bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene therapy clinical trials worldwide to 2012 – an update
Authors: Ginn Samantha L. , Alexander Ian E. , Edelstein Michael L. , Abedi Mohammad R. , Wixon Jo
Published: January 2013

To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors.

This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future. Copyright © 2013 John Wiley & Sons, Ltd.
New Efficient and Flexible Synthetic Route to Emivirine and Its Analogs
Authors: Li Li , Ma Liying , Wang Xiaowei , Liu Junyi
Published: January 2013

A revised synthetic route to Emivirine (MKC‐442) via properly substituted β‐keto ester converted from Meldrum's Acid was developed. This method could be applied to the synthesis of a variety of MKC‐442 analogues and open the way for their systematic biological evaluation.
Diesel‐lubricated ta‐C coatings
Authors: Makowski S. , Weihnacht V. , Leson A.
Published: January 2013

Samples coated with tetrahedral amorphous carbon were investigated in two different oscillating test setups regarding their friction and wear properties. As lubricants petrodiesel, rapeseed methyl ester biodiesel and a mixture thereof were used. Compared with a petrodiesel‐lubricated uncoated system, friction was reduced for more than 50% when a tetrahedral amorphous carbon coating was applied and biodiesel added to the lubricant. Impurities of monoglycerides are assumed to be the cause for the friction‐modifying effect. Copyright © 2013 John Wiley & Sons, Ltd.
Roles of phosphorylated JNK in esophageal squamous cell carcinomas of kazakh ethnic
Authors: Qin Xu , Zheng Shutao , Liu Tao , Liu Qing , Liang Meng , Li Xiuling , Sheyhidin Ilyar , Lu Xiaomei
Published: January 2013

The c‐Jun NH2‐terminal kinase (JNK) signal pathway has been implicated in the growth, cellular proliferation, and apoptosis in many kinds of carcinomas. However, the role of JNK in the development of esophageal squamous cell carcinomas (ESCCs) is unknown. To investigate the role of JNK in ESCC, in vitro, esophageal cancer cell line Eca109 was pretreated using SP600125, JNK specific inhibitor, then was subjected to MTT assay to examine cellular proliferation, flow cytometric analysis to detect apoptosis and cell cycle, and wound healing assay to evaluate cell migration. Meanwhile, the mRNA and protein expression of JNK in Eca109 cells pretreated with SP600125 were examined by real‐time quantitative reverse transcription PCR (qRT‐PCR) and Western blotting, respectively. In vivo, 12 paired of fresh ESCC and normal adjacent tissues (NAT) from Kazakh patients were used to validate the expression of JNK by qRT‐PCR and Western blotting. Furthermore, to reconfirm the expression trend of activation JNK (p‐JNK), enlarged 72 paired of Kazakh's ESCC and NAT were subjected to immunohistochemistry. Our results showed that the suppression of p‐JNK could lead to apoptosis and reduce proliferation in Eca109 cells. However, there was an elevated expression of p‐JNK protein in NAT compared with ESCC tissues, and there was significant difference between p‐JNK expression and pathological differentiation (P < 0.05) in Kazakh populations. Together, all the data we obtained in the present study indicated that the p‐JNK MAPK pathway was involved in pathogenesis of Kazakh's ESCC, and played a different roles in carcinogenesis and development of Kazakh's ESCC. © 2013 Wiley Periodicals, Inc.
Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine‐induced ulcerative cystitis in rat bladder
Authors: Chuang Shu‐Mien , Liu Keh‐Min , Li Yi‐Lun , Jang Mei‐Yu , Lee Hei‐Hwa , Wu Wen‐Jeng , Chang Wei‐Chiao , Levin Robert M. , Juan Yung‐Shun
Published: January 2013

Aims

The aims of the present study were to investigate voiding patterns, tissue constituents and the expressions of cyclooxygenase‐2 (COX‐2) and nitric oxide synthase (NOS) involved in ketamine‐induced ulcerative cystitis in rat urinary bladder.

Methods

Thirty Sprague–Dawley rats were distributed into three groups which received saline or ketamine (25 mg/kg/day) for a period of 14 and 28 days. In each group, cystometry was performed weekly and the concentration of ketamine and its metabolites (norketamine) was assayed. Paraffin‐embedded sections were stained with Masson's trichrome stain, and ketamine‐induced morphological changes were examined. Western blot analyses were carried out to examine the expressions of COX‐2 and different NOS isoforms in bladder tissues. Immunofluorescence study was done to evaluate the expressions of COX‐2 and macrophage infiltration (stained with ED‐1 macrophage cell surface antigen) within the bladder.

Results

Ketamine treatment resulted in bladder hyperactivity and the non‐voiding contractions were significantly increased. The urine concentrations of ketamine and norketamine were much higher in ketamine‐treated group. Moreover, ulcerated urothelium and mononuclear cell infiltration were noted in ketamine‐treated group. These alterations in urodynamic functions and tissue constituents were accompanied by increases in the expression of COX‐2. Two NOS isoforms (iNOS and eNOS) were also overexpressed, but no significant change was observed for nNOS. COX‐2 positive stained cells were significantly increased. Meanwhile, increased amounts of ED‐1 positive stained macrophages were present and most of COX‐2 expressed cells were co‐stained with ED‐1 in the early stage of ketamine treatment.

Conclusions

Ketamine treatment affected bladder tissues by enhancing interstitial fibrosis and accelerating macrophages infiltration. Ketamine also initiated the up‐regulations of COX‐2 and iNOS and eNOS expressions. These up‐regulated enzymes might play an important role in contributing to ketamine‐induced alterations in micturition patterns and ulcerative cystitis. Neurourol. Urodynam. 32:1137–1143, 2013. © 2013 Wiley Periodicals, Inc.
Improved Bloch‐Siegert based B1 mapping by reducing off‐resonance shift
Authors: Duan Qi , van Gelderen Peter , Duyn Jeff
Published: January 2013

An MRI method based on the Bloch‐Siegert (BS) shift phenomenon was recently proposed as a fast and precise way to map a radio frequency (RF) transmit field (B1+ field). For MRI at high field, the mapping sensitivity of this approach was limited by tissue heating associated with a BS irradiation pulse. To mitigate this, we investigated the possibility of lowering the off‐resonance frequency of this pulse since theoretical analysis indicated that the sensitivity of Bloch‐Siegert based B1+ mapping could be substantially improved when irradiating closer to resonance. Using optimized irradiation pulse shape and gradient crushers to minimize direct excitation effects, in vivo experiments on human brains at 7 T confirmed improved sensitivity with this approach. Improved sensitivity translated into an 80% reduction in B1+ estimation errors without increasing tissue heating. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
Robust network design: Formulations, valid inequalities, and computations
Authors: Koster Arie M.C.A. , Kutschka Manuel , Raack Christian
Published: January 2013

Traffic in communication networks fluctuates heavily over time. Thus, to avoid capacity bottlenecks, operators highly overestimate the traffic volume during network planning. In this article we consider telecommunication network design under traffic uncertainty, adapting the robust optimization approach of Bertsimas and Sim [Oper Res 52 (2004), 35–53]. We present two different mathematical formulations for this problem, provide valid inequalities, study the computational implications, and evaluate the realized robustness. To enhance the performance of the mixed‐integer programming solver, we derive robust cutset inequalities generalizing their deterministic counterparts. Instead of a single cutset inequality for every network cut, we derive multiple valid inequalities by exploiting the extra variables available in the robust formulations. We show that these inequalities define facets under certain conditions and that they completely describe a projection of the robust cutset polyhedron if the cutset consists of a single edge. For realistic networks and live traffic measurements, we compare the formulations and report on the speed‐up achieved by the valid inequalities. We study the “price of robustness” and evaluate the approach by analyzing the real network load. The results show that the robust optimization approach has the potential to support network planners better than present methods. © 2013 Wiley Periodicals, Inc. NETWORKS, 2013
A particle‐based method for mechanical analyses of planar fiber‐based materials
Authors: Persson J. , Isaksson P.
Published: January 2013

A new discrete element model to deal with rapid deformation and fracture of flat fibrous materials is derived. The method is based on classical mechanical theories and is a combination of traditional particle dynamics and nonlinear engineering beam theory. It is assumed that a fiber can be seen as a beam that is represented by discrete particles, which are moving according to Newton's laws of motion. Damage is dealt with by fracture of fiber‐segments and fiber–fiber bonds when the potential energy of a segment or bond exceeds the critical fracture energy. This allows fractures to evolve as a result of material properties only. To validate the model, four examples are shown and compared with analytical results found in literature. Copyright © 2013 John Wiley & Sons, Ltd.
The effect of surface treatments on the mechanical properties of basalt‐reinforced epoxy composites
Authors: Varley Russell J. , Tian Wendy , Leong K.H. , Leong Alan Y. , Fredo Flavio , Quaresimin Marino
Published: January 2013

Basalt fiber is an emerging alternative reinforcement to glass or carbon depending upon the application. An important contributing parameter to ultimate performance of any composite is the fiber–‐matrix interface, to which toughness and compressive strength are intimately related. To better understand this matrix fiber interaction in controlling properties, we compared different modification strategies and the impact upon the properties of composites. Strategies focussing upon mechanical interlocking through increased surface roughness and covalent chemical bonding using sol/get methods were explored. Combined methods were also used to explore synergistic behavior as well as the use of aliphatic triethylenetetramine (TETA) to react with any covalently attached epoxy groups. Results from single ply composites showed that when the properties were fiber or fiber/matrix dominated, the sol/gel or epoxy silane method gave the largest improvement in ultimate tensile strength increasing 66% and 27% for uni‐weave 0° and 45° laminas. The combined surface modification methods exhibited increases of 45% and 13% for the same laminas. When properties were matrix dominated, the combined strategies produced the highest improvements in ultimate tensile strength of about 55% compared with 37% for sol/gel modification. For 16‐ply plain weave laminates, epoxy silane surface treatments produced the greatest improvements in compressive and interlaminar shear strengths, increasing 52% and 21%, respectively. This correlated with fiber‐ and fiber/matrix‐dominated results from single ply laminas. The combined treatment using TETA however decreased shear and compressive strength by about 20%, while scanning electron microscopy (SEM) evaluation and dynamic mechanical thermal analysis (DMTA) attributed this to increased resin ductility and plasticization. © 2013 Society of Plastics Engineers
Nearly a third of abnormalities found after first‐trimester screening are different than expected:10‐year experience from a single center
Authors: Alamillo Christina M. L. , Krantz David , Evans Mark , Fiddler Morris , Pergament Eugene
Published: January 2013

Objective

This study aimed to assess the efficacy of first‐trimester aneuploidy screening in a single clinical setting.

Methods

Maternal age, nuchal translucency, and maternal serum levels of pregnancy‐associated plasma protein A and free beta human chorionic gonadotrophin comprised first‐trimester risk assessment for Down syndrome and trisomies 13/18. Means, screen positive rates, detection rates, and predictive values were calculated for Down syndrome and trisomies 13/18.

Results

Of the 23 329 first‐trimester screenings, 6.3% were screen positive: 5.7% for Down syndrome only, 0.4% for trisomies 13/18 only, and 0.3% for Down syndrome and trisomies 13/18. An abnormal karyotype was present in 3.9% of screen positives for Down syndrome, 13.8% of screen positives for trisomies 13/18, and 45.9% of screen positives for both Down syndrome and trisomies 13/18. Of the 97 pregnancies found to have an abnormal karyotype, 29.9% had chromosome abnormalities other than trisomy 13, 18, or 21, with expected clinical outcomes ranging from likely benign to uniformly lethal.

Conclusion

As expected, first‐trimester screening is effective for detecting aneuploidy for chromosomes 13, 18, and 21; however, a significant number of chromosomally abnormal pregnancies initially identified by first‐trimester screening have a different karyotype. With the possible exception of 47,XYY and 45,X, the dataset suggested that these different chromosome complements were likely to be randomly distributed. Nevertheless, prior to diagnostic testing, prospective parents should be counseled concerning the possibility of a chromosome abnormality other than the trisomies 13, 18, or 21. © 2013 John Wiley & Sons, Ltd.
Comparison of three methods of cervical measurement in the first trimester: single‐line, two‐line, and tracing
Authors: Retzke J. D. , Sonek J. D. , Lehmann J. , Yazdi B. , Kagan K. O.
Published: January 2013

Objectives

To compare three methods of cervical length measurements using ultrasound in the first trimester: single‐line, two‐line, and tracing.

Methods

Images appropriate for cervical length measurements were obtained using transvaginal ultrasound between 11 + 0 and 13 + 6 weeks’ gestation. The cervix was measured on stored images using three methods: a single straight line, two segments (two‐line method), and by tracing the distance along the cervical canal. Results were compared for intraoperator repeatability and interoperator variability. The degree of the cervical curvature was measured.

Results

The mean cervical measurement using the single‐line measurement was 32.8 (SD 4.4) mm. The mean cervical length was essentially the same using the two‐line and tracing measurement: 34.4 (SD 4.7) mm and 34.5 (SD 4.7) mm, respectively. Both intra‐ and interoperator agreement was high. The degree of curvature of the cervical canal was variable, with a resultant variability in the difference between the single straight line measurement and the other two types of measurement.

Conclusions

Using stored images, each of the measurement techniques is highly reproducible. Both the two‐line and the tracing methods yield larger measurements than the single‐line technique. Therefore, it appears that in select cases the straight line measurement significantly underestimates the actual cervical length. © 2013 John Wiley & Sons, Ltd.
Nano ZnO as cure activator and reinforcing filler in natural rubber
Authors: Panampilly Bindu , Thomas Sabu
Published: January 2013

Zinc oxide (ZnO) nanoparticles of size 20–90 nm and surface area 9.56 m2/g were synthesized from ZnCl2 and Chitosan and characterized by X‐ray diffraction, high resolution transmission electron microscopy (HRTEM), and scanning electron microscopy (SEM). Natural rubber (NR) vulcanizates containing nano ZnO was prepared by mill mixing and characterized by SEM, energy dispersive X‐ray analysis (EDAX), and HRTEM. Cure characteristics, free volume studies, bound rubber, crosslink density, and dynamic mechanical properties were evaluated and compared with that of NR vulcanizate containing conventional micro ZnO. Considering the cure characteristics, it was found that NR vulcanizate with 0.5 phr (parts per 100 g rubber) of nano ZnO showed low values of optimum cure time (t90) and very high cure rate index compared with 5 phr of conventional micro ZnO. The study shows that micro ZnO can be successfully replaced with nano ZnO for accelerated sulfur vulcanization process in NR, and preparation of vulcanizate containing nano ZnO with better properties as that of micro ZnO. The optimum dosage of nano ZnO as a cure activator in NR vulcanization was found to be 0.5 phr compared with conventional grade micro ZnO. This will lead to substantial cost reduction in the manufacture of rubber products and alleviate environmental pollution due to excess ZnO in rubber compounds. POLYM. ENG. SCI., 2013 © 2013 Society of Plastics Engineers
Pharmacologic Therapy for Nonalcoholic Fatty Liver Disease in Adults
Authors: Malinowski Scott S. , Byrd Jennifer S. , Bell Allison M. , Wofford Marion R. , Riche Daniel M.
Published: January 2013

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in hepatocytes in the absence of excessive alcohol intake, ranging in severity from simple steatosis to nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis can ultimately progress to cirrhosis and hepatocellular carcinoma. NAFLD is associated with cardiometabolic risk factors and is the most common chronic liver disease among adults in the Western Hemisphere. Although simple steatosis is generally considered a self‐limiting disease, evidence suggests an increased risk of cardiovascular disease, and, less conclusively, mortality, among individuals with NAFLD and/or NASH. The current standard of care for the treatment of patients with NAFLD focuses on lifestyle interventions, particularly diet and exercise. There is a lack of consensus regarding the most effective and appropriate pharmacologic therapy. A PubMed search was conducted using the medical subject heading terms “fatty liver” and “steatohepatitis.” This review focuses on the current pharmacologic options available for treating adults with NAFLD and/or NASH. Continued investigation of drugs or combinations that improve NAFLD progression is crucial. Clinicians, particularly pharmacists, must take an active role in identification and appropriate selection of pharmacotherapy for NAFLD.
Cellulose derivatives and graft copolymers as blocks for functional materials
Authors: Kang Hongliang , Liu Ruigang , Huang Yong
Published: January 2013

In this review, recent progresses in the synthesis of new cellulose derivatives and graft copolymers are summarized. Cellulose derivatives synthesized in new cellulose solvents, such as ionic liquids andNaOH/urea, and the regioselective synthesis of cellulose derivatives have attracted increasing attention in recent years and could be a more active field for cellulose in the future. Cellulose graft copolymers with well‐defined architectures synthesized by controlled/living radical polymerizations such as atomic transfer radical polymerization and their stimuli‐induced assembly have been investigated extensively. Stimuli‐responsive functional materials can be fabricated using either cellulose derivatives or graft copolymers, and they can be used as biosensors and carriers for controlled delivery of drugs and genes. The fabrication of functional materials with cellulosic blocks and their applications have a bright future. © 2013 Society of Chemical Industry
ESI, APCI, and MALDI tandem mass spectrometry of poly(methyl acrylate)s: A comparison study for the structural characterization of polymers synthesized via CRP techniques and the software application to analyze MS/MS data
Authors: Altuntaş Esra , Krieg Andreas , Baumgaertel Anja , Crecelius Anna C. , Schubert Ulrich S.
Published: January 2013

Research in polymer science and engineering is moving from classical methodologies to advanced analytical strategies in which mass spectrometry (MS)‐based techniques play a crucial role. The molecular complexity of polymers requires new characterization tools and approaches to elucidate the detailed structural information. In this contribution, a comparison study of poly(methyl acrylate)s (PMA) using different tandem mass spectrometry techniques (ESI, APCI, and MALDI MS/MS) is reported to provide insights into the macromolecular structure with the aid of a special MS/MS data interpretation software. Collision‐induced dissociation (CID) was utilized to examine the fragmentation pathways of PMAs synthesized via various controlled radical polymerization techniques. All three mass spectrometry techniques are used to analyze structural details of PMAs and the labile end‐groups are determined based on the fragmentation behavior in CID. Fragmentation products were identified which are characteristics for the cleavage between the polymer chain and the end‐group. The application of a tailor‐made software is shown to analyze complex MS/MS data, and it is proven that this kind of software will be helpful for polymer scientists to identify fragmentation products obtained by tandem mass spectrometry similar to the fields of proteomics, metabolomics, genomics, and glycomics. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013
Synthesis of thermosetting polyetherimide‐containing allyl groups
Authors: Lin Ching Hsuan , Chang Sheng Lung , Wang Yu Ru , Hsu Chin Kuang , Juang Tzong Yuan
Published: January 2013

An allyl‐containing diphenol, 1‐(3‐allyl‐4‐hydroxyphenyl)‐1‐(4‐hydoxyphenyl)‐1‐(6‐oxido‐6H ‐dibenz[c,e][1,2]oxaphosphorin‐6‐yl)ethane (1), was prepared from a one‐pot reaction of 9,10‐dihydro‐oxa‐10‐phosphaphenanthrene‐10‐oxide, 4‐hydroxyacetophenone, and 2‐allylphenol in the presence of p‐toluenesulfonic acid monohydrate. Then, an allyl‐containing dietheramine, 1‐(4‐(4‐aminophenoxy)phenyl)‐1‐(3‐allyl 4‐(4‐aminophenoxy)‐phenyl)‐1‐(6‐oxido‐6H‐dibenz[c,e][1,2] oxaphosphorin‐6‐yl)ethane (3), was prepared from the nucleophilic substitution of (1) with 4‐fluoronitrobenzene, followed by the reduction of the dinitro groups by Fe/HCl. A flexible polyetherimide (PEI) (4) with a curable characteristic was prepared from the condensation of (3) and 4,4′‐oxydiphthalic anhydride (ODPA) in m‐cresol in the presence of isoquinoline. Curing PEI (4) at 300 °C leads to PEI (5), which exhibits much a higher Tg value (307 °C) and a lower coefficient of thermal expansion (CTE) (29 ppm/°C) than PEI (4) (Tg = 253 °C, CTE 52 ppm/°C). © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013
The Food Stamps Program and Economic Security Among Low‐Income Families, Part I
Authors: Wagle Udaya R.
Published: January 2013

Part I: This analysis examines the role of the Food Stamps Program (FSP) in promoting economic security from 2004 to 2007. The goal is to explain how FSP has affected labor supply, income, and poverty at the family level. This analysis is published in two parts. This first article surveys the relevant research, develops the appropriate theoretical and empirical propositions, and presents and discusses the impact of FSP receipts on the poverty status of families. Findings suggest a significant contribution of the program's near‐cash Food Stamps toward increasing income and reducing poverty. The second article, to appear in issue 5.1, presents findings from a more systematic analysis of the complex relationship of FSP with labor supply, income, and poverty.
Non‐invasively derived respiratory severity score and oxygenation index in ventilated newborn infants
Authors: Iyer Narayan P. , Mhanna Maroun J.
Published: January 2013

Objective

To evaluate the association between the Respiratory Severity Score (RSS) and Oxygenation Index (OI) in intubated, mechanically ventilated, newborn infants.

Study Design

In a retrospective cohort study (December 2006 to June 2010) medical records of all infants who were admitted to our Neonatal Intensive Care Unit (NICU) and required invasive mechanical ventilation were reviewed for patients' demographics, ventilator settings, and arterial blood gas (ABG).

Results

During the study period 2,332 infants were admitted to our NICU, and 425 infants were intubated and had an ABG with a gestational age of 30.5 ± 4.9 weeks and a birth weight of 1,635 ± 923 g (mean ± standard deviation). There was a strong association between RSS and OI in infants with oxygen saturation (SaO2) between 88% and 94% (R2 = 0.982, n = 101; P < 0.001).

Conclusion

In intubated newborn infants, there is a strong association between RSS and OI at SaO2 between 88% and 94%. Pediatr Pulmonol. 2013; 48:364–369. © 2013 Wiley Periodicals, Inc.
Optimization of anti‐pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: VI. Executive summary
Authors: Zobell Jeffery T. , Young David C. , Waters C. Dustin , Ampofo Krow , Stockmann Chris , Sherwin Catherine M.T. , Spigarelli Michael G.
Published: January 2013

Acute pulmonary exacerbations (APE) are well‐described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti‐pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an overview of the classes of intravenous anti‐pseudomonal antibiotics, the findings of anti‐pseudomonal antibiotic utilization surveys, the current antibiotic dosing recommendations from the U.S. and Europe, and the pharmacokinetic (PK) and pharmacodynamic (PD) differences between CF and non‐CF individuals. Anti‐pseudomonal antibiotic classes include beta‐lactams, aminoglycosides, fluoroquinolones, and colistimethate sodium. Recent surveys of antibiotic utilization in CF Foundation‐accredited care centers have shown that a large number of centers are not following recommended dosing strategies despite published recommendations in the U.S. and Europe. The recommended doses for anti‐pseudomonal antibiotics may be higher than FDA‐approved doses due to PK and PD differences. As a large portion of CF patients will not regain their lung function following an APE, it seems possible that currently available anti‐pseudomonal agents are being used sub‐optimally. As new anti‐pseudomonal agents are not currently available, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat pulmonary exacerbations in an effort to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Pediatr Pulmonol. 2013; 48:525–537. © 2013 Wiley Periodicals, Inc.
Cloning and characterization of canine prostate‐specific membrane antigen
Authors: Schmidt Sonja , Fracasso Giulio , Colombatti Marco , Naim Hassan Y.
Published: January 2013

BACKGROUND

Prostate‐specific membrane antigen (PSMA) is a promising biomarker in the diagnosis of prostate cancer and a potential target for antibody‐based therapeutic strategies. We isolated the canine PSMA cDNA and investigated the cellular and biochemical characteristics of the recombinant protein as a potential target for animal preclinical studies of antibody based‐therapies.

METHODS

Canine PSMA cDNA was isolated by PCR, cloned into expression vectors and transfected into COS‐1 and MDCK cells. The biosynthesis and glycosylation of the recombinant protein were investigated in pulse‐chase experiments, the cellular localization by confocal laser microscopy, the mode of association of PSMA with the membrane with solubilization in different detergents and its quaternary structure in sucrose‐density gradients.

RESULTS

Canine PSMA shows 91% amino acid homology to human PSMA, whereby the major difference is a longer cytoplasmic tail of canine PSMA compared to its human counterpart. Canine PSMA is trafficked efficiently along the secretory pathway, undergoes homodimerization when it acquires complex glycosylated mature form. It associates with detergent‐resistant membranes, which act as platforms along its intracellular trafficking. Confocal analysis revealed canine PSMA at the cell surface, Golgi, and the endoplasmic reticulum. A similar distribution is revealed for human PSMA, yet with reduced cell surface levels.

CONCLUSIONS

The cloning, expression, biosynthesis, processing and localization of canine PSMA in mammalian cells is described. We demonstrate that canine PSMA reveals similar characteristics to human PSMA rendering this protein useful as a translational model for investigations of prostate cancer as well as a suitable antigen for targeted therapy studies in dogs. Prostate 73: 642–650, 2013. © 2012 Wiley Periodicals, Inc.
Sequence recombination improves target specificity in a redesigned collagen peptide abc‐type heterotrimer
Authors: Giddu Sumana , Xu Fei , Nanda Vikas
Published: January 2013

Stability of the collagen triple helix is largely governed by its imino acid content, namely the occurrence of proline and 4R‐hydroxyproline at the X and Y positions, respectively, of the periodic (Gly‐X‐Y)n sequence. Although other amino acids at these positions reduce stability of the triple helix, this can be partially compensated by introducing intermolecular side‐chain salt bridges. This approach was previously used to design an abc‐type heterotrimer composed of one basic, one acidic, and one neutral imino acid rich chain (Gauba and Hartgerink, J Am Chem Soc 2007;129:15034–15041). In this study, an abc‐type heterotrimer was designed to be the most stable species using a sequence recombination strategy that preserved both the amino acid composition and the network of interchain salt bridges of the original design. The target heterotrimer had the highest Tm of 50°C, 7°C greater than the next most stable species. Stability of the heterotrimer decreased with increasing ionic strength, consistent with the role of intermolecular salt bridges in promoting stability. Quantitative meta‐analysis of these results and published stability measurements on closely related peptides was used to discriminate the contributions of backbone propensity and side‐chain electrostatics to collagen stability. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Impact of deglycosylation and thermal stress on conformational stability of a full length murine igG2a monoclonal antibody: Observations from molecular dynamics simulations
Authors: Wang Xiaoling , Kumar Sandeep , Buck Patrick M. , Singh Satish K.
Published: January 2013

With the rise of antibody based therapeutics as successful medicines, there is an emerging need to understand the fundamental antibody conformational dynamics and its implications towards stability of these medicines. Both deglycosylation and thermal stress have been shown to cause conformational destabilization and aggregation in monoclonal antibodies. Here, we study instabilities caused by deglycosylation and by elevated temperature (400 K) by performing molecular dynamic simulations on a full length murine IgG2a mAb whose crystal structure is available in the Protein Data bank. Cα‐atom root mean square deviation and backbone root mean square fluctuation calculations show that deglycosylation perturbs quaternary and tertiary structures in the CH2 domains. In contrast, thermal stress pervades throughout the antibody structure and both Fabs and Fc regions are destabilized. The thermal stress applied in this study was not sufficient to cause large scale unfolding within the simulation time and most amino acid residues showed similar average solvent accessible surface area and secondary structural conformations in all trajectories. CH3 domains were the most successful at resisting the conformational destabilization. The simulations helped identify aggregation prone regions, which may initiate cross‐β motif formation upon deglycosylation and upon applying thermal stress. Deglycosylation leads to increased backbone fluctuations and solvent exposure of a highly conserved APR located in the edge β‐strand A of the CH2 domains. Aggregation upon thermal stress is most likely initiated by two APRs that overlap with the complementarity determining regions. This study has important implications for rational design of antibody based therapeutics that are resistant towards aggregation. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Role of tyrosine hot‐spot residues at the interface of colicin E9 and immunity protein 9: A comparative free energy simulation study
Authors: Luitz Manuel P. , Zacharias Martin
Published: January 2013

The endonuclease activity of the bacterial colicin 9 enzyme is controlled by the specific and high‐affinity binding of immunity protein 9 (Im9). Molecular dynamics simulation studies in explicit solvent were used to investigate the free energy change associated with the mutation of two hot‐spot interface residues [tyrosine (Tyr): Tyr54 and Tyr55] of Im9 to Ala. In addition, the effect of several other mutations (Leu33Ala, Leu52Ala, Val34Ala, Val37Ala, Ser48Ala, and Ile53Ala) with smaller influence on binding affinity was also studied. Good qualitative agreement of calculated free energy changes and experimental data on binding affinity of the mutations was observed. The simulation studies can help to elucidate the molecular details on how the mutations influence protein–protein binding affinity. The role of solvent and conformational flexibility of the partner proteins was studied by comparing the results in the presence or absence of solvent and with or without positional restraints. Restriction of the conformational mobility of protein partners resulted in significant changes of the calculated free energies but of similar magnitude for isolated Im9 and for the complex and therefore in only modest changes of binding free energy differences. Although the overall binding free energy change was similar for the two Tyr–Ala mutations, the physical origin appeared to be different with solvation changes contributing significantly to the Tyr55Ala mutation and to a loss of direct protein–protein interactions dominating the free energy change due to the Tyr54Ala mutation. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Dielectric and piezoelectric properties of manganese‐modified PbHfO3–PbTiO3–Pb(Mg1/3Nb2/3)O3 ternary ceramics with morphotropic phase boundary compositions
Authors: Wang Dawei , Cao Maosheng , Zhao Quanliang , Cui Yan , Zhang Shujun
Published: January 2013

High piezoelectric and electromechanical properties were reported in the PbHfO3–PbTiO3–Pb(Mg1/3Nb2/3)O3 ternary system with morphotropic phase boundary (MPB) compositions. This work focuses on the effect of MnO2 addition on 0.8Pb(Hf0.443Ti0.557)O3–0.2PMN (0.8PHT–0.2PMN) ceramics. It was observed that the Mn acceptor modification induced a “hardening” effect in 0.8PHT–0.2PMN, with decreased piezoelectric coefficients d33 and dielectric loss tan δ and a significantly increased mechanical quality factor Qm. Moreover, the 0.2 wt% MnO2‐doped 0.8PHT–0.2PMN ceramics exhibited good piezoelectric and electromechanical properties with d33, planar electromechanical coupling kp and Qm being on the order of 360 pC/N, 61% and 700, respectively, showing advantages compared to those of commercial hard PZT4 ceramics, which is attractive for high power applications. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Monitoring Correlated Profile and Multivariate Quality Characteristics
Authors: Amiri Amirhossein , Zou Changliang , Doroudyan Mohammad H.
Published: January 2013

Monitoring multivariate quality characteristics is very common in production and service environment. Therefore, many control charts have been suggested by authors for monitoring multivariate processes. In another side, profile monitoring is a new approach in the area of statistical process control. In this approach, the quality of a product or a process is characterized by a relation between one response variable and one or more independent variables. In practice, sometimes the quality of a product or a process is represented by a correlated profile and multivariate quality characteristics. To the best of our knowledge, there is no method for monitoring this type of quality characteristics. Note that monitoring correlated profile and multivariate quality characteristics separately leads to misleading results. In this article, we specifically focus on correlated simple linear profile and multivariate normal quality characteristics and propose a method using multivariate exponentially weighted moving average control chart to monitor the correlated profile and multivariate quality characteristics simultaneously. The performance of the proposed control chart is evaluated by simulation studies in terms of average run length criterion. Finally, the proposed method is applied to a real case in the electronics industry. Copyright © 2013 John Wiley & Sons, Ltd.
A repeated measures model for analysis of continuous outcomes in sequential parallel comparison design studies
Authors: Doros Gheorghe , Pencina Michael , Rybin Denis , Meisner Allison , Fava Maurizio
Published: January 2013

Previous authors have proposed the sequential parallel comparison design (SPCD) to address the issue of high placebo response rate in clinical trials. The original use of SPCD focused on binary outcomes, but recent use has since been extended to continuous outcomes that arise more naturally in many fields, including psychiatry. Analytic methods proposed to date for analysis of SPCD trial continuous data included methods based on seemingly unrelated regression and ordinary least squares. Here, we propose a repeated measures linear model that uses all outcome data collected in the trial and accounts for data that are missing at random. An appropriate contrast formulated after the model has been fit can be used to test the primary hypothesis of no difference in treatment effects between study arms. Our extensive simulations show that when compared with the other methods, our approach preserves the type I error even for small sample sizes and offers adequate power and the smallest mean squared error under a wide variety of assumptions. We recommend consideration of our approach for analysis of data coming from SPCD trials. Copyright © 2013 John Wiley & Sons, Ltd.
The care of dying men
Authors: Jeyakumar Jana , Feuer David
Published: January 2013

The care of dying patients begins long before they approach the last few days of life. The authors explain how advance care planning, involving the whole multidisciplinary team and supporting the family are as important as symptom control in the last few hours of life. Copyright © 2013 John Wiley & Sons
Decay of correlations for non-uniformly expanding systems with general return times
Authors: MELBOURNE IAN , TERHESIU DALIA
Published: January 2013

We give a unified treatment of decay of correlations for non-uniformly expanding systems with a good inducing scheme. In addition to being more elementary than previous treatments, our results hold for general integrable return time functions under fairly mild conditions on the inducing scheme.
AN UPPER BOUND FOR THE NUMBER OF ODD MULTIPERFECT NUMBERS
Authors: YUAN PINGZHI
Published: January 2013

A natural number $n$ is called $k$-perfect if $\sigma (n)= kn$. In this paper, we show that for any integers $r\geq 2$ and $k\geq 2$, the number of odd $k$-perfect numbers $n$ with $\omega (n)\leq r$ is bounded by $\left({\lfloor {4}^{r} { \mathop{ \log } \nolimits }_{3} 2\rfloor + r\atop r} \right){ \mathop{ \sum } \nolimits }_{i= 1}^{r} \left({\lfloor kr/ 2\rfloor \atop i} \right)$, which is less than ${4}^{{r}^{2} } $ when $r$ is large enough.
Ronald Reagan in Ireland, 1984: A Different Cold War?
Authors: GOSSE VAN
Published: January 2013

On 2–5 June 1984, Ronald Reagan toured Ireland. He was met by widespread protest regarding US policies in Central America, including reproofs from the Irish government, and snubs from the Catholic hierarchy. Yet for Irish diplomats, engaged in a long-term effort to encourage Britain towards a settlement of the civil war in Northern Ireland, the visit was a success. This article argues that these immediate resonances have wider meanings, which complicate our understanding of the Cold War. Both large and small “cold wars” (the US in Central America; the US versus the Soviets; Ireland versus Britain) got mixed up with each other during this visit, contributing to the resolution of all three: the Europeans pushed the US to the negotiating table in Central America; following re-election, Reagan began his rapprochement with Mikhail Gorbachev; in September 1984, the President began nudging his closest ally, Margaret Thatcher, towards a rapprochment with the Irish Republic. The relationship between these overlapping frames underlines the article's claims that “cold wars” are a useful category of international relations, in which small nations can be significant factors. Tensions over Ronald Reagan in Ireland remind us that the global Cold War was always much more complex than superpower rivalries.
Putting Personalisation into Practice: Work-Focused Interviews in Jobcentre Plus
Authors: TOERIEN MERRAN , SAINSBURY ROY , DREW PAUL , IRVINE ANNIE
Published: January 2013

The principle of personalisation is widespread across the UK's public sector, but precisely what this means is unclear. A number of theoretical typologies have been proposed but there has been little empirical study of how personalisation is translated into practice on the frontline. We address this gap through analysis of a unique dataset: over 200 audio and video recordings of work-focused interviews in Jobcentre Plus offices. Through detailed analysis of these recordings, we show that personalisation reflects two key dimensions: the substantive (what advisers do) and the procedural (how they do it). We illustrate these dimensions, showing how each represents a continuum, and propose a typology of personalisation in practice, reflecting how the dimensions interact. We conclude with some thoughts on the relevance of our findings for advisory practice in the future under the Coalition government's new Work Programme.
Analysis of Complaints in a Rural Emergency Medical Service System
Authors: Risavi Brian L. , Buzzard Erik , Heile Christopher J.
Published: January 2013

Introduction

The health care industry is increasingly focused on customer service, one aspect of which is dealing with customer complaints. The purpose of this study was to assess the prevalence and nature of complaints against prehospital providers in a rural Emergency Medical Services (EMS) system.

Methods

This retrospective study of logged complaints utilized data from May 28, 1999 through September 26, 2008. All complaints were investigated by a single trained staff member of the regional EMS office. He interviewed witnesses, and reviewed statements and other documentation related to the complaints. Each complaint was classified into one of four categories: (1) operational; (2) clinical; (3) educational; or (4) customer service. In addition, each complaint was examined to determine if the grievance was founded. The study was conducted in a seven-county region of western Pennsylvania with a population of 639,641 and more than 3,000 EMS providers.

Results

There were 110 complaints over a nine-year period (approximately 12 per year). Forty were considered unfounded complaints (43%) and 49 persons (45%) had made more than a single complaint. No EMS provider had an EMS certification suspended or revoked based on a clinically-related complaint. The data revealed a substantial number of complaints for which insufficient information was available to allow a conclusion based on reasonable certainty or the degree of certainty expected of a reasonable person evaluating the facts.

Conclusion

One hundred ten complaints were logged for the study EMS program. No complaints violated treatment protocols. Forty complaints were unfounded. There were 49 “repeat” complaints against providers who had previously had complaints made against them.

RisaviBL, BuzzardE, HeileCJ. Analysis of complaints in a rural emergency medical services system. Prehosp Disaster Med. 2013;28(2):1-3.
The Utility of Parent Report in the Assessment of Working Memory among Childhood Brain Tumor Survivors
Authors: Howarth Robyn A. , Ashford Jason M. , Merchant Thomas E. , Ogg Robert J. , Santana Victor , Wu Shengjie , Xiong Xiaoping , Conklin Heather M.
Published: January 2013

Childhood brain tumor survivors are at increased risk for neurocognitive impairments, including working memory (WM) problems. WM is typically assessed using performance measures. Little is known about the value of parent ratings for identifying WM difficulties, the relationship between rater and performance measures, or predictors of parent-reported WM problems in this population. Accordingly, the current study examined the utility of parent report in detecting WM difficulties among childhood brain tumor survivors treated with conformal radiation therapy (n= 50) relative to siblings (n= 40) and solid tumor survivors not receiving central nervous system-directed therapy (n= 40). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants were administered WM measures (digit span, self-ordered search tasks). Findings revealed parents rated brain tumor survivors as having significantly more WM problems (p< .01) compared to controls. However, the BRIEF-WM scale demonstrated poor sensitivity and specificity for detecting performance-based problems. Significant, albeit modest, correlations were found between the BRIEF-WM scale and performance measures (r= −.24–.22;p< .05) for the combined group. Age at testing, socioeconomic status, and IQ were significant predictors of parent reported WM problems. Rater and performance measures offer complimentary yet different information in assessing WM, which reiterates the importance of using both within the context of clinical assessment. (JINS, 2013,19, 1–10)