Dynamics of model polycyclic aromatic hydrocarbon compound-epoxy composites: A dielectric study

Publication date: 31 January 2018
Source:Polymer, Volume 136
Author(s): Rui Ding, Sabrina W. Torres, Jamie Messman, Daniel E. Bowen, Nicola Bowler
A model polycyclic aromatic hydrocarbon (PAH) compound, anthracene, was incorporated into a thermosetting epoxy matrix as a reinforcing moiety via physical dispersion and/or chemical modification. In order to understand the "additive effect" of glass transition temperature (Tg) observed with the variation of free anthracene (AN) and bonded 2-aminoanthracene (2-AM) loading, the relaxation dynamics were investigated by broadband dielectric spectroscopy. Within the measurement range of 0.01 Hz–1 MHz and −60 to 130 °C, three relaxation processes, namely normal mode (n-mode) relaxation, α relaxation, and β relaxation, were observed for all epoxy composites with bonded and/or unbound anthracene. After eliminating the strong effect of ionic conduction by using the logarithmic derivative approximation ε''∝∂ε'∂lnω, derived from the Kramers-Kronig relations, the n-mode relaxation occurring at low frequencies above Tg for the rigid epoxy system is revealed. The Arrhenius diagram showing the temperature dependence of each relaxation process for the PAH-epoxy composites was obtained after parametric fitting using the Havriliak-Negami (HN) function in the frequency domain. The segmental α relaxation was more strongly impacted than the long-range n-mode relaxation by the different reinforcing approaches. The correlation of Tg -scaled fragility to molecular structures reveals the different mechanisms for the retardation effects on cooperative segmental and chain relaxation time. The localized β relaxation below Tg was not seemingly affected by the incorporation of bound and/or unbound anthracenes as indicated by the characteristic relaxation time and the activation energy.

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Microfluidics for producing poly (lactic-co-glycolic acid)-based pharmaceutical nanoparticles

Publication date: Available online 24 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Xuanyu Li, Xingyu Jiang
Microfluidic chips allow the rapid production of a library of nanoparticles (NPs) with distinct properties by changing the precursors and the flow rates, significantly decreasing the time for screening optimal formulation as carriers for drug delivery compared to conventional methods. The batch-to-batch reproducibility which is essential for clinical translation is achieved by precisely controlling the precursors and the flow rate, regardless of operators. Poly (lactic-co-glycolic acid) (PLGA) is the most widely used Food and Drug Administration (FDA)-approved biodegradable polymers. Researchers often combine PLGA with lipids or amphiphilic molecules to assemble into a core/shell structure to exploit the potential of PLGA-based NPs as powerful carriers for cancer-related drug delivery. In this review, we discuss the advantages associated with microfluidic chips for producing PLGA-based functional nanocomplexes for drug delivery. These laboratory-based methods can readily scale up to provide sufficient amount of PLGA-based NPs in microfluidic chips for clinical studies and industrial-scale production.

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Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing

Publication date: Available online 24 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Magdalena Schneider, Peter Angele, Tero A.H. Järvinen, Denitsa Docheva
Due to the increasing age of our society and a rise in engagement of young people in extreme and/or competitive sports, both tendinopathies and tendon ruptures present a clinical and financial challenge. Tendon has limited natural healing capacity and often responds poorly to treatments, hence it requires prolonged rehabilitation in most cases. Till today, none of the therapeutic options has provided successful long-term solutions, meaning that repaired tendons do not recover their complete strength and functionality. Our understanding of tendon biology and healing increases only slowly and the development of new treatment options is insufficient.In this review, following discussion on tendon structure, healing and the clinical relevance of tendon injury, we aim to elucidate the role of stem cells in tendon healing and discuss new possibilities to enhance stem cell treatment of injured tendon. To date, studies mainly apply stem cells, often in combination with scaffolds or growth factors, to surgically created tendon defects. Deeper understanding of how stem cells and vasculature in the healing tendon react to growth factors, common drugs used to treat injured tendons and promising cellular boosters could help to develop new and more efficient ways to manage tendon injuries.

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Abnormal cortical brain integration of somatosensory afferents in ALS

Publication date: Available online 24 December 2017
Source:Clinical Neurophysiology
Author(s): Sina Sangari, Alain Giron, Guillaume Marrelec, Pierre-François Pradat, Véronique Marchand-Pauvert
ObjectivesInfraclinical sensory alterations have been reported at early stages of amyotrophic lateral sclerosis (ALS). While previous studies mainly focused on early somatosensory evoked potentials (SEPs), late SEPs, which reflect on cortical pathways involved in cognitive-motor functions, are relatively underinvestigated. Early and late SEPs were compared to assess their alterations in ALS.MethodsMedian and ulnar nerves were electrically stimulated at the wrist, at 9 times the perceptual threshold, in 21 ALS patients without clinical evidence of sensory deficits, and 21 age- and gender-matched controls. SEPs were recorded at the Erb point using surface electrodes and using a needle inserted in the scalp, in front of the primary somatosensory area (with reference electrode on the ear lobe).ResultsCompared to controls, ALS patients showed comparable peripheral (N9) and early cortical component (N20, P25, N30) reductions, while the late cortical components (N60, P100) were more depressed than the early ones.ConclusionsThe peripheral sensory alteration likely contributed to late SEP depression to a lesser extent than that of early SEPs.SignificanceLate SEPs may provide new insights on abnormal cortical excitability affecting brain areas involved in cognitive-motor functions.



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Editorial Board

Publication date: February 2018
Source:Archives of Oral Biology, Volume 86





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Structural optimization of N1-aryl-benzimidazoles for the discovery of new non-nucleoside reverse transcriptase inhibitors active against wild-type and mutant HIV-1 strains

Publication date: Available online 24 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Anna Maria Monforte, Laura De Luca, Maria Rosa Buemi, Fatima E. Agharbaoui, Christophe Pannecouque, Stefania Ferro
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of human immunodeficiency virus (HIV) infection. These regimens are extremely effective in suppressing virus replication. Recently, our research group identified some N1-aryl-2-arylthioacetamido-benzimidazoles as a novel class of NNRTIs. In this research work we report the design, the synthesis and the structure-activity relationship studies of new compounds (20-34) in which some structural modifications have been introduced in order to investigate their effects on reverse trascriptase (RT) inhibition and to better define the features needed to increase the antiviral activity. Most of the new compounds proved to be highly effective in inhibiting both RT enzyme at nanomolar concentrations and HIV-1 replication in MT4 cells with minimal cytotoxicity. Among them, the most promising N1-aryl-2-arylthioacetamido-benzimidazoles and N1-aryl-2-aryloxyacetamido-benzimidazoles were also tested toward a panel of single- and double-mutants strain responsible for resistance to NNRTIs, showing in vitro antiviral activity toward single mutants L100I, K103N, Y181C, Y188L and E138K. The best results were observed for derivatives 29 and 33 active also against the double mutants F227L and V106A.. Computational approaches were applied in order to rationalize the potency of the new synthesized inhibitors.

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Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors

Publication date: Available online 24 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Edita Čapkauskaitė, Audrius Zakšauskas, Virginijus Ruibys, Vaida Linkuvienė, Vaida Paketurytė, Marius Gedgaudas, Visvaldas Kairys, Daumantas Matulis
The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.

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New Photodynamic Molecular Beacons (PMB) as potential cancer-targeted agents in PDT

Publication date: Available online 24 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Aurélie Stallivieri, Ludovic Colombeau, Jérôme Devy, Nicolas Etique, Carine Chaintreuil, Bauyrzhan Myrzakhmetov, Mathilde Achard, Francis Baros, Philippe Arnoux, Régis Vanderesse, Céline Frochot
Further improvements in Photodynamic therapy (PDT) necessitate that the dye targets more selectively tumour tissues or neovascularization than healthy cells. Different enzymes such as matrix metalloproteinases (MMPs) are overexpressed in tumour areas. Among these MMPs, gelatinases (MMP-2 and MMP-9) and its activator MMP-14 are known to play a key role in tumour angiogenesis and the growth of many cancers such as glioblastoma multiforme (GBM), an aggressive malignant tumour of the brain. These last years, the concept of photodynamic molecular beacons (PMB) became interesting for controlling the photosensitizer's ability to generate singlet oxygen (¹O2) close to target biomolecules as MMPs. We report herein novel PMBs triggered by MMP-2 and/or MMP-9 and/or MMP-14, comprising a photosensitizer and a singlet oxygen quencher linked by MMP cleavable peptide linker (H-GRIGFLRTAKGG-OH). First of all, we focused on the synthesis and the photophysical study of different derivatives photosensitizer-peptide. This preliminary work concluded on an influence of the nature and the distance from the peptide, but not of the position of the photosensitizer in these derivatives on the proteolytic enzymatic action. The nature of the quencher used (a blackberry quencher (BBQ-650) or a black hole quencher (BHQ3)) does not influence the enzymatic action. We also studied the influence of an additionnal PEG spacer. Finally, the synthesis, the singlet oxygen quenching efficiency and the enzymatic activation of these new MMP- cleavable-PMBs were compared.

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Identification of highly potent and orally available free fatty acid receptor 1 agonists bearing isoxazole scaffold

Publication date: Available online 24 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Zheng Li, Chunxia Liu, Wei Shi, Xingguang Cai, Yuxuan Dai, Chen Liao, Wenlong Huang, Hai Qian
The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50 = 7.9 nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE = 0.32) and ligand lipophilicity efficiency (LLE = 6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration.

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Discovery of chromenes as inhibitors of macrophage migration inhibitory factor

Publication date: Available online 24 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Tjie Kok, Hannah Wapenaar, Kan Wang, Constantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Giordano Proietti, Nikolaos Eleftheriadis, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Robbert Cool, Gerrit J. Poelarends, Alexander Dömling, Frank J. Dekker
Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aim to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC50's in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.

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Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[1,2-b]pyridazine-based p38 MAP Kinase Inhibitors

Publication date: Available online 24 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Akira Kaieda, Masashi Takahashi, Takafumi Takai, Masayuki Goto, Takahiro Miyazaki, Yuri Hori, Satoko Unno, Tomohiro Kawamoto, Toshimasa Tanaka, Sachiko Itono, Terufumi Takagi, Teruki Hamada, Mikio Shirasaki, Kengo Okada, Gyorgy Snell, Ken Bragstad, Bi-Ching Sang, Osamu Uchikawa, Seiji Miwatashi
We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.

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Superior Reproducibility of the Leading to Leading Edge and Inner to Inner Edge Methods in the Ultrasound Assessment of Maximum Abdominal Aortic Diameter

Publication date: Available online 23 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Jens Borgbjerg, Martin Bøgsted, Jes S. Lindholt, Carsten Behr-Rasmussen, Arne Hørlyck, Jens B. Frøkjær
ObjectivesControversy exists regarding optimal caliper placement in ultrasound assessment of maximum abdominal aortic diameter. This study aimed primarily to determine reproducibility of caliper placement in relation to the aortic wall with the three principal methods: leading to leading edge (LTL), inner to inner edge (ITI), and outer to outer edge (OTO). The secondary aim was to assess the mean difference between the OTO, ITI, and LTL diameters and estimate the impact of using either of these methods on abdominal aortic aneurysm (AAA) prevalence in a screening program.MethodsRadiologists (n=18) assessed the maximum antero-posterior abdominal aortic diameter by completing repeated caliper placements with the OTO, LTL, and ITI methods on 50 still abdominal aortic images obtained from an AAA screening program. Inter-observer reproducibility was calculated as the limit of agreement with the mean (LoA), which represents expected deviation of a single observer from the mean of all observers. Intra-observer reproducibility was assessed averaging the LoA for each observer with their repeated measurements. Based on data from an AAA screening trial and the estimated mean differences between the three principal methods, AAA prevalence was estimated using each of the methods.ResultsThe inter-observer LoA of the OTO, ITI, and LTL was 2.6, 1.9, and 1.9 mm, whereas the intra-observer LoA was 2.0, 1.6, and 1.5 mm, respectively. Mean differences of 5.0 mm were found between OTO and ITI measurements, 2.6 mm between OTO and LTL measurements, and 2.4 mm between LTL and ITI measurements. The prevalence of AAA almost doubled using OTO instead of ITI, while the difference between ITI and LTL was minor (3.3% vs. 4.0% AAA).ConclusionsThe study shows superior reproducibility of LTL and ITI compared with the OTO method of caliper placement in ultrasound determination of maximum abdominal aortic diameter, and the choice of caliper placement method significantly affects the prevalence of AAAs in screening programs.



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Local Control and Toxicity of External Beam Reirradiation with Pulsed Low-Dose-Rate Technique

Publication date: Available online 23 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Charles T. Lee, Yanqun Dong, Tianyu Li, Samuel Freedman, Jordan Anaokar, Thomas J. Galloway, Mark A. Hallman, Stephanie E. Weiss, Shelly B. Hayes, Robert A. Price, C-M Charlie Ma, Joshua E. Meyer
PurposeTo evaluate the efficacy and toxicity of external beam reirradiation using pulsed low-dose-rate (PLDR) technique.Methods/MaterialsWe evaluated patients treated with PLDR reirradiation between 2009-2016 at a single institution. Toxicity was graded based on CTCAE4.0 and local control was assessed using RECIST1.1. In the univariate analysis (UVA), Chi-square, and Fisher's Exact test were used to assess toxicity outcomes; competing risk analysis via cumulative incidence function estimates were used to assess local progression.ResultsThirty-nine patients were treated to 41 disease sites with PLDR reirradiation, with a median follow-up of 8.8 months (range 0.5-64.7 months). Targets were thoracic, abdominal and pelvic, including 36 symptomatic sites. The median time between the first radiation course and reirradiation was 26.2 months; the median doses of the first and second courses of radiation were 50.4 Gy and 50 Gy, respectively. Five patients (13%) received concurrent systemic therapy.Out of 39 patients, 9 (23%) developed grade 2+ acute toxicity, most commonly radiation dermatitis (5/9). None developed grade 4+ acute/subacute toxicity. The only grade 2+ late toxicity was 1 patient with grade 2 late skin toxicity. In UVA, toxicity was not significantly associated with dose of the first course of radiation or reirradiation, time interval to reirradiation, or reirradiation site.Of the 41 disease sites treated with PLDR, 32 had pre and post-PLDR scans to evaluate for local control. Local progression was 16.5% at 6 months and 23.8% at 12 months, and was not associated with the dose of reirradiation, reirradiation site, or concurrent systemic therapy in UVA. Of 36 symptomatic disease sites, 25 (69%) sites achieved symptomatic response after PLDR, including 6 (17%) with complete symptomatic relief.ConclusionReirradiation with PLDR is effective and well-tolerated. Risk of late toxicity and durability of local control was limited by the relatively short follow up in this cohort.



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The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway

Publication date: Available online 23 December 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Desmaré van Rooyen, Rachelle Gent, Lise Barnard, Amanda C. Swart
Increased circulating 11β-hydroxyprogesterone (11OHP4), biosynthesised in the human adrenal, is associated with 21-hydroxylase deficiency in congenital adrenal hyperplasia. 17α-hydroxyprogesterone levels are also increased, with the steroid's metabolism to dihydrotestosterone in the backdoor pathway contributing to hyperandrogenic clinical conditions. In this study we investigated the in vitro biosynthesis and downstream metabolism of 11OHP4. Both cytochrome P450 11β-hydroxylase and aldosterone synthase catalyse the biosynthesis of 11OHP4 from progesterone (P4) which is converted to 11-ketoprogesterone (11KP4) by 11β-hydroxysteroid dehydrogenase type 2, while type 1 readily catalysed the reverse reaction. We showed in HEK-293 cells that these C11-oxy C21 steroids were metabolised by steroidogenic enzymes in the backdoor pathway–5α-reductase (SRD5A) and 3α-hydroxysteroid type 3 (AKR1C2) converted 11OHP4 to 5α-pregnan-11β-ol,3,20-dione and 5α-pregnan-3α,11β-diol-20-one, while 11KP4 was converted to 5α-pregnan-3,11,20-trione and 5α-pregnan-3α-ol-11,20-dione (alfaxalone), respectively. Cytochrome P450 17α-hydroxylase/17,20-lyase catalysed the hydroxylase and lyase reaction to produce the C11-oxy C19 steroids demonstrated in the conversion of alfaxalone to 11-ketoandrosterone. In LNCaP cells, a prostate cancer cell model endogenously expressing the relevant enzymes, 11OHP4 and 11KP4 were metabolised to the potent androgen, 11-ketodihydrotestosterone (11KDHT), thus suggesting the C11-oxy C21 steroids contribute to the pool of validating the in vitro biosynthesis of C11-oxy C19 steroids from C11-oxy C21 steroids.The in vitro reduction of 11KP4 at C3 and C5 by AKR1C2 and SRD5A has confirmed the metabolic route of the urinary metabolite, 3α,20α-dihydroxy-5β-pregnan-11-one. Although our assays have demonstrated the conversion of 11OHP4 and 11KP4 by steroidogenic enzymes in the backdoor pathway yielding 11KDHT, thus suggesting the C11-oxy C21 steroids contribute to the pool of potent androgens, the in vivo confirmation of this metabolic route remains challenging.

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The transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis

Publication date: Available online 24 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Yapeng Li, Bing Liu, Laura Harmacek, Zijie Long, Jinyi Liang, Kara Lukin, Sonia M. Leach, Brian O'Connor, Anthony N. Gerber, James Hagman, Axel Roers, Fred D. Finkelman, Hua Huang
BackgroundHistamine is a critical mediator of IgE/mast cell-mediated anaphylaxis. Histamine is synthesized by decarboxylating the amino acid histidine, a reaction catalyzed by the Hdc-gene encoded enzyme histidine decarboxylase. However, regulation of the Hdc gene in mast cells is poorly understood.ObjectiveWe sought to investigate the in vivo regulation of IgE/mast cell mediated anaphylaxis by transcription factors GATA2 and MITF and the mechanisms by which GATA2 and MITF regulate Hdc gene expression in mouse and human mast cells.Methodsmice deficient in the transcription factors Gata2, Ahr, Ahrr, or Bhlhe40 were assessed for anaphylactic reactions. Chromatin immunoprecipitation sequencing analysis identified putative Hdc enhancers. Luciferase reporter transcription assay confirmed enhancer activities of putative enhancers in the Hdc gene. The shRNA knock down approach was used to determine the role of MITF in regulating mouse and human HDC gene expression.ResultsConnective tissue mast cell (CTMC)-specific Gata2 deficient mice failed to develop IgE/mast cell-mediated anaphylaxis. GATA2 induced the expression of Mitf, Ahr, Ahrr and Bhlhe40 in mast cells. MITF, but not AHR, AHRR or BHLHE40, was required for anaphylaxis. MITF bound to an enhancer located 8.8 kb upstream of the transcription start site of the Hdc gene and directed enhancer activity. MITF overexpression largely restored Hdc gene expression in the Gata2 deficient-mast cells. In human mast cell line LAD2, MITF was required for the HDC gene expression and histamine synthesis.ConclusionThe transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis.

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Editorial Board

Publication date: January 2018
Source:Cancer Treatment Reviews, Volume 62





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Acknowledgement to Reviewers 2017

Publication date: January 2018
Source:Cancer Treatment Reviews, Volume 62





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The mTOR promotes oxidative stress-induced apoptosis of mesangial cells in diabetic nephropathy

Publication date: Available online 24 December 2017
Source:Molecular and Cellular Endocrinology
Author(s): Qian Lu, Yuexian Zhou, Meng Hao, Chengcheng Li, Jin Wang, Fanglin Shu, Lei Du, Xia Zhu, Qiaoli Zhang, Xiaoxing Yin
Glomerular mesangial cell (MC) apoptosis is one of the important mechanisms of glomerulosclerosis, which induces an increased severity of albuminuria and promotes the development of diabetic nephropathy (DN). However, the mechanism by which high glucose (HG) induces MCs apoptosis is not fully understood. In the present study, we investigated the effects of mTOR signalling on apoptosis in cultured MCs exposed to HG and in type I diabetes, and tried to clarify the specific mechanisms underlying these effects. In vitro, exposure of MCs to HG stimulated ROS production, decreased the antioxidant enzyme superoxide dismutase (SOD) activity and glutathione (GSH) level, increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, upregulated P53 expression and Bax/Bcl-2 ratio and enhanced cleavage of caspase 3, resulting in an increase in programmed cell death. Pretreatment of the cells with rapamycin ameliorated oxidative stress, reduced the number of apoptotic cells induced by HG and caused the downstream effects of mTOR activation. In vivo, compared with control rats, diabetic rats had more apoptotic cells in glomeruli. Induction of diabetes increased the level of MDA and NADPH oxidase activity, decreased the SOD activity and GSH level, elevated the Bax/Bcl ratio and P53 expression and activated caspase 3. mTOR inhibitor rapamycin treatment prevented these changes further alleviated albuminuria and improved renal function. Taken together, our data suggest that mTOR plays a key role in mediating ROS-induced MC apoptosis in diabetic nephropathy, and these effects have been associated with the promotion of ROS production by upregulating the antioxidant enzyme and downregulating the NADPH oxidase activity.



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The Ikaros family in lymphocyte development

Publication date: April 2018
Source:Current Opinion in Immunology, Volume 51
Author(s): Beate Heizmann, Philippe Kastner, Susan Chan
The IKZF family of transcription factors are essential regulators of lymphopoiesis. Ikaros, Helios, Aiolos and Eos function as transcriptional repressors and activators during T and B cell differentiation and in mature cell function, depending on the stage of development and/or cell type. Their potential mechanisms of action are varied. Ikaros family proteins partner with multiple complexes, including NuRD, PRC2 and transcription elongation factors, to modulate gene expression and the chromatin state. In humans, mutations in the IKZF genes are associated with B cell deficiency, leukemias and autoimmunity. In this review, we focus on the function of Ikaros family proteins in early T and B lymphocyte development, and discuss the molecular and physiological activities of this family.



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Motor practice in a force modulation task in young and middle-aged adults

Publication date: Available online 24 December 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Ben Godde, Mireille Trautmann, Peter Erhard, Claudia Voelcker-Rehage
Learning new motor skills is important for everyday life and independent living in older age. While studies on motor sequence learning and motor adaptation revealed age differences that are mostly related to frontal decline with increasing age, data for fine finger force modulation are missing.Twelve young (YA, 18-28 years) and twelve middle-aged older (OA, 55-65 years) adults practiced a force modulation task in precision grip while lying in a 3T MR scanner. Participants followed a sine wave between 5 and 25 % of their maximum voluntary contraction (MVC) at a frequency of 0.3 Hz. Ten trials of 30 seconds were performed to examine learning curves and related changes in Blood Oxygen Level Dependent (BOLD) responses were assessed with functional magnetic resonance imaging (fMRI).Training slopes were similar for YA and OA, with only a trend for differences in performance level. Both age groups revealed decreasing activations with practice in frontal and parietal regions as well as in the cerebellum. Particularly, the hippocampus was activated in initial trials, but activity immediately decreased with practice. Increase in activation during practice was found only for YA in occipital cortex, cingulate cortex, and thalamus. After practice, OA revealed a pattern similar to the one that YA showed before practice. Described differences between YA and OA in neural activation related to motor practice may indicate compensational mechanisms in OA to enable similar learning slopes as in YA.



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Academy of Nutrition and Dietetics: Revised 2017 Scope of Practice for the Nutrition and Dietetics Technician, Registered

Publication date: Available online 24 December 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Denise Andersen, Shari Baird, Denise L. Chapel, Alana D. Cline, Shyamala N. Ganesh, Margaret Garner, Barbara L. Grant, Kathryn K. Hamilton, Krista Jablonski, Sherri L. Jones, Alexandra G. Kazaks, Susan H. Konek, Kelly K. Leonard, Kimi G. McAdam, Beth N. Ogata, Egondu M. Onuoha, Gretchen Y. Robinson, Darrin W. Schmidt, Nancy G. Walters, Pauline Williams, Pamela Wu, Karen Hui, Carol Gilmore, Mujahed Khan, Dana Buelsing, Sharon M. McCauley
The Academy of Nutrition and Dietetics (Academy) is the world's largest organization of food and nutrition professionals and the association that represents credentialed nutrition and dietetics practitioners—nutrition and dietetics technicians, registered (NDTRs) and registered dietitian nutritionists (RDNs). An NDTR's scope of practice in nutrition and dietetics has flexible boundaries to capture the depth and breadth of the individual's practice. The NDTR's practice expands with advances in many areas, including nutrition, food production, food safety, food systems management, health care, public health, community health, and information and communication technology. The Revised 2017 Scope of Practice for the NDTR reflects the position of the Academy on the essential role of the NDTR in the management and delivery of food and nutrition services. The scope of practice for the NDTR is composed of education and credentialing, practice resources, Academy Standards of Practice and Standards of Professional Performance, codes of ethics, accreditation standards, state and federal regulations, national guidelines, and organizational policy and procedures. The Revised 2017 Scope of Practice for the NDTR is used in conjunction with the Revised 2017 Standards of Practice in Nutrition Care and the Standards of Professional Performance for NDTRs. The Standards of Practice address activities related to direct patient and client care. The Standards of Professional Performance address behaviors related to the technical role of NDTRs. These standards reflect the minimum competent level of nutrition and dietetics practice and professional performance for NDTRs. A companion document addresses the scope of practice for the RDN.



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Academy of Nutrition and Dietetics: Revised 2017 Standards of Practice in Nutrition Care and Standards of Professional Performance for Nutrition and Dietetics Technicians, Registered

Publication date: Available online 24 December 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): The Academy Quality Management CommitteeDeniseAndersenMS RDN LD CLCShariBairdMS RD CPHQ LSSBBDenise L.ChapelMPH MS RDN FANDAlana D.ClinePhD RDNShyamala N.GaneshMS RD LDMargaretGarnerMS RDN LD FAND CICBarbara L.GrantMS RDN CSO FANDKathryn K.HamiltonMA RDN CSO CDN FANDKristaJablonskiMS RDN LDNSherri L.JonesMS MBA RDN LDN FANDAlexandra G.KazaksPhD RDN CDESusan H.KonekMA RDN CSP LD FANDKelly K.LeonardMS RDNKimi G.McAdamMS RDBeth N.OgataMS RDN CSP CDEgondu M.OnuohaMS RDN CDE IBCLC CDN GPC FANDGretchen Y.RobinsonMS RDN LD FADA FANDDarrin W.SchmidtNDTR FANDNancy G.WaltersMMSC RDN CSG FAND LDNPaulineWilliamsPhD MPA RDN CDPamelaWuDPA RDNKarenHuiRDN LDNCarolGilmoreMS RDN LD FADA FANDMujahedKhanMBA RDN LDNDanaBuelsingMSSharon M.McCauleyMS MBA RDN LDN FADA FAND
Nutrition and dietetics technicians, registered (NDTRs) face complex situations every day. Competently addressing the unique needs of each situation and applying standards appropriately are essential to providing safe, timely patient-/client-/customer-centered quality nutrition and dietetics care and services. The Academy of Nutrition and Dietetics (Academy) leads the profession by developing standards that can be used by NDTRs (who are credentialed by the Commission on Dietetic Registration) for self-evaluation to assess quality of practice and performance. The Standards of Practice reflect the NDTR's role under the supervision of registered dietitian nutritionists in nutrition screening and the Nutrition Care Process and workflow elements, which includes nutrition screening, nutrition assessment, nutrition diagnosis, nutrition intervention/plan of care, nutrition monitoring and evaluation, and discharge planning and transitions of care. The Standards of Professional Performance consist of six domains of professional performance: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Within each standard, indicators provide measurable action statements that illustrate how the standard can be applied to practice. The Academy's Revised 2017 Standards of Practice and Standards of Professional Performance for NDTRs along with the Academy/Commission on Dietetic Registration Code of Ethics, and the Scope of Practice for the NDTR provide minimum standards and tools for demonstrating competence and safe practice, and are used collectively to gauge and guide an NDTR's performance in nutrition and dietetics practice.



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Adolescent Anorexia: Guiding Principles and Skills for the Dietetic Support of Family-Based Treatment

Publication date: Available online 24 December 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Bryan Lian, Sarah E. Forsberg, Kathleen Kara Fitzpatrick




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Nuclear accident consequence assessment in Hong Kong using JRODOS

Publication date: March 2018
Source:Journal of Environmental Radioactivity, Volume 183
Author(s): W.H. Leung, W.M. Ma, Philip K.Y. Chan
The JRODOS (Java-based Real-time Online DecisiOn Support) is a decision support system for off-site emergency management for releases of radioactive material into the environment. This paper documents the application of JRODOS by the Hong Kong Observatory in accident consequence assessment and emergency preparedness studies. For operational considerations, the most computational efficient dispersion model in JRODOS, ATSTEP, is adopted. Verification studies for JRODOS's ATSTEP model have been conducted. Comparison with tracer experiment results showed that under neutral atmospheric conditions and distances up to 50 km, the JRODOS simulation outputs were in general of the same order of magnitude with the tracer data. To further evaluate the capability of JRODOS in short-range simulation, a case study on the Fukushima nuclear power plant accident was also carried out. JRODOS was able to produce realistic simulation results which were comparable to the actual airborne monitoring data of the Cs-137 ground deposition from the Fukushima accident.Furthermore, the results of a comprehensive study to assess the potential consequences of accidents at a nearby nuclear power station are presented. Simulation using the French S3 source term for the Guangdong Nuclear Power Station at Daya Bay showed that the projected effective doses within Hong Kong remain far below the IAEA generic criteria of projected dose for urgent protective actions in sheltering/evacuation, while the projected equivalent dose in thyroid may meet the IAEA generic criteria for use of thyroid blocking agent at some areas in the northeastern part of Hong Kong, at distances of up to about 40 km from Daya Bay depending on the prevailing weather conditions in different seasons.



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Network Science in Clinical Trials: A patient-centered approach

Publication date: Available online 24 December 2017
Source:Seminars in Cancer Biology
Author(s): Venkata Manem, Roberto Salgado, Philippe Aftimos, Christos Sotiriou, Benjamin Haibe-Kains
There has been a paradigm shift in translational oncology with the advent of novel molecular diagnostic tools in the clinic. However, several challenges are associated with the integration of these sophisticated tools into clinical oncology and daily practice. High-throughput profiling at the DNA, RNA and protein levels (omics) generate a massive amount of data. The analysis and interpretation of these is non-trivial but will allow a more thorough understanding of cancer. Linear modelling of the data as it is often used today is likely to limit our understanding of cancer as a complex disease, and at times under-performs to capture a phenotype of interest. Network science and systems biology-based approaches, using machine learning and network science principles, that integrate multiple data sources, can uncover complex changes in a biological system. This approach will integrate a large number of potential biomarkers in preclinical studies to better inform therapeutic decisions and ultimately make substantial progress towards precision medicine. It will however require development of a new generation of clinical trials. Beyond discussing the challenges of high-throughput technologies, this review will develop a framework on how to implement a network science approach in new clinical trial designs in order to advance cancer care.



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ERP components associated with an indirect emotional stop signal task in healthy and depressed participants

Publication date: Available online 24 December 2017
Source:International Journal of Psychophysiology
Author(s): D.A. Camfield, T.K. Burton, F.M. De Blasio, R.J. Barry, R.J. Croft
Recent research has provided evidence to suggest that emotional stimuli may interfere with response inhibition, due to automatic capture of attention. Whilst previous studies have provided data regarding changes to event-related potentials (ERPs) in emotional Go/NoGo tasks, few studies to-date have utilized an emotional stop signal task (SST). Thirty-five participants were included in the study; 21 healthy controls and 14 depressed. An indirect emotional SST was employed, which consisted of the presentation of neutral, negative or positive visual images. The primary two-choice reaction time task required responding to frame colour (red or blue), whilst in 33% of trials an auditory stop signal was presented, with stop signal delay adjusted according to an adaptive tracking procedure. ERPs associated with both the primary visual task and the auditory SST were analysed using temporal principle components analysis (tPCA). In the primary task, reaction times were found to be slower for negative compared to neutral images. Stop signal reaction time (SSRT) was not found to be affected by image category or depression status. However, the NoGo-N2 component was found to be reduced for positive images, whilst the NoGo-P3 component was reduced for both positive and negative images in comparison to neutral images in the stop signal task. This effect was found to be enhanced for the depressed participants, indicating that inhibitory processing in the presence of positive stimuli may be inhibited to a greater extent in depressed individuals than in healthy controls. These findings provide further evidence for the ability of emotional valence and major depressive disorder to influence inhibitory processing.



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Cortisol awakening response and emotion at extreme altitudes on Mount Kangchenjunga

Publication date: Available online 24 December 2017
Source:International Journal of Psychophysiology
Author(s): Raúl Aguilar, Carlos Martínez, José R. Alvero-Cruz
The cortisol awakening response (CAR) was examined over a 45days stay at extreme altitudes (above of about 5500m) on Mount Kangchenjunga. The CAR refers to a peak cortisol response during the waking period that is superimposed to the diurnal rhythmicity in cortisol secretion, whose function has been proposed to be the anticipation of demands of the upcoming day (the CAR anticipation hypothesis). According to this hypothesis, we distinguished between resting days on which the expedition team engaged in routine activities in the base camp, and ascent days on which it planned to climb up a very demanding track. We were also interested in examining the association of testosterone with emotional anticipation, given the role of this steroid hormone in reward-related processes in challenge situations. Results showed that the climber group had a bigger CAR on ascent days, relative to the Sherpa group at the same altitude and the non-climber group at sea level. Several methodological issues, however, made it difficult to interpret these group differences in terms of the CAR anticipation hypothesis (e.g. a seemingly influential covariate was awakening time). Although based on tentative results, correlational and regression analyses controlling for awakening time coherently showed that the CAR was associated with anticipation of a hard day and feelings of fear, and testosterone was associated with feelings of energy and positive affect. Whether or not the anticipation of a hard day played a key role in regulation of the CAR, the observation of an intact CAR in the climber group under hypobaric hypoxia conditions would require in-depth reflection from the perspective of human adaptive evolution.



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Oligodendrogenesis after traumatic brain injury

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Hajime Takase, Kazuo Washida, Kazuhide Hayakawa, Ken Arai, Xiaoying Wang, Eng H. Lo, Josephine Lok
White matter injury is an important contributor to long term motor and cognitive dysfunction after traumatic brain injury. During brain trauma, acceleration, deceleration, torsion, and compression forces often cause direct damage to the axon tracts, and pathways that are triggered by the initial injury can trigger molecular events that result in secondary axon degeneration. White matter injury is often associated with altered mental status, memory deficits, motor or autonomic dysfunction, and contribute to the development of chronic neurodegenerative diseases. The presence and proper functioning of oligodendrocyte precursor cells offer the potential for repair and recovery of injured white matter. The process of the proliferation, maturation of oligodendrocyte precursor cells and their migration to the site of injury to replace injured or lost oligodendrocytes is know as oligodendrogenesis. The process of oligodendrogenesis, as well as the interaction of oligodendrocyte precursor cells with other elements of the neurovascular unit, will be discussed in this review.



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Understanding the complexities of traumatic brain injury: A big data approach to a big disease

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Denes V. Agoston




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Editorial Board

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340





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Post-blast treatment with Nociceptin/Orphanin FQ peptide (NOP) receptor antagonist reduces brain injury-induced hypoxia and signaling proteins in vestibulomotor-related brain regions

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Hibah O. Awwad, Cindy D. Durand, Larry P. Gonzalez, Paul Tompkins, Yong Zhang, Megan R. Lerner, Daniel J. Brackett, David M. Sherry, Vibhudutta Awasthi, Kelly M. Standifer
Mild traumatic brain injury (mTBI) diagnoses have increased due to aggressive sports and blast-related injuries, but the cellular mechanisms and pathology underlying mTBI are not completely understood. Previous reports indicate that Nociceptin Orphanin/FQ (N/OFQ), an endogenous neuropeptide, contributes to post-injury ischemia following mechanical brain injury, yet its specific role in cerebral hypoxia, vestibulomotor function and injury marker expression following blast-induced TBI is not known. This study is the first to identify a direct association of N/OFQ and its N/OFQ peptide (NOP) receptor with TBI-induced changes following a single 80psi head blast exposure in male rats. N/OFQ and NOP receptor expression increased in brain tissue and plasma following TBI, concurrent with vestibular dysfunction but preceding hypoxia and appearance of injury markers compared to sham rats. A single post-blast treatment with the NOP receptor antagonist, SB-612111, transiently improved acute vestibulomotor performance. It also prevented increases in markers of TBI-induced hypoxia, pro-apoptotic proteins and injury seen 8–10days post-blast. This study reveals an apparent role for the N/OFQ-NOP receptor system in blast TBI and suggests potential therapeutic utility of NOP receptor antagonists for mTBI.

Graphical abstract

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Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post—Traumatic brain injury

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Hussein Ghazale, Naify Ramadan, Sara Mantash, Kazem Zibara, Sally El-Sitt, Hala Darwish, Farah Chamaa, Rose Mary Boustany, Stefania Mondello, Wassim Abou-Kheir, Jihane Soueid, Firas Kobeissy
Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide with 1.5 million people inflicted yearly. Several neurotherapeutic interventions have been proposed including drug administration as well as cellular therapy involving neural stem cells (NSCs). Among the proposed drugs is docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibiting neuroprotective properties. In this study, we utilized an innovative intervention of neonatal NSCs transplantation in combination with DHA injections in order to ameliorate brain damage and promote functional recovery in an experimental model of TBI. Thus, NSCs derived from the subventricular zone of neonatal pups were cultured into neurospheres and transplanted in the cortex of an experimentally controlled cortical impact mouse model of TBI. The effect of NSC transplantation was assessed alone and/or in combination with DHA administration. Motor deficits were evaluated using pole climbing and rotarod tests. Using immunohistochemistry, the effect of transplanted NSCs and DHA treatment was used to assess astrocytic (Glial fibrillary acidic protein, GFAP) and microglial (ionized calcium binding adaptor molecule-1, IBA-1) activity. In addition, we quantified neuroblasts (doublecortin; DCX) and dopaminergic neurons (tyrosine hydroxylase; TH) expression levels. Combined NSC transplantation and DHA injections significantly attenuated TBI-induced motor function deficits (pole climbing test), promoted neurogenesis, coupled with an increase in glial reactivity at the cortical site of injury. In addition, the number of tyrosine hydroxylase positive neurons was found to increase markedly in the ventral tegmental area and substantia nigra in the combination therapy group. Immunoblotting analysis indicated that DHA+NSCs treated animals showed decreased levels of 38kDa GFAP-BDP (breakdown product) and 145kDa αII-spectrin SBDP indicative of attenuated calpain/caspase activation. These data demonstrate that prior treatment with DHA may be a desirable strategy to improve the therapeutic efficacy of NSC transplantation in TBI.



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Overpressure blast injury-induced oxidative stress and neuroinflammation response in rat frontal cortex and cerebellum

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Hale Z. Toklu, Zhihui Yang, Sehkar Oktay, Yasemin Sakarya, Nataliya Kirichenko, Michael K. Matheny, Judy Muller-Delp, Kevin Strang, Philip J. Scarpace, Kevin K.W. Wang, Nihal Tümer
Background & aimOverpressure blast-wave induced brain injury (OBI) and its long-term neurological outcome pose significant concerns for military personnel. Our aim is to investigate the mechanism of injury due to OBI.MethodsRats were divided into 3 groups: (1) Control, (2) OBI (exposed 30psi peak pressure, 2–2.5ms), (3) Repeated OBI (r-OBI) (three exposures over one-week period). Lung and brain (cortex and cerebellum) tissues were collected at 24h post injury.ResultsThe neurological examination score was worse in OBI and r-OBI (4.2±0.6 and 3.7±0.5, respectively) versus controls (0.7±0.2). A significant positive correlation between lung and brain edema was found. Malondialdehyde (index for lipid peroxidation), significantly increased in OBI and r-OBI groups in cortex (p<0.05) and cerebellum (p<0.01–0.001). The glutathione (endogenous antioxidant) level decreased in cortex (p<0.01) and cerebellum (p<0.05) of r-OBI group when compared with the controls. Myeloperoxidase activity indicating neutrophil infiltration, was significantly (p<0.01–0.05) elevated in r-OBI. Additionally, tissue thromboplastin activity, a coagulation marker, was elevated, indicating a tendency to bleed. NGF and NF-κB proteins along with Iba-1 and GFAP immunoreactivity significantly augmented in the frontal cortex demonstrating microglial activation. Serum biomarkers of injury, NSE, TNF-alpha and leptin, were also elevated.ConclusionOBI triggers both inflammation and oxidative injury in the brain. This data in conjunction with our previous observations suggests that OBI triggers a cascade of events beginning with impaired cerebral vascular function leading to ischemia and chronic neurological consequences.

Graphical abstract

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Subdural hematoma decompression model: A model of traumatic brain injury with ischemic-reperfusional pathophysiology: A review of the literature

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Shoji Yokobori, Ryuta Nakae, Hiroyuki Yokota, Markus S. Spurlock, Stefania Mondello, Shyam Gajavelli, Ross M. Bullock
The prognosis for patients with traumatic brain injury (TBI) with subdural hematoma (SDH) remains poor. In accordance with an increasing elderly population, the incidence of geriatric TBI with SDH is rising.An important contributor to the neurological injury associated with SDH is the ischemic damage which is caused by raised intracranial pressure (ICP) producing impaired cerebral perfusion. To control intracranial hypertension, the current management consists of hematoma evacuation with or without decompressive craniotomy. This removal of the SDH results in the immediate reversal of global ischemia accompanied by an abrupt reduction of mass lesion and an ensuing reperfusion injury. Experimental models can play a critical role in improving our understanding of the underlying pathophysiology and in exploring potential treatments for patients with SDH.In this review, we describe the epidemiology, pathophysiology and clinical background of SDH.



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PrPC expression and calpain activity independently mediate the effects of closed head injury in mice

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Richard Rubenstein, Kevin K. Wang, Allen Chiu, Natalia Grinkina, Deep R. Sharma, Sanjeev Agarwal, Fan Lin, Zhihui Yang
The normal cellular prion protein (PrP^C) is a sialoglycoprotein with a glycophosphatidylinositol anchor and expressed in highest levels within the CNS particularly at neuronal synapses. This membrane-bound protein is involved with many cell functions including cell signaling and neuroprotection.Calpains are calcium-activated cysteine proteases that typically undergo controlled activation. PrP^C is a calpain substrate and is neurotoxic if it undergoes aberrant processing with cytosol accumulation. Following traumatic brain injury (TBI), there is an abnormal influx of Ca⁺² and overactivation of calpains resulting in neuronal dysfunction and cell death. We investigated whether PrP^C expression and calpain activity have an effect on, or are affected by, TBI.PrP^C expression in the hippocampus, cortex and cerebellum of WT and Tga20 (PrP^C overexpression) mice were unchanged after closed head injury (CHI). Further, PrP^C in WT and Tga20 mice was resistant to TBI-induced calpain proteolysis.CHI-induced calpain activation resulted in breakdown products (BDPs) of αII-spectrin (SBDPs) and GFAP (GBDP-44K) in all brain regions and mouse lines. CHI caused significant increases in SBDP145, GFAP and GBDP-44K when compared to sham. With few exceptions, the calpain inhibitor, SNJ-1945, reduced SBDP145 and GBDP-44K levels. Behavioral studies suggested that PrP^C and calpain independently affect learning and memory. Overall, we conclude that: (i) there is SNJ-1945-sensitive calpain activation in both neuron and glial cells following CHI, (ii) closed head trauma is not affected by, nor does it have an influence on, PrP^C expression, and (iii) PrP^C expression plays a minor role, if any, in CHI-induced calpain activation in vivo.



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Brain structure alterations and cognitive impairment following repetitive mild head impact: An in vivo MRI and behavioral study in rat

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Yang Qin, Gai-Li Li, Xian-Hua Xu, Zhi-Yong Sun, Jian-Wen Gu, Fa-Bao Gao
Mild traumatic brain injury (mTBI) or concussion is a common health issue. Several people repeatedly experience head impact milder than that causing concussion. The present study aimed to confirm the effects of such repeated impact on the brain structure and cognitive abilities. Rat models were established by closed skull weight-drop injury. The animals were anesthetized, subjected to single (s)-sham, s-mTBI, repetitive (r)-sham, and r-mTBI, and recovery times were recorded. MRI, including T2-weighted and diffusion tensor imaging (DTI), as well as, neurological severity scores (mNSS) were assessed for the dynamics of the brain structure and neurological function. Morris water maze (MWM) was used to evaluate the cognitive function. The histological examination of r-mTBI rats revealed the basis of structural changes in the brain. There was no significant difference in the recovery time, MRI, mNSS, and MWM between the s-sham and the s-mTBI groups. Compared with r-sham, r-mTBI induced significant differences in the following aspects. The recovery time was prolonged and beam balance test (BBT) in mNSS increased from day 5. MWM performances were worse even after the BBT was recovered. The volumes of the cortex (CT), hippocampus (HP), and lateral ventricle had changed from day 5, which reached a maximum at day 14. Abnormal DTI parameters were observed in CT, corpus callosum, and HP. Histological analyses showed that both in CT and HP, neuron counts reduced at the end of the experiment. Altogether, these findings indicate that non-symptomatic head injury may result in brain atrophy and cognitive impairment when occurred repeatedly.



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Stem cells and combination therapy for the treatment of traumatic brain injury

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): AmiraSan Dekmak, Sarah Mantash, Abdullah Shaito, Amer Toutonji, Naify Ramadan, Hussein Ghazale, Nouhad Kassem, Hala Darwish, Kazem Zibara
TBI is a nondegenerative, noncongenital insult to the brain from an external mechanical force; for instance a violent blow in a car accident. It is a complex injury with a broad spectrum of symptoms and has become a major cause of death and disability in addition to being a burden on public health and societies worldwide. As such, finding a therapy for TBI has become a major health concern for many countries, which has led to the emergence of many monotherapies that have shown promising effects in animal models of TBI, but have not yet proven any significant efficacy in clinical trials. In this paper, we will review existing and novel TBI treatment options. We will first shed light on the complex pathophysiology and molecular mechanisms of this disorder, understanding of which is a necessity for launching any treatment option. We will then review most of the currently available treatments for TBI including the recent approaches in the field of stem cell therapy as an optimal solution to treat TBI. Therapy using endogenous stem cells will be reviewed, followed by therapies utilizing exogenous stem cells from embryonic, induced pluripotent, mesenchymal, and neural origin. Combination therapy is also discussed as an emergent novel approach to treat TBI. Two approaches are highlighted, an approach concerning growth factors and another using ROCK inhibitors. These approaches are highlighted with regard to their benefits in minimizing the outcomes of TBI. Finally, we focus on the consequent improvements in motor and cognitive functions after stem cell therapy. Overall, this review will cover existing treatment options and recent advancements in TBI therapy, with a focus on the potential application of these strategies as a solution to improve the functional outcomes of TBI.



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Training of the impaired forelimb after traumatic brain injury enhances hippocampal neurogenesis in the Emx1 null mice lacking a corpus callosum

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Melanie Neumann, Wei Liu, Chongran Sun, Shih Yen Yang, Linda J. Noble-Haeusslein, Jialing Liu
Unilateral brain injury is known to disrupt the balance between the two cortices, as evidenced by an abnormally high interhemispheric inhibitory drive from motor cortex M1intact to M1lesioned transmitted transcallosally. Our previous work has shown that the deletion of homeobox gene Emx1 not only led to the agenesis of the corpus callosum (cc), but also to reduced hippocampal neurogenesis. The current study sought to determine whether lacking the cc affected the recovery of forelimb function and hippocampal plasticity following training of the affected limb in mice with unilateral traumatic brain injuries (TBI). One week after TBI, produced by a controlled cortical impact to impair the preferred limb, Emx1 wild type (WT) and knock out (KO) mice were subjected to the single-pellet reaching task with the affected limb for 4 weeks. Both TBI and Emx1 deletion had overall adverse effects on the successful rate of reaching. However, TBI significantly affected reaching performance only in the WT mice and not in the KO mice. Both TBI and Emx1 gene deletion also negatively affected hippocampal neurogenesis, demonstrated by a reduction in doublecortin (DCX)-expressing immature neurons, while limb training enhanced DCX expression. However, limb training increased DCX cells in KO mice only in the TBI-treated group, whereas it induced neurogenesis in both WT mice groups regardless of the treatment. Our finding also suggests that limb training enhances neuroplasticity after brain injury at functionally remote regions including the hippocampus, which may have implications for promoting overall recovery of function after TBI.



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GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1α

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Mushfiquddin Khan, Tajinder S. Dhammu, Mauhamad Baarine, Jinsu Kim, Manjeet K. Paintlia, Inderjit Singh, Avtar K. Singh
Traumatic brain injury (TBI) causes sustained disability due to compromised neurorepair mechanisms. Crucial to neurorepair and functional recovery following both TBI and stroke is hypoxia-inducible factor-1 alpha (HIF-1α). Based on reports that HIF-1α could be stabilized via S-nitrosylation, we tested the hypothesis that the S-nitrosylating agent S-nitrosoglutathione (GSNO) would stabilize HIF-1α, thereby stimulating neurorepair mechanisms and aiding in functional recovery. TBI was induced by controlled cortical impact (CCI) in adult rats. GSNO (0.05mg/kg) was administered at two hours after CCI. The treatment was repeated daily until the 14th day after CCI. Functional recovery was assessed by motor and cognitive functions, and the recovery was compared with the expression of HIF-1α. The mechanisms of GSNO-mediated S-nitrosylation of HIF-1α were determined using brain endothelial cells. While non-treated TBI animals showed sustained neurobehavioral deficits, GSNO treatment of TBI improved neurobehavioral functions. GSNO also increased the expression of HIF-1α and VEGF. The beneficial effects of GSNO on neurobehavioral functions in TBI animals were blocked by treatment with the HIF-1α inhibitor 2-methoxyestradiol (2-ME). The stimulatory effect of GSNO on VEGF was reversed not only by 2-ME but also by the denitrosylating agent dithiothreitol, confirming our hypothesis that GSNO's benefits are mediated by the stabilization of HIF-1α via S-nitrosylation. GSNO's S-nitrosylation of HIF-1α was further confirmed using a biotin switch assay in endothelial cells. The data provide evidence that GSNO treatment of TBI aids functional recovery through stabilizing HIF-1α via S-nitrosylation. GSNO is a natural component of the human brain/body, and its exogenous administration has not shown adverse effects in humans. Therefore, the translational potential of GSNO therapy in TBI is high.



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Reduced P3b brain response during sustained visual attention is associated with remote blast mTBI and current PTSD in U.S. military veterans

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Casey S. Gilmore, Craig A. Marquardt, Seung Suk Kang, Scott R. Sponheim
Approximately 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Combat-related mTBI is frequently associated with comorbid mental health disorders, especially posttraumatic stress disorder (PTSD). Attention problems, including sustained attention, are common cognitive complaints of veterans with TBI and PTSD. The present study sought to examine neural correlates of sustained attention in veterans with blast mTBI and/or current PTSD. In 124 veterans of Operations Enduring and Iraqi Freedom (OEF/OIF), we examined event-related potentials (ERPs) elicited by targets and non-targets during performance of a degraded-stimulus continuous performance task (DS-CPT). Four groups, consisting of veterans with blast-related mTBI only, current PTSD only, both blast mTBI and PTSD, and a control group, were studied. Compared to all other groups, blast mTBI only participants were more likely to respond regardless of stimulus type during the DS-CPT. During target detection, the three mTBI/PTSD groups showed reduced amplitude of the P3b (i.e., P300) ERP at Pz compared to the control group. P3b of the three affected groups did not differ from each other. These results suggest that parietal P3b amplitude reduction during target detection in the DS-CPT task may be an index of brain pathology after combat trauma, yet the diminished brain response fails to differentiate independent effects of blast-related mTBI or severity of PTSD symptomatology.



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Protein profiling in serum after traumatic brain injury in rats reveals potential injury markers

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Eric Peter Thelin, David Just, Arvid Frostell, Anna Häggmark-Månberg, Mårten Risling, Mikael Svensson, Peter Nilsson, Bo-Michael Bellander
IntroductionThe serum proteome following traumatic brain injury (TBI) could provide information for outcome prediction and injury monitoring. The aim with this affinity proteomic study was to identify serum proteins over time and between normoxic and hypoxic conditions in focal TBI.Material and methodsSprague Dawley rats (n=73) received a 3mm deep controlled cortical impact ("severe injury"). Following injury, the rats inhaled either a normoxic (22% O2) or hypoxic (11% O2) air mixture for 30min before resuscitation. The rats were sacrificed at day 1, 3, 7, 14 and 28 after trauma. A total of 204 antibodies targeting 143 unique proteins of interest in TBI research, were selected. The sample proteome was analyzed in a suspension bead array set-up. Comparative statistics and factor analysis were used to detect differences as well as variance in the data.ResultsWe found that complement factor 9 (C9), complement factor B (CFB) and aldolase c (ALDOC) were detected at higher levels the first days after trauma. In contrast, hypoxia inducing factor (HIF)1α, amyloid precursor protein (APP) and WBSCR17 increased over the subsequent weeks. S100A9 levels were higher in hypoxic-compared to normoxic rats, together with a majority of the analyzed proteins, albeit few reached statistical significance. The principal component analysis revealed a variance in the data, highlighting clusters of proteins.ConclusionsProtein profiling of serum following TBI using an antibody based microarray revealed temporal changes of several proteins over an extended period of up to four weeks. Further studies are warranted to confirm our findings.



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Memantine improves outcomes after repetitive traumatic brain injury

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Zhengrong Mei, Jianhua Qiu, Sasha Alcon, Jumana Hashim, Alexander Rotenberg, Yan Sun, William P. Meehan, Rebekah Mannix
Repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions) is common and results in significant cognitive impairment. Targeted therapies for rmTBI are lacking, though evidence from other injury models indicates that targeting N-methyl-d-aspartate (NMDA) receptor (NMDAR)-mediated glutamatergic toxicity might mitigate rmTBI-induced neurologic deficits. However, there is a paucity of preclinical or clinical data regarding NMDAR antagonist efficacy in the rmTBI setting. To test whether NMDAR antagonist therapy improves outcomes after rmTBI, mice were subjected to rmTBI injury (4 injuries in 4days) and randomized to treatment with the NMDA antagonist memantine or with vehicle. Functional outcomes were assessed by motor, anxiety/impulsivity and mnemonic behavioral tests. At the synaptic level, NMDAR-dependent long-term potentiation (LTP) was assessed in isolated neocortical slices. At the molecular level, the magnitude of gliosis and tau hyper-phosphorylation was tested by Western blot and immunostaining, and NMDAR subunit expression was evaluated by Western blot and polymerase chain reaction (PCR). Compared to vehicle-treated mice, memantine-treated mice had reduced tau phosphorylation at acute time points after injury, and less glial activation and LTP deficit 1 month after injury. Treatment with memantine also corresponded to normal NMDAR expression after rmTBI. No corresponding protection in behavior outcomes was observed. Here we found NMDAR antagonist therapy may improve histopathological and functional outcomes after rmTBI, though without consistent corresponding improvement in behavioral outcomes. These data raise prospects for therapeutic post-concussive NMDAR antagonism, particularly in athletes and warriors, who suffer functional impairment and neurodegenerative sequelae after multiple concussions.



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TRPM7 functions in non-neuronal and neuronal systems: Perspectives on its role in the adult brain

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Nashat Abumaria, Wei Li, Yuqiang Liu
Transient receptor potential melastatin-like 7 (TRPM7) has a unique dual protein structure. It is an ion channel that has biophysical characteristics enabling divalent cations transport and a kinase domain involved in molecular events starting from modulating signaling pathways to inducing chromatin remodeling. Over the past 15 years, significant progress in the molecular and functional characterization of TRPM7 has been made in peripheral tissue and/or cell lines. TRPM7 appears to be involved in a plethora of physiological and pathological processes including embryonic development, organogenesis, cell proliferation and survival, and cell death following certain triggers. In the post-mitotic neuronal cells, however, the functional role of TRPM7 remains unclear. Majority of the progress in this area of research has focused on the potential role of TRPM7 in mediating neuronal death following ischemia-like and neuronal injuries-like conditions. Here, we summarize major progress on the biological roles of the TRPM7 during development and in mitotic systems (cell lines). Then, we address the recent developments made in neuronal systems. Besides its role in neuronal death, we emphasize on direct and indirect evidences that could link TRPM7 to fundamental neurobiological processes such as synaptic transmission, synapse remodeling, plasticity, cognitive functions as well as to some mental disorders. Therefore, we propose that an equivalent effort is demanded to systematically characterize the role of TRPM7 in healthy neural system before presenting it as a potential molecular target to treat neurodegenerative disorders or to prevent neuronal death following ischemia and/or neuronal injuries.



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Limb remote ischemic conditioning increases Notch signaling activity and promotes arteriogenesis in the ischemic rat brain

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Changhong Ren, Sijie Li, Brian Wang, Rongrong Han, Ning Li, Jinhuan Gao, Xiaohua Li, Kunlin Jin, Xunming Ji
Background and purposeWe tested the hypothesis that limb remote ischemic conditioning (LRIC) treatment promotes arteriogenesis and increases Notch signaling activity during stroke recovery.MethodsAdult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO). LRIC was applied after the onset of focal ischemia (per-conditioning), followed by repeated short episodes of remote ischemia 24h after reperfusion (post-conditioning). Cerebral blood flow (CBF) was measured by Laser Doppler Flowmetry. Immunohistochemistry was used to reveal α-smooth muscle actin (α-SMA) immunopositive cells in the arteries of the brain. The cerebral angioarchitecture was visualized with a latex perfusion technique.ResultsLRIC treatment significantly elevated local cerebral blood flow and increased arteriogenesis as indicated by increased arterial diameter and vascular smooth muscle cell proliferation in the ischemic brain. The increased arteriogenesis significantly correlated with the functional outcome after stroke. Furthermore, LRIC treatment upregulated the expressions of Notch1 and Notch intracellular domain (NICD) in arteries surrounding the ischemic area.ConclusionThese results suggest that the therapeutic effects of LRIC may involve the promotion of arteriogenesis during the recovery phase after focal cerebral ischemia and that Notch1 signaling seems to be an important player in limb remote ischemia-mediated arteriogenesis.



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Factors affecting post-stroke motor recovery: Implications on neurotherapy after brain injury

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Ali Alawieh, Jing Zhao, Wuwei Feng
Neurological disorders are a major cause of chronic disability globally among which stroke is a leading cause of chronic disability. The advances in the medical management of stroke patients over the past decade have significantly reduced mortality, but at the same time increased numbers of disabled survivors. Unfortunately, this reduction in mortality was not paralleled by satisfactory therapeutics and rehabilitation strategies that can improve functional recovery of patients. Motor recovery after brain injury is a complex, dynamic, and multifactorial process in which an interplay among genetic, pathophysiologic, sociodemographic and therapeutic factors determines the overall recovery trajectory. Although stroke recovery is the most well-studied form of post-injury neuronal recovery, a thorough understanding of the pathophysiology and determinants affecting stroke recovery is still lacking. Understanding the different variables affecting brain recovery after stroke will not only provide an opportunity to develop therapeutic interventions but also allow for developing personalized platforms for patient stratification and prognosis. We aim to provide a narrative review of major determinants for post-stroke recovery and their implications in other forms of brain injury.



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Combat blast related traumatic brain injury (TBI): Decade of recognition; promise of progress

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Ralph G. DePalma, Stuart W. Hoffman
Between April 2007 and December 2015, the Veterans Health Administration (VHA) screened one million combat veterans for traumatic brain injury (TBI), among 2.6 million deployed during operations Enduring Freedom, Iraqi Freedom and New Dawn (OEF/OIF/OND). Since 2007, among those reporting, screened and referred for definitive evaluation, approximately 8.4% of these Veterans received a diagnosis of TBI, the majority characterized as mTBI/Concussion (mTBI) and, in great proportion, related to blast exposures. Mild Traumatic brain injury called "a signature injury" is also known as 'the invisible injury' of these conflicts. Identifying and assessing neuropathological, cellular and resulting cognitive, emotional, behavioral and neurological consequences of mTBI comprise vast clinical and research challenges. We provide a brief overview of current history, injury mechanisms related to blast exposure, coordinated research support, and the need to understand specific cellular and neurological changes occurring with blast injury, particularly mTBI.



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Both hemorrhagic and non-hemorrhagic traumatic MRI lesions are associated with the microstructural damage of the normal appearing white matter

Publication date: 15 March 2018
Source:Behavioural Brain Research, Volume 340
Author(s): Arnold Toth, Balint Kornyei, Noemi Kovacs, Tamas Rostas, Andras Buki, Tamas Doczi, Peter Bogner, Attila Schwarcz
Traumatic microbleeds (TMBs) and non-hemorrhagic lesions (NHLs) on MRI are regarded as surrogate markers of diffuse axonal injury. However, the actual relation between lesional and diffuse pathology remained unclear, since lesions were related to clinical parameters, largely influenced by extracranial factors.The aim of this study is to directly compare TMBs, NHLs and their regional features with the co-existing diffuse injury of the normal appearing white matter (NAWM) as measured by diffusion tensor imaging (DTI).Thirty-eight adults with a closed traumatic brain injury (12 mild, 4 moderate and 22 severe) who underwent susceptibility weighted imaging (SWI), T1-, T2 weighted and FLAIR MRI and routine CT were included in the study. TMB (on SWI) and NHL (on T1-, T2 weighted and FLAIR images) features and Rotterdam scores were evaluated. DTI metrics such as fractional anisotropy (FA) and mean diffusivity (MD) were measured over different NAWM regions. Clinical parameters including age; Glasgow Coma Scale; Rotterdam score; TMB and NHL features were correlated to regional NAWM diffusivity using multiple regression.Overall NHL presence and basal ganglia area TMB load were significantly, negatively correlated with the subcortical NAWM FA values (partial r=−0.37 and −0.36; p=0.006 and 0.025, respectively).The presence of any NHL, or TMBs located in the basal ganglia area indicates diffuse NAWM damage even after adjusting for clinical and CT parameters. To estimate DAI, a conventional lesional MRI pathology evaluation might at least in part substitute the use of quantitative DTI, which is yet not widely feasible in a clinical setting.



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Quality of Prostate Cancer Screening Information on the Websites of Nationally-Recognized Cancer Centers and Health Organizations

Publication date: Available online 24 December 2017
Source:Practical Radiation Oncology
Author(s): Bogdan-Alexandru Manole, Daniel V. Wakefield, Austin Dove, Caleb R. Dulaney, Samuel R. Marcrom, David L. Schwartz, Michael R. Farmer




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Chest wall toxicity after hypofractionated proton beam therapy for liver malignancies

Publication date: Available online 24 December 2017
Source:Practical Radiation Oncology
Author(s): Rosanna Yeung, Stephen R. Bowen, Tobias R. Chapman, Grayden T. MacLennan, Smith Apisarnthanarax
PurposeNormal liver-sparing with proton beam therapy (PBT) allows for dose escalation in the treatment of liver malignancies, but may result in high doses to the chest wall (CW). CW toxicity (CWT) data after PBT for liver malignancies are limited, with most published reports describing toxicity after a combination of hypofractionated proton and photon radiotherapy. We examined the incidence and associated factors for CWT after hypofractionated PBT for liver malignancies.Methods and MaterialsWe retrospectively reviewed the charts of 37 consecutive patients with liver malignancies (30 hepatocellular carcinoma, 6 intrahepatic cholangiocarcinoma and 1 metastasis) treated with hypofractionated PBT. CWT was scored using CTCAEv4. Receiver-operating characteristic (ROC) curves were used to identify patient and dosimetric factors associated with CWT and to determine optimal DVH parameters/cut-offs. Cox regression univariate analysis was used to associate factors to time-dependent onset of CWT.ResultsThirty-nine liver lesions were treated with a median dose of 60 GyE (range, 35–67.5 GyE) in 15 fractions (range, 13–20 fractions). Median follow-up was 11months (range, 2–44months). Grade≥2 and 3 CW pain occurred in 7 (19%) and 4 (11%) patients, respectively. Median time to onset of pain was 6months (range, 1–14months). No patients had radiographic rib fracture. On univariate analysis, CW EQD2α/β=3V57>20cm³ (HR 2.7, p=0.004), V63>17cm³ (HR 2.7, p=0.003), and V78>8cm³ (HR 2.6, p=0.003) had the strongest association with grade≥2 CW pain as did tumor dose of >75Gy EQD2α/β=10 (HR 8.7, p=0.03). No other patient factors were associated with CWT.ConclusionsCWT after hypofractionated PBT for liver malignancies is clinically relevant. For a 15-fraction regimen, V47>20cm³, V50>17cm³, and V58>8cm³ were associated with higher rates of CWT. Further investigation of PBT techniques to reduce CW dose are warranted.



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Urolift as a surrogate for fiducial markers in IGRT planning of prostate cancer in BPH patients

Publication date: Available online 24 December 2017
Source:Practical Radiation Oncology
Author(s): Nrusingh C. Biswal, Beth Swann, Michael McKenna, Rachana Singh




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Five Years Experience with a Customized Electronic Checklist for Radiotherapy Planning Quality Assurance in a Multi-campus Institution

Publication date: Available online 24 December 2017
Source:Practical Radiation Oncology
Author(s): Sean L Berry, Kevin Tierney, Sharif Elguindi, James Mechalakos
IntroductionAn electronic checklist has been designed with the intention of reducing errors while minimizing the user effort in completing the checklist. We analyze the clinical use and evolution of the checklist over the past 5years and review data in an incident learning system (ILS) to investigate whether it has contributed to an improvement in patient safety.Methods and MaterialsThe checklist is written as a standalone HTML application utilizing VBScript. User selection of pertinent demographic details limits the display of checklist items only to those necessary for the particular clinical scenario. Ten common clinical scenarios were used to illustrate the difference between the maximum possible number of checklist items available in the code versus the number displayed to the user at any one time. An ILS database of errors and near misses was reviewed to evaluate whether the checklist influenced the occurrence of reported events.ResultsOver five years, the number of checklist items available in the code nearly doubled, while the number displayed to the user at any one time stayed constant. Events reported in our ILS related to the beam energy used with pacemakers, projection of anatomy on digitally reconstructed radiographs, orthogonality of setup fields, and field extension beyond matchlines, did not recur after the items were added to the checklist. Other events related to bolus documentation and breakpoints continued to be reported.ConclusionOur checklist is adaptable to the introduction of new technologies, transitions between planning systems, and to errors and near misses recorded in the ILS. The electronic format allows us to restrict user display to a small, relevant, subset of possible checklist items, limiting the planner effort needed to review and complete the checklist.SummaryAn electronic safety checklist for radiotherapy treatment planning has been in use at our institution for more than five years. We demonstrate that the electronic format allows the user display to be restricted to a small, relevant, subset of possible checklist items. The electronic checklist can be modified to adapt to the introduction of new technologies, transitions between planning systems, and in response to errors and near misses in the clinic.



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Intra-patient study comparing 3D printed bolus versus standard vinyl gel sheet bolus for postmastectomy chest wall radiation therapy

Publication date: Available online 24 December 2017
Source:Practical Radiation Oncology
Author(s): James L. Robar, Kathryn Moran, James Allan, James Clancey, Tami Joseph, Krista Chytyk-Praznik, R. Lee MacDonald, John Lincoln, Parisa Sadeghi, Robert Rutledge
PurposeThis patient study evaluated the use of 3D printed bolus for chest wall radiotherapy, with comparison to standard sheet bolus with regard to accuracy of fit, surface dose measured in vivo and efficiency of patient setup. By alternating bolus type over the course of therapy, each patient served as her own control.Methods and materialsFor sixteen patients undergoing chest wall radiotherapy, custom 5.0mm thick bolus was designed based on the treatment planning CT and 3D printed using polylactic acid (PLA). Cone beam CT was used to image and quantify the accuracy of fit of the two bolus types with regard to air gaps between the bolus and skin. As a QA measure for the 3D printed bolus, Optically Stimulated Luminescent Dosimetry provided in vivo comparison of surface dose at seven points on the chest wall. Durations of patient setup and image guidance were recorded and compared.ResultsIn 13 of 16 patients the bolus was printed without user intervention and the median print time was 12.6hours. The accuracy of fit of the bolus to the chest wall was improved significantly relative to standard sheet bolus with the frequency of air gaps 5mm or greater reduced from 30% to 13% (p<0.001), and maximum air gap dimension diminished from 0.5 +/− 0.3mm to 0.3 +/− 0.3mm, on average. Surface dose was within 3% for both standard sheet and 3D printed bolus. On average, the use of 3D printed bolus reduced the setup time from 104 to 76seconds.ConclusionsThis study demonstrates 3D printed bolus in post-mastectomy radiation therapy improves fit of the bolus and reduces patient setup time marginally compared with standard vinyl gel sheet bolus. The time savings on patient setup must be weighed against the considerable time for the 3D printing process.



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Tacrolimus: An updated review on delivering strategies for multifarious diseases

Publication date: 1 March 2018
Source:European Journal of Pharmaceutical Sciences, Volume 114
Author(s): Divya Dheer, Jyoti, Prem N. Gupta, Ravi Shankar
From the current trends, tacrolimus (TAC) has become an important therapeutic option for the optimal individualization of immunosuppressive therapy especially in case of transplant recipients. TAC is used most frequently in comparison to other immunosuppressants because it offers better safety profile with increased long-term survival in patients especially in children and adolescents. This drug has developed an immense interest in the research field owing to its potential pharmacological scope but due to its poor water solubility, need of concomitant steroids and higher incidences of nephrotoxicity, there comes a need for future research to minimize such limitations and decipher maximum use of the drug. In addition, there are number of formulations attempted to enhance its erratic bioavailability through various techniques namely solid dispersions, inclusion complexes, prodrug approach, SMEDDS etc. The present review aims to acknowledge the TAC pharmacokinetic profile and novel drug delivery systems in multiple diseased conditions by particularly enhancing its poor biopharmaceutical issues as well as dose related toxicity. Collectively, we have updated the data pertaining to the drug delivery prospects of TAC for the period of last 8–10years.

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A complete rethink is needed on how greenhouse gas emissions are quantified for national reporting

Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): Adrian Leip, Ute Skiba, Alex Vermeulen, Rona L. Thompson




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Editorial Board

Publication date: February 2018
Source:Atmospheric Environment, Volume 174





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Intercomparison of OH and OH reactivity measurements in a high isoprene and low NO environment during the Southern Oxidant and Aerosol Study (SOAS)

Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): Dianne Sanchez, Daun Jeong, Roger Seco, Ian Wrangham, Jeong-Hoo Park, William H. Brune, Abigail Koss, Jessica Gilman, Joost de Gouw, Pawel Misztal, Allen Goldstein, Karsten Baumann, Paul O. Wennberg, Frank N. Keutsch, Alex Guenther, Saewung Kim
We intercompare OH and OH reactivity datasets from two different techniques, chemical ionization mass spectrometry (CIMS) and laser-induced fluorescence (LIF) in a high isoprene and low NO environment in a southeastern US forest during the Southern Oxidant and Aerosol Study (SOAS). An LIF instrument measured OH and OH reactivity at the top of a tower, a CIMS instrument measured OH at the top of the tower, and a CIMS based comparative reactivity method (CRM-CIMS) instrument deployed at the base of the tower measured OH reactivity. Averaged diel variations of OH and OH reactivity from these datasets agree within analytical uncertainty and correlations of LIF versus CIMS for OH and OH reactivity have slopes of 0.65 and 0.97, respectively. However, there are systematic differences between the measurement datasets. The CRM-CIMS measurements of OH reactivity were ∼16% lower than those by the LIF technique in the late afternoon. We speculate that it is caused by losses in the sampling line down to the CRM-CIMS instrument. On the other hand, we could not come up with a reasonable explanation for the difference in the LIF and CIMS OH datasets for early morning and late afternoon when OH is below 1 × 10⁶ molecules cm⁻³. Nonetheless, results of this intercomparison exercise strengthen previous publications from the field site on OH concentrations and atmospheric reactivity.



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Corrigendum to “Risk assessment of bioaccessible trace elements in smoke haze aerosols versus urban aerosols using simulated lung fluids” [Atmos. Environ. 125PB (2016) 505–511]

Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): Xian Huang, Raghu Betha, Li Yun Tan, Rajasekhar Balasubramanian




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Exertional Tolerance Assessments after Mild Traumatic Brain Injury: A Systematic Review

Publication date: Available online 23 December 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Catherine Quatman-Yates, Anna Bailes, Sara Constand, Mary Claire Sroka, Katharine Nissen, Brad Kurowski, Jason Hugentobler
ObjectiveThe objective of this study was to review the literature to identify and summarize strategies for evaluating responses to physical exertion after mild traumatic brain injury (mTBI) for clinical and research purposes.Data sourcesPubMed and EBSCOHost through December 31, 2016.Study SelectionTwo independent reviewers selected studies based on the following criteria: 1) inclusion of participants with mTBI/concussion, 2) use of a measurement of physiological or psychosomatic response to exertion, 3) a repeatable description of the exertion protocol was provided, 4) a sample of at least 10 participants with a mean age between 8-65 years, and 5) the article was in English. The search process yielded 2,685 articles, of which 14 studies met the eligibility requirements.Data ExtractionA quality assessment using a checklist was conducted for each study by two independent study team members and verified by a third team member. Data were extracted by a one team member and verified by a second team member.Data SynthesisA qualitative synthesis of the studies revealed that most protocols employed a treadmill or cycle ergometer as the exercise modality. Protocol methods varied across studies including differences in initial intensity determination, progression parameters, and exertion duration. Common outcome measures were self-reported symptoms, heart rate, and blood pressure.Summary/conclusionsThe strongest evidence indicates that exertional assessments can provide important insight about mTBI recovery and should be administered using symptoms as a guide. Additional studies are needed to verify an optimal modes and protocols for post-mTBI exertional assessments.



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Interaction between p22phox and Nox4 in the endoplasmic reticulum SUGGESTS A UNIQUE mechanism of NADPH oxidase complex formation

Publication date: Available online 24 December 2017
Source:Free Radical Biology and Medicine
Author(s): Melinda Zana, Zalán Péterfi, Hajnal A. Kovács, Zsuzsanna E. Tóth, Balázs Enyedi, Françoise Morel, Marie-Hélène Paclet, Ágnes Donkó, Stanislas Morand, Thomas L. Leto, Miklós Geiszt
The p22^phox protein is an essential component of the phagocytic- and inner ear NADPH oxidases but its relationship to other Nox proteins is less clear. We have studied the role of p22^phox in the TGF-β1-stimulated H2O2 production of primary human and murine fibroblasts. TGF-β1 induced H2O2 release of the examined cells, and the response was dependent on the expression of both Nox4 and p22^phox. Interestingly, the p22^phox protein was present in the absence of any detectable Nox/Duox expression, and the p22^phox level was unaffected by TGF-β1. On the other hand, Nox4 expression was dependent on the presence of p22^phox, establishing an asymmetrical relationship between the two proteins. Nox4 and p22^phox proteins localized to the endoplasmic reticulum and their distribution was unaffected by TGF-β1. We used a chemically induced protein dimerization method to study the orientation of p22^phox and Nox4 in the endoplasmic reticulum membrane. This technique is based on the rapamycin-mediated heterodimerization of the mammalian FRB domain with the FK506 binding protein. The results of these experiments suggest that the enzyme complex produces H2O2 into the lumen of the endoplasmic reticulum, indicating that Nox4 contributes to the development of the oxidative milieu within this organelle.

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Priming plant resistance by activation of redox-sensitive genes

Publication date: Available online 24 December 2017
Source:Free Radical Biology and Medicine
Author(s): Carmen González-Bosch
Priming by natural compounds is an interesting alternative for sustainable agriculture, which also contributes to explore the molecular mechanisms associated with stress tolerance. Although hosts and stress types eventually determine the mode of action of plant-priming agents, it highlights that many of them act on redox signalling. These include vitamins thiamine, riboflavin and quercetin; organic acids like pipecolic, azelaic and hexanoic; volatile organic compounds such as methyl jasmonate; cell wall components like chitosans and oligogalacturonides; H2O2, etc. This review provides data on how priming inducers promote stronger and faster responses to stress by modulating the oxidative environment, and interacting with signalling pathways mediated by salycilic acid, jasmonic acid and ethylene. The histone modifications involved in priming that affect the transcription of defence-related genes are also discussed. Despite the evolutionary distance between plants and animals, and the fact that the plant innate immunity takes place in each plant cell, they show many similarities in the molecular mechanisms that underlie pathogen perception and further signalling to activate defence responses. This review highlights the similarities between priming through redox signalling in plants and in mammalian cells. The strategies used by pathogens to manipulate the host´s recognition and the further activation of defences also show similarities in both kingdoms. Moreover, phytochemicals like sulforaphane and 12-oxo-phytodienoic acid prime both plant and mammalian responses by activating redox-sensitive genes. Hence research data into the priming of plant defences can provide additional information and a new viewpoint for priming mammalian defence, and vice versa.

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The A to Z of Modulated Cell Patterning by Mammalian Thioredoxin Reductases

Publication date: Available online 24 December 2017
Source:Free Radical Biology and Medicine
Author(s): Markus Dagnell, Edward E Schmidt, Elias S.J. Arnér
Mammalian thioredoxin reductases (TrxRs) are selenocysteine-containing proteins (selenoproteins) that propel a large number of functions through reduction of several substrates including the active site disulfide of thioredoxins (Trxs). Well-known enzymatic systems that in turn are supported by Trxs and TrxRs include deoxyribonucleotide synthesis through ribonucleotide reductase, antioxidant defense through peroxiredoxins and methionine sulfoxide reductases, and redox modulation of a number of transcription factors. Although these functions may be essential for cells due to crucial roles in maintenance of cell viability and proliferation, findings during the last decade reveal that mammals have major redundancy in their cellular reductive systems. The synthesis of glutathione (GSH) and reductive functions of GSH-dependent pathways typically act in parallel with Trx-dependent pathways, with only one of these systems often being sufficient to support viability. Importantly, this does not imply that a modulation of the Trx system will remain without consequences, even when GSH-dependent pathways remain functional. As suggested by several recent findings, the Trx system in general and the TrxRs in particular, function as key regulators of signaling pathways. In this review article we will discuss findings that collectively suggest that modulation in mammalian systems of cytosolic TrxR1 (TXNRD1) or mitochondrial TrxR2 (TXNRD2) influence cell patterning and cellular stress responses. Effects of lower activities include increased adipogenesis, insulin responsiveness, glycogen accumulation, hyperproliferation, and distorted embryonic development, while increased activities correlate with decreased proliferation and extended lifespan, as well as worse cancer prognosis. The molecular mechanisms that underlie these diverse effects, involving regulation of protein phosphorylation cascades and of key transcription factors that guide cellular differentiation pathways, will be discussed. We conclude that the selenium-dependent oxidoreductases TrxR1 and TrxR2 should be considered as key components of signaling pathways that control cell differentiation and cellular stress responses.

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Entrainment of the mouse circadian clock: Effects of stress, exercise, and nutrition

Publication date: Available online 23 December 2017
Source:Free Radical Biology and Medicine
Author(s): Yu Tahara, Shigenobu Shibata
The circadian clock system in mammals plays a fundamental role in maintaining homeostasis. Entrainment is an important characteristic of the internal clock, by which appropriate timing is maintained according to external daily stimuli, such as light, stress, exercise, and/or food. Disorganized entrainment or a misaligned clock time, such as jet lag, increases health disturbances. The central clock in the suprachiasmatic nuclei, located in the hypothalamus, receives information about arousal stimuli, such as physical stress or exercise, and changes the clock time by modifying neural activity or the expression of circadian clock genes. Although feeding stimuli cannot entrain the central clock in a normal light–dark cycle, the central clock can partially detect the metabolic status. Local clocks in the peripheral tissues, including liver and kidney, have a strong direct response to the external stimuli of stress, exercise, and/or food that is independent of the central clock. The mechanism underlying entrainment by stress/exercise is mediated by glucocorticoids, sympathetic nerves, oxidative stress, hypoxia, pH, cytokines, and temperature. Food/nutrition-induced entrainment is mediated by fasting-induced hormonal or metabolic changes and re-feeding-induced insulin or oxyntomodulin secretion. Chrono-nutrition is a clinical application based on chronobiology research. Future studies are required to elucidate the effects of eating and nutrient composition on the human circadian clock. Here, we focus on the central and peripheral clocks mostly in rodents' studies and review the findings of recent investigations of the effects of stress, exercise, and food on the entrainment system.

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