhibited decreased migration and invasion abilities compared with the control cells. Furthermore, the linc‐ITGB1 knockdown decreased the expression of mesenchymal markers N‐cadherin and vimentin while increasing the expression of the epithelial marker E‐cadherin. Key cell cycle regulators Cdc25C and Cyclin B1 were also decreased by the linc‐ITGB1 knockdown. These data suggest that linc‐ITGB1 promotes breast cancer progression by inducing cell cycle arrest and interrupting the epithelial‐to‐mesenchymal transition process.
Cell‐Like Nanostructured Environments Alter Diffusion and Reaction Kinetics in Cell‐Free Gene Expression
Authors: Hansen Maike M. K. , Paffenholz Sabine , Foschepoth David , Heus Hans A. , Thiele Julian , Huck Wilhelm T. S.
Published: November 2015

In highly crowded and viscous intracellular environments, the kinetics of complex enzymatic reactions are determined by both reaction and diffusion rates. However in vitro studies on transcription and translation often fail to take into account the density of the prokaryotic cytoplasm. Here we mimic the cellular environment by using a porous hydrogel matrix, to study the effects of macromolecular crowding on gene expression. We found that within microgels gene expression is localized, transcription is enhanced up to fivefold, and translation is enhanced up to fourfold. Our results highlight the need to consider the role of the physical environment on complex biochemical reactions, in this case macromolecular crowding, nanoscale spatial organization, and confinement.
Subtypes of firesetters
Authors: Dalhuisen Lydia , Koenraadt Frans , Liem Marieke
Published: November 2015

Background

Prior research has classified firesetters by motive. The multi‐trajectory theory of adult firesetting (M‐TTAF) takes a more aetiological perspective, differentiating between five hypothesised trajectories towards firesetting: antisocial cognition, grievance, fire interest, emotionally expressive/need for recognition and multifaceted trajectories.

Aim

The objective of this study was to validate the five routes to firesetting as proposed in the M‐TTAF.

Methods

All 389 adult firesetters referred for forensic mental health assessment to one central clinic in the Netherlands between 1950 and 2012 were rated on variables linked to the M‐TTAF. Cluster analysis was then applied.

Results

A reliable cluster solution emerged revealing five subtypes of firesetters – labelled instrumental, reward, multi‐problem, disturbed relationship and disordered. Significant differences were observed regarding both offender and offence characteristics.

Discussion

Our five‐cluster solution with five subtypes of firesetters partially validates the proposed M‐TTAF trajectories and suggests that for offenders with and without mental disorder, this classification may be useful. If further validated with larger and more diverse samples, the M‐TTAF could provide guidance on staging evidence‐based treatment. Copyright © 2015 John Wiley & Sons, Ltd.
Patent ductus arteriosus balloon sizing: A new technique to evaluate the size in complex cases
Authors: Butera Gianfranco , Lovin Nicusor , Basile Domenica Paola
Published: November 2015

Patent ductus arteriosus (PDA) transcatheter closure is a widespread procedure. However in some cases PDA measurements may be unclear and choice of the proper device could be quite difficult. This may happen in large PDA and in particular in adults. We have developed a new technique using an ASD sizing balloon to measure the PDA in order to better understand PDA anatomy and size. The first step is to create an artero‐venous circuit across the PDA. A 24 or a 34 mm Amplatzer balloon sizing for ASD closure is placed over the wire from the venous access in the descending aorta. Then, the balloon is inflated and gently pulled back across the PDA toward the pulmonary artery. The frame where the balloon is exactly across the PDA is chosen and measurements performed. In conclusion, a new method for PDA measurement in large PDA is reported. The procedure is safe and reliable. © 2015 Wiley Periodicals, Inc.
Organocatalytic Asymmetric Conjugate Additions to Cyclopent‐1‐enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core
Authors: Bernardi Luca , Fochi Mariafrancesca , Carbone Riccardo , Martinelli Ada , Fox Martin E. , Cobley Christopher J. , Kandagatla Bhaskar , Oruganti Srinivas , Dahanukar Vilas H. , Carlone Armando
Published: November 2015

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α‐amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent‐1‐enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona‐derived phase‐transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol % in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost‐effective preparation of pharmaceuticals.
Metal‐Directed Self‐Assembly of a Polyoxometalate‐Based Molecular Triangle: Using Powerful Analytical Tools to Probe the Chemical Structure of Complex Supramolecular Assemblies
Authors: Izzet Guillaume , Macdonell Andrew , Rinfray Corentin , Piot Madeleine , Renaudineau Séverine , Derat Etienne , Abécassis Benjamin , Afonso Carlos , Proust Anna
Published: November 2015

A polyoxometalate‐based molecular triangle has been synthesized through the metal‐driven self‐assembly of covalent organic/inorganic hybrid oxo‐clusters with remote pyridyl binding sites. The new metallomacrocycle was unambiguously characterized by using a combination of 1H NMR spectroscopy, 2D diffusion NMR spectroscopy (DOSY), electrospray ionization travelling wave ion mobility mass spectrometry (ESI‐TWIM‐MS), small‐angle X‐ray scattering (SAXS) and molecular modelling. The collision cross‐sections obtained from TWIM‐MS and the hydrodynamic radii derived from DOSY are in good agreement with the geometry‐optimized structures obtained by using theoretical calculations. Furthermore, SAXS was successfully employed and proved to be a powerful technique for characterizing such large supramolecular assemblies.
Diazo Strategy for the Synthesis of Pyridazines: Pivotal Impact of the Configuration of the Diazo Precursor on the Process
Authors: Nikolaev Valerij A. , Cantillo David , Kappe C. Oliver , Medvedev Jury J. , Prakash G. K. Surya. , Supurgibekov Murat B.
Published: November 2015

Phosphazenes of vinyldiazocarbonyl compounds having cis stereochemistry of the functional groups on the vinyl bond readily produce pyridazines by a diaza‐Wittig process, whereas their counterparts with trans configuration remain intact under similar reaction conditions. Upon UV irradiation trans‐phosphazenes furnish pyridazines through a tandem trans‐to‐cis isomerization followed by intramolecular cyclization. At elevated temperatures trans‐(triphenyl)phosphazenes dissociate to give the initial vinyldiazo compounds, which produce pyrazoles in high yields. The first theoretical study on the mechanism of the diaza‐Wittig process by DFT calculations at the M06‐2X/6‐31G(d) level of theory suggest that for the cis‐phosphazenes a rapid tandem [2+2] cycloaddition/cycloelimination process with low energy barriers is preferred over trans isomers.
Carboranes as a Tool to Tune Phosphorescence
Authors: Li Xiang , Yan Hong , Zhao Qiang
Published: November 2015

Phosphorescent transition‐metal complexes (PTMCs) have attracted great interest because of their excellent properties which may lead to promising applications in optoelectronics. In recent years, carboranes have been demonstrated to be a novel and effective tool to tune phosphorescence of PTMCs. This Concept article deals with the advances of carborane‐functionalized PTMCs for potential optical applications. The discussions are focused on the design strategies and synthetic procedures leading to carborane‐functionalized PTMCs, the influence of carboranes on the optical properties of PTMCs, and the promising optical applications of this interesting class of phosphorescent materials.
Scalable Synthesis of Efficient Water Oxidation Catalysts: Insights into the Activity of Flame‐Made Manganese Oxide Nanocrystals
Authors: Liu Guanyu , Hall Jeremy , Nasiri Noushin , Gengenbach Thomas , Spiccia Leone , Cheah Mun Hon , Tricoli Antonio
Published: November 2015

Chemical energy storage by water splitting is a promising solution for the utilization of renewable energy in numerous currently impracticable needs, such as transportation and high temperature processing. Here, the synthesis of efficient ultra‐fine Mn3O4 water oxidation catalysts with tunable specific surface area is demonstrated by a scalable one‐step flame‐synthesis process. The water oxidation performance of these flame‐made structures is compared with pure Mn2O3 and Mn5O8, obtained by post‐calcination of as‐prepared Mn3O4 (115 m2 g−1), and commercial iso‐structural polymorphs, probing the effect of the manganese oxidation state and synthetic route. The structural properties of the manganese oxide nanoparticles were investigated by XRD, FTIR, high‐resolution TEM, and XPS. It is found that these flame‐made nanostructures have substantially higher activity, reaching up to 350 % higher surface‐specific turnover frequency (0.07 μmol
 m−2 s−1) than commercial nanocrystals (0.02 μmol
 m−2 s−1), and production of up to 0.33 mmol
 molMn−1 s−1. Electrochemical characterization confirmed the high water oxidation activity of these catalysts with an initial current density of 10 mA cm−2 achieved with overpotentials between 0.35 and 0.50 V in 1 m NaOH electrolyte.
Measurement of microvesicle levels in human blood using flow cytometry
Authors: Chandler Wayne L.
Published: November 2015

Microvesicles are fragments of cells released when the cells are activated, injured, or apoptotic. Analysis of microvesicle levels in blood has the potential to shed new light on the pathophysiology of many diseases. Flow cytometry is currently the only method that can simultaneously separate true lipid microvesicles from other microparticles in blood, determine the cell of origin and other microvesicle characteristics, and handle large numbers of clinical samples with a reasonable effort, but expanded use of flow cytometric measurement of microvesicle levels as a clinical and research tool requires improved, standardized assays. The goal of this review is to aid investigators in applying current best practices to microvesicle measurements. First pre‐analytical factors are evaluated and data summarized for anticoagulant effects, sample transport and centrifugation. Next flow cytometer optimization is reviewed including interference from background in buffers and reagents, accurate microvesicle counting, swarm interference, and other types of coincidence errors, size calibration, and detection limits using light scattering, impedance and fluorescence. Finally current progress on method standardization is discussed and a summary of current best practices provided. © 2016 Clinical Cytometry Society