bluuebunny/crossref_metadata_2025 huggingface dataset:
Dipeptidyl peptidase-4 inhibitor use is not associated with elevated risk of severe joint pain in patients with type 2 diabetes: a population-based cohort study
Authors: Hou Wen-Hsuan , Chang Kai-Cheng , Li Chung-Yi , Ou Huang-Tz
Published: April 2016

This is the first large longitudinal cohort study to investigate the putative association of severe joint pain (SJP) with dipeptidyl peptidase-4 inhibitor (DPP4i) use in patients with type 2 diabetes. The propensity score-matched population-based cohort study was performed between 2009 and 2013 in a group of type 2 diabetes patients with stable metformin use. In total, 4743 patients with type 2 diabetes used a DPP4i as the second-line antidiabetic drug (ie, DPP4i users), and the same number of matched non-DPP4i users was selected. The 2 study groups were followed up until SJP diagnosis (International Classification of Diseases, Ninth Reversion, Clinical Modification code 719.4), health insurance policy termination, or the end of 2013. The incidence rate of SJP was estimated under the Poisson assumption. Multiple Cox proportional hazard model was used to estimate the covariate-adjusted hazard ratio and 95% CI of SJP in association with DPP4i use. Over a maximum follow-up of 5 years, 679 DPP4i users and 767 non-DPP4i users were newly diagnosed with SJP, representing incidence rates of 47.20 and 50.66 per 1000 person-years, respectively. Cox proportional hazard model indicated that DPP4i use slightly but nonsignificantly reduced the risk of SJP (adjusted hazard ratio: 0.92 [95% CI: 0.83-1.02]). Such null results were also observed among all age and sex stratifications and in a sensitivity analysis using all nonspecific arthropathies as the study endpoint. This study provides no support for the putative risk of SJP related to DPP4i use in type 2 diabetes patients during a maximum follow-up of 5 years.
Osteochondral Allograft Transplantation in the Knee
Authors: Zouzias Ioannis C. , Bugbee William D.
Published: April 2016

The technique of osteochondral allograft (OCA) transplantation has been used to treat a wide spectrum of cartilage deficiencies in the knee. Its use has been supported by basic science and clinical studies that show it is a safe and effective treatment option. What sets fresh OCA transplantation apart from other cartilage procedures in the knee, is the ability to treat large defects with mature hyaline cartilage. Studies looking at transplantation of fresh OCAs in the general population have shown reliable pain relief and return to activities of daily living. Reports of cartilage injuries in athletes have risen over the years and more research is needed in evaluating the successfulness of OCA transplantation in the athletic population.
Autologous Chondrocyte Implantation: Past, Present, and Future
Authors: Welch Tyler , Mandelbaum Bert , Tom Minas
Published: April 2016

Focal cartilage defects of the knee are relatively common and may increase the risk of developing osteoarthritis. Autologous chondrocyte implantation (ACI) aims to restore the integrity of isolated cartilage lesions through the induction of hyaline-like cartilage formation. Although ACI has traditionally been used as a second-line treatment, recent evidence suggests that ACI should be considered as a first-line treatment option in certain patients. Recent controlled trials also suggest that there are improved clinical outcomes among those patients who undergo ACI over the mid-term and long-term compared with those treated with microfracture or osteochondral autograft/mosaicplasty, regardless of lesion size. Recent literature also indicates that arthroscopic, second-generation and third-generation techniques are associated with better outcomes and fewer complications than first-generation ACI. In summary, ACI is an effective tool for cartilage restoration that may be more efficacious and durable than other cartilage restoration techniques for appropriate candidates.
Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders
Authors: Chiang Mark Y. , Radojcic Vedran , Maillard Ivan
Published: April 2016

Purpose of review

This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses the therapeutic potential of Notch inhibition.

Recent findings

NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B-cell malignancies truncate the C-terminal proline (P), glutamic acid (E), serine (S), threonine (T)-rich (PEST) domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein–protein interactions at Notch-dependent superenhancers that underlie oncogenic Notch functions.

Notch signaling is a recurrent oncogenic pathway in multiple T- and B-cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.
Allergan Style 410 Implants for Breast Reconstruction: A Prospective Study in Efficacy, Safety, and Symmetry
Authors: Unger Jacob G. , Carreras Jennel M. , Nagarkar Purushottam , Jeong Haneol S. , Carpenter William
Published: April 2016

Background:

Implant-based breast reconstruction is performed with both saline and silicone. In 2001, a study was conducted in which a novel implant made of highly cohesive silicone gel in anatomical shape was used. It differs from others because it holds its anatomical shape and forces tissue to conform to the implant.

Methods:

Two hundred twelve consecutive patients who underwent reconstruction with Allergan 410 cohesive gel anatomical implants were enrolled prospectively over a 12-year period. Complications and satisfaction rates were recorded.

Results:

Average age of the patients was 48.5 years and average body mass index was 24.1 kg/m2. Bilateral reconstruction was performed in 83 percent of patients. Long-term follow-up was achieved in all patients and averaged 3.3 years (range, 0.5 to 10.2 years). The overall complication rate was 19.8 percent; most were minor complications, such as rippling (9.4 percent) and asymmetry (4.2 percent). Major complications included infection (2.4 percent), malposition (1.4 percent), capsular contracture (0.9 percent), seroma (0.5 percent), extrusion (0.5 percent), and implant rupture (0.5 percent). The rate of implant-related reoperation, excluding cancer recurrence, was 9.0 percent, consisting of implant replacement (5.7 percent), implant removal (1.9 percent), and implant repositioning (1.4 percent). Patient satisfaction averaged 4.83 (range, 2 to 5) on a five-point scale. Surgeon satisfaction averaged 4.9 (range, 2 to 5).

Conclusions:

Allergan 410 cohesive gel anatomical implants have a favorable risk profile in reconstruction, with excellent patient and surgeon satisfaction. This novel implant allows for a paradigm shift in implant-based breast reconstruction. Surgeons can now use an implant to help shape the final contour of the breast mound rather than rely on mastectomy flaps and suture techniques to create aesthetic contours needed to create an attractive breast reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Subcortical source and modulation of the narrowband gamma oscillation in mouse visual cortex
Authors: Saleem Aman B , Lien Anthony D , Krumin Michael , Haider Bilal , Rosón Miroslav Román , Ayaz Asli , Reinhold Kimberly , Busse Laura , Carandini Matteo , Harris Kenneth D
Published: April 2016

Primary visual cortex (V1) exhibits two types of gamma rhythm: broadband activity in the 30–90 Hz range, and a narrowband oscillation seen in mice at frequencies close to 60 Hz. We investigated the sources of the narrowband gamma oscillation, the factors modulating its strength, and its relationship to broadband gamma activity. Narrowband and broadband gamma power were uncorrelated. Increasing visual contrast had opposite effects on the two rhythms: it increased broadband activity, but suppressed the narrowband oscillation. The narrowband oscillation was strongest in layer 4, and was mediated primarily by excitatory currents entrained by the synchronous, rhythmic firing of neurons in the lateral geniculate nucleus (LGN). The power and peak frequency of the narrowband gamma oscillation increased with light intensity. Silencing the cortex optogenetically did not affect narrowband oscillation in either LGN firing or cortical excitatory currents, suggesting that this oscillation reflects unidirectional flow of signals from thalamus to cortex.

Highlights

•Local field potential in mouse primary visual cortex exhibits a pronounced narrowband gamma oscillation close to 60 Hz.

•Narrowband gamma is highest in the thalamorecipient layer 4

•Narrowband gamma increases with light intensity and arousal state, and is suppressed by visual contrast.

•Lateral geniculate nucleus neurons fire synchronously at the narrowband gamma frequency, independent of V1 activity.
Accurate classification of protein subcellular localization from high throughput microscopy images using deep learning
Authors: Pärnamaa Tanel , Parts Leopold
Published: April 2016

High throughput microscopy of many single cells generates high-dimensional data that are far from straightforward to analyze. One important problem is automatically detecting the cellular compartment where a fluorescently tagged protein resides, a task relatively simple for an experienced human, but difficult to automate on a computer. Here, we train an 11-layer neural network on data from mapping thousands of yeast proteins, achieving per cell localization classification accuracy of 91%, and per protein accuracy of 99% on held out images. We confirm that low-level network features correspond to basic image characteristics, while deeper layers separate localization classes. Using this network as a feature calculator, we train standard classifiers that assign proteins to previously unseen compartments after observing only a small number of training examples. Our results are the most accurate subcellular localization classifications to date, and demonstrate the usefulness of deep learning for high throughput microscopy.
Urbanization drives parallel adaptive clines in plant populations
Authors: Thompson Ken A. , Renaudin Marie , Johnson Marc T.J.
Published: April 2016

Urban areas are a new and increasingly dominant feature of terrestrial landscapes that dramatically alter environments. It is unclear whether wild populations can adapt to the unique challenges presented by urbanization. To address this problem, we sampled the frequency of a Mendelian-inherited trait—cyanogenesis—in white clover (Trifolium repensL.) plants along urbanization gradients in four large cities. Cyanogenesis protects plants from herbivores, but also reduces freezing tolerance. Plants evolved reduced cyanogenesis with increasing proximity to the urban center in three of the four cities. In an experiment, we demonstrate that gradients in herbivore pressure do not cause these clines. Instead, urban areas experience relatively cold minimum winter ground temperatures because of reduced snow cover within cities, which selects against cyanogenesis. Together, our study demonstrates that wild populations exhibit parallel adaptive evolution in response to urbanization, which likely facilitates the persistence of these plants and promotes pollinator abundance and diversity.
A qualitative model of the rod photoreceptor in natural context
Authors: Dubuc Timothée T. , Roesch Etienne B.
Published: April 2016

Given the intricacies of the retinal neural circuit, which bears a striking resemblance to that of the brain, it is proposed that retinal function goes beyond mere spatiotemporal prefiltering. We hypothesise that aspects related to motion detection and discrimination, anticipation and adaptation to environmental and contextual conditions, which have traditionally been ascribed to the brain, may be supported by neurons in the retina. Such early computations may be dependent on compensative and adaptive mechanisms that stem from qualities intrinsic to the retinal neural circuit and its interaction with the environment (neural transduction time, connectivity patterns, regularities in the input signal, temporal dynamics and light variations).

With a view to investigating the contribution of the photoreceptor population to the processing performed by the retina in natural scotopic conditions, we present a continuous model of the rod photoreceptor. Our model permits the reproduction and exploration of a set of qualitative features displayed in vitro, such as excitation-dependent activation level and time-to-membrane current integration. We captured qualitative aspects of key features selected for their presumed importance in early visual function. Further, we subjected our model to extensive parameter sensitivity analyses, aiming to provide a visual representation of their contribution to the observed qualitative behavior.

Author Summary

Primate rod photoreceptor cells constitute the very first processing step in retinal function. This layer influences most of the visual field and presents itself as a tightly packed photosensitive array. Yet, no computational formulation of this neuron is suited for large-scale, time continuous modeling. With a view to studying retinal function in natural contexts, we describe a qualitative, continuous model of the rod. We subject this model to parameter analyses against selected behavioral features. We aim to provide a model that can integrate in further experiments, as well as in large scale network simulation.
Shhand ZRS enhancer co-localisation is specific to the zone of polarizing activity
Authors: Williamson Iain , Lettice Laura A. , Hill Robert E. , Bickmore Wendy A.
Published: April 2016

Limb-specificShhexpression is regulated by the (~1 Mb distant) ZRS enhancer. In the mouse, limb bud restricted spatiotemporal expression ofShhoccurs from ~E10-E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation ofShhin expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies ofShh/ZRS co-localisation only in theShhexpressing regions of the limb bud. However,Shh-ZRS spatial distances were consistently shorter than intervening distances to a neural enhancer in all tissues and developmental stages analysed. 5C identified a topologically associating domain (TAD) over theShh/ZRS genomic region and enriched interactions betweenShhand ZRS throughout E11.5 embryos.Shh/ZRS co-localisation, therefore, correlates with the spatiotemporal domain of limb bud-specificShhexpression, but closeShh/ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigateShhexpression.
The mRNA-bound proteome of the early fly embryo
Authors: Wessels Hans-Hermann , Imami Koshi , Baltz Alexander G. , Kolinski Marcin , Beldovskaya Anastasia , Selbach Matthias , Small Stephen , Ohler Uwe , Landthaler Markus
Published: April 2016

Early embryogenesis is characterized by the maternal to zygotic transition (MZT), in which maternally deposited messenger RNAs are degraded while zygotic transcription begins. Before the MZT, post-transcriptional gene regulation by RNA-binding proteins (RBPs) is the dominant force in embryo patterning. We used two mRNA interactome capture methods to identify RBPs bound to polyadenylated transcripts within the first 2 h of Drosophila melanogaster embryogenesis. We identified a high-confidence set of 476 putative RBPs and confirmed RNA-binding activities for most of 24 tested candidates. Most proteins in the interactome are known RBPs or harbor canonical RBP features, but 99 exhibited previously uncharacterized RNA-binding activity. mRNA-bound RBPs and TFs exhibit distinct expression dynamics, in which the newly identified RBPs dominate the first 2 h of embryonic development. Integrating our resource with in situ hybridization data from existing databases showed that mRNAs encoding RBPs are enriched in posterior regions of the early embryo, suggesting their general importance in posterior patterning and germ cell maturation.
Hydrogen-bond-reversal symmetry and its violation in ice nanotubes
Authors: Kirov Mikhail V.
Published: April 2016

Recently, a new type of generalized symmetry of ice structures was introduced which takes into account the change of direction of all hydrogen bonds. The energy nonequivalence of pairs of configurations with opposite direction of all hydrogen bonds was established in the course of computer simulation of bilayer ice and other four-coordinated structures without `dangling' hydrogen atoms. In this article, the results of detailed investigations of the violation of the hydrogen-bond-reversal symmetry in ice nanotubes consisting of stackedn-membered rings are presented. A comprehensive classification of all possible hydrogen-bonding configurations and their division into two classes (antisymmetrical and non-antisymmetrical) are given. Attention is focused on the most stable configurations that have no longitudinally arranged water molecules. This restriction made the asymmetry very difficult to find. For example, it was established that the asymmetry (non-antisymmetrical configurations) in ice nanotubes with square, pentagonal and hexagonal cross sections appears only when the number of transverse rings in the unit cell is more than six. It is shown that this is related to the well known combinatorial problem of enumerating the symmetry-distinct necklaces of black and white beads. It was found that, among the ice nanotubes that had been considered, hydrogen-bond-reversal asymmetry is most conspicuous in wide nanotubes such as heptagonal and octagonal. In this case the asymmetry is observed for unit cells of any length. In order to verify the results of the symmetry analysis and to confirm the energy nonequivalence of some (non-antisymmetrical) configurations, approximate calculations of the binding energy have been performed using the packageTINKER.
Chlorido{(E)-1-[(2-methoxyphenyl)diazenyl]naphthalen-2-olato}palladium(II)
Authors: Mili Assia , Chetioui Souheyla , Rouag Djamil-Azzeddine , Djukic Jean-Pierre , Bailly Corinne
Published: April 2016

In the title complex, [Pd(C17H13N2O2)Cl], the PdIIatom is tetracoordinated by an N and two O atoms of an (E)-1-[(2-methoxyphenyl)diazenyl]naphthalen-2-olate ligand and by a Cl atom, and has a square-planar coordination. In the crystal, molecules are linked by pairs of C—H...Cl hydrogen bonds, forming inversion dimers. The dimers are linkedviaoffset π–π interactions [intercentroid distance = 3.546 (3) Å], forming chains running parallel to [100].
1,3,6-Tribromo-9-ethyl-9H-carbazole
Authors: Bezuglyi Mkola , Bagdziunas Gintautas , Grazulevicius Juozas Vidas
Published: April 2016

In the title compound, C14H10Br3N, the carbazole ring system is almost planar, with an r.m.s. deviation of 0.023 Å from the best fit mean plane of the 13 non-H atoms of the three rings. The methyl C atom lies 1.232 (3) Å out of this plane. No hydrogen bonds are found in the crystal structure but weak C—Br...π contacts at approximately 3.721 Å may stabilize the structure.
Boards attributes that increase firm risk – evidence from the UK
Authors: Mathew Sudha , Ibrahim Salma , Archbold Stuart
Published: April 2016

Purpose

The purpose of this paper is to identify the board attributes that significantly increase firm risk. The study aims to find whether board size, percentage of non-executive directors, women on the board, a powerful chief executive officer, equity ownership amongst executive board directors and institutional investor ownership are associated with firm risk. This is the first study that examines which board attributes increase firm risk using a UK-based sample.

Design/methodology/approach

This empirical study collected secondary data from Bloomberg and Morningstar databases. The data sample is an unbalanced panel of 260 companies’ secondary data on FTSE 350 index in the UK, from 2005 to 2010. The data were statistically analysed using STATA.

Findings

The study establishes the board attributes that were significantly related to firm risk. The results show that a board which can increase firm risk is one that is small in size, has high equity ownership amongst executive board directors and has high institutional investor ownership.

Research limitations/implications

The governance culture and regulatory system in the UK is different from other countries. As the data are a UK-based sample, the results can lack generalisability.

Practical implications

The results are useful for investors who invest in large firms, to have the knowledge about the board attributes that can increase firm risk. Regulators can also use the results to strengthen regulatory guidelines.

Originality/value

This study fills the gap in knowledge in UK governance literature on the board attributes that can increase firm risk.
TDAS: a touch dynamics based multi-factor authentication solution for mobile devices
Authors: Teh Pin Shen , Zhang Ning , Teoh Andrew Beng Jin , Chen Ke
Published: April 2016

Purpose

The use of mobile devices in handling our daily activities that involve the storage or access of sensitive data (e.g. on-line banking, paperless prescription services, etc.) is becoming very common. These mobile electronic services typically use a knowledge-based authentication method to authenticate a user (claimed identity). However, this authentication method is vulnerable to several security attacks. To counter the attacks and to make the authentication process more secure, this paper aims to investigate the use of touch dynamics biometrics in conjunction with a personal identification number (PIN)-based authentication method, and demonstrate its benefits in terms of strengthening the security of authentication services for mobile devices.

Design/methodology/approach

The investigation has made use of three light-weighted matching functions and a comprehensive reference data set collected from 150 subjects.

Findings

The investigative results show that, with this multi-factor authentication approach, even when the PIN is exposed, as much as nine out of ten impersonation attempts can be successfully identified. It has also been discovered that the accuracy performance can be increased by combining different feature data types and by increasing the input string length.

Originality/value

The novel contributions of this paper are twofold. Firstly, it describes how a comprehensive experiment is set up to collect touch dynamics biometrics data, and the set of collected data is being made publically available, which may facilitate further research in the problem domain. Secondly, the paper demonstrates how the data set may be used to strengthen the protection of resources that are accessible via mobile devices.
Midstream social marketing intervention to influence retailers’ compliance with the minimum legal drinking age law
Authors: Kamin Tanja , Kokole Daša
Published: April 2016

Purpose

Alcohol availability is strongly related to excessive alcohol consumption. This study aims to examine social marketing’s response to concerns about retailers’ noncompliance with the minimum legal drinking age (MLDA) law by proposing and evaluating a social marketing intervention directed at sellers in off-premise stores.

Design/methodology/approach

The study is based on a non-randomized quasi-experimental design, focusing on an evaluation of the implementation of the “18 rules!” intervention in four cities in Slovenia. Two waves of underage purchase attempts were conducted pre- and post-intervention in 24 off-premise businesses, following a mystery shopping protocol.

Findings

The initial rate of retailers’ noncompliance with the MLDA law in off-premise establishments was high. After the social marketing intervention, an increase with compliance with the law was observed; the proportion of cashiers selling alcohol to minors after the intervention decreased from 96 to 67 per cent. Qualitative insight suggests an existence of retailers’ dilemma in complying with the MLDA.

Research limitations/implications

A social marketing approach could contribute to a better understanding of the social working of the MLDA law.

Practical implications

A social marketing approach could complement the usual enforcement strategies and contribute to a better understanding of the social working of the MLDA law, and encourage deliberate retailers’ compliance with it while developing valuable exchanges among people and stakeholders.

Originality/value

The paper conceptualizes retailers’ dilemma in complying with the minimal legal drinking age law and offers social marketing response to it. Results of the study show that also solely non-coercive measures have the potential in increasing retailers’ compliance with regulations.
Leaf traits of African woody savanna species across climate and soil fertility gradients: evidence for conservative versus acquisitive resource‐use strategies
Authors: Wigley Benjamin J. , Slingsby Jasper A. , Díaz Sandra , Bond William J. , Fritz Hervé , Coetsee Corli
Published: April 2016

Establishing trade‐offs among traits and the degree to which they covary along environmental gradients has become a key focal point in the effort to develop community ecology into a predictive science. While there is evidence for these relationships across global data sets, they are often too broad in scale and do not consider the particularities of local to regional species pools. This decreases their usefulness for developing predictive models at scales relevant for conservation and management.

We tested for trade‐offs between traits and relationships with environmental gradients in trees and shrubs sampled across southern African savannas and explored evidence for acquisitive versus conservative resource‐use strategies using a phylogenetically explicit approach.

We found a distinct trade‐off between two major poles of specialization indicative of acquisitive (high leaf nitrogen concentration, leaf phosphorus concentration, leaf N:P, specific leaf area and average leaf area) and conservative resource‐use strategies (high leaf carbon to nitrogen ratios (C:N), tensile strength and leaf dry matter content). Although we found that trait variance and species occurrence were constrained by phylogeny, phylogenetically informed analyses did not contradict non‐phylogenetic analyses, strengthening relationships in most cases.

The high intrasite trait variability and weak relationships with soils and climate may in part be explained by the high levels of deciduousness and disturbance (i.e. fire and herbivory) inherent in African savannas.

Synthesis. The relationships between traits and between traits and environmental gradients were far weaker than, and often contradictory to, broad‐scale studies that compare these relationships across biomes and growth forms, cautioning against making generalizations about relationships at specific sites based on broad‐scale analyses.
Managing five paradoxes of knowledge exchange in networked organizations: new priorities for HRM?
Authors: Mabey Christopher , Zhao Shasha
Published: April 2016

The life‐blood of most organizations is knowledge. Too often, the very mechanisms set up to facilitate knowledge flow militate against it. This is because they are instituted in a top‐down way, they are cumbersome to manage and the bridges of trust fail to get built. In their thirst for innovation, the tendency is for firms to set up elaborate transmission channels and governance systems. As a result, staff are drowned in a deluge of mundane intranet messages and bewildered by matrix structures, while off‐the‐wall ideas and mould‐breaking insights are routinely missed. Added to this is the challenge of operating across professional, cultural, regional and linguistic boundaries, where ways of sharing knowledge differ markedly, even within the same project team. Drawing upon extensive research with scientists in the ATLAS collaboration (a high‐energy particle physics experiment comprising 3,500 scientists from 38 countries), we explore five paradoxes associated with knowledge exchange in global networks. Each paradox leads to a proposition which takes the theory and practice of knowledge management in a fresh direction. We conclude by outlining a number of HRM priorities for international knowledge‐intensive organizations.
Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?
Authors: Gur Serap , Peak Taylor , Yafi Faysal A. , Kadowitz Philip J. , Sikka Suresh C. , Hellstrom Wayne J.G.
Published: April 2016

Objective

To examine the effects of mirabegron, a selective β3‐adrenoceptor agonist that has recently been approved for the treatment of overactive bladder (OAB), on erectile function. Stimulation of β3‐adrenoceptors localised in cavernosal smooth muscle cells may play a physiological role in mediating penile erection, and offer a beneficial pharmacological action for patients who have OAB and erectile dysfunction (ED).

Materials and Methods

Corpus cavernosal (CC) specimens were obtained from patients with ED and Peyronie's disease undergoing penile prosthesis implantation. Erectile responses were also evaluated in vivo after intracavernosal injection (ICI) of mirabegron in anaesthetised rats. Mirabegron‐elicited relaxation responses (10–8–10–3 m) on phenylephrine‐induced contraction were seen in human CC (HCC) and rat CC strips in isolated organ‐bath studies. The effects of inhibitors, namely L‐NAME [NG‐nitro‐L‐arginine methyl ester, a competitive inhibitor of nitric oxide synthase (NOS), 100 μm], ODQ [1H‐(1,2,4) oxadiazolo(4,3‐α) quinoxalin‐1‐one, a soluble guanylyl cyclase (sGC) inhibitor, 30μm], methylene blue (a NOS and sGC inhibitor, 20μm), SR59230A (β3‐adrenoceptor blocker, 1 μm), and fasudil [Rho‐associated protein kinase (ROCK) inhibitor, 0.1 μm], on mirabegron‐induced relaxation responses were evaluated. Responses to mirabegron were compared with responses to isoprenaline and nebivolol. Immunohistochemistry was used to localise β3‐adrenoceptors and ROCK in CC smooth muscle cells. In vivo rat data were expressed as intracavernosal pressure (ICP)/mean arterial pressure, and total ICP.

Results

Mirabegron resulted in a relaxation of phenylephrine‐evoked CC contractions in a concentration‐dependent manner and SR59230A antagonised the mirabegron‐induced relaxations in HCC and rat CC. Other inhibitors, L‐NAME, ODQ, and methylene blue, did not affect the mirabegron‐induced relaxation responses. Mirabegron relaxation responses at concentrations (0.1–10 μm) were enhanced by fasudil (ROCK inhibitor) in rat but not in HCC strips. KCl‐induced contractions in HCC and rat CC were partially inhibited by mirabegron. In vivo, ICI of mirabegron (doses of 0.1–1 mg/kg) had a minor effect on ICP when compared with vehicle administration. Immunohistochemistry data showed β3‐adrenoceptors localised in the smooth muscle cells of the HCC and rat CC.

Conclusions

Mirabegron markedly relaxed isolated CC strips by activating β3‐adrenoceptors independently of the NO‐cGMP pathway. There is also evidence of the existence of a close functional link between β3‐adrenoceptors and the RhoA/ROCK pathway. These results may support further clinical studies using combinations of mirabegron with ROCK and phosphodiesterase type 5 inhibitors (PDE5i) for the treatment of ED, especially in patients who do not respond to PDE5i therapy.
Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30‐week randomized placebo‐controlled study
Authors: Hackett Geoffrey , Cole Nigel , Saghir Atif , Jones Peter , Strange Richards C. , Ramachandran Sudarshan
Published: April 2016

Objective

To evaluate the sexual function response to 30 weeks’ treatment with long‐acting testosterone undecanoate (TU) or placebo in 199 men with type 2 diabetes and either severe or mild hypogonadism (HG).

Patients and Methods

Men with HG were identified from seven primary care type 2 diabetes registers. A 30‐week randomized placebo‐controlled study of TU was carried out in 199 of these men (placebo, n = 107, TU, n = 92). The patient‐reported outcome measure was the 15‐item International Index of Erectile Function score. Men completing the study (n=189) were stratified, firstly, by baseline total testosterone (TT) or free testosterone (FT) into mild HG (TT 8.1–12 nmol/L or FT 0.18–0.25 nmol/L) and severe HG groups (TT ≤8 nmol/L and FT ≤0.18 nmol/L), and secondly, by intervention (placebo or TU), thereby creating four groups: mild HG/placebo; mild HG/TU; severe HG/placebo and severe HG/TU.

Statistical Analysis

Changes in sexual function score (a secondary outcome of the study) at each visit within group (from baseline) and between groups (TU vs placebo) at each assessment (6, 18 and 30 weeks) were compared using a Wilcoxon signed‐rank and Wilcoxon rank‐sum test, respectively.

Results

Significant improvement in erectile function was evident only in the severe HG group after 30 weeks of TU treatment; this finding persisted when TU was compared with placebo. Intercourse satisfaction and sexual desire scores were also improved at 6, 18 and 30 weeks in the severe HG group after TU treatment; this increase in scores was also evident when compared with placebo. TU did not appear to alter orgasmic function significantly in any of the patient groups.

Conclusions

The present study suggests that benefit in sexual symptoms after TU treatment is evident principally in patients with HG with TT levels ≤8 nmol/L and FT levels ≤0.18 nmol/L. We also suggest that 30 weeks of treatment is necessary before evaluating improvement in erectile function.
Reconstruction of an Extensive Midfacial Defect Using Additive Manufacturing Techniques
Authors: Fernandes Nelson , van den Heever Jacobus , Hoogendijk Christiaan , Botha Sarel , Booysen Gerrie , Els Johan
Published: April 2016

Malignant peripheral nerve sheath tumors are extremely rare tumors arising in peripheral nerves. Only 17 cases involving the trigeminal nerve have ever been reported. These tumors have a very poor prognosis and very high rates of recurrence and metastases. Their recommended treatment involves complete tumor resection followed by radiation. This can be problematic in the head and neck region. We present a clinical case involving a 33‐year‐old female patient presenting with a slow‐growing, exophytic mass of the anterior maxilla. Incisional biopsy and subsequent histological examination revealed a diagnosis of a malignant peripheral nerve sheath tumor. Surgical resection involved a complete maxillectomy, rhinectomy, and resection of the upper lip and aspects of the left and right cheeks. Reconstruction of the subsequent defect incorporated the placement of four zygomatic oncology implants to aid in retention of a facial prosthesis. These implants, however, were subsequently lost; and an anatomical model of the hard tissues was manufactured via 3D printing. This model was used to design and manufacture a titanium frame (customized implant) for the patient. The frame was then fixated and secured intraoperatively with 21 cortical screws. A maxillary denture and silicone facial prosthesis were also made to fit onto this frame. This is the first known case where additive manufacturing, via the use of rapid prototyping and 3D printing, was employed to manufacture a facial prosthesis.
Human Nature and Moral Sprouts: Mencius on the Pollyanna Problem
Authors: Kim Richard T.
Published: April 2016

This article responds to a common criticism of Aristotelian naturalism known as the Pollyanna Problem, the objection that Aristotelian naturalism, when combined with recent empirical research, generates morally unacceptable conclusions. In developing a reply to this objection, I draw upon the conception of human nature developed by the ancient Chinese philosopher Mencius, and build up an account of ethical naturalism that provides a satisfying response to the Pollyanna Problem while also preserving what is most attractive about Aristotelian naturalism.
Large optical nonlinearity of indium tin oxide in its epsilon-near-zero region
Authors: Alam M. Zahirul , De Leon Israel , Boyd Robert W.
Published: April 2016

Nonlinear optics: A surprise in store?

At ultrafast data rates, the ability to use light to control things could speed information processing. However, photons tend not to interact with each other, and so a nonlinear optical material is needed and the response of such materials is typically weak. Alam
et al.
report a surprising finding: that indium tin oxide, a commercially available transparent conducting oxide widely used in microelectronics, exhibits a large nonlinear response. They used a wavelength regime where the permittivity of the material is close to zero and observed a large and fast nonlinear optical response. The finding offers the possibility that other, so far unexplored, materials may be out there for nonlinear optical applications.

Science
, this issue p.
795
Extracellular electron transfer systems fuel cellulose oxidative degradation
Authors: Kracher Daniel , Scheiblbrandner Stefan , Felice Alfons K. G. , Breslmayr Erik , Preims Marita , Ludwicka Karolina , Haltrich Dietmar , Eijsink Vincent G. H. , Ludwig Roland
Published: April 2016

The fuel for fungal enzymes

Many microorganisms have specialized enzymes to target and break down plant biomass. In fungi, these enzymes, called lytic polysaccharide monooxygenases (LPMOs), partner with electron transfer partners to oxidatively cleave the polysaccharide backbone of lignocellulosic polymers. Kracher
et al.
examined several potential extracellular electron transfer partners for LPMO, including other enzymes and small redoxactive metabolites (see the Perspective by Martínez). All three were able to donate electrons to the single-copper active site. Such versatility helps these fungi adapt to a range of redox conditions and potentially use other extracellular electron donors to fuel biomass degradation.

Science
, this issue p.
1098
; see also p.
1050
Full-Genome Sequences of Seven Fatal Enterovirus 71 Strains Isolated in Shenzhen, China, in 2014
Authors: Chen Long , He Ya-Qing , Meng Jun , Xiong Ling-Hong , Wang Chao , Yao Xiang-Jie , Zhang Hai-Long , Zhang Ren-Li , Yang Hong
Published: April 2016

The whole-genome sequences of seven fatal enterovirus 71 (EV71) strains, isolated in southern China, in 2014, were determined. The complete genome sequences of these strains displayed close relationships to native EV71 strains and showed 94.2% to 99.8% identity to each other. All of these strains were assigned to subgenotype C4a based on phylogenetic analysis of the VP1 gene.
Revisiting the continuum model of tendon pathology: what is its merit in clinical practice and research?
Authors: Cook J L , Rio E , Purdam C R , Docking S I
Published: April 2016

The pathogenesis of tendinopathy and the primary biological change in the tendon that precipitates pathology have generated several pathoaetiological models in the literature. The continuum model of tendon pathology, proposed in 2009, synthesised clinical and laboratory-based research to guide treatment choices for the clinical presentations of tendinopathy. While the continuum has been cited extensively in the literature, its clinical utility has yet to be fully elucidated. The continuum model proposed a model for staging tendinopathy based on the changes and distribution of disorganisation within the tendon. However, classifying tendinopathy based on structure in what is primarily a pain condition has been challenged. The interplay between structure, pain and function is not yet fully understood, which has partly contributed to the complex clinical picture of tendinopathy. Here we revisit and assess the merit of the continuum model in the context of new evidence. We (1) summarise new evidence in tendinopathy research in the context of the continuum, (2) discuss tendon pain and the relevance of a model based on structure and (3) describe relevant clinical elements (pain, function and structure) to begin to build a better understanding of the condition. Our goal is that the continuum model may help guide targeted treatments and improved patient outcomes.
COAGULATION SCREENS REQUESTED IN AN EMERGENCY DEPARTMENT: CLINICALLY INDICATED OR NOT?
Authors: Park K , Ahmed N , Probst F , Mitra A , Ajayi A , Zafar K
Published: April 2016

Objectives & Background

Emergency Department (ED) staff order blood tests for diagnostic work-up and to facilitate prompt treatment. However, with the emerging use of Rapid Assessment and Treatment (RAT) models aiming to provide early assessment by doctors, inappropriate investigations can be requested as a consequence. Our objectives were to establish whether coagulation screens performed in our London ED were clinically appropriate, and to determine its subsequent financial implications.

Methods

Retrospective analysis of blood investigations performed was done using the ED computer system (Ascribe Symphony, UK). The first cohort was a random selection of approximately one-third of ED attendances during a one-week period in July 2013. Inclusion criteria were only patients who were seen by ED clinicians; patients seen directly by other specialties were excluded. Clinical notes were reviewed for every patient who had coagulation screens requested. A recently revised ED ‘investigation matrix’ was used as a local departmental standard.

Up-to-date costs were obtained from the Pathology Department for common investigations (including a coagulation screen and D-Dimer for 2013/14). On the basis of initial results, implementations were introduced in the form of: staff teaching sessions, displaying of up-to-date cost figures, daily team read file and local posters highlighting the importance of cost prevention.

The re-audit (second cohort) was performed 9 months later in May 2014 for all consecutive patients investigated by ED clinicians in a one-week period. Patients were included and excluded on the basis of the same criteria, with the same ‘blood matrix’ as a standard.

Results

70% of patients in the first cohort had blood tests (n=137). 54% of these patients had coagulation screens (n=74), 66% of them not being clinically indicated (n=49). From our initial findings, we projected an estimated loss of>£90,000 per year.

52% patients in the second cohort had blood tests (n=370). 23% of these patients had coagulation screens (n=84), with 68% clinically inappropriate (n=57) based on our clinical criteria.

Conclusion

Coagulation screens are sent in the majority of patients in the absence of clinical indications. A huge financial implication is associated with the investigations. A different approach is required in the ED to avoid inappropriate use of coagulation screens.
Dietary vitamin E supplementation on cholesterol, vitamin E content, and fatty acid profile in chicken muscles
Authors: Zdanowska-Sąsiadek Ż. , Michalczuk M. , Poławska E. , Damaziak K. , Niemiec J. , Radzik-Rant A.
Published: April 2016

The aim of the study was to determine the effect of dietary vitamin E level on cholesterol and vitamin E content and fatty acid profile in broiler chicken breast and leg muscles. Chickens (420 cocks) were randomly divided into two feeding groups (210 birds each). The control group was fed with standard diet containing 44 mg kg−1of vitamin E, whereas the experimental group was supplemented with extra 200 mg kg−1of vitamin E. The dietary addition of vitamin E caused a significant increase in its content in the muscles, with a higher value noted in the leg muscles. Meat of chickens fed with the higher dose of vitamin E was also characterized by a lower cholesterol level. The addition of vitamin E as well as type of the muscles had a significant effect on the fatty acid profile and values of atherogenicity (AI) and thrombogenicity (TI) indices. The recorded increase in the content of n-3 polyunsaturated fatty acids (PUFAs) and a decrease in the n-6/n-3 fatty acid ratio indicate a positive effect of vitamin E on the fatty acid profile. In turn, lower values of AI and TI in leg muscles of chickens with a high intake of vitamin E prove the beneficial fatty acid profile in these muscles upon such supplementation.
EZRA MISHAN, CONTRARIAN AND SAGE: AN APPRECIATION
Authors: SINCLAIR PETER
Published: April 2016

For many of us, the world is far too complicated to allow economic analysis to furnish a clear answer on an issue of policy. Ezra Mishan disagreed. For him, as for his teacher and mentor, Milton Friedman, economics was a system of reasoning that cried out to be used for that purpose - and especially so if prevailing orthodoxy was in error. Mishan was the first economist to attack the then universally held view that economic growth must be beneficial. Fifty years later, as we mourn his recent death, he is an inspiring and central figure in environmental economics, and an example of what can be done with practical welfare economics.
Power Line Communication Simulation Considering Cyclostationary Noise for Metering Systems
Authors: Xiao Yong , Zhang Jie , Pan Feng , Shen Yanhua
Published: April 2016

In this paper, a comprehensive power line test bed for the automatic meter reading (AMR) system is developed. Such a test bed builds a 220[Formula: see text]V power line environment in which the intensity and types of simulated noise can be configured very flexibly. It facilitates the fast analysis of the running condition of AMR system and power line carrier communication (PLCC). In particular, a new simulation technique, which is dedicated to modeling the power line cyclostationary noise, is proposed in this paper through analyzing many unique power line noise characteristics. It is further integrated with a noise simulator which handles the controllable noise replayer and time-varying loads to make the whole simulation system more salient. The experimental results demonstrate that the proposed simulator is highly effective. Our simulator can handle the communication tests with a wide frequency range, from 10[Formula: see text]kHz to 500[Formula: see text]kHz with high accuracy.
ANTECEDENTS TO RADICAL INNOVATIONS: A LONGITUDINAL LOOK AT FIRMS IN THE INFORMATION TECHNOLOGY INDUSTRY BY AGGREGATION OF PATENTS
Authors: DATTA AVIMANYU
Published: April 2016

Radicalness of innovation is often contingent upon access to technologies whose applications exceed their technological definition (technology distinctness (TD)) and sourcing innovation outside a firm’s focal industry (exterior sourcing (ES)). However, going outside one’s focal industry can be expensive and can lead to inconclusive results. We posit that exterior sourcing and technology distinctness, both have inverse U relationship with radicalness. In addition, we argue that exterior sourcing negatively moderates the relationship between technology distinctness and radicalness such that high technology distinctness, and fewer and focused exterior sourcing will have the strongest relationship with radicalness. To test our assertions, we used patent filings between 1996 and 2009 from the information technology (IT) industry from the standard & Poor’s (S&P) 500 database. The empirical evidence supported our claims. Findings suggest that there is an optimum recombination of exterior sourcing and technology distinctness in which radicalness is maximised. We conclude the paper by summarising the key findings, discussing implications for theory and practice, and suggesting avenues for future research.