A comparison of antibacterial and antibiofilm efficacy of phenothiazinium dyes between Gram positive and Gram negative bacterial biofilm

Publication date: Available online 21 January 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Lama Misba, Sahar Zaidi, Asad U. Khan
BackgroundAntimicrobial photodynamic therapy (APDT) is a process that generates reactive oxygen species (ROS) in presence of photosensitizer, visible light and oxygen which destroys the bacterial cells. We investigated the photoinactivation efficiency of phenothiazinium dyes and the effect of ROS generation on Gram positive and Gram negative bacterial cell as well as on biofilm.Material and MethodsEnterococcus faecalis and Klebsiella pneumonia were incubated with all the three phenothiazinium dyes and exposed to 630nm of light. After PDT, colony forming unit (CFU) were performed to estimate the cell survival fraction. Intracellular reactive oxygen species (ROS) was detected by DCFH-DA. Crystal violet (CV) assay and extracellular polysaccharides (EPS) reduction assay were performed to analyze antibiofilm effect. Confocal laser electron microscope (CLSM) scanning electron microscope (SEM) was performed to assess the disruption of biofilm.Results8log10 reduction in bacterial count was observed in Enterococcus faecalis while 3log10 in Klebsiella pneumoniae. CV and EPS reduction assay revealed that photodynamic inhibition was more pronounced in Enterococcus faecalis. In addition to this CLSM and SEM study showed an increase in cell permeability of propidium iodide and leakage of cellular constituents in treated preformed biofilm which reflects the antibiofilm action of photodynamic therapy.ConclusionWe conclude that Gram-positive bacteria (Enterococcus faecalis) are more susceptible to APDT due to increased level of ROS generation inside the cell, higher photosensitizer binding efficiency and DNA degradation. Phenothiazinium dyes are proved to be highly efficient against both planktonic and biofilm state of cells.



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Positively charged phthalocyanine-arginine conjugates as efficient photosensitizer for photodynamic therapy

Publication date: Available online 21 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ao Wang, Rongrong Zhou, Lin Zhou, Kang Sun, Jianchun Jiang, Shaohua Wei
Positively charged drugs usually have enhanced water solubility, cellular uptake efficiency and anticancer activity. However, the common quaternized and protonated cationic photosensitizers both have some drawbacks such as needing potentially dangerous agents for preparation and easily being deprotonated in alkaline circumstance. Arginine is unique among the amino acids as its guanidine group has exceptionally high basicity in aqueous solution, which may make it positively charged in a wide range of pH. In this paper, two arginine substituted zinc phthalocyanines (ArgEZnPc and ArgZnPc) were reported. They can be positively charged in the range of pH 5 to 9. Moreover, the photobiological, photochemical properties, subcellular localization, and in vitro anticancer activities of the them were also carried out. The results show that ArgZnPc may be not a good photosensitizer because of its poor photobiological activities though it is positively charged in a wide range of pHs. This may be attributed to the formation of inner salts between guanidine and carboxyl groups of ArgZnPc, which weakens its photobiological and in vitro anticancer activity. While in contrast, ArgEZnPc shows preferential localization in the lysosomes of HeLa cells, exhibits high water solubility, excellent ¹O2 and intracellular reactive oxygen species generation efficiency as well as high in vitro anticancer activity, making it a promising photosensitizer for photodynamic therapy.

Graphical abstract

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Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1)

Publication date: Available online 21 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sergey S. Laev, Nariman F. Salakhutdinov, Olga I. Lavrik
Human apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein which is essential in the base excision repair (BER) pathway of DNA lesions caused by oxidation and alkylation. This protein hydrolyzes DNA adjacent to the 5'-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3'-hydroxyl group and a 5'-deoxyribose phosphate moiety or activates the DNA binding activity of certain transcription factors through its redox function. Studies have indicated a role for APE1/Ref-1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs. Thus, this protein has potential as a target in cancer treatment. As a result, major efforts have been directed to identify small molecule inhibitors against APE1/Ref-1 activities. These agents have the potential to become anticancer drugs. The aim of this review is to present recent progress in studies of all published small molecule APE1/Ref-1 inhibitors. The structures and activities of APE1/Ref-1 inhibitors, that target both DNA repair and redox activities, are presented and discussed. To date, there is an urgent need for further development of the design and synthesis of APE1/Ref-1 inhibitors due to high importance of this protein target.

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A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of Rasagiline and Tamsulosin

Publication date: Available online 21 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Davide Brenna, Margherita Pirola, Laura Raimondi, Anthony J. Burke, Maurizio Benaglia
The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.

Graphical abstract

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TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis

Publication date: Available online 22 January 2017
Source:Trends in Biochemical Sciences
Author(s): Shigetsugu Hatakeyama
Tripartite motif (TRIM) family proteins, most of which have E3 ubiquitin ligase activities, have various functions in cellular processes including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. The ubiquitin system is one of the systems for post-translational modifications, which play crucial roles not only as markers for degradation of target proteins by the proteasome but also as regulators of protein–protein interactions and of the activation of enzymes. Accumulating evidence has shown that TRIM family proteins have unique, important roles and that their dysregulation causes several diseases classified as cancer, immunological disease, or developmental disorders. In this review we focus on recent emerging topics on TRIM proteins in the regulation of autophagy, innate immunity, and carcinogenesis.



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A Golden Age for Working with Public Proteomics Data

Publication date: Available online 22 January 2017
Source:Trends in Biochemical Sciences
Author(s): Lennart Martens, Juan Antonio Vizcaíno
Data sharing in mass spectrometry (MS)-based proteomics is becoming a common scientific practice, as is now common in the case of other, more mature 'omics' disciplines like genomics and transcriptomics. We want to highlight that this situation, unprecedented in the field, opens a plethora of opportunities for data scientists. First, we explain in some detail some of the work already achieved, such as systematic reanalysis efforts. We also explain existing applications of public proteomics data, such as proteogenomics and the creation of spectral libraries and spectral archives. Finally, we discuss the main existing challenges and mention the first attempts to combine public proteomics data with other types of omics data sets.



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Comparison of the local effects of a 600-μm bare fibre at high laser power on lung parenchyma: Nd:YAG laser 1320 vs. 1064 nm

Abstract

Lung metastases are often resected non-anatomically with a laser using a diode-pumped Nd:YAG laser at a wavelength of 1320 nm with a laser output of up to 60 W. Usually the removal of lesions is carried out in contact mode by means of a bare fibre. We compared the local effects of an Nd:YAG laser at a wavelength of 1064 nm with those at a wavelength of 1320 nm using a 600-μm bare fibre in contact mode in an experimental model. The investigations were carried out on porcine lungs freshly withdrawn at the abattoir. The 600-μm laser fibre was fixed vertically in contact with the lung surface on a fibre holder. The fibre holder was connected to a feeding device that advances the laser fibre at constant speeds (5, 10 or 20 mm/s). In each case, two laser powers were examined: 20 and 60 W. The lung lesions produced by the laser fibre were excised for histological examination. After haematoxylin–eosin staining, the depth of the vaporisation and coagulation zones (in μm) from the laser cuts was measured. For each setting, an average value was calculated. The individual groups were compared for significance using a non-parametric Mann–Whitney U test (p < 0.05). At a low speed of the bare fibre of 5 mm/s and a laser output of 20 W, the average depth of the vaporisation zone was 858 ± 3.3 μm (λ = 1064 nm) compared to 766.0 ± 7.5 μm (λ = 1320 nm) (p < 0.01). Upon faster movement (20 mm/s), the extension of the vaporisation zone decreased to 320.3 ± 7.1 μm (λ = 1064 nm). The depth of the vaporisation zone increased significantly at 60 W, both at λ = 1064 and 1320 nm with 1517.0 ± 1.7 μm and 1414.0 ± 4.9 μm, respectively. The extent of the coagulation zone was significantly smaller at 20 W and the low speed of 5 mm/s, namely, 200.4 ± 3.7 μm (λ = 1064 nm) and 224.1 ± 2.8 μm (1320-nm laser). Upon faster movement of the laser fibre at the same output, the extent of the coagulation zone decreased in both groups. At a laser power of 60 W, the extent of the coagulation zone was significantly less with the 1064-nm laser (110.3 ± 2.4 μm) than with the 1320-nm laser (324.8 ± 1.9 μm; p < 0.001). When the laser fibre moves more rapidly, the extent of the coagulation zone decreases further. The Nd:YAG laser with a wavelength of 1320 nm still has the optimal ratio of cutting and coagulation capacity on the resection surface. With the 1064-nm Nd:YAG laser, a higher cutting capacity is associated with a decrease of the coagulation capacity.

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In vivo near-infrared imaging and phototherapy of tumors using a cathepsin B-activated fluorescent probe

Publication date: April 2017
Source:Biomaterials, Volume 122
Author(s): Xiaoqiang Chen, Dayoung Lee, Sungsook Yu, Gyoungmi Kim, Songyi Lee, Yejin Cho, Haengdueng Jeong, Ki Taek Nam, Juyoung Yoon
The development of multifunctional reagents for simultaneous specific near-infrared (NIR) imaging and phototherapy of tumors is of great significance. This work describes the design of a cathepsin B-activated fluorescent probe (CyA-P-CyB) and its applications as an NIR imaging probe for tumor cells and as a phototherapy reagent for tumors. In vitro experiments demonstrated that CyA-P-CyB was activated via the cleavage of a peptide linker by cathepsin B in tumor cells to produce fluorescence in the NIR region based on a FRET mechanism. MTT assays showed that the phototoxicity of CyA-P-CyB toward cells depended on the activity of cathepsin B, and the probe exhibited specific phototoxicity toward tumor cells. CyA-P-CyB was also successfully applied to the in vivo imaging and phototherapy of tumors. Histological analysis indicated that CyA-P-CyB had no cytotoxic effects on seven mouse tissues (lung, liver, heart, kidney, pancreas, spleen and brain) after the CyA-P-CyB treatment and laser irradiation.

Graphical abstract

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Tackling the salinity-pollution nexus in coastal aquifers from arid regions using nitrate and boron isotopes

Abstract

Salinization and nitrate pollution are generally ascertained as the main issues affecting coastal aquifers worldwide. In arid zones, where agricultural activities also result in soil salinization, both phenomena tend to co-exist and synergically contribute to alter groundwater quality, with severe negative impacts on human populations and natural ecosystems' wellbeing. It becomes therefore necessary to understand if and to what extent integrated hydrogeochemical tools can help in distinguishing among possible different salinization and nitrate contamination origins, in order to provide adequate science-based support to local development and environmental protection. The alluvial plain of Bou-Areg (North Morocco) extends over about 190 km² and is separated from the Mediterranean Sea by the coastal Lagoon of Nador. Its surface is covered for more than 60% by agricultural activities, although the region has been recently concerned by urban population increase and tourism expansion. All these activities mainly rely on groundwater exploitation and at the same time are the main causes of both aquifer and lagoon water quality degradation. For this reason, it was chosen as a case study representative of the typical situation of coastal aquifers in arid zones worldwide, where a clear identification of salinization and pollution sources is fundamental for the implementation of locally oriented remedies and long-term management strategies. Results of a hydrogeochemical investigation performed between 2009 and 2011 show that the Bou-Areg aquifer presents high salinity (often exceeding 100 mg/L in TDS) due to both natural and anthropogenic processes. The area is also impacted by nitrate contamination, with concentrations generally exceeding the WHO statutory limits for drinking water (50 mg/L) and reaching up to about 300 mg/L, in both the rural and urban/peri-urban areas. The isotopic composition of dissolved nitrates (δ¹⁵N_NO3 and δ¹⁸O_NO) was used to constrain pollution drivers. The results indicate two main origins for human-induced pollution: (i) manure and septic effluents, especially in urban areas, and (ii) synthetic fertilizers in agricultural areas. In the latter, δ¹⁵N-enriched values highlight a mixture of those sources, possibly related to unbalanced fertilization and agricultural return flow. Boron isotopes (δ¹¹B) were hence studied to further distinguish the nitrate origin in the presence of multiple sources and mixing processes. The results indicate that in the study area, the high geochemical background for B and Cl, associated to the complex water-rock interaction processes, limit the application of the coupled δ¹¹B and δ¹⁵N isotopic systematics to the detection of sources of groundwater pollution. In fact, despite the exceedingly high nitrate contents, the depleted δ¹¹B values that characterize synthetic fertilizers and sewage leakages could not be detected. Therefore, even if in saline groundwater the anthropogenic contribution has a negligible effect in terms of salinity input, with both sewage and irrigation water not very charged, the associated nitrate content fuels up water-rock interaction processes, eventually leading to a mineralization increase.

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Influence of environmental and anthropogenic factors at the bottom sediments in a Doce River tributary in Brazil

Abstract

In developing countries, it is uncommon to find watersheds that have been the object of detailed environmental studies. It makes the assessment of the magnitude of environmental impacts and pollution of these sites difficult. This research demonstrated ways to understand the dynamics of river bottom sediments contamination, even for watersheds with a lack of environmental data. Based on geochemical affinity, we conducted a comprehensive study on the concentration of metals and metalloids. Then, we discussed the probable origin of the concentration of these elements at the bottom sediment along the Matipó River. The Matipó River is an important tributary of the Doce River, which stood out in international headlines because of the mining tailing dam disaster in Mariana, Minas Gerais, in 2015. The bottom sediment samples were taken in 25 stations located along the basin in different seasonal periods. The results showed that copper ( \( \overline{x} \) = 464.7 mg kg⁻¹) and zinc ( \( \overline{x} \) = 287.7 mg kg⁻¹) probably have natural origin, despite of the high concentrations. Lead ( \( \overline{x} \) = 28.0 mg kg⁻¹), chromium ( \( \overline{x} \) = 153.2 mg kg⁻¹), and nickel ( \( \overline{x} \) = 41.8 mg kg⁻¹) also had high concentrations at some collecting stations, and this probably reflected the local natural conditions. The bedrock of the studying basin is dominantly composed of metabasalts and metatonalites interlayered with calcitic and dolomitic metalimestone. On the other hand, the concentration was worrisome in stations near human activities, possibly due to impacts caused by unsustainably agriculture and livestock.

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Symptom burden and dysphagia associated with osteoradionecrosis in long-term oropharynx cancer survivors: A cohort analysis

Publication date: March 2017
Source:Oral Oncology, Volume 66
Author(s): Angela T.T. Wong, Stephen Y. Lai, G. Brandon Gunn, Beth M. Beadle, Clifton D. Fuller, Martha P. Barrow, Theresa M. Hofstede, Mark S. Chambers, Erich M. Sturgis, Abdallah Sherif Radwan Mohamed, Jan S. Lewin, Katherine A. Hutcheson
ObjectiveThe purpose is to examine the relationship between mandibular osteoradionecrosis (ORN) and chronic dysphagia in long-term oropharynx cancer (OPC) survivors, and to determine the perceived symptom burden associated with ORN.Materials and methodsMedical records of 349 OPC patients treated with bilateral IMRT and systemic therapy were reviewed. ORN was graded using a published 4-point classification schema. Patients were considered to have chronic dysphagia if they had aspiration pneumonia, stricture or aspiration detected by fluoroscopy or endoscopy, and/or feeding tube dependence in long-term follow-up ⩾1year following radiotherapy. MD Anderson Symptom Inventory – Head and Neck Module (MDASI-HN) scores were analyzed in a nested cross-sectional survey sample of 118 patients.Results34 (9.7%, 95% CI: 6.8–13.3%) patients developed ORN and 45 (12.9%, 95% CI: 9.6–16.9%) patients developed chronic dysphagia. Prevalence of chronic dysphagia was significantly higher in ORN cases (12/34, 35%) compared to those who did not develop ORN (33/315, 11%, p<0.001). ORN grade was also significantly associated with prevalence of dysphagia (p<0.001); the majority of patients with grade 4 ORN requiring major surgery (6 patients, 75%) were found to have chronic dysphagia. Summary MDASI-HN symptom scores did not significantly differ by ORN grade. Significantly higher symptom burden was reported, however, among ORN cases compared to those without ORN for MDASI-HN swallowing (p=0.033), problems with teeth and/or gums (p=0.016) and change in activity (p=0.015) item scores.ConclusionsORN is associated with excess burden of chronic dysphagia and higher symptom severity related to swallowing, dentition and activity limitations.



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Effects of two grading techniques of zirconia material on the fatigue limit of full-contour 3-unit fixed dental prostheses

Publication date: Available online 21 January 2017
Source:Dental Materials
Author(s): Regina Furbino Villefort, Marina Amaral, Gabriel Kalil Rocha Pereira, Tiago Moreira Bastos Campos, Yu Zhang, Marco Antonio Bottino, Luiz Felipe Valandro, Renata Marques de Melo
ObjectiveThis study evaluated the effects of two grading techniques of zirconia material on the fatigue limit of full-contour 3-unit fixed dental prostheses (FDPs).MethodsPresintered blocks of 3Y-TZP were milled to obtain sixty-nine 3-unit FDPs, which were divided into three groups (n=23). The control group (CTL) was sintered and glazed following manufacturer's instructions. In the two experimental groups presintered FDPs received a surface silica/glass infiltration treatment before the sintering process. Silica sol–gel group (SSG) was graded by the sol–gel processing route, while the glass-zirconia-glass group (GZG) was graded by an enameling technique. Graded groups did not receive a glaze layer after sintering. All FDPs were then luted with a dual-curing resin cement on composite abutments, embedded in polyurethane and stored in water for five days. The initial load of the fatigue test was calculated based on the results of the monotonic testing applied on three specimens of each group. To determine the fatigue limit, 20 samples of each group were subjected to staircase testing (100,000 cycles/5Hz).ResultsThe fatigue limits (in Newtons) were CTL=1607.27, SSG=1824.31, and GZG=2006.57, and the Dixon and Mood test indicated statistically significant differences among groups (95% confidence interval) (GZG > SSG > CTL).SignificanceThe infiltration of silica and glass on bulk zirconia, by two different grading methods, increased the fatigue limits of monolithic zirconia FDPs.



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Crystallization kinetics of syndiotactic polypropylene confined in nanoporous alumina

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Linling Li, Jingwen Liu, Linlin Qin, Chen Zhang, Ye Sha, Jing Jiang, Xiaoliang Wang, Wei Chen, Gi Xue, Dongshan Zhou
Crystalline polymers can exhibit anomalous crystallization behaviors as restricted into nanodomains. Herein, syndiotactic polypropylene (sPP) was infiltrated into nanoporous alumina templates with different pore diameters, and their nonisothermal and isothermal crystallization kinetics were investigated. As located inside nanopores, the crystallization of sPP becomes sluggish. The crystallization temperatures reveal a pronounced cooling rate dependence for sPP in large nanopores. At fast cooling rates, the homogeneous nucleation is dominated. While, at slow cooling rates, the splits of crystallization peaks can be ascribed to fractionated crystallizations initiated by heterogeneous and homogeneous nucleation, respectively. For sPP in small nanopores, the homogeneous nucleation always predominates, which induces less cooling rate effect. In addition, based on the Avrami equation and Lauritzen-Hoffman growth theory, isothermal crystallization experiments indicate that the characteristic crystallization times of sPP under confinement are much longer, and both of the nuclei density and secondary nucleation rate are decreased for sPP confined in nanopores.

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Highly-branched cross-linked poly(ethylene oxide) with enhanced ionic conductivity

Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Nachiket Paranjape, Praphulla Chandra Mandadapu, Gang Wu, Haiqing Lin
Polymers containing poly(ethylene oxide) (PEO) have been investigated for solid electrolytes for lithium-ion batteries, which are preferred to be amorphous and have flexible polymer chains to achieve high Li ion conductivity. This paper reports ionic conductivity in a series of cross-linked PEOs prepared from poly(ethylene glycol) methyl ether acrylate (PEGMEA, monomer) and poly(ethylene glycol) diacrylate (PEGDA, cross-linker) via photopolymerization. The resulting copolymers contain short PEO side chains and thus high content of amorphous PEO. While the cross-linking enhances mechanical strength for solid electrolytes, the introduction of PEGMEA with methoxyl chain end groups decreases Tg and increases ionic conductivity. The use of acrylate groups for polymerization, instead of methacrylate groups, also yields low Tg and thus high conductivity. The effect of PEGMEA content, salt content, and temperature on the ionic conductivity was thoroughly investigated, and it was satisfactorily described using the Vogel-Fulcher-Tammann (VFT) equation. The effectiveness of PEO-based polymers used for solid electrolytes in advanced lithium batteries was also elucidated based on the VFT equation.

Graphical abstract

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Crosslinking of an ethylene-glycidyl methacrylate copolymer with amine click chemistry

Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Massimiliano Mauri, Nina Tran, Oscar Prieto, Thomas Hjertberg, Christian Müller
Commonly used crosslinking methods for polyethylenes result in the release of harmful by-products. Here, we demonstrate that an epoxy-bearing polyethylene copolymer, which contains 8 wt% glycidyl methacrylate, can be efficiently crosslinked without by-product formation. Click chemistry based on multifunctional amine curing agents, which carry at least two functional groups separated by a flexible spacer, was used to prepare thermosets. Compounding of the crosslinker and copolymer through extrusion at 120 °C could be carried out without onset of the curing reactions. Careful adjustment of the curing time and temperature, ranging from 20 to 120 min and 160–200 °C, resulted in a high network density of at least 2.8 crosslinks per 1000 carbons at a curing agent stoichiometry of as little as 0.5 wt%.

Graphical abstract

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Iron Mapping in Multiple Sclerosis

Publication date: Available online 20 January 2017
Source:Neuroimaging Clinics of North America
Author(s): Stefan Ropele, Christian Enzinger, Franz Fazekas

Teaser

Increased iron deposition in cerebral deep gray matter has been considered a global marker for neurodegeneration in multiple sclerosis (MS); it scales with disease duration and severity. Iron accumulation in white matter and MS lesions might be more directly related to disease activity and has been discussed as a contributor to the inflammatory and neurodegenerative cascade. New insights into iron and MS are expected from MR imaging. We discuss findings from MR iron mapping proposed. Because of the confounding magnetic properties of myelin, iron mapping in white matter remains an unresolved issue.


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Conductive nanogel-interfaced neural microelectrode arrays with electrically controlled in-situ delivery of manganese ions enabling high-resolution MEMRI for synchronous neural tracing with deep brain stimulation

Publication date: April 2017
Source:Biomaterials, Volume 122
Author(s): Wei-Chen Huang, Yu-Chih Lo, Chao-Yi Chu, Hsin-Yi Lai, You-Yin Chen, San-Yuan Chen
Chronic brain stimulation has become a promising physical therapy with increased efficacy and efficiency in the treatment of neurodegenerative diseases. The application of deep brain electrical stimulation (DBS) combined with manganese-enhanced magnetic resonance imaging (MEMRI) provides an unbiased representation of the functional anatomy, which shows the communication between areas of the brain responding to the therapy. However, it is challenging for the current system to provide a real-time high-resolution image because the incorporated MnCl2 solution through microinjection usually results in image blurring or toxicity due to the uncontrollable diffusion of Mn²⁺. In this study, we developed a new type of conductive nanogel-based neural interface composed of amphiphilic chitosan-modified poly(3,4 -ethylenedioxythiophene) (PMSDT) that can exhibit biomimic structural/mechanical properties and ionic/electrical conductivity comparable to that of Au. More importantly, the PMSDT enables metal-ligand bonding with Mn²⁺ ions, so that the system can release Mn²⁺ ions rather than MnCl2 solution directly and precisely controlled by electrical stimulation (ES) to achieve real-time high-resolution MEMRI. With the integration of PMSDT nanogel-based coating in polyimide-based microelectrode arrays, the post-implantation DBS enables frequency-dependent MR imaging in vivo, as well as small focal imaging in response to channel site-specific stimulation on the implant. The MR imaging of the implanted brain treated with 5-min electrical stimulation showed a thalamocortical neuronal pathway after 36 h, confirming the effective activation of a downstream neuronal circuit following DBS. By eliminating the susceptibility to artifact and toxicity, this system, in combination with a MR-compatible implant and a bio-compliant neural interface, provides a harmless and synchronic functional anatomy for DBS. The study demonstrates a model of MEMRI-functionalized DBS based on functional neural interface engineering and controllable delivery technology, which can be utilized in more detailed exploration of the functional anatomy in the treatment of neurodegenerative diseases.



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Fibroin particle-supported cationic lipid layers for highly efficient intracellular protein delivery

Publication date: April 2017
Source:Biomaterials, Volume 122
Author(s): Woo-Jin Kim, Bong-Soo Kim, Young-Dan Cho, Won-Joon Yoon, Jeong-Hwa Baek, Kyung-Mi Woo, Hyun-Mo Ryoo
Directly delivering therapeutic proteins into cells has promise as an intervention without side effects for protein deficiencies caused by genetic defects. However, as negatively charged macromolecules, proteins require carriers for achieving cellular uptake and maintaining their activity in the cytoplasm. The biodegradable natural polymer silk fibroin has demonstrated outstanding advantages as a protein drug scaffold in vitro and in vivo, but its usage has been limited in the extracellular space because of its negatively charged character. Here, we present an intracellular protein delivery system based on fibroin particles coated with cationic lipid layers, denoted as Fibroplex, the surface charge of which can be modulated. Fibroplex showed higher delivery efficiency than conventional delivery methods as well as long-term cargo release in the cytoplasm without toxicity. Furthermore, in vivo experiments showed that Fibroplex efficiently delivered tyrosinase and horseradish peroxidase, which led to hyper-pigmentation and tumor regression, respectively, suggesting its potential for therapeutic protein applications in hereditary diseases or cancer.



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Aurantiamide Acetate from Baphicacanthus cusia root exhibits Anti-Inflammatory and Anti-viral Effects via inhibition of the NF-κB Signaling Pathway in Influenza A virus-infected Cells

Publication date: Available online 21 January 2017
Source:Journal of Ethnopharmacology
Author(s): Beixian Zhou, Zifeng Yang, Qitong Feng, Xiaoli Liang, Jing Li, Mark Zanin, Zhihong Jiang, Nanshan Zhong
Ethnopharmacological relevanceBaphicacanthus cusia root also names "Nan Ban Lan Gen" has been traditionally used to prevent and treat influenza A virus infections. Here, we identified a peptide derivative, aurantiamide acetate (compound E17), as an active compound in extracts of B. cusia root. Although studies have shown that aurantiamide acetate possesses antioxidant and anti-inflammatory properties, the effects and mechanism by which it functions as an anti-viral or as an anti-inflammatory during influenza virus infection are poorly defined. Here we investigated the anti-viral activity and possible mechanism of compound E17 against influenza virus infection.Materials and MethodsThe anti-viral activity of compound E17 against Influenza A virus (IAV) was determined using the cytopathic effect (CPE) inhibition assay. Viruses were titrated on Madin-Darby canine kidney (MDCK) cells by plaque assays. Ribonucleoprotein (RNP) luciferase reporter assay was further conducted to investigate the effect of compound E17 on the activity of the viral polymerase complex. HEK293T cells with a stably transfected NF-κB luciferase reporter plasmid were employed to examine the activity of compound E17 on NF-κB activation. Activation of the host signaling pathway induced by IAV infection in the absence or presence of compound E17 was assessed by western blotting. The effect of compound E17 on IAV-induced expression of pro-inflammatory cytokines was measured by real-time quantitative PCR and Luminex assays.ResultsCompound E17 exerted an inhibitory effect on IAV replication in MDCK cells but had no effect on avian IAV and influenza B virus. Treatment with compound E17 resulted in a reduction of RNP activity and virus titers. Compound E17 treatment inhibited the transcriptional activity of NF-κB in a NF-κB luciferase reporter stable HEK293 cell after stimulation with TNF-α. Furthermore, compound E17 blocked the activation of the NF-κB signaling pathway and decreased mRNA expression levels of pro-inflammatory genes in infected cells. Compound E17 also suppressed the production of IL-6, TNF-α, IL-8, IP-10 and RANTES from IAV-infected lung epithelial (A549) cells.ConclusionsThese results indicate that compound E17 isolated from B. cusia root has potent anti-viral and anti-inflammatory effects on IAV-infected cells via inhibition of the NF-κB pathway. Therefore, compound E17 could be a potential therapeutic agent for the treatment of influenza.

Graphical abstract

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New aspects on the hepatoprotective potential associated with the antioxidant, hypocholesterolemic and anti-inflammatory activities of Vernonia condensata Baker

Publication date: Available online 21 January 2017
Source:Journal of Ethnopharmacology
Author(s): Jucélia Barbosa da Silva, Renata de Freitas Mendes, Vívian Tomasco, Nícolas de Castro Campos Pinto, Luiz Gustavo de Oliveira, Matheus Nehrer Rodrigues, Danielle Maria de Oliveira Aragão, Jair Adriano Kopke de Aguiar, Maria Silvana Alves, Maria Christina Nogueira Marques Castañon, Antônia Ribeiro, Elita Scio
Ethnopharmacological RelevanceVernonia condensata Baker (Asteraceae) is traditionally used in South American Countries as an anti-inflammatory, analgesic and hepatoprotective.Aim of the studyThis study aimed to investigate the in vivo hepatoprotective and antioxidant, and the in vitro anti-inflammatory activities of the ethyl acetate partition (EAP) from the ethanolic extract of this medicinal plant leaves.Materials and methodsFor the in vivo hepatoprotective activity, rats were pretreated orally for seven days with vehicle, silymarin 100mg/kg or EAP 50, 100 and 200mg/kg. Then, acetaminophen 3g/kg was also orally administrated. Animals were euthanatized 24h after the damage inducement. The levels of the serum enzymes ALT, AST and ALP were determined, as well as the triglycerides, total cholesterol and fractions. The antioxidant activity was evaluated by TBARS assay and by the measurement of glutathione reductase, superoxide dismutase and catalase activities in the rats liver tissue. The in vitro anti-inflammatory assay using Raw 264.7 cell line induced by lipopolysaccharide was conducted to verify EAP ability to inhibit pro-inflammatory cytokines.ResultsEAP was able to inhibit all the acute biochemical alterations caused by acetaminophen overdose. EAP inhibited malondialdehyde formation, maintained the catalase and increased the glutathione reductase activities. Also, EAP decreased NO, IL-6 and TNF-α levels at concentrations from 10 to 20µg/mL. 1,5-dicaffeoylquinic acid was isolated and identified as the major compound in EAP. Apigenin, luteolin, chlorogenic acid were also identified. EAP anti-inflammatory action may be due to its antioxidant activity or its capacity to inhibit the pro-inflammatory cytokines.ConclusionThese results strongly suggested that V. condensata may be useful as a possible therapy against liver damage.

Graphical abstract

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Hawthorn (Crataegus pinnatifida Bunge) leave flavonoids attenuate atherosclerosis development in apoE knock-out mice

Publication date: Available online 21 January 2017
Source:Journal of Ethnopharmacology
Author(s): Pengzhi Dong, Lanlan Pan, Xiting Zhang, Wenwen Zhang, Xue Wang, Meixiu Jiang, Yuanli Chen, Yajun Duan, Honghua Wu, Yantong Xu, Peng Zhang, Yan Zhu
Ethnopharmacological relevanceHawthorn (Crataegus pinnatifida Bunge) leave have been used to treat cardiovascular diseases in China and Europe. Hawthorn leave flavonoids (HLF) are the main part of extraction. Whether hawthorn leave flavonoids could attenuate the development of atherosclerosis and the possible mechanism remain unknown.Materials and methodsHigh-fat diet (HFD) mixed with HLF at concentrations of 5mg/kg and 20mg/kg were administered to apolipoprotein E (apoE) knock out mice. 16 weeks later, mouse serum was collected to determine the lipid profile while the mouse aorta dissected was prepared to measure the lesion area. Hepatic mRNA of genes involved in lipid metabolism were determined. Peritoneal macrophages were collected to study the impact of HLF on cholesterol efflux, formation of foam cell and the expression of ATP binding cassette transporter A1 (ABCA1). Besides, in vivo reverse cholesterol transport (RCT) was conducted.ResultsHLF attenuated the development of atherosclerosis that the mean atherosclerotic lesion area in en face aortas was reduced by 23.1% (P<0.05). In mice fed with 20mg/kg HLF, Total cholesterol (TC) level was decreased by 18.6% and very low density lipoprotein cholesterol plus low density lipoprotein cholesterol (VLDLc+LDLc) level were decreased by 23.1% whereas high density lipoprotein cholesterol (HDLc) and triglyceride (TG) levels were similar compared to that of the control group. Peroxisome proliferator activated receptor alpha (PPARα) mRNA was increased by 31.2% (P<0.05) and 60.9% (P<0.05) in mice fed with 5mg/kg and 20mg/kg HLF respectively. Sterol regulatory element binding protein-1c (SREBP-1c) was decreased by 59.3% in the group of 20mg/kg. Carnitine palmitoyl transferase 1 (CPT-1) mRNA level of 20mg/kg group was induced 66.7% (P<0.05). Superoxide dismutase 1 and 2 (SOD1 and SOD2) mRNA were induced 25.4% (P<0.05) and 71.4% (P<0.05) while induced by 36.3% (P<0.05) and 73.2% (P<0.05) in group of 20mg/kg. Glutathione peroxidase 3 (Gpx3) mRNA in the group of 20mg/kg was induced by 96.7% (P<0.05). Hepatic hydroxymethylglutaryl CoA reductase (HMG-CoAR) expression was as same level as the control group while LDL receptor (LDLR) mRNA and protein were induced by 84.2% (P<0.05) and 98.8% (P<0.05) in group of 20mg/kg. HLF inhibit the formation of foam cell by 27.9% (P<0.05) in the dosage of 25μg/ml, and 33.3% (P<0.05) in the dosage of 50μg/ml. HLF increased the reverse cholesterol transport (RCT) in vivo.Discussion and conclusionHawthorn leave flavonoids can slow down the development of atherosclerosis in apoE knockout mice via induced expression of genes involved in antioxidant activities, inhibition of the foam cell formation and promotion of RCT in vivo, which implies the potential use in the prevention of atherosclerosis.

Graphical abstract

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Investigations on anti-inflammatory and analgesic activities of Alnus nitida Spach (Endl). stem bark in Sprague Dawley rats

Publication date: Available online 21 January 2017
Source:Journal of Ethnopharmacology
Author(s): Moniba Sajid, Muhammad Rashid Khan, Sayed Afzal Shah, Muhammad Majid, Hammad Ismail, Sonia Maryam, Riffat Batool, Tahira Younis
Ethnopharmacological relevanceStem bark of Alnus nitida (Spach) Endl. (family Betulaceae) is used by local communities in northern areas of Pakistan as a remedy for swelling, injuries and pain. However no pharmacological study of this plant has been reported to confirm these activities. In this study anti-inflammatory and analgesic effect of A. nitida stem bark have been evaluated.MethodsPowder of the stem bark of A. nitida was extracted with methanol (ANBM) and partitioned in escalating polarity to get the n-hexane (ANBH), chloroform (ANBC), ethyl acetate (ANBE) and the residual soluble aqueous (ANBA) fractions. The methanol extract and derived fractions were evaluated for anti-inflammatory activity by using in vitro heat induced albumin denaturation assay and various in vivo assays; carrageenan-induced hind paw edema method, Freunds' complete adjuvant induced arthritis, histamine induced paw edema and xylene induced ear edema in Sprague Dawley rat. The extracts/fractions were also evaluated for analgesic effects by using hot plate analgesic test and acetic acid induced writhing test in rat. The ANBM composition was analyzed by HPLC-DAD and GC-MS analysis.ResultsResults of heat induced albumin denaturation activity indicated that among the extract/fractions ANBC at concentration range of 100 − 500µg/ml remarkably protected the heat induced albumin denaturation. The pretreatment with ANBC significantly reduced the carrageenan induced edema with 90.81±1.6% after 4h, comparing with 86.63±3.42% reduction produced by the reference drug diclofenac potassium. Histopathological alterations of the gastric and hind paw were decreased with the extract/fractions. Furthermore, anti-inflammatory effects of ANBC were evident in Freunds' complete adjuvant induced arthritis, histamine induced paw edema and xylene induced ear edema. The latency time in hot plate analgesic assay with ANBC (61.59±0.38%) after 90min was comparable to standard drug morphine (69.31±2.67%) and aspirin (67.24±2.08%). Similarly ANBC significantly (p < 0.01) inhibited the pain sensation in acetic acid induced writhing test in rat. HPLC-DAD analysis of ANBM indicated the presence of gallic acid, catechin and rutin while the GC-MS analysis of ANBM indicated the presence of 30 compounds predominantly of neophytadiene, 3,7,11,15 tetramethyl-2-hexadecen-1-ol, phytol, vitamin E and linalool.ConclusionThe results of this study suggested that the presence of polyphenols, sterols, terpenoids and other constituents might contributed towards the anti-inflammatory and analgesic activities of the crude methanol extract of A. nitida bark and its derived fractions. This study endorsed the folklore use of A. nitida bark for inflammation related disorders.

Graphical abstract

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Water extract of Helminthostachys zeylanica attenuates LPS-induced acute lung injury in mice by modulating NF-κB and MAPK pathways

Publication date: Available online 21 January 2017
Source:Journal of Ethnopharmacology
Author(s): Chian-Jiun Liou, Yu-Ling Huang, Wen-Chung Huang, Kuo-Wei Yeh, Tzu-Yi Huang, Chwan-Fwu Lin
Ethnopharmacological relevancePrevious studies showed that Helminthostachys zeylanica (L.) Hook. could reduce inflammatory responses in macrophage and brain astrocytes.Aim of the studyIn the present study, we evaluated whether an ethyl acetate extract (HZE) or a water extract (HZW) of H. zeylanica could reduce inflammatory responses in lung epithelial cells and ameliorate lipopolysaccharide (LPS)-induced acute lung injury in mice.MethodsHuman lung epithelial A549 cells were pre-treated with HZE or HZW (1–10μg/mL), then stimulated with LPS. BALB/c mice received oral HZW for 7 consecutive days, then an intratracheal instillation of LPS to induce lung injury.ResultsHZW reduced chemokine and proinflammatory cytokine production in LPS-activated A549 cells. HZW also suppressed ICAM-1 expression and reduced the adherence of acute monocytic leukemia cells to inflammatory A549 cells. HZE had less efficacy than HZW in suppressing inflammatory responses in A549 cells. In vivo, HZW significantly suppressed neutrophil infiltration and reduced the TNF-α and IL-6 levels in bronchoalveolar lavage fluid and serum from LPS-treated mice. HZW also modulated superoxide dismutase activity, glutathione, and myeloperoxidase activity in lung tissues from LPS-treated mice. HZW decreased the phosphorylation of mitogen-activated protein kinase and nuclear factor kappa B, and promoted heme oxygenase-1 expression in inflamed lung tissue from LPS-treated mice.ConclusionOur findings suggested that HZW reduced lung injury in mice by reducing oxidative stress and inflammatory responses. HZW also reduced inflammatory responses in human lung epithelial cells.

Graphical abstract

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Antiosteoporotic Effect of Hemidesmus indicus Linn. on Ovariectomised Rats

Publication date: Available online 21 January 2017
Source:Journal of Ethnopharmacology
Author(s): Sharad Desai, Parth Babaria, Madhavi Nakarani, Kunal Shah, Archana Paranjape
Pharmacological relevanceRoot of Hemidesmus indicus (L). R. Br., an herbal drug of India is traditionally used to prevent or treat female hormonal disturbance related disorders and assuaging symptoms of menopausal conditions.Aim of the studyLack of scientific data for potential use in bone loss, the present study was undertaken to investigate the effects of ethanol extract of Hemidesmus indicus root for osteoporosis in ovariectomised rats.Materials and MethodsThirty wistar female rats were randomly divided into five groups. One group was sham operated and other four groups were undergone dorsal ovariectomy (OVX). After four weeks of post-operative recovery, three OVX groups, viz. Group1, Group2 and Group3 were treated for ninety days with standard raloxifene (RLX) 1mg/kg/day, Hemidesmus indicus root extract (HIRE) 100mg/kg/day and HIRE 200mg/kg/day respectively. Sham and OVX control groups were fed with equal 1% vehicle volume. Serum and urine biochemistry (alkaline phosphatase, tartrate resistant acid phosphatase, triglyceride, total cholesterol, calcium, phosphorous and hydroxyproline), weight of body, uterus and vagina, femur parameters, three point bending of tibia and fourth lumbar vertebra compression were examined. Furthermore, bone architecture and uterine hypertrophy were examined by histopathological studies.ResultsApplication of HIRE has increased bone strength and restored bone turnover markers such as alkaline phosphatase, tartrate resistant acid phosphatase and hydroxyproline moreover, improved femur parameters indicated mineralized bones, similar to the results observed with raloxifene treatment. Histopathology studies showed fibrocartilaginous proliferation of trabecular bone and absence of uterine hypertrophy.ConclusionThe results strongly suggest that HIRE prevents bone loss in OVX induced osteoporosis without estrogen like side effects. It might be a potential remedy like raloxifene for postmenopausal or estrogen deficiency caused osteoporosis.

Graphical abstract

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Editorial Board

Publication date: February 2017
Source:Free Radical Biology and Medicine, Volume 103





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Chorda tympani nerve management in endoscopic stapes surgery

Publication date: Available online 20 January 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): Ahmed Amin Omran, Ahmed Aly Ibrahim, Wael K.A. Hussein, Yasser Osman
ObjectivesTo demonstrate different techniques in manipulating the chorda tympani nerve during endoscopic stapedotomy for otosclerotic patients.MaterialsTwenty patients presented with clinically diagnosed otosclerosis were randomly selected from outpatient ENT clinic in a tertiary referral Hospital over a period of 2years (2013–2015) for endoscopic stapes surgery.MethodsThis prospective study demonstrates different management modalities of chorda tympani nerve in endoscopic stapes surgery according to the endoscopic anatomical relationship between the length of the chorda tympani nerve and the degree of scutum overhanging the oval window niche structures (endoscopic scutum- chorda tympani relationship).ResultsThree management techniques were carried out to deal with chorda tympani based on its endoscopic anatomical relationship with the scutum (no manipulation, upward-displacement, downward-displacement). All patients had significant improvement of postoperative hearing. Only 2 patients were managed by downward displacement technique had postoperative change in taste sensation and tongue numbness that improved over a period of 6months.Conclusiontrans-Canal fully endoscopic stapedotomy provides feasible and safe handling of the chorda tympani nerve with best postoperative taste sensation preservation.



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Vertical supranuclear gaze palsy in a toddler with Niemann-Pick type C

Publication date: Available online 21 January 2017
Source:Pediatric Neurology
Author(s): Tatiana Bremova, Michael Strupp




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Analysis of 22Na using a spectral summation technique on high-volume aerosol samples

Publication date: April 2017
Source:Journal of Environmental Radioactivity, Volumes 169–170
Author(s): I. Hoffman, B. Lewis, P. Chan, K. Ungar
Measurement of cosmogenic ²²Na in daily aerosol samples is often difficult due to low atmospheric production rates. A new technique based upon spectral summation of sequential high-volume aerosol samples to measure ²²Na is described and validated. This summation technique has broad applications to any detection system that produces sequential representative sample measurements in which radioisotopes are just below the detection limit, provided the energy calibration is stable. It is anticipated that a global dataset of this radionuclide will have many important environmental science applications.



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On the divergences in assessment of environmental impacts from ionising radiation following the Fukushima accident

Publication date: April 2017
Source:Journal of Environmental Radioactivity, Volumes 169–170
Author(s): P. Strand, S. Sundell-Bergman, J.E. Brown, M. Dowdall
The accident at the Fukushima-Daiichi Nuclear Power Station on March 11, 2011, led to significant contamination of the surrounding terrestrial and marine environments. Whilst impacts on human health remain the primary concern in the aftermath of such an accident, recent years have seen a significant body of work conducted on the assessment of the accident's impacts on both the terrestrial and marine environment. Such assessments have been undertaken at various levels of biological organisation, for different species, using different methodologies and coming, in many cases, to divergent conclusions as to the effects of the accident on the environment. This article provides an overview of the work conducted in relation to the environmental impacts of the Fukushima accident, critically comparing and contrasting methodologies and results with a view towards finding reasons for discrepancies, should they indeed exist. Based on the outcomes of studies conducted to date, it would appear that in order to avoid the fractured and disparate conclusions drawn in the aftermath of previous accidents, radioactive contaminants and their effects can no longer simply be viewed in isolation with respect to the ecosystems these effects may impact. A combination of laboratory based and field studies with a focus on ecosystem functioning and effects could offer the best opportunities for coherence in the interpretation of the results of studies into the environmental impacts of ionising radiation.



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The possible role of cerium oxide (CeO2) nanoparticles in prevention of neurobehavioral and neurochemical changes in 6-hydroxydopamine-induced parkinsonian disease

Publication date: Available online 20 January 2017
Source:Alexandria Journal of Medicine
Author(s): Maha Abd Elkader Hegazy, Hala Mohamed Maklad, Doaa A. Abd Elmonsif, Fatma Yosry Elnozhy, Malik Ahmad Alqubiea, Fisal Aliwi Alenezi, Obaid Mahdi Al abbas, Mahdi Mana Al abbas
Cerium oxide nanoparticles (CeO2NPs) is an efficient neuroprotective agent and showed promising effects in some neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis. However, the implication of CeO2NPs in Parkinsonism remains to be investigated.The aim of this study was to assess the possible role of CeO2NPs as a neuroprotective agent against the development of behavioral and biochemical changes in rat model of Parkinson's disease. Thirty rats were included and received left intrastriatal injection of either saline (controls, n=10) or 6-hydroxy dopamine (6-OHDA) in untreated group (n=10) and 10 rats were received intraperitoneal injection of low dose CeO2NPs two hours before surgery, and continued once daily for 6 weeks (preventive group). At the end of experimental period, rats were subjected to behavioral assessment and then killed for biochemical analysis of striatal dopamine levels, oxidative stress markers and caspase-3 activity. Results showed that CeO2NPs resulted in partial neuroprotection against disturbances in motor performance. It also partially decreased apoptosis and oxidative stress in preventive group, while it failed to increase striatal dopamine level as compared to untreated rats. The present study verified some neuroprotective effects of CeO2NPs in 6-OHDA-induced Parkinsonian rats through their antioxidant and anti apoptotic effects. Some of these effects persisted till the end of six weeks whereas others declined after three weeks. A larger dose may be needed to produce more valuable effects and to maintain protection for a longer period.



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Prospective comparative study between un-enhanced multidetector computed tomography and ultrasonography in evaluation of acute renal colic

Publication date: Available online 21 January 2017
Source:Alexandria Journal of Medicine
Author(s): Rehab Abdel Rahman El Bakry




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Changes in fMRI activation in anterior hippocampus and motor cortex during memory retrieval after an intense exercise intervention

Publication date: Available online 21 January 2017
Source:Biological Psychology
Author(s): Gerd Wagner, Marco Herbsleb, Feliberto de la Cruz, Andy Schumann, Stefanie Köhler, Christian Puta, Holger W. Gabriel, Jürgen R. Reichenbach, Karl-Jürgen Bär
Strong evidence indicates that regular aerobic training induces beneficial effects on cognitive functions. The present controlled fMRI study was designed to investigate the impact of a short-term intense aerobic exercise on the pattern of functional activation during the retrieval of learned pair-associates in 17 young and healthy male adults compared to 17 matched control subjects. We further aimed to relate putative changes in hippocampal activation to postulated changes in the exercised-induced brain derived neurotrophic factor (BDNF). The supervised exercise program was performed on a bicycle ergometer and lasted six weeks, with three aerobic sessions per week.We found profound improvement of physical fitness in most subjects indicated by the target parameter 'individual anaerobic threshold'. Significant improvements in the cognitive performance were detected in the exercise group, but also in the control group. We observed significant differences in the activation pattern of the left anterior hippocampus during the pair-associates task after the intervention. We could also show a significant positive correlation between changes in exercise-induced BDNF and left anterior as well as right hippocampal activation. Moreover, we observed the brain's motor network to be significantly stronger activated after the exercise intervention. Thus, our results suggest BDNF dependent activation changes of the hippocampus in addition to previously described structural changes after exercise.



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Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification

Publication date: March 2017
Source:Molecular Immunology, Volume 83
Author(s): Yi-Ching Lin, Yu-Chih Lin, Ming-Yii Huang, Po-Lin Kuo, Cheng-Chin Wu, Min-Sheng Lee, Chong-Chao Hsieh, Hsuan-Fu Kuo, Chang-Hung Kuo, Wen-Chan Tsai, Chih-Hsing Hung
The treatment of rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-α) inhibitors could lead to adverse effects. Therefore, the identification of downstream therapeutic targets is important. Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is related to RA disease activity, and epigenetic modifications are hypothesized to regulate gene expression in RA pathogenesis. We studied the effects of two TNF-α inhibitors, etanercept and adalimumab, on CCL2 expression and the potentially associated intracellular mechanisms, including epigenetic regulation. Etanercept and adalimumab decreased CCL2 production in THP-1 cells and human primary monocytes, as detected using enzyme-linked immunosorbent assays, and these changes in the CCL2 levels were independent of the TNF-α levels. Etanercept and adalimumab suppressed mitogen-activated protein kinase (MAPK) phospho-p38, phospho-JNK, phospho-ERK and nuclear factor-κB (NF-κB) phospho-p65, as demonstrated using western blot analyses. The investigation of epigenetic modifications using chromatin immunoprecipitation revealed that etanercept and adalimumab down-regulated acetylation of histone (H)3 and H4 in the CCL2 promoter region by decreasing the recruitment of the NF-κB associated acetyltransferases p300, CBP and PCAF. Etanercept and adalimumab also down-regulated trimethylation of H3K4, H3K27, H3K36 and H3K79 in the CCL2 promoter region by decreasing the expression of the related methyltransferases WDR5 and Smyd2. We demonstrated that TNF-α inhibitors exert immunomodulatory effects on CCL2 expression in human monocytes via MAPKs, NF-κB and epigenetic modifications. These findings broaden the mechanistic knowledge related to TNF-α inhibitors and provide novel therapeutic targets for RA.

Graphical abstract

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Electroencephalographic characteristics of status epilepticus after cardiac arrest

Publication date: Available online 21 January 2017
Source:Clinical Neurophysiology
Author(s): Sofia Backman, Erik Westhall, Irina Dragancea, Hans Friberg, Malin Rundgren, Susann Ullén, Tobias Cronberg
ObjectiveTo describe the electrophysiological characteristics and pathophysiological significance of electrographic status epilepticus (ESE) after cardiac arrest and specifically compare patients with unequivocal ESE to patients with rhythmic or periodic borderline patterns defined as possible ESE.MethodsRetrospective cohort study of consecutive patients treated with targeted temperature management and monitored with simplified continuous EEG. Patients with ESE were identified and electrographically characterised until 72 hours after ESE start using the standardised terminology of the American Clinical Neurophysiology Society.ResultsESE occurred in 41 of 127 patients and 22 fulfilled the criteria for unequivocal ESE, which typically appeared early and transiently. Three of the four survivors had unequivocal ESE, starting after rewarming from a continuous background. There were no differences between the groups of unequivocal ESE and possible ESE regarding outcome, neuron-specific enolase levels or prevalence of reported clinical convulsions.ConclusionESE is common after cardiac arrest. The distinction between unequivocal and possible ESE patterns was not reflected by differences in clinical features or survival.SignificanceA favourable outcome is seen infrequently in patients with ESE, regardless of using strict or liberal ESE definitions.



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Effect of piroxicam on lipid membranes: Drug encapsulation and gastric toxicity aspects

Publication date: 30 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 100
Author(s): Natalia Wilkosz, Sami Rissanen, Małgorzata Cyza, Renata Szybka, Maria Nowakowska, Alex Bunker, Tomasz Róg, Mariusz Kepczynski
Uptake of piroxicam, a non-steroidal anti-inflammatory drug, from the intestines after oral intake is limited due to its low solubility and its wide use is associated with several side effects related to the gastrointestinal tract. In this study, all-atom molecular dynamics (MD) simulations and fluorescent spectroscopy were employed to investigate the interaction of piroxicam in neutral, zwitterionic, and cationic forms with lipid bilayers composed of phosphatidylcholine, cholesterol, and PEGylated lipids. Our study was aimed to assess the potential for encapsulation of piroxicam in liposomal carriers and to shed more light on the process of gastrointestinal tract injury by the drug. Through both the MD simulations and laser scanning confocal microscopy, we have demonstrated that all forms of piroxicam can associate with the lipid bilayers and locate close to the water-membrane interface. Conventional liposomes used in drug delivery are usually stabilized by the addition of cholesterol and have their bloodstream lifetime extended through the inclusion of PEGylated lipids in the formulation to create a protective polymer corona. For this reason, we tested the effect of these two modifications on the behavior of piroxicam in the membrane. When the bilayer was PEGylated, piroxicam localize to the PEG layer and within the lipid headgroup region. This suggests that PEGylated liposomes are capable of carrying a larger quantity of piroxicam than the conventional ones.

Graphical abstract

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Effect of 6-gingerol on AMPK- NF-κB axis in high fat diet fed rats

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Reem M. Hashem, Laila A. Rashed, Kamel M.A. Hassanin, Mona H. Hetta, Asmaa O. Ahmed
ObjectivesAdenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in metabolic homeostasis and regulation of inflammatory responses through attenuation of nuclear factor kappa-B (NF-κB), Thus AMPK may be a promising pharmacologic target for the treatment of various chronic inflammatory diseases. We examined the effect of 6-gingerol, an active ingredient of ginger on AMPK-NF-κB pathway in high fat diet (HFD) rats in comparison to fish oil.MethodsProtein levels of AMPK-α1 and phosphorylated AMPK-α1 were measured by western blot while Sirtuin 6 (Sirt-6), resistin and P65 were estimated by RT-PCR, TNF-α was determined by ELISA, FFAs were estimated chemically as well as the enzymatic determination of the metabolic parameters.Results6-Gingerol substantially enhanced phosphorylated AMPK-α1 more than fish oil and reduced the P65 via upregulation of Sirt-6 and downregulation of resistin, and resulted in attenuation of the inflammatory molecules P65, FFAs and TNF-α more than fish oil treated groups but in an insignificant statistical manner, those effects were accompanied by a substantial hypoglycemic effect.ConclusionGingerol treatment effectively modulated the state of inflammatory privilege in HFD group and the metabolic disorders via targeting the AMPK-NF-κB pathway, through an increment in the SIRT-6 and substantial decrement in resistin levels.



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Cutaneous alternariosis in a renal transplant patient successfully treated with posaconazole: Case report and literature review

Publication date: Available online 21 January 2017
Source:Medical Mycology Case Reports
Author(s): Rajinder Bajwa, Amy L. Wojciechowski, Chiu-Bin Hsiao
Cutaneous alternariosis is an uncommon fungal infection that most commonly presents in organ transplant patients on immunosuppressive therapy. There are no clinical trials or guidelines to guide treatment of this condition, however itraconazole is the most commonly used antifungal in published cases. Here we report on a case of cutaneous alternariosis in a renal transplant recipient treated with a newer antifungal, posaconazole. A review of published reports of cutaneous alternariosis since 2008 is also discussed.



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Cranial Nerve Injury After Carotid Endarterectomy: Incidence, Risk Factors, and Time Trends

Publication date: Available online 21 January 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): J.D. Kakisis, C.N. Antonopoulos, G. Mantas, K.G. Moulakakis, G. Sfyroeras, G. Geroulakos
Objective/BackgroundΤo review the incidence of post-carotid endarterectomy (CEA) cranial nerve injury (CNI), and to evaluate the risk factors associated with increased CNI risk.MethodsThe study was a meta-analysis. Pooled rates with 95% confidence intervals (CIs) were calculated for CNIs after primary CEA. Odds ratios (ORs) were calculated for potential risk factors. A fixed-effects model or a random effects model (Mantel–Haenszel method) was used for non-heterogeneous and heterogeneous data, respectively. Meta-regression analysis was performed to examine the influence of publication year upon CNI rate.ResultsTwenty-six articles, published between 1970 and 2015, were included in the meta-analysis, corresponding to 20,860 CEAs. Meta-analysis revealed that the vagus nerve was the most frequently injured cranial nerve (pooled injury rate 3.99%, 95% CI 2.56–5.70), followed by the hypoglossal nerve (3.79%, 95% CI 2.73–4.99). Fewer than one seventh of these injuries are permanent (vagus nerve: 0.57% [95% CI 0.19–1.10]; hypoglossal nerve: 0.15% [95% CI 0.01–0.39]). A statistically significant influence of publication year on the vagus and hypoglossal nerve injury rate was found, with the injury rate having decreased from about 8% to 2% and 1%, respectively, over the last 35 years. Urgent procedures (OR 1.59, 95% CI 1.21–2.10; p = .001), as well as return to the operating room for a neurological event or bleeding (OR 2.21, 95% CI 1.35–3.61; p = .002) were associated with an increased risk of CNI, whereas no statistically significant association was found between CNIs and the type of anaesthesia, the use of a patch, redo operation, and the use of a shunt.ConclusionThe vagus nerve appears to be the most frequently injured cranial nerve after CEA, followed by the hypoglossal nerve, with only a small proportion of these injuries being permanent. The CNI rate has significantly decreased over the past 35 years to a point indicating that CNIs should not be considered a major influencing factor in the decision making process between CEA and stenting.



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In-vitro performance of CAD/CAM-fabricated implant-supported temporary crowns

Abstract

Objectives

The aim of this study was to investigate the in-vitro performance and fracture resistance of a temporary computer-aided designed and computer-aided manufactured polymethylmethacrylate (CAD/CAM-PMMA) material as implant or tooth-supported single crown with respect to the clinical procedure (permanently bonded/temporarily cemented).

Materials and methods

Sixty-four crowns were fabricated on implants or human molar teeth simulating (a) labside procedure on prefabricated titanium-bonding base ([TiBase] implant crown bonded in laboratory, screwed chairside), (b) labside procedure ([LAB] standard abutment and implant crown bonded in laboratory, screwed chairside), (c) chairside procedure ([CHAIR] implant crown bonded to abutment), and (d) reference ([TOOTH] crowns luted on prepared human teeth). Crowns were made of a CAD/CAM-PMMA temporary material (TelioCAD, Ivoclar-Vivadent). For investigating the influence of fixation, half of the crowns were permanently (P) or temporarily (T) bonded. Combined thermal cycling and mechanical loading (TCML) was performed simulating a 5-year clinical situation. Fracture force was determined. Data were statistically analyzed (Kolmogorov-Smirnov test, one-way ANOVA; post hoc Bonferroni, α = 0.05).

Results

All restorations survived TCML without visible failures. Fracture results varied between 3034.3 (Tooth-P) and 1602.9 N (Tooth-T) [TOOTH], 1510.5 (TiBase-P) and 963.6 N (TiBase-T) [TiBase], 2691.1 (LAB-P) and 2064.5 N (LAB-T) [LAB], and 1609.4 (Chair-P) and 1253.0 N (Chair-T) [CHAIR]. Tested groups showed significantly (p < 0.001) different fracture values. Failure pattern was characterized by fractures in mesial-distal, buccal-oral, or mixed (mesial-distal/buccal-oral) directions, with differences for the individual groups.

Conclusions

Temporary CAD/CAM crowns showed no different in-vitro performance but provided different fracture results that depended on cementation, screw channel, and type of abutment.

Clinical relevance

All bonded and screwed PMMA crowns were in a range where clinical application seems not restricted.

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Gingival recessions of lower incisors after proclination by orthodontics alone or in combination with anterior mandibular alveolar process distraction osteogenesis

Abstract

Objectives

The aim of this study was to longitudinally compare periodontal conditions in consecutive patients who had orthodontic treatment with proclination of lower incisors either by orthodontics alone or in combination with anterior mandibular alveolar process distraction osteogenesis (DO).

Materials and methods

Nineteen patients had orthodontic treatment with DO, 18 with extraction of lower premolars (Ex), and 18 without extractions (Nonex). Lateral cephalograms were used to evaluate lower incisor proclination, while study casts and intraoral photographs were used to evaluate labial and lingual gingival recessions before (T1) and at an average of 4.5 years (T2) after treatment.

Results

No differences in labial recessions on lower incisors were present between the patient groups despite greater lower incisor proclination in the Nonex and DO groups. The Ex group showed no new development of lingual recessions in contrast to the Nonex (eight sites; two subjects) and DO groups (seven sites; three subjects). Severe lingual recessions (increased ≥1 mm) were more present in the Nonex group (five sites; two subjects) compared to the Ex group (no sites). Proclination of lower incisors of 10° or more either by orthodontic tooth movement or displacement of the whole alveolar process increased the risk of lingual gingival recessions 17 times. This was not the case with labial gingival recessions.

Conclusions

Orthodontic or surgical proclination of lower incisors beyond a 10° limit increases the risk of inducing lingual gingival recessions.

Clinical relevance

During orthodontic treatment, with or without DO, one should avoid proclining lower incisors more than 10° to decrease the risk of gingival recessions.

http://ift.tt/2jAKcDq

In vivo magnetic resonance imaging investigating the development of experimental brain metastases due to triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC), when associated with poor outcome, is aggressive in nature with a high incidence of brain metastasis and the shortest median overall patient survival after brain metastasis development compared to all other breast cancer subtypes. As therapies that control primary cancer and extracranial metastatic sites improve, the incidence of brain metastases is increasing and the management of patients with breast cancer brain metastases continues to be a significant clinical challenge. Mouse models have been developed to permit in depth evaluation of breast cancer metastasis to the brain. In this study, we compare the efficiency and metastatic potential of two experimental mouse models of TNBC. Longitudinal MRI analysis and end point histology were used to quantify initial cell arrest as well as the number and volume of metastases that developed in mouse brain over time. We showed significant differences in MRI appearance, tumor progression and model efficiency between the syngeneic 4T1-BR5 model and the xenogeneic 231-BR model. Since TNBC does not respond to many standard breast cancer treatments and TNBC brain metastases lack effective targeted therapies, these preclinical TNBC models represent invaluable tools for the assessment of novel systemic therapeutic approaches. Further pursuits of therapeutics designed to bypass the blood tumor barrier and permit access to the brain parenchyma and metastatic cells within the brain will be paramount in the fight to control and treat lethal metastatic cancer.

http://ift.tt/2kdxu0u

Reduced proliferation and colony formation of head and neck squamous cell carcinoma (HNSCC) after dual targeting of EGFR and hedgehog pathways

Abstract

Purpose

The hedgehog signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened, and based on molecular data, may prevent resistance to EGFR targeting.

Methods

To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation. Colony formation (CF) of primary HNSCC cells was studied utilizing the FLAVINO-protocol. Combinatory effects were analysed regarding antagonism, additivity or synergism. Associations between the ex vivo detected mode of action of vismodegib with other treatments related to patient characteristics were assessed and progression-free survival (PFS) in patient groups compared using Kaplan–Meier curves.

Results

Vismodegib suppressed BrdU incorporation significantly stronger than MTT turnover; CF was significantly inhibited at ≥20 µM vismodegib while concentrations <20 µM acted hormetic. Combining 20 µM vismodegib plus docetaxel (T), cisplatin (P), and cetuximab (E), additively enhanced anti-tumoral activity in HNSCC samples from patients with superior PFS highlighting a potential role for ex-vivo testing of this combination for use as a prognostic classifier.

Conclusion

We provide ex-vivo evidence for vismodegib's potential in HNSCC therapies, especially if combined with cetuximab, cisplatin and docetaxel.

http://ift.tt/2iXbce9

Soil compaction effects on soil health and cropproductivity: an overview

Abstract

Soil compaction causes substantial reduction in agriculture productivity and has always been of great distress for farmers. Intensive agriculture seems to be more crucial in causing compaction. High mechanical load, less crop diversification, intensive grazing, and irrigation methods lead to soil compaction. It is further exasperated when these factors are accompanied with low organic matter, animal trampling, engine vibrations, and tillage at high moisture contents. Soil compaction increases soil bulk density and soil strength, while decreases porosity, aggregate stability index, soil hydraulic conductivity, and nutrient availability, thus reduces soil health. Consequently, it lowers crop performance via stunted aboveground growth coupled with reduced root growth. This paper reviews the potential causes of compaction and its consequences that have been published in last two decades. Various morphological and physiological alterations in plant as result of soil compaction have also been discussed in this review.

http://ift.tt/2jJZMyq

Adsorption of nickel ions by oleate-modified magnetic iron oxide nanoparticles

Abstract

In this work, magnetic nanoparticles of iron oxide (MNPs) were synthesized, and then the surface was recovered with an oleate double layer in order to investigate the ability of this material to adsorb nickel ions. First, the solution chemistry of oleate ions was investigated in order to determine the critical micellar concentration (CMC) value and the arrangements of ions above the CMC. Then, the synthesized oleate-modified MNP was characterized (TEM, DLS, XRD, FTIR, zeta potential, magnetometry). Finally, adsorption experiments were carried out as a function of pH and as a function of nickel concentration in 0.1 g L⁻¹ suspensions of oleate-modified MNP. The results show that CMC of oleate ranges from 1 to 2.5∙10⁻³ mol L⁻¹. Above CMC, arrangement of oleate ions as droplets, vesicles, or micelles depends on pH and influences the average size and solution absorbance. Potentiometric titrations allowed determining a pKa value of 7.8 for sodium oleate. The high stability in aqueous suspensions and characterization of oleate-modified MNP confirm that oleate ions are arranged as a bilayer coating at the surface of MNP. Retention of nickel was found to be highly dependent on pH, with a maximum adsorption (90%) beginning from pH = 7.5. The sorption isotherms were well fitted with the Langmuir model and the maximum nickel adsorption capacities were found to be 44 and 80 mg g⁻¹ for pH = 6.8 and 7.2, respectively. The efficient removal of nickel combined with the magnetic properties of the NMP make the oleate-modified MNP an interesting water purification tool.

http://ift.tt/2j4wCtg

Biochemical and physiological responses of halophilic nanophytoplankton ( Dunaliella salina ) from exposure to xeno-estrogen 17α-ethinylestradiol

Abstract

The environmental impacts of various pollutants on the entire levels of organisms are under investigation. Among these pollutants, endocrine-disrupting compounds (EDCs) present a serious hazard, even though the environmental significance of these compounds remains basically unknown. To drop some light on this field, we assessed the effects of a 11-day exposure of 17α-ethinylestradiol (EE2) on the growth, metabolic content, antioxidant response, oxidative stress, and genetic damage of Dunaliella salina, isolated from Tunisian biotopes. The results showed that at 10 ng L⁻¹, EE2 could stimulate the growth of D. salina and increase its cellular content of photosynthetic pigments and metabolites; however, it did not significantly increase the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) or the level of malondialdehyde (MDA) and hydrogen peroxide (H₂O₂). In contrast, exposure to high levels of EE2 concentrations significantly inhibited the growth of D. salina (P < 0.05), decreased the cellular content of photosynthetic pigments, increased the cellular content of all of the metabolites and the SOD activity, and inhibited CAT and GPx activities. Nevertheless, the balance between oxidant and antioxidant enzymes was disrupted because H₂O₂ content along with MDA content simultaneously increased. Contrary to expected results, DNA damage (strand breaks) decreased after the exposure of algae to EE2. The results of this study suggest that EE2 toxicity could result in environmental impacts with consequences on the whole aquatic community.

Graphical abstract

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Association between heavy metal and metalloid levels in topsoil and cancer mortality in Spain

Abstract

Spatio-temporal cancer mortality studies in Spain have revealed patterns for some tumours which display a distribution that is similar across the sexes and persists over time. Such characteristics would be common to tumours that shared risk factors, including the geochemical composition of the soil. The aim of this study was to assess the possible association between heavy metal and metalloid levels in topsoil (upper soil horizon) and cancer mortality in mainland Spain. Ecological cancer mortality study at a municipal level, covering 861,440 cancer deaths (27 different tumour locations) in 7917 Spanish mainland towns, from 1999 to 2008. The elements included in this analysis were Al, As, Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn. Topsoil levels (partial extraction) were determined by ICP-MS at 13,317 sampling points. For the analysis, the data on the topsoil composition have been transformed by the centred logratio (clr-transformation). Principal factor analysis was performed to obtain independent latent factors for the transformed variables. To estimate the effect of heavy metal levels in topsoil composition on mortality, we fitted Besag, York and Mollié models, which included each town's factor scores as the explanatory variable. Integrated Nested Laplace Approximation (INLA) was used as a tool for Bayesian inference. All results were adjusted for sociodemographic variables. The results showed an association between trace contents of heavy metals and metalloids in topsoil and mortality due to tumours of the digestive system in mainland Spain. This association was observed in both sexes, something that would support the hypothesis that the incorporation of heavy metals into the trophic chain might be playing a role in the aetiology of some types of cancer. Topsoil composition and the presence of potentially toxic elements in trace concentrations might be an additional component in the aetiology of some types of cancer, and go some way to determine the ensuing geographic differences in mortality in Spain. The results support the interest of inclusion of heavy metal levels in topsoil as a hypothesis in analytical epidemiological studies using biological markers of exposure to heavy metals and metalloids.

http://ift.tt/2jhsS5g

Heavy metals and nutrients (carbon, nitrogen, and phosphorus) in sediments: relationships to land uses, environmental risks, and management

Abstract

Management of sediments in polluted rivers requires an inventory of sediment quantities as well as their nutrient and metal contents and the chemical forms of pollutants. We investigated the influence of three major land uses (i.e., orange plantation—OP, OP + residential + industrial—OPRI, and residential + industrial—RI) on the quality of surface sediments (0–20 cm below water/sediment interface) at the Sanyang Wetland (China). The total contents of metals (As, Cd, Cr, Cu, Ni, Pb, and Zn) and nutrients (C, N, and P) as well as metal speciation in sediments were examined. GIS technology was used to estimate the volume of sediments needed to calculate the amounts of stored nutrients and metals in sediments. The surface sediments in the 3.2-km² study area contain more than 2800 Mg C, 200 Mg N, and 100 Mg P. OPRI and RI land uses contribute more total C, N, P, Zn, and Cd to sediments than OP land use. High contents of C, N, and P may provide options to recycle the sediments as fertilizer but must be used with caution due to high levels of metals. Total Cd in sediments is at an order of magnitude (up to 59 mg kg−1) higher than the Level III criterion in the Chinese Environmental Quality Standards for Soil. Sediments in all land uses have very high risks due to >50% exchangeable + carbonate-bound Zn, Ni, and Cd. It is suggested that toxicity tests be conducted to better assess the environmental risks associated with any potential use of sediments.

http://ift.tt/2j4yLVM

The nexus of oil consumption, CO 2 emissions and economic growth in China, Japan and South Korea

Abstract

This article attempts to explore the nexus between oil consumption, economic growth and carbon dioxide (CO₂) emissions in three East Asian oil importing countries (i.e. China, South Korea and Japan) over the period 1980–2013, by using the Granger causality, Johansen cointegration test, Generalised Impulse Response functions (GIRF) and variance decompositions. The empirical findings provide evidence for the existence of a long-run relationship between oil consumption and economic growth in China and Japan. The results also point to a uni-directional causality from running from oil consumption to economic growth in China and Japan, and from oil consumption to CO₂ emissions in South Korea. The overall results of GIRF reveal that while economic growth in China and South Korea shows a positive response to oil consumption, this variable responses negatively to the same shock in Japan. In addition, oil consumption spikes cause a negative response of CO₂ emissions in Japan and China, as well as a U-shape response in South Korea.

http://ift.tt/2iWZIHO

Cadherin-11 as a therapeutic target in chronic, inflammatory rheumatic diseases

Publication date: Available online 21 January 2017
Source:Clinical Immunology
Author(s): Petros P. Sfikakis, Nikolaos I. Vlachogiannis, Panagiotis F. Christopoulos
Cadherin-11 has been identified as a key regulator of synovial architecture mediating contact between Fibroblast-like Synoviocytes and organization in the lining layer. A central role for cadherin-11 has also been suggested in the formation of the rheumatoid pannus. Therapeutic targeting of cadherin-11 results in amelioration of autoimmune experimental arthritis, as well as of experimental fibrosis. In addition, cadherin-11 expression is upregulated in the synovium of patients with chronic inflammatory arthritis, whereas detection of cadherin-11 mRNA transcripts in the peripheral blood has been associated with more severe disease phenotypes in two prototypic conditions of chronic joint inflammation and fibrosis, namely, rheumatoid arthritis and systemic sclerosis, respectively. Currently, a monoclonal antibody against cadherin-11 is in early phases of clinical trials in patients with rheumatoid arthritis. Herein, we review the current knowledge regarding the potential role of cadherin-11 in pathogenesis, as well as a biomarker and therapeutic target in chronic inflammatory rheumatic diseases.



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Development of a model to predict the 10-year cumulative risk of second primary cancer among cancer survivors

Publication date: April 2017
Source:Cancer Epidemiology, Volume 47
Author(s): Marie Moitry, Michel Velten, Brigitte Trétarre, Simona Bara, Laetitia Daubisse-Marliac, Bénédicte Lapôtre-Ledoux, Xavier Troussard, Florence Molinié, Karine Ligier, Anne-Sophie Woronoff, Véronique Bouvier, Marc Colonna, Delphine Klein, Anne-Valérie Guizard, Jérémie Jégu
BackgroundTo develop a prediction model to quantify the cumulative risk of Second Primary Cancer (SPC) among cancer patients given that they survive their disease.MethodsA cohort of 293,435 patients based on data from twelve French cancer registries was analyzed. For five first cancer sites, SPC incidence rates were estimated using Poisson regression models. The cumulative risks of SPC were computed for different follow-up times. For comparison purpose, the same method was used to estimate the probability of cancer in the general population.ResultsIn this population-based cohort, 27,320 patients presented with a SPC. The cumulative risk of SPC varied depending on first cancer site, with a 10-year cumulative probability of SPC ranging from 6.2% for women with breast cancer to 44.0% for men with head and neck cancer. Compared with the general population, the 10-year cumulative risk of SPC was dramatically elevated for tobacco-related first cancers, with an increase of +7.3% for men aged 55 to 64 with a first lung cancer and +35.6% for men aged 45 to 54 with a first head and neck cancer. Lower differences were observed among patients diagnosed with a first prostate cancer (+5.5% among men aged 55 to 64), colorectal (+4.1% for women aged 55 to 64 and +6.3% for men aged 55 to 64), and breast (+2.0% among females aged 75 and older) cancers.ConclusionThis study provides physicians with a practical estimate to assess the risk of SPC of their patients more accurately.



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Les néoplasies intra-épithéliales bowénoïdes HPV-induites du pénis

Publication date: Available online 20 January 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): J.-.N. Dauendorffer, B. Cavelier Balloy, M. Bagot, C. Renaud-Vilmer




http://ift.tt/2jZAIRG

Splenic Enlargement and Bone Marrow Hyperplasia in Patients Receiving Trastuzumab-Emtansine for Metastatic Breast Cancer

Abstract

Background

An association between trastuzumab-emtansine (T-DM1) and splenic enlargement is reported in preclinical data, and has been noted anecdotally in patients receiving T-DM1 at our institution. Use of whole-body MRI examinations (WB-MRI) allows for detailed bone marrow assessment and semi-automated splenic volume calculations.

Objective

To retrospectively evaluate changes in splenic volume versus evidence of bone marrow hyperplasia and/or changes in portal venous pressure in patients receiving T-DM1 for metastatic breast cancer.

Patients and Methods

Twelve metastatic breast cancer patients underwent 29 WB-MRIs before and during T-DM1 therapy. Splenic volume, portal vein diameter, bone marrow diffusion-weighted normalised signal intensity (nSI), quantitative water diffusivity (apparent diffusion coefficient, ADC) and fat fraction (rF%) were measured and correlated.

Results

Splenic volume increases were observed in 92% of patients. Mean splenic volume increased from 144 cm³ (95% CI 110–177 cm³) to 209 cm³ (95% CI 161–257 cm³) on T-DM1 therapy (p = 0.006). Splenic volume increases correlated with treatment duration (r² = 0.43). Bone marrow hyperplasia was evidenced by an increase in bone marrow nSI (3.5 to 4.8, p = 0.12), and decreases in rF% (64.3% to 57.3%, p = 0.12) and ADC (655 μm²/s to 543 μm²/s, p = 0.11). No changes to portal vein diameter were seen.

Conclusions

Previously unreported increases in splenic volume and bone marrow hyperplasia are observed on WB-MRI in patients on T-DM1 therapy. Caution must be applied to avoid misinterpreting T-DM1-induced bone marrow hyperplasia as diffuse disease progression in bone.

http://ift.tt/2jj4a4B

CXCR4 antagonist AMD3100 reverses the neurogenesis promoted by enriched environment and suppresses long-term seizure activity in adult rats of temporal lobe epilepsy

Publication date: 30 March 2017
Source:Behavioural Brain Research, Volume 322, Part A
Author(s): Zhike Zhou, Tingting Liu, Xiaoyu Sun, Xiaopeng Mu, Gang Zhu, Ting Xiao, Mei Zhao, Chuansheng Zhao
It has been showed that enriched environment (EE) enhances the hippocampal neurogenesis and improves the cognitive impairments, accompanied by the increased expressions of stromal cell-derived factor-1 (SDF-1) in adult rats of temporal lobe epilepsy (TLE). We examined whether the enhanced neurogenesis and improved cognitive functions induced by EE following seizures were mediated by SDF-1/CXCR4 pathway. Therefore, we investigated the effects of the EE combined with CXCR4 antagonist AMD3100 on neurogenesis, cognitive functions and the long-term seizure activity in the TLE model. Adult rats were randomly assigned as control rats, rats treated with EE, rats subjected to status epilepticus (SE), post-SE rats treated with EE, AMD3100 or EE combined with AMD3100 respectively. We used immunofluorescence staining to analyze the hippocampal neurogenesis and Nissl staining to evaluate hippocampal damage. Electroencephalography was used to measure the frequency and mean duration of spontaneous seizures. Cognitive function was evaluated by Morris water maze test. EE treatment significantly, as well as improved cognitive impairments and decreased long-term seizure activity, and that these effects might be mediated through SDF-1/CXCR4 pathway during the chronic stage of TLE. Although AMD3100 reversed the effect of EE on neurogenesis, it did not abolish the cognitive improvement induced by EE following seizures. More importantly, EE combined with AMD3100 treatment significantly suppressed long-term seizure activity, which provided promising evidences to treat TLE.



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Effect of ZBD-2 on chronic pain, depressive-like behaviors, and recovery of motor function following spinal cord injury in mice

Publication date: 30 March 2017
Source:Behavioural Brain Research, Volume 322, Part A
Author(s): Xiao-ming Li, Jia Meng, Lin tao Li, Ting Guo, Liu-kun Yang, Qi-xin Shi, Xu-bo Li, Yong Chen, Qi Yang, Jian-ning Zhao
In addition to debilitating sensory and motor deficits, patients with spinal cord injury (SCI) may experience chronic hyperpathic pain (SCI-pain). Recent studies have revealed that translocator protein (TSPO) is involved in repairing neural cells as well as reducing anxiety and depression. However, the role of TSPO in SCI-pain and pain-induced depression remains unknown. The present study aimed to determine the effects of a new TSPO ligand, ZBD-2, on SCI-pain and consequent pain-induced depressive-like behaviors in mice. Treatment with ZBD-2 at either dose significantly attenuated the symptoms of chronic SCI-pain and pain-induced depressive-like behaviors. ZBD-2 reversed SCI-induced elevation of serum corticosterone levels, an index of hyper-activation of the hypothalamic–pituitary–adrenal (HPA) axis. Additionally, administration of ZBD-2 inhibited decreases in the expression of synaptic plasticity-related signaling proteins, including brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding protein (CREB). Moreover, ZBD-2 administration reversed chronic, SCI-induced gliocyte activation at the lesion site. Therefore, ZBD-2 may improve chronic SCI-pain and pain-induced depressive-like behaviors via suppression of gliocyte activation and restoration of the synaptic plasticity-related signaling systems.



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Modulation on brain gray matter activity and white matter integrity by APOE ε4 risk gene in cognitively intact elderly: A multimodal neuroimaging study

Publication date: 30 March 2017
Source:Behavioural Brain Research, Volume 322, Part A
Author(s): Suping Cai, Yuanyuan Jiang, Yubo Wang, Xiaoming Wu, Junchan Ren, Min Seob Lee, Sunghoon Lee, Liyu Huang
Apolipoprotein E (APOE) ε4 allele is the genetic risk factor with the most established evidence for sporadic Alzheimer's disease. Previous neuroimaging studies have demonstrated insufficiently consistent functional and structural changes among healthy APOE ε4 carriers when compared to non-carriers. Here, in a cognitively intact elderly group (a total of 110: 45 APOE ε4 carriers, 65 non-carriers), we aimed to investigate the potential role of APOE ε4 in the modulation of grey matter activity, white matter integrity, and brain morphology before the development of clinically significant symptoms and signs, by methods of: amplitude of low frequency fluctuations and regional homogeneity analysis based on resting state fMRI, and fiber tractography approach based on diffusion tensor imaging. Our results revealed that compared to non-carriers, APOE ε4 carriers showed: (1) an inconsistent pattern of activity change in the default mode network, including increased gray matter activity in anterior cingulate cortex and medial prefrontal cortex and decreased activity in precuneus; (2) lower mean diffusivity (MD) in fibers of corona radiata and corpus callosum, and lower axial diffusivity in genu of corpus callosum; and (3) significant positive correlation between the MD value of the right superior corona radiate and gross white matter volume; significant negative correlation between the MD value of the right superior corona radiate and Mini-Mental State Examination (MMSE) score. Our results suggested that APOE ε4 gene can modulate gray matter activity and white matter integrity in cognitive and memory related regions, even before any clinical or neuropsychic symtoms or signs of imminent disease.



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Virtual reality conditioned place preference using monetary reward

Publication date: 30 March 2017
Source:Behavioural Brain Research, Volume 322, Part A
Author(s): Emma Childs, Robert S. Astur, Harriet de Wit
Computerized tasks based on conditioned place preference (CPP) methodology offer the opportunity to study learning mechanisms involved in conditioned reward in humans. In this study, we examined acquisition and extinction of a CPP for virtual environments associated with monetary reward ($).Healthy men and women (N=57) completed a computerized CPP task in which they controlled an avatar within a virtual environment. On day 1, subjects completed 6 conditioning trials in which one room was paired with high $ and another with low $. Acquisition of place conditioning was assessed by measuring the time spent in each room during an exploration test of the virtual environments and using self-reported ratings of room liking and preference. Twenty-four hours later, retention and extinction of CPP were assessed during 4 successive exploration tests of the virtual environments.Participants exhibited a place preference for (spent significantly more time in) the virtual room paired with high $ over the one paired with low $ (p=0.015). They also reported that they preferred the high $ room (p<0.001) and liked it significantly more than the low $ room (p<0.001). However, these preferences were short-lived: 24h later subjects did not exhibit a behavioral or subjective preference for the high $ room.These findings show that individuals exhibit transient behavioral and subjective preferences for a virtual environment paired with monetary reward. Variations on this task may be useful to study mechanisms and brain substrates involved in conditioned reward and to examine the influence of drugs upon appetitive conditioning.



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The effects of neonatal amygdala or hippocampus lesions on adult social behavior

Publication date: 30 March 2017
Source:Behavioural Brain Research, Volume 322, Part A
Author(s): Eliza Bliss-Moreau, Gilda Moadab, Anthony Santistevan, David G. Amaral
The present report details the final phase of a longitudinal evaluation of the social behavior in a cohort of adult rhesus monkeys that received bilateral neurotoxic lesions of the amygdala or hippocampus, or sham operations at 2 weeks of age. Results were compared to previous studies in which adult animals received amygdala lesions and were tested in a similar fashion. Social testing with four novel interaction partners occurred when the animals were between 7 and 8 years of age. Experimental animals interacted with two male and two female partners in two conditions – one in which physical access was restricted (the constrained social access condition) and a second in which physical access was unrestricted (the unconstrained social access condition). Across conditions and interaction partners, there were no significant effects of lesion condition on the frequency or duration of social interactions. As a group, the hippocampus-lesioned animals generated the greatest number of communicative signals during the constrained social access condition. Amygdala-lesioned animals generated more frequent stress-related behaviors and were less exploratory. Amygdala and hippocampus-lesioned animals demonstrated greater numbers of stereotypies than control animals. Subtle, lesion-based differences in the sequencing of behaviors were observed. These findings suggest that alterations of adult social behavior are much less prominent when damage to the amygdala occurs early in life rather than in adulthood.



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Unraveling the Role of Ataxin-2 in Metabolism

Publication date: Available online 21 January 2017
Source:Trends in Endocrinology & Metabolism
Author(s): Sara Carmo-Silva, Clevio Nobrega, Luís Pereira de Almeida, Claudia Cavadas
Ataxin-2 is a polyglutamine protein implicated in several biological processes such as RNA metabolism and cytoskeleton reorganization. Ataxin-2 is highly expressed in various tissues including the hypothalamus, a brain region that controls food intake and energy balance. Ataxin-2 expression is influenced by nutritional status. Emerging studies discussed here now show that ataxin-2 deficiency correlates with insulin resistance and dyslipidemia, an action mediated via the mTOR pathway, suggesting that ataxin-2 might play key roles in metabolic homeostasis including body weight regulation, insulin sensitivity, and cellular stress responses. In this review we also discuss the relevance of ataxin-2 in the hypothalamic regulation of energy balance, and its potential as a therapeutic target in metabolic disorders such as obesity.



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Reply to Vinson et al.

Publication date: Available online 20 January 2017
Source:The Journal of Emergency Medicine
Author(s): Adam J. Singer




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Hemorrhagic Pericardial Cyst Diagnosis Accelerated by Emergency Physician Echocardiography: A Case Report

Publication date: Available online 20 January 2017
Source:The Journal of Emergency Medicine
Author(s): Michael F. Yip, Brooks M. Walsh
BackgroundThe differential diagnosis for chest pain in the emergency department is broad and includes both benign and life-threatening conditions–with pericardial cyst as a rare example. Emergency physician-performed point-of-care focused cardiac ultrasound (FOCUS) is increasingly recognized as a useful modality in the evaluation of patients with chest pain.Case ReportWe report a case of hemorrhagic pericardial cyst in a young woman presenting with chest pain in which findings on FOCUS contradicted findings on chest x-ray study and thus, accelerated diagnosis and definitive treatment. We also comment on epidemiology, pathophysiology, clinical presentation, diagnosis, and management of this uncommon, potentially fatal cause of chest pain.Why Should an Emergency Physician Be Aware of This?This case report aims to bring an uncommon case to the attention of emergency providers and emphasize the importance of facility with FOCUS. Although definitive diagnosis and management were not accomplished at the bedside in this case, an abnormal finding on FOCUS prompted further investigation and timely treatment.



http://ift.tt/2iN6KDM