bluuebunny/crossref_metadata_2025 huggingface dataset:
Early clinical experience with a novel self‐expanding percutaneous stent‐valve in the native right ventricular outflow tract
Authors: Cao Qi‐Ling , Kenny Damien , Zhou Daxin , Pan Wenzhi , Guan Lihua , Ge Junbo , Hijazi Ziyad M.
Published: May 2014

Introduction

Balloon expandable transcatheter pulmonary valve systems are not applicable to the large majority of patients with chronic severe pulmonary regurgitation (PR) following surgical right ventricular outflow tract (RVOT) rehabilitation. This report describes the clinical use and short‐term follow‐up of a novel transcatheter self‐expanding pulmonary valve system (Venus P Valve) for rehabilitation of the RVOT in patients with chronic severe PR.

Methods

Patients with native RVOT and severe PR were selected on a case‐by‐case basis as part of early clinical experience with this valve. Patient demographics and pre‐procedural, intra‐procedural, and follow‐up data were reviewed.

Results

Five patients (four females) with a mean weight of 54.8 ± 11.4 kg were selected for attempted valve deployment. Patients were either NYHA class II (n = 3) or class III (n = 2) at baseline. PR was grade 4 in all cases with mean right ventricular end‐diastolic volumes of 155.0 ± 16.6 ml/m2 on cardiac MRI. Mean minimum “annular” diameter on transthoracic echocardiogram was 22.8 ± 2.5 mm and mean RVOT diameter was 31.8 ± 5.1 mm. Uncomplicated successful valve delivery was achieved in all five cases with a mean fluoroscopy time of 22.8 ± 8.8 min. Valve sizes used were 26 (n = 3), 30 (n = 1), and 32 (n = 1). Mean pulmonary artery diastolic pressure increased from 3 ± 3.7 mm Hg to 9.9 ± 6.9 mm Hg (P = 0.06). On mean follow‐up of 3.4 ± 2.5 months PR grade is 0 (n = 3) or 1 (n = 2) in all cases. NYHA class has improved at least one class in all cases and right ventricular volumes assessed by echocardiography have normalized in all three patients with follow‐up to 3 months.

Conclusions

The Venus P Valve provides excellent short‐term pulmonary valvar function in the native RVOT of patients with surgically induced chronic severe PR. © 2014 Wiley Periodicals, Inc.
Study of the Role of Surface Oxygen Functional Groups on Carbon Nanotubes in the Selective Oxidation of Acrolein
Authors: Zhong Bingwei , Liu Hongyang , Gu Xianmo , Su Dang Sheng
Published: May 2014

Carbon nanotubes (CNTs) are promising candidates for metal‐based catalysts in the selective catalytic oxidation of acrolein. It has been proposed that the surface functional groups play an important role in this reaction. We employ the simple calcination and reduction method to selectively remove the oxygen functional groups on the CNT surface. With the assistance of different characterization techniques such as temperature‐programmed desorption and X‐ray photoelectron spectroscopy, epoxy and lactone oxygen groups on the CNT surface are recognized as the active sites for acrolein selective oxidation. Through adjusting the amount of epoxy and lactone groups, a top catalytic performance (51.2 % acrolein conversion and 79.7 % acrylic acid selectivity) is achieved. Our results indicate that CNTs can be selectively functionalized and used as catalysts for the selective oxidation reaction.
Rhodium‐Complex‐Linked Hybrid Biocatalyst: Stereo‐Controlled Phenylacetylene Polymerization within an Engineered Protein Cavity
Authors: Fukumoto Kazuki , Onoda Akira , Mizohata Eiichi , Bocola Marco , Inoue Tsuyoshi , Schwaneberg Ulrich , Hayashi Takashi
Published: May 2014

The front cover artwork for Issue 5/2014 is a collaboration between Osaka Univesrsity (Japan) and RWTH Aachen Univesrity (Germany). The image shows the reengineering of the hybrid biocatalyst for stereocontrolled polymerization. See the Full Paper itself at http://dx.doi.org/10.1002/cctc.201301055.
Room‐Temperature ortho‐Alkoxylation and ‐Halogenation of N‐Tosylbenzamides by Using Palladium(II)‐Catalyzed CH Activation
Authors: Péron Florent , Fossey Christine , Sopkova‐de Oliveira Santos Jana , Cailly Thomas , Fabis Frédéric
Published: May 2014

The N‐tosylcarboxamide group can direct the room‐temperature palladium‐catalyzed CH alkoxylation and halogenation of substituted arenes in a simple and mild procedure. The room‐temperature stoichiometric cyclopalladation of N‐tosylbenzamide was first studied, and the ability of the palladacycle to react with oxidants to form CX and CO bonds under mild conditions was demonstrated. The reaction conditions were then adapted to promote room‐temperature ortho‐alkoxylations and ortho‐halogenations of N‐tosylbenzamides using palladium as catalyst. The scope and limitation of both alkoxylations and halogenations was studied and the subsequent functional transformation of the N‐tosylcarboxamide group through nucleophilic additions was evaluated. This methodology offers a simple and mild route to diversely functionalized arenes.
Formation and Dissolution of Twin ZnO Nanostructures Promoted by Water and Control over Their Emitting Properties
Authors: Distaso Monica , Mačković Mirza , Spiecker Erdmann , Peukert Wolfgang
Published: May 2014

By using ZnO as a model system, the formation of twinned nanostructures has been investigated under microwave irradiation, exploiting experimental conditions ranging from purely solvothermal when N,N‐dimethylformamide was used, to purely hydrothermal when water was the solvent. A progressive increase in size, elongation and roughness of the surface was observed with increasing water content in the solvent mixture. Particular attention was paid to the reactivity of the ZnO surfaces towards dissolution. Our results show that the formation of twinned nanorods is a dynamic process and that the coupling interphase itself is highly reactive. Consequently, the twinned rods undergo a number of complex dissolution processes that are responsible for the appearance of a wide distribution of defects either on the surface or inside the structure. Poly(N‐vinyl pyrrolidone) influences the photoluminescent properties of the as‐synthesised materials and allows control of the ratio of the intensity of the UV and visible emission.
Host Perturbation in a β‐Hydroquinone Clathrate Studied by Combined X‐ray/Neutron Charge‐Density Analysis: Implications for Molecular Inclusion in Supramolecular Entities
Authors: Clausen Henrik F. , Jørgensen Mads R. V. , Cenedese Simone , Schmøkel Mette S. , Christensen Mogens , Chen Yu‐Sheng , Koutsantonis George , Overgaard Jacob , Spackman Mark A. , Iversen Bo B.
Published: May 2014

X‐ray/neutron (X/N) diffraction data measured at very low temperature (15 K) in conjunction with ab initio theoretical calculations were used to model the crystal charge density (CD) of the host–guest complex of hydroquinone (HQ) and acetonitrile. Due to pseudosymmetry, information about the ordering of the acetonitrile molecules within the HQ cavities is present only in almost extinct, very weak diffraction data, which cannot be measured with sufficient accuracy even by using the brightest X‐ray and neutron sources available, and the CD model of the guest molecule was ultimately based on theoretical calculations. On the other hand, the CD of the HQ host structure is well determined by the experimental data. The neutron diffraction data provide hydrogen anisotropic thermal parameters and positions, which are important to obtain a reliable CD for this light‐atom‐only crystal. Atomic displacement parameters obtained independently from the X‐ray and neutron diffraction data show excellent agreement with a |ΔU| value of 0.00058 Å2indicating outstanding data quality. The CD and especially the derived electrostatic properties clearly reveal increased polarization of the HQ molecules in the host–guest complex compared with the HQ molecules in the empty HQ apohost crystal structure. It was found that the origin of the increased polarization is inclusion of the acetonitrile molecule, whereas the change in geometry of the HQ host structure following inclusion of the guest has very little effect on the electrostatic potential. The fact that guest inclusion has a profound effect on the electrostatic potential suggests that nonpolarizable force fields may be unsuitable for molecular dynamics simulations of host–guest interaction (e.g., in protein–drug complexes), at least for polar molecules.
Regioselective Hydroarylation Reactions of C3 Electrophilic N‐Acetylindoles Activated by FeCl3: An Entry to 3‐(Hetero)arylindolines
Authors: Beaud Rodolphe , Guillot Régis , Kouklovsky Cyrille , Vincent Guillaume
Published: May 2014

A method for the direct and rare umpolung of the 3 position of indoles is reported. The activation of N‐acetylindole with iron(III) chloride allows the CH addition of aromatic and heteroaromatic substrates to the C2C3 double bond of the indole nucleus to generate a quaternary center at C3 and leads regioselectively to 3‐arylindolines. Optimization, scope (50 examples), practicability (gram scale, air atmosphere, room temperature), and mechanistic insights of this process are presented. Synthetic transformations of the indoline products into drug‐like compounds are also described.
Solar Hydrogen from an Aqueous, Noble‐Metal‐Free Hybrid System in a Continuous‐Flow Sampling Reaction System
Authors: Li Xiaobo , Ward Antony J. , Masters Anthony F. , Maschmeyer Thomas
Published: May 2014

We introduce the visible‐light photocatalytic H2 evolution reaction as catalyzed by a cobaloxime/carbon nitride (C3N4) noble‐metal‐free hybrid photosystem by using a continuous‐flow sampling reaction system. The photocatalytic H2 evolution rate is highly dependent on the structure of C3N4, in which porous C3N4 shows the best activity compared with bulk C3N4 (lamellar) and C3N4 nanosheets. When using porous C3N4, the system is neither affected by the solution pH, nor the C3N4 concentration, nor the structure of the cobaloxime complex.
Sulfate‐Selective Recognition by Using Neutral Dipeptide Anion Receptors in Aqueous Solution
Authors: Elmes Robert B. P. , K. Y. Yuen Karen , Jolliffe Katrina A.
Published: May 2014

The synthesis of six small peptide anion receptors based on thiourea and squaramide recognition moieties is described. These new receptors bind to tetrahedral sulfate anions with remarkable affinity and selectivity in aqueous solution as shown by NMR spectroscopy. Molecular modelling suggests that selectivity is mediated by a hydrogen bond network incorporating the amide backbone protons in a manner similar to that found in the sulfate‐binding protein.
Nanoengineering of Stimuli‐Responsive Protein‐Based Biomimetic Protocells as Versatile Drug Delivery Tools
Authors: Zhao Fenfang , Shen Guizhi , Chen Chengjun , Xing Ruirui , Zou Qianli , Ma Guanghui , Yan Xuehai
Published: May 2014

We present a general strategy to nanoengineer protein‐based colloidal spheres (biomimetic protocells) as versatile delivery carriers with stimuli responsiveness by the electrostatic assembly of binary components (proteins and polypeptides) in association with intermolecular disulfide cross‐linking. The size of the colloidal spheres, ranging from nanoscale to microscale, is readily tuned through parameters like protein and polypeptide concentration, the ratio between both, pH, and so on. Moreover, such colloidal spheres show versatile encapsulation of various guest molecules including small organic molecules and biomacromolecules. The pH and redox dual‐responsiveness facilitates the rapid release of the payload in an acidic and reductant‐enriched ambient such as in lysosomes. Thus, nanoengineering of protein‐based biomimetic protocells opens a new alternative avenue for developing delivery vehicles with multifunctional properties towards a range of therapeutic and diagnostic applications.
Probing the Role of Surface Energetics of Electrons and their Accumulation in Photoreduction Processes on TiO2
Authors: Molinari Alessandra , Maldotti Andrea , Amadelli Rossano
Published: May 2014

We address the role of the energetics of photogenerated electrons in the reduction of 4‐nitrobenzaldehyde on TiO2. This model molecule bears two functional groups featuring different reducibilities. Electrochemistry shows that reduction to 4‐aminobenzyl alcohol occurs in entirely distinct potential ranges. Partial reduction of the NO2 group, affording 4‐aminobenzaldehyde, takes place through surface states at potentials positive of the flatband potential (Efb). Dark currents caused by reduction of the aldehyde group are observed only at potentials more negative than Efb, and the process requires an electron accumulation regime. Photocatalysis with TiO2 suspensions agrees with the electrochemical data. In particular, reduction of the nitro group is a relatively fast process (k=0.059 s−1), whereas that of the aldehyde group is slower (k=0.001 s−1) and requires electron photoaccumulation. Control of the photogenerated charge is a prospective means for achieving chemoselective reductions.
Electron Transport of Photoconductive n‐Type Liquid Crystals Based on a Redox‐Active Tetraazanaphthacene Framework
Authors: Isoda Kyosuke , Abe Tomonori , Funahashi Masahiro , Tadokoro Makoto
Published: May 2014

The preparation of two liquid crystals composed of a redox‐active tetraazanaphthacene (TANC) framework is reported. The materials form smectic A (SmA) thin‐film liquid‐crystalline (LC) phases over a wide temperature range. Cyclic voltammetry analysis revealed that LC TANCs behave as organic electron acceptors. The electron mobilities of the thin films were determined by time‐ of‐flight (TOF) measurements, which are the order of 10−4 cm2 V−1 s−1 in the SmA LC phase. This value is two orders of magnitude larger than those of amorphous organic semiconductors. To the best of our knowledge, very few reports exist on the electron‐transporting behaviors of LC N‐heteroacene semiconductors.
Iridium‐Catalyzed Isomerization/Bromination of Allylic Alcohols: Synthesis of α‐Bromocarbonyl Compounds
Authors: Gómez Antonio Bermejo , Erbing Elis , Batuecas María , Vázquez‐Romero Ana , Martín‐Matute Belén
Published: May 2014

α‐Brominated ketones and aldehydes, with two adjacent electrophilic carbon atoms, are highly valuable synthetic intermediates in organic synthesis, however, their synthesis from unsymmetrical ketones is very challenging, and current methods suffer from low selectivity. We present a new, reliable, and efficient method for the synthesis of α‐bromocarbonyl compounds in excellent yields and with excellent selectivities. Starting from allylic alcohols as the carbonyl precursors, the combination of a 1,3‐hydrogen shift catalyzed by iridium(III) with an electrophilic bromination gives α‐bromoketones and aldehydes in good to excellent yields. The selectivity of the process is determined by the structure of the starting allylic alcohol; thus, α‐bromoketones formally derived from unsymmetrical ketones can be synthesized in a straightforward and selective manner.
Asymmetric Synthesis of Fortucine and Reassignment of Its Absolute Configuration
Authors: Beaulieu Marc‐André , Ottenwaelder Xavier , Canesi Sylvain
Published: May 2014

Invited for the cover of this issue is the group of Sylvain Canesi at the Université du Québec à Montréal and Xavier Ottenwaelder at Concordia University. The image depicts the asymmetric total synthesis of the alkaloid fortucine isolated from the species of plant Fortune Narcissus of­ Amarillydaceaes. Read the full text of the article at 10.1002/chem.201402323.
Biomechanical investigation of thoracolumbar spine in different postures during ejection using a combined finite element and multi‐body approach
Authors: Du Chengfei , Mo Zhongjun , Tian Shan , Wang Lizhen , Fan Jie , Liu Songyang , Fan Yubo
Published: May 2014

The aim of this study is to investigate the dynamic response of a multi‐segment model of the thoracolumbar spine and determine how the sitting posture affects the response under the impact of ejection. A nonlinear finite element model of the thoracolumbar‐pelvis complex (T9–S1) was developed and validated. A multi‐body dynamic model of a pilot was also constructed so an ejection seat restraint system could be incorporated into the finite element model. The distribution of trunk mass on each vertebra was also considered in the model. Dynamics analysis showed that ejection impact induced obvious axial compression and anterior flexion of the spine, which may contribute to spinal injuries. Compared with a normal posture, the relaxed posture led to an increase in stress on the cortical wall, endplate, and intradiscal pressure of 43%, 10%, 13%, respectively, and accordingly increased the risk of inducing spinal injuries. Copyright © 2014 John Wiley & Sons, Ltd.
Does Tautomerization of FapyG Influence Its Mutagenicity?
Authors: Jena Nihar R. , Mark Alan E. , Mishra Phool C.
Published: May 2014

Oxidative degradation of guanine to 2,6‐diamino‐4‐oxo‐5‐formamidopyrimidine (FapyG) is believed to be mutagenic. It has been proposed recently that the enol tautomer of FapyG is mainly responsible for this effect leading to a guanine‐to‐thymine mutation (T. H. Gehrke, U. Lischke, K. L. Gasteiger, S. Schneider, S. Arnold, H. C. Muller, D. S. Stephenson, H. Zipse, T. Carell, Nat. Chem. Biol.­ 2013, 9, 455–461). Here, density functional methods suggest that the enol tautomer of FapyG might not be responsible for the proposed guanine‐to‐thymine mutation. Instead, it might result in a guanine‐to‐adenine mutation.
Catalytic Role of TiO2 Terminal Oxygen Atoms in Liquid‐Phase Photocatalytic Reactions: Oxidation of Aromatic Compounds in Anhydrous Acetonitrile
Authors: Montoya Juan F. , Bahnemann Detlef W. , Peral José , Salvador Pedro
Published: May 2014

On the basis of experiments carried out with controlled amounts of residual oxygen and water, or by using oxygen‐isotope‐labeled Ti18O2 as the photocatalyst, we demonstrate that 18Os atoms behave as real catalytic species in the photo‐oxidation of acetonitrile‐dissolved aromatic compounds such as benzene, phenol, and benzaldehyde with TiO2. The experimental evidence allows a terminal‐oxygen indirect electron‐transfer (TOIET) mechanism to be proposed, which is a new pathway that involves the trapping of free photogenerated valence‐band holes at Os species and their incorporation into the reaction products, with simultaneous generation of oxygen vacancies at the TiO2 surface and their subsequent healing with oxygen atoms from either O2 or H2O molecules that are dissolved in the liquid phase. According to the TOIET mechanism, the TiO2 surface is not considered to remain stable, but is continuously changing in the course of the photocatalytic reaction, challenging earlier interpretations of TiO2 photocatalytic phenomena.
Synergistic Fusion of Vertical Graphene Nanosheets and Carbon Nanotubes for High‐Performance Supercapacitor Electrodes
Authors: Seo Dong Han , Yick Samuel , Han Zhao Jun , Fang Jing Hua , Ostrikov Kostya (Ken)
Published: May 2014

Graphene and carbon nanotubes (CNTs) are attractive electrode materials for supercapacitors. However, challenges such as the substrate‐limited growth of CNTs, nanotube bundling in liquid electrolytes, under‐utilized basal planes, and stacking of graphene sheets have so far impeded their widespread application. Here we present a hybrid structure formed by the direct growth of CNTs onto vertical graphene nanosheets (VGNS). VGNS are fabricated by a green plasma‐assisted method to break down and reconstruct a natural precursor into an ordered graphitic structure. The synergistic combination of CNTs and VGNS overcomes the challenges intrinsic to both materials. The resulting VGNS/CNTs hybrids show a high specific capacitance with good cycling stability. The charge storage is based mainly on the non‐Faradaic mechanism. In addition, a series of optimization experiments were conducted to reveal the critical factors that are required to achieve the demonstrated high supercapacitor performance.
Different calcium influx characteristics upon Kv1.3 and IKCa1 potassium channel inhibition in T helper subsets
Authors: Orbán Csaba , Bajnok Anna , Vásárhelyi Barna , Tulassay Tivadar , Toldi Gergely
Published: May 2014

Functional imbalance between T helper subsets plays important role in the pathogenesis of autoimmune disorders. Transient increase of cytoplasmic calcium level, and sustention of negative membrane potential by voltage sensitive Kv1.3 and calcium‐dependent IKCa1 potassium channels are essential for short‐term lymphocyte activation, thus present possible target for selective immunomodulation. We aimed to investigate calcium influx sensitivity to the inhibition of potassium channels in the main T helper subsets. Peripheral blood from 11 healthy individuals was drawn and calcium influx kinetics following activation with phytohemagglutinin in Th1, Th2, Th17, and Treg cells were evaluated. Alteration of calcium influx induced by specific inhibitors of Kv1.3 and IKCa1 potassium channels, and the expression of Kv1.3 channels were also assessed. Highest cytoplasmic calcium concentration was observed in stimulated Th1 cells, while the lowest level was measured in Treg cells. In Th1 and Th17 cells, inhibition of both investigated potassium channels decreased calcium influx. In Th2 cells only the inhibitor of Kv1.3 channels, while in Treg cells none of the inhibitors had significant effect. Upon the inhibition of IKCa1 channels, short‐term activation of proinflammatory cells was specifically decreased without affecting anti‐inflammatory subsets, indicating that selective immunomodulation is possible in healthy individuals. © 2014 International Society for Advancement of Cytometry
Clinical significance of HPV DNA cotesting in Korean women with ASCUS or ASC‐H
Authors: Lee Sanghoon , Kim Jae Won , Hong Jin Hwa , Song Jae Yun , Lee Jae Kwan , Kim In Sun , Lee Nak Woo
Published: May 2014

The purpose of this study was to evaluate the clinical significance of Human papillomavirus (HPV) DNA cotesting in Korean women with abnormal Papanicolaou (Pap) smear results based on colposcopic pathology. A total of 1012 women underwent liquid‐based Pap smears and hybrid capture II HPV DNA tests followed by colposcopy at the Korea University Hospital from January 2007 to May 2012. Of these women, 832 women were included in this retrospective study. The mean patient age was 45.4 ± 13.7 years (range:15–80). The distribution of Pap smear results was normal (4.7%), atypical squamous cells of uncertain significance (ASCUS) (42.1%), low‐grade squamous intraepithelial lesion (26.8%), ASC‐H (7.0%), and high‐grade squamous intraepithelial lesion (HSIL) (19.5%). In women with ASCUS, none of the 87 HPV‐negative had ≥cervical intraepithelial neoplasia (CIN2) (P < 0.001). In women with ASC‐H, only one out of 17 HPV‐negative vs. 14 out of 41 HPV‐positive had ≥CIN2 (P = 0.025). In patients with HSIL, 54.5% of HPV‐negative had ≥CIN2, as compared to 80.8% of HPV‐positive with ≥CIN2 (P = 0.039). Patients were further analyzed by age groups: <30 and ≥30 years. In HPV‐negative women, there was a significant difference in the ratio of ≥CIN2 (30.8% <30 vs. 4.5% ≥30, P = 0.005). When the HPV DNA test was negative in women ≥30, the risk of ≥CIN2 was significantly lower (P < 0.001). HPV DNA cotesting in women with ASCUS and ASC‐H furnish healthcare providers with informative data. There is a lower proportion of ≥CIN2 in HPV‐negative women and a higher proportion of ≥CIN2 in HPV‐positive. When HPV data were further evaluated by age group, the risk of ≥CIN2 was lower in HPV‐negative women, especially in women ≥30. Diagn. Cytopathol. 2014;42:1058–1062. © 2014 Wiley Periodicals, Inc.
Peripheral Synergism between Tramadol and Ibuprofen in the Formalin Test
Authors: Chavarria‐Bolaños Daniel , Perez‐Urizar José , Grandfils Christian , Pozos‐Guillén Amaury
Published: May 2014

Preclinical Research

Analgesics with different mechanisms of action can be combined in order to obtain pharmacological synergism, employing lower doses of each agent, thus diminishing side effects. For instance, an atypical dual analgesic such as tramadol (TMD) and a nonsteroidal anti‐inflammatory drug such as ibuprofen (IBU) are good candidates to be evaluated when combined and applied peripherally. The present study was conducted to evaluate possible local synergism between TMD and IBU when combined peripherally using the formalin test in rats. The effects of the individual analgesics and their combinations were evaluated simultaneously using a 5% formalin dilution. Dose–effect curves were determined for TMD (50–400 μg/paw) and IBU (1–100 μg/paw). Experimental effective doses were evaluated and isobolographic analyses were constructed to evaluate TMD‐IBU combination synergism. Both drugs produced a dose‐dependent analgesic effect when applied separately. Isobolographic analysis showed synergism during phase 1 (0–10 min) and phase 2 (15–60 min) when compared with theoretical doses (P < 0.05), with interaction indexes of 0.06 and 0.09, respectively. The present information supports the peripheral analgesic effect of TMD and IBU, especially when combined at appropriate doses.
The Evolving Drug Development Landscape: From Blockbusters to Niche Busters in the Orphan Drug Space
Authors: Kumar Kakkar Ashish , Dahiya Neha
Published: May 2014

Strategy, Management and Health Policy

Large pharmaceutical companies have traditionally focused on the development of blockbuster drugs that target disease states with large patient populations. However, with large‐scale patent expirations and competition from generics and biosimilars, anemic pipelines, escalating clinical trial costs, and global health‐care reform, the blockbuster model has become less viable. Orphan drug initiatives and the incentives accompanied by these have fostered renewed research efforts in the area of rare diseases and have led to the approval of more than 400 orphan products. Despite targeting much smaller patient populations, the revenue‐generating potential of orphan drugs has been shown to be huge, with a greater return on investment than non‐orphan drugs. The success of these “niche buster” therapeutics has led to a renewed interest from “Big Pharma” in the rare disease landscape. This article reviews the key drivers for orphan drug research and development, their profitability, and issues surrounding the emergence of large pharmaceutical firms into the orphan drug space.
The effects of thyroid hormones on brown adipose tissue in humans: a PET‐CT study
Authors: Zhang Qiongyue , Miao Qing , Ye Hongying , Zhang Zhaoyun , Zuo Chuantao , Hua Fengchun , Guan Yihui , Li Yiming
Published: May 2014

Background

Brown adipose tissue (BAT) is important for energy expenditure through thermogenesis, although its regulatory factors are not well known in humans. There is evidence suggesting that thyroid hormones affect BAT functions in some mammals, but the effects of thyroid hormones on BAT activity in humans are still unclear. The aim of this study was to investigate the effects of thyroid hormones on glucose metabolism of BAT and other organs in humans.

Methods

Nine Graves' disease‐caused hyperthyroid patients who were newly diagnosed and untreated were studied. Putative brown adipose tissue activity was determined by the integrated 18F‐fluorodeoxyglucose (18F‐FDG) positron‐emission tomography and computed tomography (PET‐CT). All hyperthyroid patients were treated with methimazole and had been monitored until their symptoms disappeared and thyroid hormone levels returned to normal. At the end, a second PET‐CT scan was performed. The average follow‐up period was 77 days. Meanwhile, compared with a group of seventy‐five brown adipose tissue‐negative controls, thyroid hormones of seventy‐five BAT‐positive healthy subjects were measured.

Results

Active brown adipose tissue was not present in any of the hyperthyroid patients. However, one patient with normalized thyroid function showed active BAT after therapy. The free T3 levels and free T4 levels were significantly lower in the 75 BAT‐positive subjects than in the BAT‐negative subjects. All hyperthyroid patients showed symmetrically increased uptake of fluorodeoxyglucose in skeletal muscles before treatment, whereas, the standardized uptake value was substantially decreased after treatment.

Conclusions

Abnormally high circulating thyroid hormone levels may not increase brown adipose tissue activity, which may be limited by the increased obligatory thermogenesis of muscle in adult humans. Copyright © 2014 John Wiley & Sons, Ltd.
Benefits of exenatide on obesity and non‐alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes
Authors: Shao Ning , Kuang Hong Yu , Hao Ming , Gao Xin Yuan , Lin Wen Jian , Zou Wei
Published: May 2014

Background

The purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non‐alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D).

Methods

A total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n = 30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n = 30) were treated with insulin aspart and insulin glargine for 12 weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12 weeks following treatment.

Results

At baseline, the clinical characteristics were matched between the two groups. After 12 weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p < 0.001). Body weight and waist circumference were significantly decreased in the exenatide group but increased in the intensive insulin group (p < 0.001). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ‐glutamyl transpeptidase (γGGT) in the exenatide group were significantly lower than in the intensive insulin group (p < 0.001). The mean body weight change correlated with the levels of ALT, AST and γGGT change (ALT, r = 0.761; AST, r = 0.733; γGGT, r = 0.752; p < 0.001). Moreover, the reversal rate of fatty liver was significantly higher in the exenatide group (93.3%) than the intensive insulin group (66.7%) (p < 0.01).

Conclusions

Exenatide has a better hepatic–protective effect than intensive insulin therapy and perhaps represents a unique option for adjunctive therapy for patients with obesity, non‐alcoholic fatty liver disease with elevated liver enzymes and T2D. Copyright © 2014 John Wiley & Sons, Ltd.
Qualitative analysis of seized synthetic cannabinoids and synthetic cathinones by gas chromatography triple quadrupole tandem mass spectrometry
Authors: Gwak Seongshin , Arroyo‐Mora Luis E. , Almirall José R.
Published: May 2014

Designer drugs are analogues or derivatives of illicit drugs with a modification of their chemical structure in order to circumvent current legislation for controlled substances. Designer drugs of abuse have increased dramatically in popularity all over the world for the past couple of years. Currently, the qualitative seized‐drug analysis is mainly performed by gas chromatography‐electron ionization‐mass spectrometry (GC‐EI‐MS) in which most of these emerging designer drug derivatives are extensively fragmented not presenting a molecular ion in their mass spectra. The absence of molecular ion and/or similar fragmentation pattern among these derivatives may cause the equivocal identification of unknown seized‐substances. In this study, the qualitative identification of 34 designer drugs, mainly synthetic cannabinoids and synthetic cathinones, were performed by gas chromatography‐triple quadrupole‐tandem mass spectrometry with two different ionization techniques, including electron ionization (EI) and chemical ionization (CI) only focusing on qualitative seized‐drug analysis, not from the toxicological point of view. The implementation of CI source facilitates the determination of molecular mass and the identification of seized designer drugs. Developed multiple reaction monitoring (MRM) mode may increase sensitivity and selectivity in the analysis of seized designer drugs. In addition, CI mass spectra and MRM mass spectra of these designer drug derivatives can be used as a potential supplemental database along with EI mass spectral database. Copyright © 2014 John Wiley & Sons, Ltd.
Big catch, little sharks: Insight into Peruvian small‐scale longline fisheries
Authors: Doherty Philip D. , Alfaro‐Shigueto Joanna , Hodgson David J. , Mangel Jeffrey C. , Witt Matthew J. , Godley Brendan J.
Published: May 2014

Shark take, driven by vast demand for meat and fins, is increasing. We set out to gain insights into the impact of small‐scale longline fisheries in Peru. Onboard observers were used to document catch from 145 longline fishing trips (1668 fishing days) originating from Ilo, southern Peru. Fishing effort is divided into two seasons: targeting dolphinfish (Coryphaena hippurus; December to February) and sharks (March to November). A total of 16,610 sharks were observed caught, with 11,166 identified to species level. Of these, 70.6% were blue sharks (Prionace glauca), 28.4% short‐fin mako sharks (Isurus oxyrinchus), and 1% were other species (including thresher (Alopias vulpinus), hammerhead (Sphyrna zygaena), porbeagle (Lamnus nasus), and other Carcharhinidae species (Carcharhinus brachyurus, Carcharhinus falciformis, Galeorhinus galeus). Mean ± SD catch per unit effort of 33.6 ± 10.9 sharks per 1000 hooks was calculated for the shark season and 1.9 ± 3.1 sharks per 1000 hooks were caught in the dolphinfish season. An average of 83.7% of sharks caught (74.7% blue sharks; 93.3% mako sharks) were deemed sexually immature and under the legal minimum landing size, which for species exhibiting k‐selected life history traits can result in susceptibility to over exploitation. As these growing fisheries operate along the entire Peruvian coast and may catch millions of sharks per annum, we conclude that their continued expansion, along with ineffective legislative approaches resulting in removal of immature individuals, has the potential to threaten the sustainability of the fishery, its target species, and ecosystem. There is a need for additional monitoring and research to inform novel management strategies for sharks while maintaining fisher livelihoods.
Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)
Authors: McMurray John J. V. , Packer Milton , Desai Akshay S , Gong Jianjian , Lefkowitz Martin , Rizkala Adel R. , Rouleau Jean L. , Shi Victor C. , Solomon Scott D. , Swedberg Karl , Zile Michael R. ,   on behalf of the PARADIGM‐HF Committees Investigators
Published: May 2014

Aim

To describe the baseline characteristics and treatment of the patients randomized in the PARADIGM‐HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure) trial, testing the hypothesis that the strategy of simultaneously blocking the renin–angiotensin–aldosterone system and augmenting natriuretic peptides with LCZ696 200 mg b.i.d. is superior to enalapril 10 mg b.i.d. in reducing mortality and morbidity in patients with heart failure and reduced ejection fraction.

Methods

Key demographic, clinical and laboratory findings, along with baseline treatment, are reported and compared with those of patients in the treatment arm of the Studies Of Left Ventricular Dysfunction (SOLVD‐T) and more contemporary drug and device trials in heart failure and reduced ejection fraction.

Results

The mean age of the 8442 patients in PARADIGM‐HF is 64 (SD 11) years and 78% are male, which is similar to SOLVD‐T and more recent trials. Despite extensive background therapy with beta‐blockers (93% patients) and mineralocorticoid receptor antagonists (60%), patients in PARADIGM‐HF have persisting symptoms and signs, reduced health related quality of life, a low LVEF (mean 29 ± SD 6%) and elevated N‐terminal‐proB type‐natriuretic peptide levels (median 1608 inter‐quartile range 886–3221 pg/mL).

Conclusion

PARADIGM‐HF will determine whether LCZ696 is more beneficial than enalapril when added to other disease‐modifying therapies and if further augmentation of endogenous natriuretic peptides will reduce morbidity and mortality in heart failure and reduced ejection fraction.
Slow Magnetic Relaxation in a Redox‐Active Tetrathiafulvalene‐Based Ferromagnetic Dysprosium Complex
Authors: Pointillart Fabrice , Golhen Stéphane , Cador Olivier , Ouahab Lahcène
Published: May 2014

The association of the two 4,5‐bis(thiomethyl)‐4′‐carboxytetrathiafulvalene (HL1) and 4,5‐bis(thiomethyl)‐4′‐(2‐pyridyl‐N‐oxide)carbamoyltetrathiafulvalene (L2) with the metalloprecursor [Dy(tta)3]·2H2O (tta = 2‐thenoyltrifluoroacetonate) leads to the formation of the dinuclear complex of formula [Dy(tta)2(L1)(L2)]2·2CH2Cl2. Static magnetic measurements highlight significant ferromagnetic interactions between the DyIII ions, and dynamic magnetic measurements demonstrate single‐molecule‐magnet behaviour with an energy barrier of 20 cm–1 and a relaxation time of 8.6(9) × 10–6 s. The thermal dependence of the magnetic susceptibility was evaluated by using a crystal field approach (Stevens operators), which confirmed the Ising character of the system. Finally, electrochemistry shows a complex multiredox system with the successive oxidations of the two tetrathiafulvalene (TTF) ligands.
Application of the Palladium‐Catalysed Norbornene‐Assisted Catellani Reaction Towards the Total Synthesis of (+)‐Linoxepin and Isolinoxepin
Authors: Qureshi Zafar , Weinstabl Harald , Suhartono Marcel , Liu Hongqiang , Thesmar Pierre , Lautens Mark
Published: May 2014

Our ongoing effort towards the development of highly selective transition‐metal‐catalysed C–H activation processes has led to the expansion of the Catellani reaction. In a Pd0/PdII/PdIV‐catalysed domino reaction, an aryl iodide, alkyl iodide and tert‐butyl acrylate were combined to synthesize the carbon framework of the novel lignan (+)‐linoxepin. The enantioselective synthesis highlights the work accomplished in our group and provides an excellent procedure for the reliable and scalable synthesis of architecturally complex scaffolds. This report outlines the synthetic approaches towards this interesting class of biologically active molecules. After the key Catellani/Heck reaction, our synthesis features a Leimeux–Johnson oxidation and a titanium tetrachloride mediated aldol condensation. Finally, a tuneable Mizoroki–Heck reaction was performed to furnish not only the natural product (+)‐linoxepin but also its isoform, which we have named isolinoxepin.
Oral 2‐hydroxyoleic acid inhibits reflex hypersensitivity and open–field‐induced anxiety after spared nerve injury
Authors: Avila‐Martin G. , Galan‐Arriero I. , Ferrer‐Donato A. , Busquets X. , Gomez‐Soriano J. , Escribá P.V. , Taylor J.
Published: May 2014

Background

Recently, fatty acids have been shown to modulate sensory function in animal models of neuropathic pain. In this study, the antinociceptive effect of 2‐hydroxyoleic acid (2‐OHOA) was assessed following spared nerve injury (SNI) with reflex and cerebrally mediated behavioural responses.

Methods

Initial antinociceptive behavioural screening of daily administration of 2‐OHOA (400 mg/kg, p.o.) was assessed in Wistar rats by measuring hindlimb reflex hypersensitivity to von Frey and thermal plate stimulation up to 7 days after SNI, while its modulatory effect on lumbar spinal dorsal horn microglia reactivity was assessed with OX‐42 immunohistochemistry. In vitro the effect of 2‐OHOA (120 μM) on cyclooxygenase protein expression (COX‐2/COX‐1 ratio) in lipopolysaccharide‐activated macrophage cells was tested with Western blot analysis. Finally, the effects of 2‐OHOA treatment on the place escape aversion paradigm (PEAP) and the open–field‐induced anxiety test were tested at 21 days following nerve injury compared with vehicle‐treated sham and pregabalin‐SNI (30 mg/kg, p.o.) control groups.

Results

Oral 2‐OHOA significantly reduced ipsilateral mechanical and thermal hypersensitivity up to 7 days after SNI. Additionally 2‐OHOA decreased the COX‐2/COX‐1 ratio in lipopolysaccharide‐activated macrophage cells and OX‐42 expression within the ipsilateral lumbar spinal dorsal horn 7 days after SNI. 2‐OHOA significantly restored inner‐zone exploration in the open‐field test compared with the vehicle‐treated sham group at 21 days after SNI.

Conclusions

Oral administration of the modified omega 9 fatty acid, 2‐OHOA, mediates antinociception and prevents open–field‐induced anxiety in the SNI model in Wistar rats, which is mediated by an inhibition of spinal dorsal horn microglia activation.
Very delayed cervical lymph node metastases from hyalinizing clear cell carcinoma: Report of 2 cases
Authors: Su Henry K. , Wang Beverly Y. , Mannan Abul Ala Syed Rifat , Dewey Eliza H. , Alpert Erin H. , Reis Laura L. Dos , Urken Mark L.
Published: May 2014

Background

Hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland neoplasm most often found in the oral cavity. Although it is generally a low‐grade malignancy that is treated with wide local excision, there is a growing body of evidence pointing toward the potential for more aggressive behavior.

Methods

We reviewed available records of patients with delayed cervical lymph node metastases from HCCC.

Results

Two patients who were treated with wide local resection for HCCC and remained disease‐free at the primary site were diagnosed with cervical lymph node metastases 10 and 14 years later. We treated both with neck dissection, and 1 patient received adjuvant radiation therapy.

Conclusion

These cases illustrate the risk for occult nodal metastases from HCCC with delayed presentation. Clinician awareness of the presence of subclinical metastases in the neck requires thorough long‐term surveillance and potential intervention should nodal disease become manifest. © 2014 Wiley Periodicals, Inc. Head Neck 37: E19‐E21, 2015
Head and neck squamous cell carcinoma lymphatic spread and survival: Relevance of vascular endothelial growth factor family for tumor evaluation
Authors: de Sousa Elen Alves , Lourenço Silvia Vanessa , Moraes Flávia Paiva Prudente de , Vartanian José Guilherme , Gonçalves–Filho João , Kowalski Luiz Paulo , Soares Fernando Augusto , Coutinho–Camillo Cláudia Malheiros
Published: May 2014

Background

Head and neck squamous cell carcinoma (HNSCC) is primarily a locoregional disease in which the cervical lymph nodes are the chief site of metastasis. The purpose of this study was to examine the relationship between lymphangiogenesis and clinicopathological aspects of HNSCC and its metastasis.

Methods

Fifty‐two patients with HNSCC and metastatic lymph nodes from 21 of these subjects were analyzed by immunohistochemistry.

Results

The HNSCC samples were predominantly negative for vascular endothelial growth factor (VEGF)‐C, VEGF‐D, and vascular endothelial growth factor receptor (VEGFR)3. There was an association between the density of lymph vessels (measured by D2‐40 staining) in the lymph nodes and advanced‐stage tumors. There was no link between the expression of these proteins and survival rates.

Conclusion

Although lymphatic spread is a significant event in the progression of HNSCC, the expression of VEGF‐C, VEGF‐D, and VEGFR3 does not correlate with clinicopathological characteristics, suggesting that other signaling pathways mediate lymphangiogenesis in HNSCC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1410–1416, 2015
Laryngeal osteosarcoma: Case report and literature review
Authors: Kuba Kiyomi , Inoue Hitoshi , Hayashi Takahiro , Matsumura Satoko , Minami Kazuhiko , Takajo Humihiko , Morita Kei , Nakahira Mitsuhiko , Sugasawa Masashi
Published: May 2014

Background

Sarcomas of the larynx are uncommon tumors, and osteosarcoma is the rarest. Only 24 cases of osteosarcoma of the larynx have been reported. The only case reported in Asia was from Thailand in 1981.

Methods

A 55‐year‐old male patient was referred to our hospital because of an 8‐month history of odynophagia and a gradually enlarging left neck mass. A neck CT scan was performed. A literature review was also performed for this report.

Results

The CT scan revealed extensive calcification with enlargement of the thyroid cartilage. The patient was diagnosed with osteosarcoma and was successfully treated by surgery alone.

Conclusion

Adequate surgical resection is required for successful treatment of laryngeal sarcomas. Adjuvant therapy is not contraindicated, but chemotherapy may improve the prognosis in patients with high‐grade tumors or metastatic disease. © 2014 Wiley Periodicals, Inc. Head Neck 37: E26‐E29, 2015
One‐Pot Synthesis of Novel Pyrrolo[1,2‐a]quinoxaline‐4(5H)‐ones Using Benzene‐1,2‐diamine, Acetylenedicarboxylates, and β‐Nitrostyrene Derivatives
Authors: Moradi Loghman , Piltan Mohammad , Abasi Golaleh
Published: May 2014

The reaction between a variety of o‐phenylenediamines (=benzene‐1,2‐diamines), dialkyl acetylenedicarboxylates, and derivatives of nitrostyrene (=(E)‐(2‐nitroethenyl)benzene) in the presence of sulfamic acid (SA; H3NSO3) as catalyst led to the corresponding pyrrolo[1,2‐a]quinoxaline‐4(5H)‐one derivatives in high yields.
Stereoselective Total Synthesis of Phenolic Nonadecanediol
Authors: Chinnababu Baggu , Purushotham Reddy Sudina , Venkatesham Kunuru , Chandra Rao Dasireddi , Venkateswarlu Yenamandra
Published: May 2014

A simple and highly efficient synthetic route has been developed for synthesis of 1‐(4‐hydroxyphenyl)nonadecane‐3,5‐diol (1). The two stereogenic centers were generated by employing proline asymmetric α‐hydroxylation (MacMillan α‐hydroxylation), Jacobsen's hydrolytic kinetic resolution (HKR), and, finally, Yamaguchi oxirane opening as key steps (Scheme 2).
A New Polyketide from the Mangrove Endophytic Fungus Penicillium sp. sk14JW2P
Authors: Huang Xi‐Shan , Yang Bin , Sun Xue‐Feng , Xia Guo‐Ping , Liu Ya‐Yue , Ma Lin , She Zhi‐Gang
Published: May 2014

Two polyketides were isolated from the mangrove endophytic fungus, Penicillium sp. sk14JW2P, and one derivative with a modified structure. The structures were elucidated by spectroscopic analyses, the structure of the compound 1 was further confirmed by single‐crystal X‐ray diffraction, and its absolute configuration was determined. Compound 1 and 2 showed acetylcholinesterase (AchE) inhibitory activities with IC50 values of 12±0.3 and 79±2 nM, respectively.
Spectroscopic, Thermal, and Structural Studies of Two New Co‐Crystals of [4,4′‐Bithiazole]‐2,2′‐diamine
Authors: Rashidi Ranjbar Zohreh , Morsali Ali , Ghoreishi Amiri Maryam
Published: May 2014

Two new 2 : 1 co‐crystals based on [4,4′‐bithiazole]‐2,2′‐diamine (=2,2′‐diamino‐4,4′‐bithiazole (DABTZ)) with 2,2′‐bipyridine (bipy) and benzo‐18‐crown‐6 (bk) were synthesized by slow‐evaporation method in MeOH. These co‐crystals were characterized by means of elemental analysis, and IR, and 1H‐ and 13C‐NMR spectroscopy. Also, thermal analyses under air atmosphere and X‐ray crystallography have been performed on these structures. X‐Ray single‐crystal analyses revealed that these networks contain large vacant voids. These structures, [(DABTZ)2(bipy)] and [(DABTZ)2(bk)(MeOH)], crystallized in monoclinic and triclinic forms with space groups of P21/c and P$\bar 1$, respectively. The self‐assembly of these compounds in the solid state is likely caused by both H‐bonding and ππ stacking.
Pintoxolanes A–C, Highly Functionalized 3,14‐Oxa‐bridged Cembranoids from the Caribbean Gorgonian Coral Eunicea pinta
Authors: Figueroa Janet , Vera Brunilda , Rodríguez Abimael D.
Published: May 2014

Three new cembrane‐based diterpenes possessing the rare 3,14‐oxa‐bridged moiety were isolated from the hexane extract of a southwestern Caribbean gorgonian octocoral, Eunicea pinta, together with seven known cembranoid diterpenes. The structures of pintoxolanes A–C (1–3, resp.), including their relative configurations, were deduced from spectroscopic data and chemical‐correlation experiments. Experimental evidence hinting to a plausible biogenesis of the 3,14‐oxalane moiety is provided. Preliminary cytotoxicity data for compounds 1–3 toward human cancer cell lines are also provided.