An injectable particle-hydrogel hybrid system for glucose-regulatory insulin delivery

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Fuli Zhao, Di Wu, Dan Yao, Ruiwei Guo, Weiwei Wang, Anjie Dong, Deling Kong, Jianhua Zhang
Long-term and daily subcutaneous injections of insulin for the treatment of insulin-dependent diabetic patients often lead to poor patient compliance and undesired complications. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, their applications are limited by clinically irrelevant glucose-responsive range, slow response rate, low tissue-adhesiveness and poor biodegradability, undesirable leakage at normoglycemic state. Herein, we report a novel implantable insulin hydrogel for glucose-regulated delivery of insulin based on a unique particle-hydrogel hybrid platform featuring fast glucose responsiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, and full biodegradability for safe use. The system was thoroughly characterized both in vitro and in vivo and was demonstrated to hold these unique functions. Using streptozotocin-induced diabetic mice as a model, it was shown that a single subcutaneous injection of the insulin-loaded particle-hydrogel formulation led to quasi-steady-state blood glucose levels within the normal range for about two weeks. In addition, the preparation of the formulation only involved simple mixing and self-assembling processes, and thus it had great scalability and reproducibility for practical use. The highly feasible preparation, excellent performance, inherent biocompatibility and biodegradability make this novel composite hydrogel promising platform for diabetes therapy.Statement of SignificancePhenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, these hydrogels, mostly based on a variety of PBA-containing acrylamide monomers, are still far from clinical reality. Building upon a unique particle-hydrogel hybrid platform, herein we report a novel implantable insulin storage and delivery system with multifunctionalities including fast glucose-sensitiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, biodegradable materials for safe use and well-controlled insulin release. These unique functions were demonstrated through research both in vitro and in vivo. In addition, the preparation of the formulation was simple, and thus it had great scalability and reproducibility for practical use.

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Hierarchical structure and compressive deformation mechanisms of bighorn sheep (Ovis canadensis) horn

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Wei Huang, Alireza Zaheri, Jae-Young Jung, Horacio D. Espinosa, Joanna Mckittrick
Bighorn sheep (Ovis canadensis) rams hurl themselves at each other at speeds of ∼9 m/s (20 mph) to fight for dominance and mating rights. This necessitates impact resistance and energy absorption mechanisms, which stem from material-structure components in horns. In this study, the material hierarchical structure as well as correlations between the structure and mechanical properties are investigated. The major microstructural elements of horns are found as tubules and cell lamellae, which are oriented with (∼30⁰) angle with respect to each other. The cell lamellae contain keratin cells, in the shape of pancakes, possessing an average thickness of ∼2 µm and diameter of ∼20–30 µm. The morphology of keratin cells reveals the presence of keratin fibers and intermediate filaments with diameter of ∼200 nm and ∼12 nm, respectively, parallel to the cell surface. Quasi-static and high strain rate impact experiments, in different loading directions and hydration states, revealed a strong strain rate dependency for both dried and hydrated conditions. A strong anisotropy behavior was observed under impact for the dried state. The results show that the radial direction is the most preferable impact orientation because of its superior energy absorption. Detailed failure mechanisms under the aforementioned conditions are examined by bar impact recovery experiments. Shear banding, buckling of cell lamellae, and delamination in longitudinal and transverse direction were identified as the cause for strain softening under high strain rate impact. While collapse of tubules occurs in both quasi-static and impact tests, in radial and transverse directions, the former leads to more energy absorption and impact resistance.Statement of SignificanceBighorn sheep (Ovis canadensis) horns show remarkable impact resistance and energy absorption when undergoing high speed impact during the intraspecific fights. The present work illustrates the hierarchical structure of bighorn sheep horn at different length scales and investigates the energy dissipation mechanisms under different strain rates, loading orientations and hydration states. These results demonstrate how horn dissipates large amounts of energy, thus provide a new path to fabricate energy absorbent and crashworthiness engineering materials.

Graphical abstract

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Viscoelastic properties of α-keratin fibers in hair

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Yang Yu, Wen Yang, Marc André Meyers
Considerable viscoelasticity and strain-rate sensitivity are a characteristic of α-keratin fibers, which can be considered a biopolymer. The understanding of viscoelasticity is an important part of the knowledge of the overall mechanical properties of these biological materials. Here, horse and human hairs are examined to analyze the sources of this response. The dynamic mechanical response of α-keratin fibers over a range of frequencies and temperatures is analyzed using a dynamic mechanical analyzer. The α-keratin fibers behave more elastically at higher frequencies while they become more viscous at higher temperatures. A glass transition temperature of ∼55°C is identified. The stress relaxation behavior of α-keratin fibers at two strains, 0.02 and 0.25, is established and fit to a constitutive equation based on the Maxwell-Wiechert model. The constitutive equation is further compared to the experimental results within the elastic region and a good agreement is obtained. The two relaxation constants, 14s and 359s for horse hair and 11s and 207s for human hair, are related to two hierarchical levels of relaxation: the amorphous matrix-intermediate filament interfaces, for the short term, and the cellular components for the long term. Results of the creep test also provide important knowledge on the uncoiling and phase transformation of the α-helical structure as hair is uniaxially stretched. SEM results show that horse hair has a rougher surface morphology and damaged cuticles. It also exhibits a lower strain-rate sensitivity of 0.05 compared to that of 0.11 for human hair. After the horse and human hairs are chemically treated and the disulfide bonds are cleaved, they exhibit a similar strain-rate sensitivity of ∼0.05. FTIR results confirms that the human hair is more sensitive to the –S–S– cleavage, resulting in an increase of cysteic acid content. Therefore, the disulfide bonds in the matrix are experimentally identified as one source of the strain-rate sensitivity and viscoelasticity in α-keratin fibers.Statement of significanceHair has outstanding mechanical strength which is equivalent to metals on a density-normalized basis. It possesses, in addition to the strength, a large ductility that is enabled by either the unfolding of the alpha helices and/or the transformation of these helices to beta sheets. We identify the deformation and failure mechanisms and connect them to the hierarchical structure, with emphasis on the significant viscoelasticity of these unique biological materials.

Graphical abstract

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Temporal development of near-native functional properties and correlations with qMRI in self-assembling fibrocartilage treated with exogenous lysyl oxidase homolog 2

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Pasha Hadidi, Derek D. Cissell, Jerry C. Hu, Kyriacos A. Athanasiou
Advances in cartilage tissue engineering have led to constructs with mechanical integrity and biochemical composition increasingly resembling that of native tissues. In particular, collagen cross-linking with lysyl oxidase has been used to significantly enhance the mechanical properties of engineered neotissues. In this study, development of collagen cross-links over time, and correlations with tensile properties, were examined in self-assembling neotissues. Additionally, quantitative MRI metrics were examined in relation to construct mechanical properties as well as pyridinoline cross-link content and other engineered tissue components. Scaffold-free meniscus fibrocartilage was cultured in the presence of exogenous lysyl oxidase, and assessed at multiple time points over 8weeks starting from the first week of culture. Engineered constructs demonstrated a 9.9-fold increase in pyridinoline content, reaching 77% of native tissue values, after 8weeks of culture. Additionally, engineered tissues reached 66% of the Young's modulus in the radial direction of native tissues. Further, collagen cross-links were found to correlate with tensile properties, contributing 67% of the tensile strength of engineered neocartilages. Finally, examination of quantitative MRI metrics revealed several correlations with mechanical and biochemical properties of engineered constructs. This study displays the importance of culture duration for collagen cross-link formation, and demonstrates the potential of quantitative MRI in investigating properties of engineered cartilages.Statement of SignificanceThis is the first study to demonstrate near-native cross-link content in an engineered tissue, and the first study to quantify pyridinoline cross-link development over time in a self-assembling tissue. Additionally, this work shows the relative contributions of collagen and pyridinoline to the tensile properties of collagenous tissue for the first time. Furthermore, this is the first investigation to identify a relationship between qMRI metrics and the pyridinoline cross-link content of an engineered collagenous tissue.

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Nanocomposite hydrogels stabilized by self-assembled multivalent bisphosphonate-magnesium nanoparticles mediate sustained release of magnesium ion and promote in-situ bone regeneration

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Kunyu Zhang, Sien Lin, Qian Feng, Chaoqun Dong, Yanhua Yang, Gang Li, Liming Bian
Hydrogels are appealing biomaterials for applications in regenerative medicine due to their tunable physical and bioactive properties. Meanwhile, therapeutic metal ions, such as magnesium ion (Mg²⁺), not only regulate the cellular behaviors but also stimulate local bone formation and healing. However, the effective delivery and tailored release of Mg²⁺ remains a challenge, with few reports on hydrogels being used for Mg²⁺ delivery. Bisphosphonate exhibits a variety of specific bioactivities and excellent binding affinity to multivalent cations such as Mg²⁺. Herein, we describe a nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. These nanoparticles bearing acrylate groups on the surface not only function as effective multivalent crosslinkers to strengthen the hydrogel network structure, but also promote the mineralization of hydrogels and mediate sustained release of Mg²⁺. The released Mg²⁺ ions facilitate stem cell adhesion and spreading on the hydrogel substrates in the absence of cell adhesion ligands, and promote osteogenesis of the seeded hMSCs in vitro. Furthermore, the acellular porous hydrogels alone can support in situ bone regeneration without using exogenous cells and inductive agents, thereby greatly simplifying the approaches of bone regeneration therapy.Statement of SignificanceIn this study, we developed a novel bioactive nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. Such hydrogels are stabilized by the multivalent crosslinking domains formed by the aggregation of Ac-BP-Mg NPs, and therefore show enhanced mechanical properties, improved capacity for mineralization, and controlled release kinetics of Mg²⁺. Moreover, the released Mg²⁺ can enhance cell adhesion and spreading, and further promote the osteogenic differentiation of hMSCs. Owing to these unique properties, these acellular hydrogels alone can well facilitate the in vivo bone regeneration at the intended sites. We believe that the strategy reported in this work opens up a new route to develop biopolymer-based nanocomposite hydrogels with enhanced physical and biological functionalities for regenerative medicine.

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Development of gelatin/ascorbic acid cryogels for potential use in corneal stromal tissue engineering

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Li-Jyuan Luo, Jui-Yang Lai, Shih-Feng Chou, Yi-Jen Hsueh, David Hui-Kang Ma
To offer an ideal hospitable environment for corneal keratocyte growth, the carrier materials can be functionalized with incorporation of signaling molecules to regulate cell biological events. This study reports, for the first time, the development of gelatin/ascorbic acid (AA) cryogels for keratocyte carriers in vitro and in vivo. The cryogel samples were fabricated by blending of gelatin with varying amounts of AA (0-300 mg) and carbodiimide cross-linking via cryogelation technique. Hydrophilic AA content in the carriers was found to significantly affect cross-linking degree and pore dimension of cryogels, thereby dictating their mechanical and biological stability and AA release profile. The cryogel carriers with low-to-moderate AA loadings were well tolerated by rabbit keratocyte cultures and anterior segment eye tissues, demonstrating good ocular biocompatibility. Although higher incorporated AA level contributed to enhanced metabolic activity and biosynthetic capacity of keratocytes grown on cryogel matrices, the presence of excessive amounts of AA molecules could lead to toxic effect and limit cell proliferation and matrix production. The cytoprotective activity against oxidative stress was shown to be strongly dependent on AA release, which further determined cell culture performance and tissue reconstruction efficiency. With the optimum AA content in carrier materials, intrastromally implanted cell/cryogel constructs exhibited better capability to enhance tissue matrix regeneration and transparency maintenance as well as to mitigate corneal damage in an alkali burn-induced animal model. It is concluded that understanding of antioxidant molecule-mediated structure-property-function interrelationships in gelatin/AA cryogels is critical to designing carrier materials for potential use in corneal stromal tissue engineering.Statement of significanceMultifunctional cryogel material can offer an ideal hospitable environment for cell-mediated tissue reconstruction. To our knowledge, this is the first report describing the use of gelatin/ascorbic acid (AA) cryogels as keratocyte carriers for corneal stromal tissue engineering. The AA loading during cryogel fabrication is found to have a significant effect on cross-linking degree and pore dimension, mechanical and biological stability, ocular biocompatibility, cell culture performance, and cytoprotective activity, giving comprehensive insight into fine-tuning the structure-property-function interrelationships of keratocyte carrier material. Using an alkali burn-induced animal model, we present evidence that with the optimum AA loading into cryogel materials, intrastromally implanted cell/carrier constructs exhibited better capability to enhance tissue matrix regeneration and transparency maintenance as well as to mitigate corneal damage.

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Constitutive modeling of human femoropopliteal artery biaxial stiffening due to aging and diabetes

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Anastasia Desyatova, Jason MacTaggart, Alexey Kamenskiy
Atherosclerotic obstructive disease of the femoropopliteal artery (Peripheral Arterial Disease, PAD) is notorious for high treatment failure rates. Older age and diabetes mellitus (DM) are among the major risk factors for PAD, and both are associated with increased arterial stiffness. Our goal was to develop a constitutive model describing multiaxial arterial stiffening, and use it to portray aging of normal and diabetic human femoropopliteal arteries (FPA). Fresh human FPAs (n=744) were obtained from 13–82-year-old donors. Arteries were tested using planar biaxial extension, and their behavior was modeled with a constitutive relation that included stiffening functions of age. FPA diameter, wall thickness, circumferential, and longitudinal opening angles increased with age, while longitudinal pre-stretch decreased. Diameter and circumferential opening angle did not change with age in subjects with DM. Younger FPAs were more compliant longitudinally but became more isotropic with age. Arteries with DM stiffened significantly faster in the circumferential direction than arteries without DM. Constitutive model accurately portrayed orthotropic stiffening with age of both normal and diabetic arteries. Constitutive description of FPA aging contributes to understanding of arterial pathophysiology and can help improve fidelity of computational models investigating device-artery interaction in PAD repair by providing more personalized arterial properties.Statement of SignificanceWe have analyzed n=744 human femoropopliteal artery (FPA) specimens using biaxial tensile testing to derive constitutive description of FPA aging in diabetic and non-diabetic subjects. The proposed model allows determination of FPA mechanical properties for subjects of any given age in the range of 13–82years. These results contribute to understanding of FPA pathophysiology and can help improve fidelity of computational models investigating device-artery interaction in peripheral arterial disease repair by providing more personalized arterial properties. In addition, they can guide the development of new materials tunable to diabetic and non-diabetic arteries.

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Editorial Board

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64





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Elasticity-based development of functionally enhanced multicellular 3D liver encapsulated in hybrid hydrogel

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Ho-Joon Lee, Myung Jin Son, Jiwon Ahn, Soo Jin Oh, Mihee Lee, Ansoon Kim, Yun-Ji Jeung, Han-Gyeul Kim, Misun Won, Jung Hwa Lim, Nam-Soon Kim, Cho-Rock Jung, Kyung-Sook Chung
Current in vitro liver models provide three-dimensional (3-D) microenvironments in combination with tissue engineering technology and can perform more accurate in vivo mimicry than two-dimensional models. However, a human cell-based, functionally mature liver model is still desired, which would provide an alternative to animal experiments and resolve low-prediction issues on species differences. Here, we prepared hybrid hydrogels of varying elasticity and compared them with a normal liver, to develop a more mature liver model that preserves liver properties in vitro. We encapsulated HepaRG cells, either alone or with supporting cells, in a biodegradable hybrid hydrogel. The elastic modulus of the 3D liver dynamically changed during culture due to the combined effects of prolonged degradation of hydrogel and extracellular matrix formation provided by the supporting cells. As a result, when the elastic modulus of the 3D liver model converges close to that of the in vivo liver (≅ 2.3 to 5.9 kPa), both phenotypic and functional maturation of the 3D liver were realized, while hepatic gene expression, albumin secretion, cytochrome p450-3A4 activity, and drug metabolism were enhanced. Finally, the 3D liver model was expanded to applications with embryonic stem cell-derived hepatocytes and primary human hepatocytes, and it supported prolonged hepatocyte survival and functionality in long-term culture. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology.Statement of SignificanceWe provide a functionally improved 3D liver model that recapitulates in vivo liver stiffness. We have experimentally addressed the issues of orchestrated effects of mechanical compliance, controlled matrix formation by stromal cells in conjunction with hepatic differentiation, and functional maturation of hepatocytes in a dynamic 3D microenvironment. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Additionally, recent advances in the stem-cell technologies have made the development of 3D organoid possible, and thus, our study also provides further contribution to the development of physiologically relevant stem-cell-based 3D tissues that provide an elasticity-based predefined biomimetic 3D microenvironment.

Graphical abstract

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Human osteoblasts grow transitional Si/N apatite in quickly osteointegrated Si3N4 cervical insert

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Giuseppe Pezzotti, Naoki Oba, Wenliang Zhu, Elia Marin, Alfredo Rondinella, Francesco Boschetto, Bryan McEntire, Kengo Yamamoto, B. Sonny Bal
Silicon nitride (Si3N4) ceramics possesses surface chemistry that accelerates bone repair, as previously established by in vitro experiments using both osteosarcoma and mesenchymal cells. The release of silicic acid and nitrogen compounds from the surface Si3N4 enhanced in vitro cellular activity. The results of this study demonstrate for the first time that the osseointegration behavior previously observed is operative with a peculiar chemistry within the human milieu. Si and N elements stimulated progenitor cell differentiation and osteoblastic activity, which ultimately resulted in accelerated bone ingrowth. At the molecular scale, insight into the effect of silicon and nitrogen ions released from the Si3N4 surface was obtained through combined histomorphometric analyses, Raman, Fourier-transform-infrared, and X-ray photoelectron spectroscopies. Identical analyses conducted on a polyetheretherketone (PEEK) spinal explant showed no chemical changes and a lower propensity for osteogenic activity. Silicon and nitrogen are key elements in stimulating cells to generate bony apatite with crystallographic imperfections, leading to enhanced bioactivity of Si3N4 biomedical devices.Statement of SignificanceThis research studies osseointegration processes comparing results from explanted PEEK and Si3N4 spinal spacers. Data show that the formation of hydroxyapatite on silicon nitride bio-ceramic surfaces happens with a peculiar mechanism inside the human body. Silicon and nitrogen were incorporated inside the bony tissue structure allowing the developing of off-stoichiometric bony apatite and stimulating progenitor cell differentiation/osteoblastic activity. Silicon and nitrogen ions released from the Si3N4 surface were detected through combined histologic analyses, Raman microspectroscopy, Fourier-transform-infrared, and X-ray photoelectron spectroscopies.

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Laponite nanoparticle-associated silated hydroxypropylmethyl cellulose as an injectable reinforced interpenetrating network hydrogel for cartilage tissue engineering

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Cécile Boyer, Lara Figueiredo, Richard Pace, Julie Lesoeur, Thierry Rouillon, Catherine Le Visage, Jean-François Tassin, Pierre Weiss, Jérôme Guicheux, Gildas Rethore
Articular cartilage is a connective tissue which does not spontaneously heal. To address this issue, biomaterial-assisted cell therapy has been researched with promising advances. The lack of strong mechanical properties is still a concern despite significant progress in three-dimensional scaffolds. This article's objective was to develop a composite hydrogel using a small amount of nano-reinforcement clay known as laponites. These laponites were capable of self-setting within the gel structure of the silated hydroxylpropylmethyl cellulose (Si-HPMC) hydrogel. Laponites (XLG) were mixed with Si-HPMC to prepare composite hydrogels leading to the development of a hybrid interpenetrating network. This interpenetrating network increases the mechanical properties of the hydrogel. The in vitro investigations showed no side effects from the XLG regarding cytocompatibility or oxygen diffusion within the composite after cross-linking. The ability of the hybrid scaffold containing the composite hydrogel and chondrogenic cells to form a cartilaginous tissue in vivo was investigated during a 6-week implantation in subcutaneous pockets of nude mice. Histological analysis of the composite constructs revealed the formation of a cartilage-like tissue with an extracellular matrix containing glycosaminoglycans and collagens. Overall, this new hybrid construct demonstrates an interpenetrating network which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, oxygen diffusion, or the ability of chondrogenic cells to self-organize in the cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects in a large animal model of articular cartilage defects.SignificanceArticular Cartilage is a tissue that fails to heal spontaneously. To address this clinically relevant issue, biomaterial-assisted cell therapy is considered promising but they are often lacking in mechanical properties. Our objective was to develop a composite hydrogel using a small amount of nano reinforcement (laponite) capable of gelling within polysaccharide based self-crosslinking hydrogel. This new hybrid construct demonstrates an interpenetrating network (IPN) which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, O2 diffusion and the ability of chondrogenic cells to self-organize in cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects will now be considered in a large animal model of articular cartilage defects.

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Hyaluronan size alters chondrogenesis of adipose-derived stem cells via the CD44/ERK/SOX-9 pathway

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Shun-Cheng Wu, Chung-Hwan Chen, Jyun-Ya Wang, Yi-Shan Lin, Je-Ken Chang, Mei-Ling Ho
Hyaluronan (HA) is a natural linear polymer that is one of the main types of extracellular matrix during the early stage of chondrogenesis. We found that the chondrogenesis of adipose-derived stem cells (ADSCs) can be initiated and promoted by the application of HA to mimic the chondrogenic niche. The aim of this study is to investigate the optimal HA molecular weight (Mw) for chondrogenesis of ADSCs and the detailed mechanism. In this study, we investigated the relationships among HA Mw, CD44 clustering, and the extracellular signal-regulated kinase (ERK)/SOX-9 pathway during chondrogenesis of ADSCs. Human ADSCs (hADSCs) and rabbit ADSCs (rADSCs) were isolated and expanded. Chondrogenesis was induced in rADSCs by culturing cells in HA-coated wells (HA Mw: 80 kDa, 600 kDa and 2000 kDa) and evaluated by examining cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and sulfated glycosaminoglycan (sGAG) deposition in vitro. Cartilaginous tissue formation in vivo was confirmed by implanting HA/rADSCs into joint cavities. CD44 clustering, ERK phosphorylation, SOX-9 expression and SOX-9 phosphorylation in cultured hADSCs were further evaluated. Isolated and expanded rADSCs showed multilineage potential and anchorage-independent growth properties. Cell aggregation, chondrogenic gene expression, and sGAG deposition increased with increasing HA Mw in rADSCs. The 2000 kDa HA had the most pronounced chondrogenic effect on rADSCs in vitro, and implanted 2000 kDa HA/rADSCs exhibited marked cartilaginous tissue formation in vivo. CD44 clustering and cell aggregation of hADSCs were enhanced by an increase in HA Mw. In addition, higher HA Mws further enhanced CD44 clustering, ERK phosphorylation, and SOX-9 expression and phosphorylation in hADSCs. Inhibiting CD44 clustering in hADSCs reduced HA-induced chondrogenic gene expression. Inhibiting ERK phosphorylation also simultaneously attenuated HA-induced SOX-9 expression and phosphorylation and chondrogenic gene expression in hADSCs. Our results indicate that HA initiates ADSC chondrogenesis and that higher Mw HAs exhibit stronger effects, with 2000 kDa HA having the strongest effect. These effects may be mediated through increased CD44 clustering and the ERK/SOX-9 signaling pathway.

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Laser processed calcium phosphate reinforced CoCrMo for load-bearing applications: Processing and wear induced damage evaluation

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Himanshu Sahasrabudhe, Susmita Bose, Amit Bandyopadhyay
To mitigate shortcomings in current biomedical CoCrMo alloy, composites of CoCrMo with calcium phosphate (CaP) were envisioned. CoCrMo alloy was reinforced with CaP to enhance the wear resistance of the alloy. A powder based direct energy additive manufacturing technique of Laser Engineered Net Shaping (LENS™) was used for processing of CoCrMo alloy with 1% and 3% (by weight) of CaP in the form of hydroxyapaptite. Addition of CaP was found to stabilize the ε (HCP) phase along with the more common γ (FCC) phase of the CoCrMo alloy, and the microstructure showed discontinuous chromium carbide phase. The resultant composite showed hardness similar to the base material, however, there was significant increase in the wear resistance of the alloy due to the addition of CaP. During wear testing, a tribo-layer or a tribofilm was found to develop on the surface. This led to the reduction in the leaching of Co and Cr ions during wear testing. The tribofilm was found to be dependent on the wear distance, and made the CoCrMo-CaP composites an in situ self-protecting system. The overall coefficient of friction of the CoCrMo-CaP composite was found to increase but was more stable with the wear distance as compared to the CoCrMo alloy with no CaP addition.Statement of SignificanceCo-based alloys, an ideal choice for biomedical load-bearing implants, show low wear rates along with low coefficient of friction (COF) and good resistance to corrosive media. However, significant material loss can occur in vivo due to wear and/or corrosion of CoCrMo over long periods of time. Release of metal ions in the human body over time leads to medical complications such as metallosis, which can often require a revision surgery that can adversely affect the quality of life for the patient. We hypothesize that metal ion release from CoCrMo alloys can be reduced during articulation using an in situ formed inorganic tribofilm, and our results validate our hypothesis in calcium phosphate reinforced CoCrMo composites.

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3D printing of hybrid biomaterials for bone tissue engineering: Calcium-polyphosphate microparticles encapsulated by polycaprolactone

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Meik Neufurth, Xiaohong Wang, Shunfeng Wang, Renate Steffen, Maximilian Ackermann, Natalie D. Haep, Heinz C. Schröder, Werner E.G. Müller
Here we describe the formulation of a morphogenetically active bio-ink consisting of amorphous microparticles (MP) prepared from Ca²⁺ and the physiological inorganic polymer, polyphosphate (polyP). Those MP had been fortified by mixing with poly-ε-caprolactone (PCL) to allow 3D-bioprinting. The resulting granular PCL/Ca-polyP-MP hybrid material, liquefied by short-time heating to 100 °C, was used for the 3D-printing of tissue-like scaffolds formed by strands with a thickness of 400 µm and a stacked architecture leaving ≈0.5 mm²-sized open holes enabling cell migration. The printed composite scaffold turned out to combine suitable biomechanical properties (Young's modulus of 1.60 ± 0.1 GPa; Martens hardness of 153 ± 28 MPa), matching those of cortical and trabecular bone, with morphogenetic activity. This scaffold was capable of attracting and promoting the growth of human bone-related SaOS-2 cells as demonstrated by staining for cell viability (Calcein AM), cell density (DRAQ5) and SEM studies. Furthermore, the hybrid material was demonstrated to upregulate the steady-state-expression of the cell migration-inducing chemokine SDF-1α. EDX analysis and FTIR measurements revealed the presence of hydroxyapatite in the mineral deposits formed on the scaffold surface. Based on the results we conclude that granular PCL/Ca-polyP-MP hybrid material is suitable for the fabrication of bioprintable scaffold which comprises not only biomechanical stability but also morphogenetic potential.Statement of SignificanceIn present-day regenerative engineering efforts, biomaterial- and cell-based strategies are proposed that meet the required functional and spatial characteristics and variations, especially in the transition regions between soft (cartilage, tendon or ligament) and hard (bone) tissues.In a biomimetic approach we succeeded to fabricate amorphous Ca-polyP nanoparticles/microparticles which are highly biocompatible. Together with polycaprolactone (PCL), polyP can be bio-printed. This hybrid material attracts the cells, as documented optically as well as by a gene-expression studies. Since PCL is already a FDA-approved organic and inert polymer and polyP a physiological biologically active component this new bio-hybrid material has the potential to restore physiological functions, including bone remodelling and regeneration if used as implant.

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Delivery of the TLR ligand poly(I:C) to liver cells in vitro and in vivo by calcium phosphate nanoparticles leads to a pronounced immunostimulation

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Viktoriya Sokolova, Zou Shi, Shunmei Huang, Yanqin Du, Mathis Kopp, Annika Frede, Torben Knuschke, Jan Buer, Dongliang Yang, Jun Wu, Astrid Maria Westendorf, Matthias Epple
The selective activation of the immune system is a concurrent problem in the treatment of persistent diseases like viral infections (e.g. hepatitis). For the delivery of the toll-like receptor ligand poly(I:C), an immunostimulatory action was discovered earlier by hydrodynamic injection. However, this technique is not clinically transferable to human patients. A modular system where the immunoactive toll-like-receptor ligand 3 (TLR-3) poly(I:C) was incorporated into calcium phosphate nanoparticles was developed. The nanoparticles had a hydrodynamic diameter of 275nm and a zeta potential of +20mV, measured by dynamic light scattering. The diameter of the solid core was 120nm by scanning electron microscopy. In vitro, the nanoparticle uptake was investigated after 1 and 24h of incubation of THP-1 cells (macrophages) with nanoparticles by fluorescence microscopy. After intravenous injection into BALB/c and C57BL/6J mice, respectively, the in vivo uptake was especially prominent in lung and liver, 1 and 3h after the injection. Pronounced immunostimulatory effects of the nanoparticles were found in vitro with primary liver cells, i.e. Kupffer cells (KC) and liver sinusoidal endothelial cells (LSEC) from wild-type C57BL/6J mice. Thus, they represent a suitable alternative to hydrodynamic injection treatments for future vaccination concepts.Statement of SignificanceThe selective activation of the immune system is a concurrent problem in the treatment of persistent diseases like viral infections (e.g. hepatitis). For the delivery of the toll-like receptor ligand poly(I:C), an immunostimulatory action has been discovered earlier by hydrodynamic injection. However, this technique is not clinically transferable to human patients. We have developed a modular system where poly(I:C) was incorporated into calcium phosphate nanoparticles. The uptake into relevant liver cells was studied both in vitro and in vivo. After intravenous injection into mice, the in vivo uptake was especially prominent in lung and liver, 1 and 3h after the injection. The corresponding strong immune reaction proves their high potential to turn up the immune system, e.g. against viral infections, without adverse side reactions.

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mPEGylated solanesol micelles as redox-responsive nanocarriers with synergistic anticancer effect

Publication date: December 2017
Source:Acta Biomaterialia, Volume 64
Author(s): Benkai Qin, Lei Liu, Xiaohe Wu, Fengguang Liang, Tian Hou, Yangyang Pan, Shiyong Song
We prepared an amphiphilic redox-responsive conjugate based on mPEGylated solanesol, solanesyl poly(ethylene glycol) dithiodipropionate (SPDP), along with its inert counterpart solanesyl poly(ethylene glycol) succinate (SPGS), which self-assembled in aqueous solution to form redox-responsive micelles. Used as efficient drug carriers for doxorubicin (DOX), the micelles acted as synergistic agents for cancer therapy. Dynamic light scattering (DLS) measurements showed that the SPDP micelles had average diameters of 111nm, which decreased to 88nm after the encapsulation of DOX. The mean diameters and size distribution of the disulfide-containing micelles changed obviously in the presence of the reducing agent glutathione (GSH), whereas no changes occurred in the case of redox-insensitive SPGS micelles. DOX could be loaded into both types of micelles, with drug loading content of about 4.0%. A significantly accelerated release of DOX was triggered by GSH for DOX-loaded SPDP micelles, compared with DOX-loaded SPGS micelles. Blank SPGS and SPDP micelles displayed higher inhibition of HeLa and MCF-7 cell proliferation but less cytotoxicity to normal L-02 cells at similar concentrations. Confocal microscopic observation indicated that a greater amount of DOX was delivered into the nuclei of cells following 9 or 12h incubation with DOX-loaded micelles. In vivo studies on H22-bearing Swiss mice demonstrated the superior anticancer activity of DOX-loaded SPDP micelles over free DOX and DOX-loaded SPGS micelles. All of the data presented here suggested that these SPDP micelles may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.Statement of SignificanceVarious nanoscale drug carriers were used to enhance therapeutic effect of many drugs. While, the metabolites of high quantities of carriers may cause additional short- or long-term toxicities. In this study, a new systems based on solanesol derivatives was developed for anticancer drug delivery. There are two features for this system. One is solanesol originated bioactivity of the carrier, which will synergistically facilitate therapeutic effect of the encapsulated drug. The other is the redox-responsive drug release behavior adaptable to the glutathione-rich atmosphere of tumor cell. All the hypothesis have been elucidated in this work through in vitro and in vivo studies. It was found that this drug delivery system may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.

Graphical abstract

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The Hierarchical Response of Human Corneal Collagen to Load

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): J.S. Bell, S. Hayes, C. Whitford, J. Sanchez-Weatherby, O. Shebanova, C. Vergari, C.P. Winlove, N Terrill, T. Sorensen, A. Elsheikh, K.M. Meek
Fibrillar collagen in the human cornea is integral to its function as a transparent lens of precise curvature, and its arrangement is now well-characterised in the literature. While there has been considerable effort to incorporate fibrillar architecture into mechanical models of the cornea, the mechanical response of corneal collagen to small applied loads is not well understood. In this study the fibrillar and molecular response to tensile load was quantified using small and wide angle X-ray scattering (SAXS/WAXS), and digital image correlation (DIC) photography was used to calculate the local strain field that gave rise to the hierarchical changes. A molecular scattering model was used to calculate the tropocollagen tilt relative to the fibril axis and changes associated with applied strain. Changes were measured in the D-period, molecular tilt and the orientation and spacing of the fibrillar and molecular networks. These measurements were summarised into hierarchical deformation mechanisms, which were found to contribute at varying strains. The change in molecular tilt is indicative of a sub-fibrillar "spring-like" deformation mechanism, which was found to account for most of the applied strain under physiological and near-physiological loads. This deformation mechanism may play an important functional role in tissues rich in fibrils of high helical tilt, such as skin and cartilage.Statement of SignificanceCollagen is the primary mediator of soft tissue biomechanics, and variations in its hierarchical structure convey the varying amounts of structural support necessary for organs to function normally. Here we have examined the structural response of corneal collagen to tensile load using X-rays to probe hierarchies ranging from molecular to fibrillar. We found a previously unreported deformation mechanism whereby molecules, which are helically arranged relative to the axis of their fibril, change in tilt akin to the manner in which a spring stretches. This "spring-like" mechanism accounts for a significant portion of the applied deformation at low strains (<3%). These findings will inform the future design of collagen-based artificial corneas being developed to address world-wide shortages of corneal donor tissue.

Graphical abstract

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Branched peptides integrate into self-assembled nanostructures and enhance biomechanics of peptidic hydrogels

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Raffaele Pugliese, Federico Fontana, Amanda Marchini, Fabrizio Gelain
Self-assembling peptides (SAP) have drawn an increasing interest in the tissue engineering community. They display unquestionable biomimetic properties, tailorability and promising biocompatibility. However their use has been hampered by poor mechanical properties making them fragile soft scaffolds. To increase SAP hydrogel stiffness we introduced a novel strategy based on multiple ramifications of (LDLK)3, a well-known linear SAP, connected with one or multiple "lysine knots". Differently branched SAPs were tested by increasing the number of (LDLK)3-like branches and by adding the neuro-regenerative functional motif BMHP1 as a single branch. While pure branched peptides did not have appealing self-assembling propensity, when mixed with the corresponding linear SAP they increased the stiffness of the overall hydrogel of multiple times. Notably, optimal results (or peak) were obtained 1) at similar molar ratio (between linear and branched peptides) for all tested sequences and 2) for the branched SAPs featuring the highest number of branches made of (LDLK)3. The functional motif BMHP1, as expected, seemed not to contribute to the increase of the storage modulus as efficiently as (LDLK)3. Interestingly, branched SAPs improved the β-sheet self-arrangement of (LDLK)3 and allowed for the formation of assembled nanofibers. Indeed in coarse-grained molecular dynamics we showed they readily integrate in the assembled aggregates providing "molecular connections" among otherwise weakly paired β-structures. Lastly, branched SAPs did not affect the usual response of human neural stem cells cultured on (LDLK)3-like scaffolds in vitro. Hence, branched SAPs may be a valuable new tool to enhance mechanical properties of self-assembling peptide biomaterials harmlessly; as neither chemical nor enzymatic cross-linking reactions are involved. As a consequence, branched SAPs may enlarge the field of application of SAPs in tissue engineering and beyond.SignificanceSelf-assembling peptides stand at the forefront of regenerative medicine because they feature biomimetic nano-architectures that mimic the complexity of natural peptide-based extracellular matrices of living tissues. Their superior biocompatibility and ease of scale-up production are hampered by weak mechanical properties due to transient non-covalent interactions among and within the self-assembled peptide chains, thus limiting their potential applications. We introduced new branched self-assembling peptides to be used as "molecular connectors" among self-assembled nanostructures made of linear SAPs. Branched SAPs could be mixed with linear SAPs before self-assembling in order to have them intermingled with different β-sheets of linear SAPs after gelation. This strategy caused a manifold increase of the stiffness of the assembled hydrogels (proportional to the number of self-assembling branches), did not affect SAP propensity to form β-sheet but, instead, further stimulated their secondary structure rearrangements. It is now possible to modularly improve SAP scaffold mechanical properties without using harmful chemical reactions. Therefore, branched SAPs represent an additional tool to be adopted for efficient and harmless SAP scaffold customization in tissue engineering.

Graphical abstract

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Injectable nanocomposite cryogels for versatile protein drug delivery

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Sandeep T. Koshy, David K.Y. Zhang, Joshua M. Grolman, Alexander G. Stafford, David J. Mooney
Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems.Statement of SignificanceHere we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein's activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications.

Graphical abstract

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Cell-instructive pectin hydrogels crosslinked via thiol-norbornene photo-click chemistry for skin tissue engineering

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Rúben F. Pereira, Cristina C. Barrias, Paulo J. Bártolo, Pedro L. Granja
Cell-instructive hydrogels are attractive for skin repair and regeneration, serving as interactive matrices to promote cell adhesion, cell-driven remodeling and de novo deposition of extracellular matrix components. This paper describes the synthesis and photocrosslinking of cell-instructive pectin hydrogels using cell-degradable peptide crosslinkers and integrin-specific adhesive ligands. Protease-degradable hydrogels obtained by photoinitiated thiol-norbornene click chemistry are rapidly formed in the presence of dermal fibroblasts, exhibit tunable properties and are capable of modulating the behavior of embedded cells, including the cell spreading, hydrogel contraction and secretion of matrix metalloproteases. Keratinocytes seeded on top of fibroblast-loaded hydrogels are able to adhere and form a compact and dense layer of epidermis, mimicking the architecture of the native skin. Thiol-ene photocrosslinkable pectin hydrogels support the in vitro formation of full-thickness skin and are thus a highly promising platform for skin tissue engineering applications, including wound healing and in vitro testing models.SignificancePhotopolymerizable hydrogels are attractive for skin applications due to its unique spatiotemporal control over the hydrogel formation. This study reports the design of a promising photo-clickable pectin hydrogel which biophysical and biochemical properties can be independently tailored to control cell behavior. A fast method for the norbornene-functionalization of pectin was developed and hydrogels fabricated through UV photoinitiated thiol-norbornene chemistry. This one-pot click reaction was performed in the presence of cells using cell-adhesive and matrix metalloproteinase-sensitive peptides, yielding hydrogels that support extensive cell spreading. Keratinocytes seeded on top of the fibroblast-loaded hydrogel formed a compact epidermis with morphological resemblance to human skin. This work presents a new protease-degradable hydrogel that supports in vitro skin formation with potential for skin tissue engineering.

Graphical abstract

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Poly-L-lactic acid for the Improvement of photodamage and rhytids of the décolletage

Summary

Background

Poly-L-lactic acid (PLLA) is a biostimulatory filler approved for use in HIV lipoatrophy as well as cosmetic improvement in facial folds and wrinkles in immunocompetent patients. Similar to the face and hands, the décolletage is commonly subject to photodamage and the resulting appearance of rhytids and crepiness, which could benefit from PLLA treatment.

Objectives

The objective of the study was to assess the safety and efficacy of injected PLLA for the improvement in rhytids and crepiness of the décolletage.

Methods

In this open-label, prospective, interventional study, 25 healthy female volunteers aged 40-to-70 years with moderate-to-severe crepiness and wrinkling of the décolletage were injected with 1 vial of PLLA at each of three treatments. The Fabi-Bolton 5-point chest wrinkling scale was used by both investigators and subjects to assign pretreatment and post-treatment follow-up scores at 1 month, 3 months, and 6 months. Adverse events were reported at each visit.

Results

All post-treatment mean scores had statistically significant improvement compared to the pretreatment baseline means as rated by both investigators and subjects. At 1 month following the last treatment, compared to baseline, investigators rated 83% of subjects had improved by at least one point on the scale. Subjects rated 74% of subjects improved by at least one point. At 6 months, 90% of subjects, as rated by the investigators, and 57% of subjects, as rated by the subjects, had improvement from baseline.

Conclusion

PLLA is safe and effective for improvement in the rhytids and skin quality of the photodamaged décolletage.

http://ift.tt/2zpeTWy

Poly-L-lactic acid for the Improvement of photodamage and rhytids of the décolletage

Summary

Background

Poly-L-lactic acid (PLLA) is a biostimulatory filler approved for use in HIV lipoatrophy as well as cosmetic improvement in facial folds and wrinkles in immunocompetent patients. Similar to the face and hands, the décolletage is commonly subject to photodamage and the resulting appearance of rhytids and crepiness, which could benefit from PLLA treatment.

Objectives

The objective of the study was to assess the safety and efficacy of injected PLLA for the improvement in rhytids and crepiness of the décolletage.

Methods

In this open-label, prospective, interventional study, 25 healthy female volunteers aged 40-to-70 years with moderate-to-severe crepiness and wrinkling of the décolletage were injected with 1 vial of PLLA at each of three treatments. The Fabi-Bolton 5-point chest wrinkling scale was used by both investigators and subjects to assign pretreatment and post-treatment follow-up scores at 1 month, 3 months, and 6 months. Adverse events were reported at each visit.

Results

All post-treatment mean scores had statistically significant improvement compared to the pretreatment baseline means as rated by both investigators and subjects. At 1 month following the last treatment, compared to baseline, investigators rated 83% of subjects had improved by at least one point on the scale. Subjects rated 74% of subjects improved by at least one point. At 6 months, 90% of subjects, as rated by the investigators, and 57% of subjects, as rated by the subjects, had improvement from baseline.

Conclusion

PLLA is safe and effective for improvement in the rhytids and skin quality of the photodamaged décolletage.

http://ift.tt/2zpeTWy

Does plant—Microbe interaction confer stress tolerance in plants: a review?

Publication date: Available online 9 November 2017
Source:Microbiological Research
Author(s): Akhilesh Kumar, Jay Prakash Verma
The biotic and abiotic stresses are major constraints for crop yield, food quality and global food security. A number of parameters such as physiological, biochemical, molecular of plants are affected under stress condition. Since the use of inorganic fertilizers and pesticides in agriculture practices cause degradation of soil fertility and environmental pollutions. Hence it is necessary to develop safer and sustainable means for agriculture production. The application of plant growth promoting microbes (PGPM) and mycorrhizal fungi enhance plant growth, under such conditions. It offers an economically fascinating and ecologically sound ways for protecting plants against stress condition. PGPM may promote plant growth by regulating plant hormones, improve nutrition acquisition, siderophore production and enhance the antioxidant system. While acquired systemic resistance (ASR) and induced systemic resistance (ISR) effectively deal with biotic stress. Arbuscular mycorrhiza (AM) enhance the supply of nutrients and water during stress condition and increase tolerance to stress. This plant-microbe interaction is vital for sustainable agriculture and industrial purpose, because it depends on biological processes and replaces conventional agriculture practices. Therefore, microbes may play a key role as an ecological engineer to solve environmental stress problems. So, it is a feasible and potential technology in future to feed global population at available resources with reduced impact on environmental quality. In this review, we have attempted to explore about abiotic and biotic stress tolerant beneficial microorganisms and their modes of action to enhance the sustainable agricultural production.



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Azacitidine in Lower‐Risk Myelodysplastic Syndromes: A Meta‐Analysis of Data from Prospective Studies

AbstractBackground.After erythropoiesis‐stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower‐risk myelodysplastic syndromes (LR‐MDS). Optimal choice of these agents as front‐line therapy in non‐del(5q) LR‐MDS is unclear. Because azacitidine clinical data mainly describe experience in higher‐risk MDS, we performed a meta‐analysis of patient‐level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion‐dependent LR‐MDS.Materials and Methods.We searched English‐language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient‐level data from identified relevant studies were provided by investigators. Meta‐analyses followed Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC‐TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS).Results.Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non‐del(5q) LR‐MDS. Pooled estimates from random‐effects models of RBC‐TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA‐refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response.Conclusion.Azacitidine effects in these patients, most with non‐del(5q) LR‐MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front‐line therapy and alternatives are limited.Implications for Practice.Lower‐risk myelodysplastic syndromes (LR‐MDS) are primarily characterized by anemia. After erythropoiesis‐stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta‐analysis of 233 azacitidine‐treated red blood cell (RBC) transfusion‐dependent patients with LR‐MDS (92.3% non‐del[5q]) from 7 studies showed 38.9% became RBC transfusion‐independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non‐del(5q) LR‐MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR‐MDS patients.

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Clinical Usefulness of 18F‐Fluorodeoxyglucose Positron Emission Tomography in the Diagnostic Algorithm of Advanced Entero‐Pancreatic Neuroendocrine Neoplasms

AbstractBackground.The role of 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG PET) in the diagnostic algorithm of entero‐pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F‐FDG PET to identify patients with more aggressive disease among those with advanced EP NENs.Subjects, Materials, and Methods. Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F‐FDG PET and computed tomography scans during a time frame of 1 month, were included.Results.A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small‐intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F‐FDG PET, whereas 18F‐FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F‐FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F‐FDG PET was significantly associated with PD at the time of study entry (p < .0001 at multivariate analysis). Although a higher proportion of 18F‐FDG PET‐positive examinations were observed in patients with higher tumor grade (p = .01), 53.8% of patients with grade 1 neuroendocrine tumors (NETs) had positive 18F‐FDG PET, and 37.5% of patients with grade 2 NETs had negative 18F‐FDG PET. Overall survival was significantly shorter in 18F‐FDG PET‐positive patients (median: 60 months) in comparison with 18F‐FDG PET‐negative patients (median not reached; p = .008).Conclusion.18F‐FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F‐FDG PET is clinically useful.Implications for Practice.The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F‐fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome.

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The Effect of Message Content and Clinical Outcome on Patients' Perception of Physician Compassion: A Randomized Controlled Trial

AbstractBackground.In a previous randomized crossover study, patients perceived a physician delivering a more optimistic message (MO) as more compassionate and professional. However, the impact of the clinical outcome of the patient on patient's perception of physician's level of compassion and professionalism has not been previously studied. Our aim was to determine if the reported clinical outcome modified the patient's perception of physician compassion, professionalism, impression, and preference for physician.Materials and Methods.One hundred twenty‐eight advanced cancer patients in an outpatient Supportive Care Center were randomized to complete validated questionnaires about patients' perception of physician's level of compassion, professionalism, impression, and preference of physician for themselves and their family after watching scripted videos depicting a physician delivering an MO versus a less optimistic (LO) message followed by a clinical vignette depicting a worse outcome.Results.Median age was 61 years and 55% were female. There was no difference in compassion score after the vignette in the MO and LO groups. However, there were significantly worse overall impression and professionalism scores in both the MO and LO groups after the vignette. In the MO group, preference for the physician for themselves and their family significantly decreased after the vignette.Conclusion.Seeing a worse clinical outcome did not change the patients' appraisal of an inappropriately optimistic physician. However, it reduced the overall impression of both physicians that conveyed an MO or an LO message and it also resulted in less likelihood of choosing the MO physician for themselves and their family.Implications for Practice.The study found that a patient's perception of a physician's compassion did not change after reading a vignette describing a negative clinical outcome, regardless of whether the physician had given a more or a less optimistic message to the patient. However, the results suggested that patients perceived worse professionalism and overall physician impression scores for both more and less optimistic physicians and lower likelihood to choose the more optimistic physician for themselves and their family.

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A Systematic Review of Health‐Related Quality of Life Reporting in Ovarian Cancer Phase III Clinical Trials: Room to Improve

AbstractBackground.Epithelial ovarian cancer (OC) remains a significant cause of morbidity and mortality for women worldwide. Patients may experience a multitude of disease‐ and treatment‐related symptoms that can impact quality of life (QOL) and should be measured and reported in clinical trials. This systematic review investigated the adequacy of reporting of QOL in randomized phase III trials in OC in both the first‐line and recurrent disease setting.Materials and Methods.A systematic review of MEDLINE and EMBASE identified randomized clinical trials of systemic therapy in OC from 1980 to 2014. The adequacy of reporting QOL was evaluated with respect to adherence to established guidelines on reporting QOL in clinical trials and the recent recommendations on the inclusion of patient‐reported outcomes in clinical trials from the Fifth Ovarian Cancer Consensus Conference.Results.Of 3,247 abstracts, 35 studies, including 24,664 patients, met inclusion criteria. Twenty‐two trials (63%) were in the first‐line setting, with 13 (37%) in the recurrent setting. The inclusion of QOL assessments increased from 2% (1980s) to 62% (2010+). Quality of life was a co–primary endpoint in only one trial.Minimal clinically important differences in QOL were defined in eight trials (23%), with results included in the abstract in 37% and article in 86%. Compliance was reported in 26 trials (74%), with 13 trials (37%) reporting specifically how they dealt with missing data. Only seven trials reported the reasons for missing data (20%).Group results were published in 29 trials (83%), with 6 (17%) reporting individual patient results. Results were more commonly reported as a mean overall score (21 trials; 60%), with specific domain scores in only 9 trials (26%). No studies reported QOL beyond progression or included predefined context‐specific endpoints based on objectives of treatment (i.e., palliation/cure/maintenance) and the patient population. Duration of benefit of palliative chemotherapy was reported in only one study.Conclusion.Inclusion and reporting of QOL as a trial endpoint has improved in phase III trials in OC, but there are still significant shortfalls that need to be addressed in future trials.Implications for Practice.The impact of treatment on quality of life (QOL) is an important consideration in patients with ovarian cancer for whom treatment is often given with palliative intent. Both the disease and treatment impact a patient's QOL and require careful evaluation in clinical trials. Matching the QOL questions to the patient population of interest is critical. Similar rigor to that used to assess progression‐based endpoints is essential to guide clinical decisions. This systematic review demonstrated that although the inclusion and reporting of QOL as a trial endpoint has improved in phase III trials there are still significant shortfalls that need to be addressed in future trials.

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Effects of Proton Center Closure on Pediatric Case Volume and Resident Education at an Academic Cancer Center

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James Galle, David Long, Tim Lautenschlaeger, Richard Zellars, Gordon Watson, Susannah Ellsworth
PurposeChanges in radiation oncology infrastructure influence referral/practice patterns, which may affect resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education.MethodsThis was a review of 412 consecutive pediatric (≤18 years) cases treated at a single institution from 2012-2016. Residents' Accreditation Council for Graduate Medical Education case logs for the same years were also analyzed. Characteristics of the patient population and resident case volumes before and after closure of the PTC are reported.ResultsOverall pediatric new starts declined by about 50%, from 35-70 per 6 months in 2012-2014 to 22-30 per 6 months in 2015-2016. CNS case volume declined sharply, from 121 patients treated in 2012-2015 to 18 patients in 2015-2016. In 2012-2014, our institution treated 36, 24, and 17 patients for medulloblastoma/intracranial PNET, ependymoma, and low grade glioma (LGG), respectively, compared to 0, 1, and 1 patients in 2015-2016. 49 patients were treated with craniospinal radiation (CSI) from 2012-2014, while only 2 patients underwent CSI between 2015-2016. Hematologic malignancy patient volume and use of total body irradiation remained relatively stable. Patients treated when the PTC was open were significantly younger (9.1 vs 10.7 years, p=0.010) and their radiation courses were longer (35.4 vs 20.9 days, p<0.0001) than those treated after its closure. Resident case logs showed only a small decline in total pediatric cases, as the percentage of pediatric cases covered by residents increased after PTC closure; however, residents logged fewer CNS cases after PTC closure vs. before.ConclusionsOverall pediatric case volume decreased following PTC closure, as did the number of patients treated for potentially curable CNS tumors. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become increasingly concentrated at specialized centers.

Teaser

Changes in radiation oncology infrastructure influence referral/practice patterns and resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education. We demonstrate a sharp decrease in overall pediatric cases and potentially curable CNS tumors treated at our center following PTC closure. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become concentrated at specialized centers.


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Delineation of neck clinical target volume specific to nasopharyngeal carcinoma based on lymph node distribution and the international consensus guidelines

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Li Lin, Yao Lu, Xiao-Ju Wang, Hui Chen, Sha Yu, Jiao Tian, Guan-Qun Zhou, Lu-Lu Zhang, Zhen-Yu Qi, Jiang Hu, Jun Ma, Ying Sun
PurposeTo establish regional lymph node (LN) distribution probability map and draw neck clinical target volume (CTV) specific to nasopharyngeal carcinoma (NPC).Methods and MaterialsOne thousand patients with pathologically-proven NPC between January 2010 and December 2011 were enrolled. Center points of LNs with a minimal axial diameter (MID) ≥ 4 mm were marked on one single treatment planning computed tomography scan. Neck node levels I – X based on the 2013 updated international consensus guidelines were also contoured. LN distribution probability maps and distribution curves were established. Relationships between LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to NPC.ResultsA total of 10651 LNs from 959 patients were marked. Based on the distribution of LNs and consensus guidelines, the majority of node levels defined in the 2013 updated consensus guidelines were confirmed to be comprehensive and applicable for NPC. However, for level Vb, 13.3% (11/83) cases had LNs beyond the posteromedial border; for level VIIa (retropharyngeal LN), 1.5% (12/819) cases had LNs above the cranial boundary and 5 cases had LNs emerged in the medial group. Moreover, we confirmed that no LN had been detected in certain areas of level Ib, II, IVa and Vc. Accordingly, a new level VIIc was proposed to include medial group of retropharyngeal LNs, and moderate extended boundaries for levels Vb and VIIa were recommended, while reduced boundaries were possibly adaptable for levels Ib, II, IV and Vc.ConclusionThe majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. While, we propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggested that boundaries for levels Ib, II, IV and Vc might be reduced.

Teaser

Neck node distribution probability maps and curves for NPC were established based on 10651 nodes from 956 patients. Relationships between node distribution and international consensus guidelines for delineation of neck node levels were analyzed. Our findings demonstrate that the majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. We propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggest that boundaries for levels Ib, II, IV and Vc might be reduced.


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Open access: Is there a predator at the door?

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Open access: Is there a predator at the door?

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Absence of the subclavius muscle with contralateral subclavius posticus muscle: first imaging report

Publication date: May–June 2018
Source:Clinical Imaging, Volume 49
Author(s): Yun Sam, Sekyoung Park, Chang Su Kim
We present a case of a 56-year-old man with pain in in his right anterior shoulder, arm, and hand. MRI studies demonstrated absence of the subclavius muscle with contralateral subclavius posticus muscle. To our knowledge, imaging of the total absence of subclavius muscle has not been previously described. Understanding and recognition of subclavius posticus muscle are important for its potential role in thoracic outlet syndrome.



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Deposition of absolute and relative airborne metals on eggshells: a field study

Abstract

A biomonitoring field study was conducted to test the deposition of airborne metals on chicken eggshell. The goal was to correlate PM2.5 particle concentration in air, absolute (metals in air) and relative (metals in PM2.5 particles) metals, and metal accumulation on eggshell. The PM2.5 sample was collected for 8 h at different air pollution sites as well as an unpolluted site with glass fiber filters via a fine particulate sampler (with and without addition of eggshell). The PM2.5 particle concentration was high at a cement factory site and low at a sugar factory site. The highest absolute total mass of metal (total mass of all metals in air) was found in the traffic site, and the highest relative total mass of metal (total mass of all metals in PM2.5 particles) was found at the tannery factory. The accumulation of Zn and Pb in eggshell was high at the tannery and sugar factory sites, and Fe was high in the other areas. Three common metals including Cd, As, and Pb were found with significant positive correlation between absolute and relative metals with the metals accumulated in eggshell. The results concluded that the eggshells might be useful tools for monitoring the airborne metals.

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Impact of improved attenuation correction featuring a bone atlas and truncation correction on PET quantification in whole-body PET/MR

Abstract

Purpose

Recent studies have shown an excellent correlation between PET/MR and PET/CT hybrid imaging in detecting lesions. However, a systematic underestimation of PET quantification in PET/MR has been observed. This is attributable to two methodological challenges of MR-based attenuation correction (AC): (1) lack of bone information, and (2) truncation of the MR-based AC maps (μmaps) along the patient arms. The aim of this study was to evaluate the impact of improved AC featuring a bone atlas and truncation correction on PET quantification in whole-body PET/MR.

Methods

The MR-based Dixon method provides four-compartment μmaps (background air, lungs, fat, soft tissue) which served as a reference for PET/MR AC in this study. A model-based bone atlas provided bone tissue as a fifth compartment, while the HUGE method provided truncation correction. The study population comprised 51 patients with oncological diseases, all of whom underwent a whole-body PET/MR examination. Each whole-body PET dataset was reconstructed four times using standard four-compartment μmaps, five-compartment μmaps, four-compartment μmaps + HUGE, and five-compartment μmaps + HUGE. The SUV_max for each lesion was measured to assess the impact of each μmap on PET quantification.

Results

All four μmaps in each patient provided robust results for reconstruction of the AC PET data. Overall, SUV_max was quantified in 99 tumours and lesions. Compared to the reference four-compartment μmap, the mean SUV_max of all 99 lesions increased by 1.4 ± 2.5% when bone was added, by 2.1 ± 3.5% when HUGE was added, and by 4.4 ± 5.7% when bone + HUGE was added. Larger quantification bias of up to 35% was found for single lesions when bone and truncation correction were added to the μmaps, depending on their individual location in the body.

Conclusion

The novel AC method, featuring a bone model and truncation correction, improved PET quantification in whole-body PET/MR imaging. Short reconstruction times, straightforward reconstruction workflow, and robust AC quality justify further routine clinical application of this method.

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The influence of dexamethasone on postoperative swelling and neurosensory disturbances after orthognathic surgery: a randomized controlled clinical trial

Orthognathic surgery is associated with considerable swelling and neurosensory disturbances. Serious swelling can lead to great physical and psychological strain. A randomized, prospective, controlled clinical...

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The role of biotic interactions in plant community assembly: What is the community species pool?

Publication date: November 2017
Source:Acta Oecologica, Volume 85
Author(s): Eva Švamberková, Alena Vítová, Jan Lepš
Differences in plant species composition between a community and its species pool are considered to reflect the effect of community filters. If we define the species pool as a set of species able to reach a site and form a viable population in a given abiotic environment (i.e. to pass the dispersal and abiotic filter), the difference in species composition should correspond to the effect of biotic interactions. However, most of the operational definitions of the species pool are based on co-occurrence patterns and thus also reflect the effect of biotic relationships, including definitions based on functional plant traits, Ellenberg indicator values or Beals index. We conducted two seed introduction experiments in an oligotrophic wet meadow with the aim of demonstrating that many species excluded, according to the above definitions, from a species pool are in fact able to establish there successfully if competition is removed. In sowing experiments, we studied the establishment and survival of species after the removal of competition (i.e. in artificial gaps) and in intact vegetation. We also investigated inter-annual variability of seed germination and seedling establishment and competitive exclusion of sown species. The investigated species also included those from very different habitats (i.e. species with very low corresponding Beals index or Ellenberg indicator values that were different from the target community weighted mean). Many of these species were able to grow in the focal wet meadow if competition was removed, but they did not establish and survive in the intact community. These species are thus not limited by abiotic conditions, but by the biotic filter. We also recorded a great inter-annual variability in seed germination and seedling establishment. Competitive exclusion of species with different ecological requirements could be quite fast (one and half seasons) in some species, but some non-resident species were able to survive several seasons; the resident species were able to persist in competition. Comparison of realized vegetation composition with the corresponding species pool greatly underestimates the potential impact of the biotic filter if the delimitation of the species pool is based on the realized niches of species and co-occurrence patterns.



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Examining the “Veggie” personality: Results from a representative German sample

Publication date: 1 January 2018
Source:Appetite, Volume 120
Author(s): Tamara M. Pfeiler, Boris Egloff
An increasing proportion of people choose to follow a vegetarian diet. To date, however, little is known about if and how individual differences in personality relate to following a vegetarian diet. In the two studies presented here, we aimed to (1) estimate the prevalence of self-defined vegetarians in two waves of a German representative sample (N = 4496 and 5125, respectively), (2) analyze the effect of socio-demographic variables on dietary behavior, and (3) examine individual differences between vegetarians and meat eaters in personality traits, political attitudes, and health-related variables. In Study 1, a strict definition of vegetarians was used, while in Study 2 the definition was laxer, to include also individuals who only predominantly followed a vegetarian diet. The prevalence of self-defined vegetarians was 2.74% in Study 1, and 5.97% in Study 2. Participants who were female, younger, and more educated were more likely to report following a vegetarian diet in both studies, and vegetarians had higher income as compared to meat eaters in Study 2. We also found differences between vegetarians and meat eaters with regard to personality traits, political attitudes, and health-related variables. Stepwise logistic regression analyses showed a unique effect beyond socio-demographic variables for openness (Studies 1 and 2), conscientiousness (Study 1), trust (Study 2), conservatism (Studies 1 and 2), and level of interest in politics (Study 1) on diet: Individuals with higher scores in openness and political interest had a higher probability of being vegetarian, whereas people with higher scores in conscientiousness and conservatism had a smaller likelihood of being vegetarian. We conclude that there are individual differences between vegetarians and meat eaters in socio-demographics, personality traits, and political attitudes.



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Copycat snacks: Can students differentiate between school and store snacks?

Publication date: 1 February 2018
Source:Appetite, Volume 121
Author(s): Georgianna Mann
In 2014, the national Smart Snacks in School nutrition standards placed regulations on all snack foods sold in schools. Many food companies reformulated common snack food products for sale in schools, called "copycat snacks", which look similar to nutritionally different foods sold in stores. It is possible that these snacks create consumer confusion among students. The purpose of this study was to determine if middle school students could differentiate, in taste and appearance, between school (copycat) and store versions of common snacks. Seventy-six middle school students evaluated three different food products offered in schools: Froot Loops, Rice Krispy Treats, and Doritos. Students tasted snacks in a series of triangle tests for difference, one for each snack food, including school and store versions. Students were also presented with packages, school and store versions of the same products, and asked to determine the expected taste, purchase intentions, and perceived healthfulness. Students could determine taste differences between school and store Rice Krispy Treats yet could not differentiate between Froot Loop and Dorito varieties. Students rated store versions of all three snacks with greater expected taste, higher intention to purchase, and as less healthy. While it seems product confusion concerning copycat snacks may not be severe in this sample, snack food brands are still a prominent feature in schools. It is possible that these copycat snacks can confuse students' perceptions of healthy foods. Alternative packaging for school foods or reformation of store versions of snack foods may be viable solutions to this problem.



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Editors / Publication Information

Publication date: 1 January 2018
Source:Appetite, Volume 120





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A short food literacy questionnaire (SFLQ) for adults: Findings from a Swiss validation study

Publication date: 1 January 2018
Source:Appetite, Volume 120
Author(s): Corinna Gréa Krause, Sigrid Beer-Borst, Kathrin Sommerhalder, Stefanie Hayoz, Thomas Abel
The short food literacy questionnaire (SFLQ) was developed to measure a broad range of skills including functional, interactive, and critical elements of FL. This study evaluated SFLQ measurement properties. We used a workplace intervention trial to reduce salt intake in Switzerland to explore the underlying structure of the questionnaire with 350 respondents and identify the ideal number of SFLQ items to capture the different elements of FL. Exploratory factor analysis showed a unidimensional structure of the final 12-item questionnaire. A sum score based on all 12 items (Cronbach's α = 0.82) showed expected positive associations with health literacy and knowledge of recommended salt intake. The findings indicate the SFLQ is a feasible and reliable tool to assess FL among adults that can be helpful in public health practices focusing on FL.



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Speech Production Quality of Cochlear Implant Users with Respect to Duration and Onset of Hearing Loss

Purpose: To assess whether postlingual onset and shorter duration of deafness before cochlear implant (CI) provision predict higher speech intelligibility results of CI users. Methods: For an objective judgement of speech intelligibility, we used an automatic speech recognition system computing the word recognition rate (WR) of 50 adult CI users and 50 age-matched control individuals. All subjects were recorded reading a standardized text. Subjects were divided into three groups: pre- or perilingual deafness (A), both >2 years before implantation, postlingual deafness 2 years before implantation (C). Results: CI users with short duration of postlingual deafness (B) had a significantly higher WR (median 74%) than CI users with long duration of postlingual deafness (C; 68%, p p Conclusions: The speech production quality of adult CI users shows dependencies on the onset and duration of deafness. These features need to be considered while planning rehabilitation.
ORL 2017;79:282-294

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Speech Production Quality of Cochlear Implant Users with Respect to Duration and Onset of Hearing Loss

Purpose: To assess whether postlingual onset and shorter duration of deafness before cochlear implant (CI) provision predict higher speech intelligibility results of CI users. Methods: For an objective judgement of speech intelligibility, we used an automatic speech recognition system computing the word recognition rate (WR) of 50 adult CI users and 50 age-matched control individuals. All subjects were recorded reading a standardized text. Subjects were divided into three groups: pre- or perilingual deafness (A), both >2 years before implantation, postlingual deafness 2 years before implantation (C). Results: CI users with short duration of postlingual deafness (B) had a significantly higher WR (median 74%) than CI users with long duration of postlingual deafness (C; 68%, p p Conclusions: The speech production quality of adult CI users shows dependencies on the onset and duration of deafness. These features need to be considered while planning rehabilitation.
ORL 2017;79:282-294

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Fast B1+ mapping using three consecutive RF pulses and balanced gradients for improved bSSFP imaging

Publication date: February 2018
Source:Magnetic Resonance Imaging, Volume 46
Author(s): Min-Oh Kim, Taehwa Hong, Dong-Hyun Kim
PurposeTo develop a B1⁺ mapping during the transient phase of balanced steady state free precession (bSSFP) imaging which can be used for subsequent B1⁺ inhomogeneity compensation.MethodsTwo images with different flip angles (FA) are acquired using single-shot spiral technique during the transient phase of bSSFP with three consecutive RF pulses and balanced gradients. Under the assumptions that the transmit (B1⁺) field varies slowly in spatial domain and T1 and T2 relaxation effects are negligible during 2·TR, B1⁺ was estimated using the two magnitude images and bSSFP data was sequentially acquired. B1⁺ estimation error due to the assumptions and other factors such as FA and off-resonance were assessed using Bloch simulation. Phantom and in vivo experiments were performed with α-2α-3α scheme.ResultsThe simulation results indicated that the proposed method was less sensitive to T1 relaxation and B1⁺ mapping FA (α) of approximately 60° produced minimum estimation error. The B1⁺-induced intensity variation was reduced with the proposed method in the phantom experiment. For both the phantom and in vivo experiments, the estimated B1⁺ map showed comparable to the conventional B1⁺ map using spin-echo DAM.ConclusionB1⁺ map was estimated during the transient phase of bSSFP and subsequently compensated bSSFP images. There was no scan time increment and hence the technique can be used in a prescan manner for B1⁺ mapping or shimming.



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Fast quantitative MRI as a nonlinear tomography problem

Publication date: February 2018
Source:Magnetic Resonance Imaging, Volume 46
Author(s): Alessandro Sbrizzi, Oscar van der Heide, Martijn Cloos, Annette van der Toorn, Hans Hoogduin, Peter R. Luijten, Cornelis A.T. van den Berg
Quantitative Magnetic Resonance Imaging (MRI) is based on a two-steps approach: estimation of the magnetic moments distribution inside the body, followed by a voxel-by-voxel quantification of the human tissue properties. This splitting simplifies the computations but poses several constraints on the measurement process, limiting its efficiency. Here, we perform quantitative MRI as a one step process; signal localization and parameter quantification are simultaneously obtained by the solution of a large scale nonlinear inversion problem based on first-principles. As a consequence, the constraints on the measurement process can be relaxed and acquisition schemes that are time efficient and widely available in clinical MRI scanners can be employed. We show that the nonlinear tomography approach is applicable to MRI and returns human tissue maps from very short experiments.



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Efficient Operator Splitting Algorithm for Joint Sparsity-Regularized SPIRiT-based Parallel MR Imaging Reconstruction

Publication date: Available online 8 November 2017
Source:Magnetic Resonance Imaging
Author(s): Jizhong Duan, Yu Liu, Peiguang Jing
Self-consistent parallel imaging (SPIRiT) is an auto-calibrating model for the reconstruction of parallel magnetic resonance imaging, which can be formulated as a regularized SPIRiT problem. The Projection Over Convex Sets (POCS) method was used to solve the formulated regularized SPIRiT problem. However, the quality of the reconstructed image still needs to be improved. Though methods such as NonLinear Conjugate Gradients (NLCG) can achieve higher spatial resolution, these methods always demand very complex computation and converge slowly. In this paper, we propose a new algorithm to solve the formulated Cartesian SPIRiT problem with the JTV and JL1 regularization terms. The proposed algorithm uses the operator splitting (OS) technique to decompose the problem into a gradient problem and a denoising problem with two regularization terms, which is solved by our proposed split Bregman based denoising algorithm, and adopts the Barzilai and Borwein method to update step size. Simulation experiments on two in vivo data sets demonstrate that the proposed algorithm is 1.3 times faster than ADMM for datasets with 8 channels. Especially, our proposal is 2 times faster than ADMM for the dataset with 32 channels.



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Correction to: Apocynin and dimethyl sulfoxide synergistically protect against ischemia-reperfusion injury in a rat hind limb ischemia-reperfusion model

Abstract

Dr. Ozer Sehirli's affiliation needs to be updated as he was transferred from Marmara University Faculty of Pharmacy to Near East University Faculty of Dentistry two years ago. The updated information is provided in the affiliation section below.

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A ravenous defense: canonical and non-canonical autophagy in immunity

Payel Sil | Ginger Muse | Jennifer Martinez

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Global oral health status of athletes with intellectual disabilities

Abstract

Background

The aim of this study is to identify the oral health status and treatment needs of Special Olympics athletes with intellectual disabilities from 181 countries by the assessment of oral health parameters and differences between world regions.

Material and methods

Data were collected through interview and oral examinations within the Healthy Athletes Screening. These data were analysed with descriptive statistics of oral health parameters of athletes from Africa, Asia Pacific, East Asia, Europe/Eurasia, Latin America, Middle East North Africa (MENA) and North America. Mean differences of untreated visible dental caries, gingival signs and missing teeth were tested between regions by one-way ANOVA test and between age groups (8–11, 12–18, 19–39 and 40+) by chi-square tests for multiple comparisons with Hochberg-adjusted p value. The level of significance for all tests was set at a p value < 0.05.

Results

A total of 149,272 athletes with intellectual disabilities were screened. More than 80% of the athletes reported that they cleaned their mouths at least once a day. Athletes in Europe/Eurasia, Latin America, and MENA presented higher rates of signs of gingival disease than other regions. The prevalence of untreated dental caries was significantly higher in Latin America and the group of 8–11-year-olds from Latin America, Europe/Eurasia and Asia Pacific.

Conclusions

The data provided by this study demonstrate that continuous efforts for preventive and restorative oral health care are needed for the oral health of these athletes with ID especially in Latin America, MENA and Europe/Eurasia regions.

http://ift.tt/2hU7Mvf

Serotonergic polymorphisms in the control of ejaculation

Publication date: Available online 2 November 2017
Source:Molecular and Cellular Endocrinology
Author(s): Patrick Jern, Daniel Ventus
Serotonin has long been implicated in the regulation of the processes that trigger the ejaculatory reflex. Most evidence of serotonergic involvement is, however, indirect, stemming either from studies on rodents or clinical trials investigating effects of serotonergic drugs. In the past decade, emerging evidence for heritability (i.e., genetic effects) of premature ejaculation (PE) symptoms has spawned a number of scholarly attempts to identify genes that regulate ejaculation, most of which have focused on candidate genes related to the serotonergic system. The aim of the present review article was to summarize the literature concerning genetic association studies of PE, with focus on serotonergic genes. However, methodological obstacles relating to the candidate gene approach predict that a priori hypotheses regarding candidate genes are likely to generate ambiguous and spurious results if samples (e.g., if samples are underpowered and/or stratified). Attempts to replicate reported novel associations between PE symptoms and serotonergic candidate genes have largely failed (thereby adding to the growing body of evidence casting doubt on the reliability of the candidate gene approach), and at present, it is not possible to determine with acceptable certainty which serotonergic genes, if any, are involved in ejaculatory function.



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Reduction of protein phosphatase 2A Cα promotes in vivo bone formation and adipocyte differentiation

Publication date: Available online 8 November 2017
Source:Molecular and Cellular Endocrinology
Author(s): Kaya Yoshida, Jumpei Teramachi, Kenta Uchibe, Mika Ikegame, Lihong Qiu, Di Yang, Hirohiko Okamura
Serine/threonine protein phosphatase 2A (PP2A) regulates diverse physiological processes such as cell cycle, growth, apoptosis, and signal transduction. Previously, we demonstrated that silencing of the α-isoform of PP2A catalytic subunit (PP2A Cα) in osteoblasts accelerated osteoblast differentiation, whereas its overexpression suppressed differentiation. In this study, we examined the role of PP2A Cα in in vivo bone formation by generating transgenic mice (PP2A-Tg), in which the dominant negative form of PP2A Cα was specifically expressed in osteoblasts. PP2A-Tg mice exhibited an increase in body weight, cortical bone mineral density, and cortical bone thickness. Interestingly, they also displayed higher amounts of adipose tissue in the bone marrow of tibiae. The co-culture study showed that PP2A Cα-knockdown osteoblasts stimulated adipocyte differentiation from undifferentiated mesenchymal cells via upregulation of the adipocyte marker genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). These results indicated that the reduction of PP2A Cα levels in osteoblasts promoted bone formation in vivo. Additionally, PP2A Cα in osteoblasts was also potentially involved in controlling adipocyte differentiation through a paracrine mechanism.

Graphical abstract

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A biolayer interferometry-based enzyme-linked aptamer sorbent assay for real-time and highly sensitive detection of PDGF-BB

Publication date: 15 April 2018
Source:Biosensors and Bioelectronics, Volume 102
Author(s): Shunxiang Gao, Xin Zheng, Jihong Wu
Accurate, fast and sensitive detection of disease-specific protein biomarkers, especially in blood, urine, or other bodily fluids, is an important approach to achieve early disease diagnosis. Platelet-derived growth factor-BB (PDGF-BB), a widely used biomarker, is involved in a substantial number of serious diseases, such as hepatic fibrosis, atherosclerosis, age-related macular degeneration and diabetic eye disease and is often over-expressed in human malignant tumors. Therefore, the development of sensitive and specific detection methods for PDGF-BB is of great importance for the early diagnosis of disease and assessments of patient recovery. In the current study, a biolayer interferometry-based enzyme-linked aptamer sorbent assay (BLI-ELASA) was successfully established for rapid (20–25min), high-throughput (8 or 16 samples) and real-time monitoring of PDGF-BB in clinical samples. The method exhibited a broad detection range from 0.5 to 1000ng/mL of PDGF-BB (good linear range from 0.5 to 10ng/mL), with a low detection limit of 0.08ng/mL. Moreover, BLI-ELASA was applied to the detection of PDGF-BB in spiked serum and urine samples and showed a high degree of selectivity for PDGF-BB, good reproducibility, and stability. We believe that the methodology in this work can be easily adapted to detect other biomolecules in clinical samples, including viruses, pathogens and toxins, in a rapid, sensitive, high-throughput and real-time manner.



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