bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Systemic Sclerosis With a Unique Colonic Microbial Consortium
Authors: Volkmann Elizabeth R. , Chang Yu‐Ling , Barroso Nashla , Furst Daniel E. , Clements Philip J. , Gorn Alan H. , Roth Bennett E. , Conklin Jeffrey L. , Getzug Terri , Borneman James , McGovern Dermot P. B. , Tong Maomeng , Jacobs Jonathan P. , Braun Jonathan
Published: January 2016

Objective

To compare colonic microbial composition in systemic sclerosis (SSc) patients and healthy controls and to determine whether certain microbial genera are associated with gastrointestinal (GI) tract symptoms in patients with SSc.

Methods

Healthy controls were age‐ and sex‐matched (1:1) with adult SSc patients. Cecum and sigmoid mucosal lavage samples were obtained during colonoscopy. The microbiota in these samples were determined by Illumina HiSeq 2000 16S sequencing, and operational taxonomic units were selected. Linear discriminant analysis effect size was used to identify the genera that showed differential expression in SSc patients versus controls. Differential expression analysis for sequence count data was used to identify specific genera associated with GI tract symptoms.

Results

Among 17 patients with SSc (88% female; median age 52.1 years), the mean ± SD total GI Tract 2.0 score was 0.7 ± 0.6. Principal coordinate analysis illustrated significant differences in microbial communities in the cecum and sigmoid regions in SSc patients versus healthy controls (both P = 0.001). Similar to the findings in inflammatory disease states, SSc patients had decreased levels of commensal bacteria, such as Faecalibacterium and Clostridium, and increased levels of pathobiont bacteria, such as Fusobacterium and γ‐Proteobacteria, compared with healthy controls. Bifidobacterium and Lactobacillus, which are typically reduced under conditions of inflammation, were also increased in abundance in patients with SSc. In SSc patients with moderate/severe GI tract symptoms, the abundance of Bacteroides fragilis was decreased, and that of Fusobacterium was increased, compared with patients who had no or mild symptoms.

Conclusion

This study demonstrates a distinct colonic microbial signature in SSc patients compared with healthy controls. This unique ecologic change may perpetuate immunologic aberrations and contribute to clinical manifestations of SSc.
Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis
Authors: Coates Laura C. , Kavanaugh Arthur , Mease Philip J. , Soriano Enrique R. , Laura Acosta‐Felquer Maria , Armstrong April W. , Bautista‐Molano Wilson , Boehncke Wolf‐Henning , Campbell Willemina , Cauli Alberto , Espinoza Luis R. , FitzGerald Oliver , Gladman Dafna D. , Gottlieb Alice , Helliwell Philip S. , Husni M. Elaine , Love Thorvardur J. , Lubrano Ennio , McHugh Neil , Nash Peter , Ogdie Alexis , Orbai Ana‐Maria , Parkinson Andrew , O'Sullivan Denis , Rosen Cheryl F. , Schwartzman Sergio , Siegel Evan L. , Toloza Sergio , Tuong William , Ritchlin Christopher T.
Published: January 2016

Objective

To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA).

Methods

GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA, based on consensus achieved at face‐to‐face meetings and via online surveys. We conducted literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin disease, and nail disease) and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, using an online questionnaire.

Results

Six overarching principles had ≥80% agreement among both health care professionals (n = 135) and patient research partners (n = 10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin disease, nail disease, and comorbidities in the setting of PsA, using the Grading of Recommendations, Assessment, Development and Evaluation process. Agreement of >80% was reached for approval of the individual recommendations and the overall schema.

Conclusion

We present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other health care providers, and patient research partners). Further updates are anticipated as the therapeutic landscape in PsA evolves.
Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis
Authors: Ahmed Ammad , Hollan Ivana , Curran Samuel A. , Kitson Susan M. , Riggio Marcello P. , Mikkelsen Knut , Almdahl Sven M. , Aukrust Pål , McInnes Iain B. , Goodyear Carl S.
Published: January 2016

Objective

Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD) via mechanisms that have not yet been defined. Inflammatory pathways, in particular within the vascular adventitia, are implicated in the pathogenesis of primary CVD but could be amplified in RA at the local tissue level. The aim of this study was to examine the aortic adventitia of coronary artery disease (CAD) patients with or without RA to determine the cytokine profile contained therein.

Methods

Aortic adventitia and internal thoracic artery biopsy specimens obtained from 19 RA patients and 20 non‐RA patients undergoing coronary artery bypass graft surgery were examined by immunohistochemistry.

Results

Interleukin‐18 (IL‐18), IL‐33, and tumor necrosis factor (TNF) were expressed in aortic adventitia biopsy specimens from both groups, and expression of these cytokines was significantly higher in RA patients. In RA patients, IL‐33 expression in endothelial cells correlated positively with the number of swollen joints, suggesting a link between the systemic disease state and the local vascular tissue microlesion.

Conclusion

The presence of the proinflammatory cytokines IL‐18, IL‐33, and TNF may play a role in the inflammatory process within the adventitia that contributes to plaque formation and destabilization. In theory, the amplified expression of these cytokines may contribute to the known increased occurrence and severity of CAD in patients with RA.
Netrin‐1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin‐Induced Pulmonary Fibrosis
Authors: Sun Huanxing , Zhu Yangyang , Pan Hongyi , Chen Xiaosong , Balestrini Jenna L. , Lam TuKiet T. , Kanyo Jean E. , Eichmann Anne , Gulati Mridu , Fares Wassim H. , Bai Hanwen , Feghali‐Bostwick Carol A. , Gan Ye , Peng Xueyan , Moore Meagan W. , White Eric S. , Sava Parid , Gonzalez Anjelica L. , Cheng Yuwei , Niklason Laura E. , Herzog Erica L.
Published: January 2016

Objective

Fibrocytes are collagen‐producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)–related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells.

Methods

We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc‐related ILD were cultured on these scaffolds, and CD45+pro‐ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin‐1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin‐1+/− mice.

Results

Compared with control lung scaffolds, lung scaffolds from patients with SSc‐related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc‐related ILD increased production of pro‐ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc‐related ILD demonstrated increased pro‐ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin‐1–expressing CD14low cells in patients with SSc‐related ILD was observed, and antibody‐mediated netrin‐1 neutralization attenuated detection of CD45+pro‐ColIα1+ cells in all settings. Netrin‐1+/− mice were protected against bleomycin‐induced lung fibrosis and fibrocyte accumulation.

Conclusion

Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin‐1–dependent pathway. Netrin‐1 regulates bleomycin‐induced pulmonary fibrosis in mice. Netrin‐1 might be a novel therapeutic target in SSc‐related ILD.
Silent Monosodium Urate Crystal Deposits Are Associated With Severe Coronary Calcification in Asymptomatic Hyperuricemia: An Exploratory Study
Authors: Andrés Mariano , Quintanilla María‐Amparo , Sivera Francisca , Sánchez‐Payá José , Pascual Eliseo , Vela Paloma , Ruiz‐Nodar Juan‐Miguel
Published: January 2016

Objective

To evaluate the association between monosodium urate (MSU) crystal deposits in patients with asymptomatic hyperuricemia and the severity and extension of coronary artery disease (CAD).

Methods

In this cross‐sectional study, consecutive inpatients with a non–ST elevation acute coronary event and asymptomatic hyperuricemia (serum uric acid concentration of ≥7.0 mg/dl) or normouricemia (serum uric acid concentration of <7.0 mg/dl) were enrolled. In patients with asymptomatic hyperuricemia, the presence of MSU crystals was determined by ultrasound evaluation of both knees and first metatarsophalangeal joints and by compensated polarized light microscopy. CAD was assessed by coronary angiography, and the following variables were considered: 1) the presence of moderate‐to‐severe coronary artery calcification, 2) the number of significant coronary stenoses, and 3) the presence of multivessel disease. The association between variables indicating the severity of CAD and the presence of MSU crystals was analyzed by multivariate regression.

Results

One hundred forty patients were enrolled. After ultrasonography and microscopic analyses were performed, the patients were classified as having normouricemia (n = 66), asymptomatic hyperuricemia alone (n = 61), and asymptomatic hyperuricemia with MSU crystals (n = 13). The prevalence of moderate‐to‐severe coronary calcification was significantly higher in the patients with asymptomatic hyperuricemia with MSU crystals compared with patients with asymptomatic hyperuricemia alone and patients with normouricemia (P = 0.003). An independent association was observed between the presence of moderate‐to‐severe calcification and asymptomatic hyperuricemia with crystals (odds ratio 16.8, P = 0.002). No significant association was observed for the other variables.

Conclusion

Silent deposition of MSU crystals in patients with asymptomatic hyperuricemia was associated with more severe coronary calcification, which suggests more severe CAD in relation to crystal deposition.
A Meta‐Analysis to Estimate the Placebo Effect in Randomized Controlled Trials in Juvenile Idiopathic Arthritis
Authors: Demirkaya Erkan , Lanni Stefano , Bovis Francesca , Galasso Roberta , Ravelli Angelo , Palmisani Elena , Consolaro Alessandro , Pederzoli Silvia , Marafon Denise , Simianer Stefan , Martini Alberto , Ruperto Nicolino , Pistorio Angela ,   for the Paediatric Rheumatology International Trials Organisation
Published: January 2016

Objective

To estimate the placebo effect in juvenile idiopathic arthritis (JIA) through a meta‐analysis of phase III clinical trials with placebo comparator.

Methods

A systematic literature search was carried out up to December 2014. For parallel design studies the outcome was evaluated as a single 1‐dimensional (1‐D) variable or as a composite score; outcomes of withdrawal studies were evaluated only as composite scores.

Results

We included 26 of 224 trials (12%). In trials with parallel study design and a 1‐D outcome, the placebo effect was 0.35 (95% confidence interval [95% CI] 0.27–0.43). Among trials with parallel study design and a composite score outcome, the placebo rate response was higher in trials that included patients with nonsystemic JIA (0.35 [95% CI 0.29–0.42]) than in trials that included only patients with systemic JIA (0.17 [95% CI 0.10–0.30]). In the withdrawal design trials, the percentages of patients receiving placebo who had disease flares during the double‐blind phase were lower in trials that included patients with nonsystemic JIA (0.55 [95% CI 0.47–0.64]) than in trials that included only patients with systemic JIA (0.68 [95% CI 0.33–0.90]).

Conclusion

In trials with a parallel study design a sizable number of patients seem to benefit from a placebo effect, although this effect is smaller in patients with systemic JIA. In trials with a withdrawal design the inverse placebo effect is similar among the different JIA categories. This placebo effect should be considered when evaluating the effectiveness of proposed interventions and for future calculations of sample size.
A practical hybrid model of application, integration, and competencies at interactive table conferences in histology (ITCH)
Authors: Ettarh Rajunor
Published: January 2016

Significant changes have been implemented in the way undergraduate medical education is structured. One of the challenges for component courses such as histology in medical and dental curricula is to restructure and deliver training within new frameworks. This article describes the process of aligning the purpose and experience in histology laboratory to the goal of applying knowledge gained to team‐based medical practice at Tulane University School of Medicine. Between 2011 and 2015, 711 medical students took either a traditional laboratory‐based histology course (353 students) or a team‐based hybrid histology course with active learning in laboratory (358 students). The key difference was in the laboratory component of the hybrid course ‐ interactive table conferences in histology—during which students developed new competencies by working in teams, reviewing images, solving problems by applying histology concepts, and sharing learning. Content, faculty and online resources for microscopy were the same in both courses. More student‐student and student‐faculty interactions were evident during the hybrid course but student evaluation ratings and grades showed reductions following introduction of table conferences when compared to previous ratings. However, outcomes at National Board of Medical Examiners® (NBME®) Subject Examination in Histology and Cell Biology showed significant improvement (72.4 ± 9.04 and 76.44 ± 9.36 for percent correct answers, traditional and hybrid courses, respectively, P < 0.0001). This model of table conferences to augment the traditional histology laboratory experience exemplifies the extent that restructuring enhancements can be used in currently taught courses in the undergraduate medical curriculum. Anat Sci Educ 9: 286–294. © 2016 American Association of Anatomists.
An Approach for the Selective Detection of Nitric Oxide in Biological Systems: An in vitro and in vivo Perspective
Authors: Gupta Neha , Imam Reja Shahi , Bhalla Vandana , Gupta Muskan , Kaur Gurcharan , Kumar Manoj
Published: January 2016

A naphthalimide‐based fluorescent probe, LyNP‐NO, was designed and synthesized for the selective detection of exogenously and endogenously generated nitric oxide (NO) in C6 glial cells. In addition, LyNP‐NO was also explored for monitoring endogenous NO levels in rat hippocampus at various tissue depths by stimulating the brain with N‐methyl‐d‐aspartate (NMDA).
Anion‐Exchange Properties of Trifluoroacetate and Triflate Salts of N‐Alkylammonium Resorcinarenes
Authors: Pan Fangfang , Beyeh Ngong Kodiah , Bertella Stefania , Rissanen Kari
Published: January 2016

The synthesis of N‐benzyl‐ and N‐cyclohexylammonium resorcinarene trifluoroacetate (TFA) and triflate (OTf) salt receptors was investigated. Solid‐state analysis by single‐crystal X‐ray diffraction revealed that the N‐alkylammonium resorcinarene salts (NARSs) with different upper substituents had different cavity sizes and different affinities for anions. Anion‐exchange experiments by mixing equimolar amounts of N‐benzylammonium resorcinarene trifluoroacetate and N‐cyclohexylammonium resorcinarene triflate, as well as N‐benzylammonium resorcinarene triflate and N‐cyclohexylammonium resorcinarene trifluoroacetate showed that the NARS with flexible benzyl groups preferred the larger OTf anion, whereas the rigid cyclohexyl groups preferred the smaller TFA anions. The anion‐exchange processes were confirmed in the solid state by single‐crystal and powder X‐ray diffraction experiments and in the gas phase by electrospray ionization mass spectrometry.
Controllability and Observability of Parallel Magnetic Suspension Systems
Authors: Mizuno Takeshi , Takasaki Masaya , Ishino Yuji
Published: January 2016

The controllability and observability of parallel magnetic suspension systems are investigated analytically. A parallel magnetic suspension system has multiple floators and electromagnets driven by a single amplifier. In this paper, the multiplicity is set to an arbitrary counting number n. Parallel systems are classified into four types based on the output of the power amplifier and the connection of the coils. This paper treats three of them: current‐controlled with series‐connected coils; voltage‐controlled with series‐connected coils; and voltage‐controlled with parallel‐connected coils. The conditions of controllability and observability of each system are clarified. The feasibility of parallel magnetic suspension is demonstrated by simulations and experiments.
Functioning and disability in autism spectrum disorder: A worldwide survey of experts
Authors: de Schipper Elles , Mahdi Soheil , de Vries Petrus , Granlund Mats , Holtmann Martin , Karande Sunil , Almodayfer Omar , Shulman Cory , Tonge Bruce , Wong Virginia V.C.N. , Zwaigenbaum Lonnie , Bölte Sven
Published: January 2016

Objective: This study is the second of four to prepare International Classification of Functioning, Disability and Health (ICF; and Children and Youth version, ICF(‐CY)) Core Sets for Autism Spectrum Disorder (ASD).The objective of this study was to survey the opinions and experiences of international experts on functioning and disability in ASD. Methods: Using a protocol stipulated by the World Health Organization (WHO) and monitored by the ICF Research Branch, an email‐based questionnaire was circulated worldwide among ASD experts, and meaningful functional ability and disability concepts were extracted from their responses. These concepts were then linked to the ICF(‐CY) by two independent researchers using a standardized linking procedure. Results: N = 225 experts from 10 different disciplines and all six WHO‐regions completed the survey. Meaningful concepts from the responses were linked to 210 ICF(‐CY) categories. Of these, 103 categories were considered most relevant to ASD (i.e., identified by at least 5% of the experts), of which 37 were related to Activities and Participation, 35 to Body functions, 22 to Environmental factors, and 9 to Body structures. A variety of personal characteristics and ASD‐related functioning skills were provided by experts, including honesty, loyalty, attention to detail and creative talents. Reported gender differences in ASD comprised more externalizing behaviors among males and more internalizing behaviors in females. Conclusion: The ICF(‐CY) categories derived from international expert opinions indicate that the impact of ASD on functioning extends far beyond core symptom domains. Autism Res 2016, 9: 959–969. © 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research
Feed additive production by fermentation of herbPolygonum hydropiperL. and cassava pulp with simultaneous flavonoid dissolution
Authors: Song Zhen‐Tao , Zhu Ming‐Jun
Published: January 2016

Fermentation of herbPolygonum hydropiperL. (PHL) and cassava pulp (CP) for feed additive production with simultaneous flavonoid dissolution was investigated, and a two‐stage response surface methodology (RSM) based on Plackett−Burman factorial design (PB design) was used to optimize the flavonoid dissolution and protein content. Using the screening function of PB design, four different significant factors for the two response variables were acquired: factors A (CP) and B (PHL) for the flavonoid dissolution versus factors G (inoculum size) and H (fermentation time) for protein content. Then, two RSMs were used sequentially to improve the values of the two response variables separately. The mutual corroboration of the experimental results in the present study confirmed the validity of the associated experimental design. The validation experiment showed a flavonoid dissolution rate of 94.00%, and a protein content of 18.20%, gaining an increase in 21.20% and 199.10% over the control, respectively. The present study confirms the feasibility of feed additive productionby Saccharomyces cerevisiaewith CP and PHL and simultaneous optimization of flavonoid dissolution and protein content using a two‐stage RSM.
Synthesis of pH‐responsive β‐CD‐based star polymer and impact of its self‐assembly behavior on pectinase activity
Authors: Hu Dong , Yang Hong , Liu Jiangtao , Lei Zhongli
Published: January 2016

A novel type of pH‐responsive star polymer based on β‐cyclodextrin (β‐CD) was synthesized and further covalently conjugated with enzyme. The impact of its self‐assembly behavior on enzyme activity was investigated. In our design, azide containing the polymer (N3)7‐β‐CD‐(PtBA)14 was synthesized via atom transfer radical polymerization of tert‐butyl acrylate using (N3)7‐β‐CD‐(Br)14 as the multifunctional initiator. The final product (N3)7‐β‐CD‐(PAA)14 was obtained via hydrolysis and covalently conjugating pectinase onto pH‐responsive polyacrylic acid (PAA) arms. PAA can change its conformation with the self‐assembly by altered pH, leading its nanostructure into micellar nanoparticles in aqueous solution and further affecting the activity of immobilized pectinase. The results were proved by fluorescence spectroscopy and dynamic light scattering. This system proves that the activity of immobilized enzyme can be tailored predictably, and this pH‐responsive polymer holds great potential for controllable delivery of enzymes.
Techno‐economic assessment of the effect of torrefaction on fast pyrolysis of pine
Authors: Winjobi Olumide , Shonnard David R. , Bar‐Ziv Ezra , Zhou Wen
Published: January 2016

Techno‐economic assessment of bio‐oil production from fast pyrolysis of pine was explored through process simulation. In this work, bio‐oil production via a one‐step pyrolysis route and a two‐step pyrolysis which included a torrefaction step before fast pyrolysis were modeled to process 1000 MT/day of dry feed (dry basis) through the pyrolyzer at a temperature of 530 °C while two‐step ‐pyrolysis was investigated at three different torrefaction temperatures of 290, 310, and 330 °C. Different scenarios that included the use of fossil energy to produce process heat as well as use of renewable energy either through the combustion of char or a portion of the condensates from ‐torrefaction were also investigated. Economic analysis indicates that a torrefaction step results in a reduction in the minimum selling price of bio‐oil produced which reduced further with ‐torrefaction ‐temperature with lowest bio‐oil price of $1.04/gal obtained for a two‐step pyrolysis at torrefaction ‐temperature of 330 °C in comparison to $1.32/gal for a one‐step process. Minimum selling price of bio‐oil on an energy basis however suggests a higher price of about $22.19/GJ for a two‐step in ‐comparison to $16.89/GJ for a one‐step. There could be a trade‐offs between the higher quality and the higher selling price considering the downstream upgrade step to hydrocarbon fuel. © 2016 Society of Chemical Industry and John Wiley & Sons, Ltd
Five recommendations to kick‐start bioeconomy innovation in the UK
Authors: Burns Caitlin , Higson Adrian , Hodgson Edward
Published: January 2016

Introduction

The UK’s bioeconomy has the potential to be world leading. However, political, economic, and social barriers are holding back innovation in this sector. Key interventions are needed to allow bioeconomic innovation to flourish. Caitlin Burns and Adrian Higson of the NNFCC The Bioeconomy Consultants, and Edward Hodgson of Aberystwyth University, make five recommendations to help the UK catch up with global competitors and stimulate investment in innovative bioeconomy. © 2016 Society of Chemical Industry and John Wiley & Sons, Ltd
Effect of dietary fibers on losartan uptake and transport in Caco‐2 cells
Authors: Iwazaki Ayano , Takahashi Naho , Miyake Reiko , Hiroshima Yuka , Abe Mariko , Yasui Airi , Imai Kimie
Published: January 2016

The objective of this study was to assess the effect of dietary fibers on the transport of losartan, an angiotensin II type 1 receptor blocker, in small intestinal cells. Using Caco‐2 cells in vitro, losartan uptake and transport were evaluated in the presence of various fibers (cellulose, chitosan, sodium alginate and glucomannan). Dietary fibers caused a decrease in the uptake of losartan, with chitosan causing a significant reduction. Chitosan and glucomannan significantly reduced the transport of losartan, while cellulose or sodium alginate did not. Dietary fibers also reduced the level of free losartan; however, this did not correlate with the observed reduction in losartan uptake and transport. In summary, chitosan had the greatest inhibitory effect on losartan uptake and transport, and this potential interaction should be considered in patients taking losartan. Copyright © 2016 John Wiley & Sons, Ltd.
Diabetes in the Cohen Rat Intensifies the Fetal Pancreatic Damage Induced by the Diabetogenic High Sucrose Low Copper Diet
Authors: Ergaz Zivanit , Neeman‐azulay Meytal , Weinstein‐Fudim Liza , Weksler‐Zangen Sarah , Shoshani‐Dror Dana , Szyf Moshe , Ornoy Asher
Published: January 2016

Intrauterine hyperglycemic environment could harm the fetus making it more susceptible to develop postnatal glucose intolerance. A possible mechanism is compromise of the fetal pancreatic development. We previously found that a high sucrose low copper diabetogenic diet induces type 2 diabetes in the Cohen diabetic sensitive rats, but not in the Sabra control rats. However, oxidative stress was observed in the placenta and term fetal liver of diabetic and nondiabetic controls. We now investigated whether the fetal pancreas is affected by this diet and whether the effects result from oxidative stress, maternal hyperglycemia, or both. Term fetal pancreases were evaluated for morphology, beta cells, oxidative stress, apoptosis, and DNA methylation. There were no microscopic changes in hematoxylin and eosin stained sections and beta cells immunostaining in the pancreas of fetuses of both strains. Fetuses of the sensitive strain fed diabetogenic diet had significantly higher activity of superoxide dismutase and catalase, elevated levels of low molecular weight antioxidants, and more intense immunostaining for nuclear factor kappa‐B and hypoxia inducing factor‐1α. Both strains fed diabetogenic diet had increased immunostaining for Bcl‐2‐like protein and caspase 3 and decreased immunostaining for 5‐methylcytosine in their islets and acini. Our data suggest that maternal diabetogenic diet alters apoptotic rate and epigenetic steady states in the term fetal pancreas, unrelated to maternal diabetes. Maternal hyperglycemia further increases pancreatic oxidative stress, aggravating the pancreatic damage. The diet‐induced insults to the fetal pancreas may be an important contributor to the high susceptibility to develop diabetes following metabolic intrauterine insults
Trends in examination performance and exposure to standardised tests in England and Wales
Authors: Goldstein Harvey , Leckie George
Published: January 2016

Schools in England and Wales since the late 1980s have been compared in terms of their performances in public examinations and standardised test scores in the form of ‘school league tables’, with Wales ceasing to produce these after 2001. One of the factors related to performance in examinations is the choice of the examination board, with five main boards currently active in England and Wales. In this paper, we study differences in student uptake and performance among boards and how this has changed over time. By contrasting the experiences of England and Wales the results of our analyses provide a commentary on recent attempts to understand the effects of league tables on school performance.
Has provoking microbiota aggression driven the obesity epidemic?
Authors: Chassaing Benoit , Gewirtz Andrew T.
Published: January 2016

Alterations in the gut microbiome have increasingly been implicated in driving obesity and its associated diseases, but underlying mechanisms remain poorly defined. Herein, in addition to reviewing the field, we hypothesize that a highly significant causative factor of such inflammatory disease‐associated microbiome alterations is a more aggressive microbiota that encroaches upon its host, with components having high potential to activate host pro‐inflammatory gene expression in a manner that drives metabolic disease. We further hypothesize that a range of societal changes, including use of antibiotics and increasing consumption of food additives, have provoked such microbiota aggression and, consequently, may be contributing factors to the increased incidence of obesity and its associated diseases.
Structure and photoluminescent properties of green‐emitting terbium‐doped GdV1−xPxO4 phosphor prepared by solution combustion method
Authors: Motloung S. J. , Shaat S. K. K. , Tshabalala K. G. , Ntwaeaborwa O. M.
Published: January 2016

Terbium‐doped gadolinium orthovanadate (GdVO4:Tb3+), orthophosphate monohydrate (GdPO4·H2O:Tb3+) and orthovanadate–phosphate (GdV,PO4:Tb3+) powder phosphors were synthesized using a solution combustion method. X‐Ray diffraction analysis confirmed the formation of crystalline GdVO4, GdPO4·H2O and GdV,PO4. Scanning electron microscopy images showed that the powder was composed of an agglomeration of particles of different shapes, ranging from spherical to oval to wire‐like structures. The chemical elements present were confirmed by energy dispersive spectroscopy, and the stretching mode frequencies were determined by Fourier transform infrared spectroscopy. UV–visible spectroscopy spectra showed a strong absorption band with a maximum at 200 nm assigned to the absorption of VO43− and minor excitation bands assigned to f → f transitions of Tb3+. Four characteristic emission peaks were observed at 491, 546, 588 and 623 nm, and are attributed to 5D4 → 7Fj (j = 6, 5, 4 and 3). The photoluminescent prominent green emission peak (5D4 → 7F5) was centred at 546 nm. The structure and possible mechanism of light emission from GdV1−xPxO4:% Tb3+ are discussed. Copyright © 2016 John Wiley & Sons, Ltd.
Integrated process for high conversion and high yield protein PEGylation
Authors: Pfister David , Morbidelli Massimo
Published: January 2016

Over the past decades, PEGylation has become a powerful technique to increase the in vivo circulation half‐life of therapeutic proteins while maintaining their activity. The development of new therapeutic proteins is likely to require further improvement of the PEGylation methods to reach even better selectivity and yield for reduced costs. The intensification of the PEGylation process was investigated through the integration of a chromatographic step in order to increase yield and conversion for the production of mono‐PEGylated protein. Lysozyme was used as a model protein to demonstrate the feasibility of such approach. In the integrated reaction/separation process, chromatography was used as fractionation technique in order to isolate and recycle the unreacted protein from the PEGylated products. This allows operating the reactor with short reaction times so as to minimize the production of multi‐PEGylated proteins (i.e., conjugated to more than one polymer). That is, the reaction is stopped before the desired product (i.e., the mono‐PEGylated protein) can further react, thus leading to limited conversion but high yield. The recycling of the unreacted protein was then considered to drive the protein overall conversion to completion. This approach has great potential to improve processes whose yield is limited by the further reaction of the product leading to undesirable by‐products. Biotechnol. Bioeng. 2016;113: 1711–1718. © 2016 Wiley Periodicals, Inc.
Mechanical thrombectomy for emergent large vessel occlusion: a critical appraisal of recent randomized controlled clinical trials
Authors: Tsivgoulis Georgios , Safouris Apostolos , Katsanos Aristeidis H. , Arthur Adam S. , Alexandrov Andrei V.
Published: January 2016

Background and Purpose

After numerous attempts to prove efficacy for endovascular treatment of ischemic stroke, a series of recent randomized controlled clinical trials (RCTs) established fast mechanical thrombectomy (MT) as a safe and effective novel treatment for emergent large vessel occlusion (ELVO) in the anterior cerebral circulation.

Methods

We reviewed five recent RCTs that evaluated the safety and efficacy of MT in ELVO patients and captured available information on recanalization/reperfusion, symptomatic intracranial hemorrhage (sICH), clinical outcome, and mortality. MT was performed with stent retrievers, aspiration techniques, or a combination of these endovascular approaches. We applied meta‐analytical methodology to evaluate the pooled effect of MT on recanalization/reperfusion, sICH, functional independence (modified Rankin scale score of 0–2) and 3‐month mortality rates in comparison to best medical therapy (BMT).

Results

MT was associated with increased likelihood of complete recanalization/reperfusion (RR: 2.22; 95%CI: 1.89–2.62; P < 0.00001) and 3‐month functional independence (RR: 1.72; 95%CI: 1.48–1.99; P < 0.00001) without any heterogeneity across trials (I2 = 0%). The absolute benefit increase in MT for complete recanalization/reperfusion and functional independence was 44 (NNT = 2) and 16 (NNT = 6), respectively. MT was not associated with increased risk of 3‐month mortality (15% with MT vs. 19% with BMT) and sICH (4.6% with MT vs. 4.3% with BMT), while small heterogeneity was detected across the included trials (I2 < 25%).

Conclusions

MT is a safe and highly effective treatment for patients with ELVO in the anterior circulation. For every six ELVO patients treated with MT three more will achieve complete recanalization at 24 h following symptom onset and one more will be functionally independent at 3 months in comparison to BMT.
Designing anti‐diabetic β‐cells microcapsules using polystyrenic sulfonate, polyallylamine, and a tertiary bile acid: Morphology, bioenergetics, and cytokine analysis
Authors: Mooranian Armin , Negrulj Rebecca , Al‐Salami Hani , Morahan Grant , Jamieson Emma
Published: January 2016

Purpose: Recently sodium alginate (SA)‐poly‐l‐ornithine (PLO) microcapsules containing pancreatic β‐cells that showed good morphology but low cell viability (<27%) was designed. In this study, two new polyelectrolytes, polystyrenic sulfonate (PSS; at 1%) and polyallylamine (PAA; at 2%) were incorporated into a microencapsulated‐formulation, with the aim of enhancing the physical properties of the microcapsules. Following incorporation, the structural characteristics and cell viability were investigated. The effects of the anti‐inflammatory bile acid, ursodeoxycholic acid (UDCA), on microcapsule morphology, size, and stability as well as β‐cell biological functionality was also examined. Methods: Microcapsules were prepared using PLO‐PSS‐PAA‐SA mixture and two types of microcapsules were produced: without UDCA (control) and with UDCA (test). Microcapsule morphology, stability, and size were examined. Cell count, microencapsulation efficiency, cell bioenergetics, and activity were also examined. Results: The new microcapsules showed good morphology but cell viability remained low (29% ± 3%). UDCA addition improved cell viability post‐microencapsulation (42 ± 5, P < 0.01), reduced swelling (P < 0.01), improved mechanical strength (P < 0.01), increased Zeta‐potential (P < 0.01), and improved stability. UDCA addition also increased insulin production (P < 0.01), bioenergetics (P < 0.01), and decreased β‐cell TNF‐α (P < 0.01), IFN‐gamma (P < 0.01), and IL‐6 (P < 0.01) secretions. Conclusions: Addition of 4% UDCA to a formulation system consisting of 1.8% SA, 1% PLO, 1% PSS, and 2% PAA enhanced cell viability post‐microencapsulation and resulted in a more stable formulation with enhanced encapsulated β‐cell metabolism, bioenergetics, and biological activity with reduced inflammation. This suggests potential application of UDCA, when combined with SA, PLO, PSS, and PAA, in β‐cell microencapsulation and diabetes treatment. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:501–509, 2016
Therapeutic angiogenesis using tumor cell‐conditioned medium
Authors: Jang Hyeon‐Ki , Kim Byung‐Soo , Han Jin , Yoon Jeong‐Kee , Lee Ju‐Ro , Jeong Gun‐Jae , Shin Jung‐Youn
Published: January 2016

Stem cell‐conditioned medium (CM), which contains angiogenic factors that are secreted by stem cells, represents a potential therapy for ischemic diseases. Along with stem cells, tumor cells also secrete various angiogenic factors. Here, tumor cells as a cell source of CM for therapeutic angiogenesis was evaluated and the therapeutic efficacy of tumor cell CM in mouse hindlimb ischemia models was demonstrated. CM obtained from a human fibrosarcoma HT1080 cell line culture was compared with CM obtained from a human bone marrow‐derived mesenchymal stem cell (MSC) culture. HT1080 CM contained higher concentrations of angiogenic factors compared with MSC CM, which was attributable to the higher cell density that resulted from a much faster growth rate of HT1080 cells compared with MSCs. For use in in vitro and in vivo angiogenesis studies, HT1080 CM was diluted such that HT1080 CM and MSC CM would have the same cell number basis. The two types of CMs induced the same extent of human umbilical vein endothelial cell (HUVEC) proliferation in vitro. The injection of HT1080 CM into mouse ischemic limbs significantly improved capillary density and blood perfusion compared with the injection of fresh medium. Although the therapeutic outcome of HT1080 CM was similar to that of MSC CM, the preparation of CM by tumor cell line culture would be much more efficient due to the faster growth and unlimited life‐time of the tumor cell line. These data suggest the potential application of tumor cell CM as a therapeutic modality for angiogenesis and ischemic diseases. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:456–464, 2016
Description of common musculoskeletal findings in Williams Syndrome and implications for therapies
Authors: Copes L.E. , Pober B.R. , Terilli C. A.
Published: January 2016

Williams syndrome (WS), also referred to as Williams‐Beuren syndrome (WBS), is a relatively rare genetic disorder affecting ∼1/10,000 persons. Since the disorder is caused by a micro‐deletion of ∼1.5 Mb, it is not surprising that the manifestations of WS are extremely broad, involving most body systems. In this paper, we primarily focus on the musculoskeletal aspects of WS as these findings have not been the subject of a comprehensive review. We review the MSK features commonly seen in individuals with WS, along with related sensory and neurological issues interacting with and compounding underlying MSK abnormalities. We end by providing perspective, particularly from the vantage point of a physical therapist, on therapeutic interventions to address the most common MSK and related features seen in WS. Clin. Anat. 29:578–589, 2016. © 2016 Wiley Periodicals, Inc.
Prader–Willi Syndrome: A spectrum of anatomical and clinical features
Authors: Hurren Bradley J. , Flack Natasha A.M.S.
Published: January 2016

Prader–Willi Syndrome (PWS) is estimated to affect 400,000 people worldwide. First described clinically in 1956, PWS is now known to be a result of a genetic mutation, involving Chromosome 15. The phenotypical appearance of individuals with the syndrome follows a similar developmental course. During infancy, universal hypotonia accompanied by feeding problems, hypogonadism, and dolichocephaly are evident. Characteristic facial features such as narrow bifrontal diameter, almond‐shaped eyes, and small mouth (with downturned corners and thin upper lip) may also be evident at this stage. In early childhood, the craniofacial features become more obvious and a global developmental delay is observed. Simultaneously, individuals develop hyperphagia that leads to excessive or rapid weight gain, which, if untreated, exists throughout their lifespan and may predispose them to numerous, serious health issues. The standard tool for differential diagnosis of PWS is genetic screening; however, clinicians also need to be aware of the characteristic features of this disorder, including differences between the genetic subtypes. As the clinical manifestations of the syndrome vary between individuals and become evident at different developmental time points, early assessment is hindered. This article focuses on the clinical and anatomical manifestations of the syndrome and highlights the areas of discrepancy and limitations within the existing literature. Clin. Anat. 29:590–605, 2016. © 2016 Wiley Periodicals, Inc.
Anticancer efficacy of the hypoxia‐activated prodrug evofosfamide (TH‐302) in osteolytic breast cancer murine models
Authors: Liapis Vasilios , Zinonos Irene , Labrinidis Agatha , Hay Shelley , Ponomarev Vladimir , Panagopoulos Vasilios , Zysk Aneta , DeNichilo Mark , Ingman Wendy , Atkins Gerald J. , Findlay David M. , Zannettino Andrew C. W. , Evdokiou Andreas
Published: January 2016

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. Evofosfamide (TH‐302) is a prodrug created by the conjugation of 2‐nitroimidazole to bromo‐isophosphoramide mustard (Br‐IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross‐linking effector, Br‐IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA‐MB‐231‐TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer‐induced bone destruction was measured using micro‐CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth. Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. Evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone.
Influence of Pre‐organised Architecture on Cell Adhesion by Using Multivalent RGD Compounds
Authors: Grassin Adrien , Jourdan Muriel , Dumy Pascal , Boturyn Didier
Published: January 2016

Multimeric RGD‐containing compounds were designed to study the influence of ligand architecture on binding avidity. We report the synthesis of a series of tetrameric RGD compounds and their in vitro biological evaluation. The further application of molecular dynamic simulations for structural studies of RGD derivatives reveals that the observed affinities correlate with the accessibility of segregated RGD motif.
Characterization of the Shigella and Salmonella Type III Secretion System Tip–Translocon Protein–Protein Interaction by Paramagnetic Relaxation Enhancement
Authors: Kaur Kawaljit , Chatterjee Srirupa , De Guzman Roberto N.
Published: January 2016

Many Gram‐negative pathogens, such as Shigella and Salmonella, assemble the type III secretion system (T3SS) to inject virulence proteins directly into eukaryotic cells to initiate infectious diseases. The needle apparatus of the T3SS consists of a base, an extracellular needle, a tip protein complex, and a translocon. The atomic structure of the assembled tip complex and the translocon is unknown. Here, we show by NMR paramagnetic relaxation enhancement (PRE) that the mixed α–β domain at the distal region of the Shigella and Salmonella tip proteins interacts with the N‐terminal ectodomain of their major translocon proteins. Our results reveal the binding surfaces involved in the tip–translocon protein–protein interaction and provide insights about the assembly of the needle apparatus of the T3SS.
A Bis(guanidinium)alcohol Attached to a Hairpin Polyamide: Synthesis, DNA Binding, and Plasmid Cleavage
Authors: Wirth‐Hamdoune Daniela , Ullrich Stefan , Scheffer Ute , Radanović Toni , Dürner Gerd , Göbel Michael W.
Published: January 2016

Bis(guanidinium)alcohols have been designed to react with phosphodiester substrates in a fast transphosphorylation step, a quasi‐intramolecular process taking place in contact ion pairs. Here the attachment of such compounds to Dervan‐type hairpin polyamides is described. The resulting conjugate 1 binds to AT‐rich DNA duplexes with affinity similar to that of the parent polyamide as shown by UV melting experiments and CD titrations. Conjugate 1 nicks plasmid DNA at concentrations ranging from micromolar to high nanomolar.
Juxta‐terminal Helix Unwinding as a Stabilizing Factor to Modulate the Dynamics of Transmembrane Helices
Authors: Mortazavi Armin , Rajagopalan Venkatesan , Sparks Kelsey A. , Greathouse Denise V. , Koeppe Roger E.
Published: January 2016

Transmembrane helices of integral membrane proteins often are flanked by interfacial aromatic residues that can serve as anchors to aid the stabilization of a tilted transmembrane orientation. Yet, physical factors that govern the orientation or dynamic averaging of individual transmembrane helices are not well understood and have not been adequately explained. Using solid‐state 2H NMR spectroscopy to examine lipid bilayer‐incorporated model peptides of the GWALP23 (acetyl‐GGALW(LA)6LWLAGA‐amide) family, we observed substantial unwinding at the terminals of several tilted helices spanning the membranes of DLPC, DMPC, or DOPC lipid bilayers. The fraying of helix ends might be vital for defining the dynamics and orientations of transmembrane helices in lipid bilayer membranes.