The retromer complex system in a transgenic mouse model of AD: influence of age

Publication date: Available online 3 January 2017
Source:Neurobiology of Aging
Author(s): Jin Chu, Domenico Praticò
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown.In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, CI-MRP, SorLA in brains of Tg2576 and controls at 3, 8 and 14 months of age. While cortex showed an age-dependent decrease in all but VPS29, levels of the same proteins in the cerebellum were unchanged at any age. Neuronal cells expressing human APP Swedish mutant had also reduced retromer complex levels. However, incubation with a pharmacological chaperone dose-dependently restored these levels together with a reduction in Aβ.Our study is the first to show that in a transgenic mouse model of AD the changes in the expression levels of the retromer complex are age and region-dependent, and that the complex is a viable therapeutic target since its deficiency can be restored pharmacologically by a retromer chaperone.



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Heightened Cortical Excitability in Aged Rodents with Memory Impairment

Publication date: Available online 3 January 2017
Source:Neurobiology of Aging
Author(s): Rebecca P. Haberman, Ming Teng Koh, Michela Gallagher
Elevated excitability in the hippocampus has emerged as a key contributor to reduced memory function in aging and in cognitive impairment prodromal to Alzheimer's disease. Here, we investigated the relationship between neural activity and memory in the hippocampus and a connectional cortical network using an aged rat model of individual differences for memory impairment. The expression of cFos was used as a measure of pharmacologically induced neural activity. Aged memory-impaired rats exhibited elevated cFos relative to young adult and aged unimpaired rats in the CA3 subfield of the hippocampus and in several cortical regions including the retrosplenial, parietal, and orbitofrontal cortices. Strong correlations between cFos intensity and task performance across the activated network showed a tight coupling between excitability and cognitive phenotype in aging. Elevated neural excitability extending beyond the hippocampus to interconnected posterior cortex (retrosplenial/parietal) was reduced by treatment with levetiracetam, a therapeutic with behavioral efficacy that has previously translated from rodent models of age-related impairment and Alzheimer's disease to humans with amnestic mild cognitive impairment.



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Computational EEG modelling of decision making under ambiguity reveals spatio-temporal dynamics of outcome evaluation

Publication date: 15 March 2017
Source:Behavioural Brain Research, Volume 321
Author(s): Lee Jollans, Robert Whelan, Louise Venables, Oliver H. Turnbull, Matteo Cella, Simon Dymond
Complex human cognition, such as decision-making under ambiguity, is reflected in dynamic spatio-temporal activity in the brain. Here, we combined event-related potentials with computational modelling of the time course of decision-making and outcome evaluation during the Iowa Gambling Task. Measures of choice probability generated using the Prospect Valence Learning Delta (PVL-Delta) model, in addition to objective trial outcomes (outcome magnitude and valence), were applied as regressors in a general linear model of the EEG signal. The resulting three-dimensional spatio-temporal characterization of task-related neural dynamics demonstrated that outcome valence, outcome magnitude, and PVL-Delta choice probability were expressed in distinctly separate event related potentials. Our findings showed that the P3 component was associated with an experience-based measure of outcome expectancy.



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Behavioral characterization of female zinc transporter 3 (ZnT3) knockout mice

Publication date: 15 March 2017
Source:Behavioural Brain Research, Volume 321
Author(s): Sarah E. Thackray, Brendan B. McAllister, Richard H. Dyck
Zinc is an important element in all cells of the body, having structural, enzymatic, and regulatory functions. In some neurons, zinc is loaded into synaptic vesicles by zinc transporter 3 (ZnT3) and released into the synaptic cleft, where it can modulate neuronal function. ZnT3 knockout (KO) mice lack ZnT3 and thus lack synaptic zinc. Previous studies have examined the behavioral phenotype of ZnT3 KO mice, mostly using mixed-sex or male-only groups. In the present study we focused specifically on the behavior of female ZnT3 KO mice (2–3 months old). An extensive battery of tests was administered to assess sensorimotor and cognitive behaviours, as well as to examine for a possible schizophrenia-like phenotype. ZnT3 KO mice performed similarly to wild type controls in the majority of tests. However, they were less accurate in the skilled reach task, suggesting impaired skilled motor learning, and faster to descend a vertical pole. ZnT3 KO mice were also slower in the open field and made fewer chamber entries in the social preference test, suggesting decreased exploratory locomotion. No differences were observed in the Morris water task or fear conditioning test. This is the first study to show a behavioural phenotype specifically for female ZnT3 KO mice. Comparing our results to previous studies, it appears that there may be sex-specific effects of eliminating ZnT3. Female ZnT3 KO mice exhibit abnormalities in locomotion and at skilled motor learning, but we were unable to detect spatial or fear learning deficits previously described in male ZnT3 KO mice.



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Fishtail points from the Pampas of South America: Their variability and life histories

Publication date: March 2017
Source:Journal of Anthropological Archaeology, Volume 45
Author(s): Nora Flegenheimer, Celeste Weitzel
Fishtail points (FTP) related to the terminal Pleistocene peopling of the South American continent present morphological, technological and functional variability. We discuss a collection of FTP recovered from central east Tandilia Range in the Pampas of Argentina. We do this by exploring the life histories of a set of 97 FTP, assessing aspects of production, use and discard through morphological, macro-fracture, and fatty acids and sterols analysis. We identify four categories: miniatures, "atypical FTP", medium-sized and large points. Although possibly all were related to the realm of hunting, only medium and large points have clear indications of use as parts of weapons. Transformation due to maintenance, impact or recycling indicates their longevity and the complexity of their life histories. Miniatures are considered representations of full sized points and large points also possibly held a special status, requiring great flintknapping skill. As artifacts covering different roles and used in different social practices repeat the FTP outline, we sustain this shape must have held some significance for the people who produced and used them. Other aspects related to FTP use lives which probably were laden with meaning are the choice of colored and translucent toolstone and their intentional place of discard.

Graphical abstract

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Inside front cover

Publication date: January 2017
Source:Journal of Anxiety Disorders, Volume 45





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Publisher Acknowledgement

Publication date: January 2017
Source:Journal of Anxiety Disorders, Volume 45





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Trends of classification, incidence, mortality, and survival of MDS patients in Switzerland between 2001 and 2012

Publication date: February 2017
Source:Cancer Epidemiology, Volume 46
Author(s): Nicolas Bonadies, Anita Feller, Alicia Rovo, Axel Ruefer, Sabine Blum, Bernhard Gerber, Georg Stuessi, Rudolf Benz, Nathan Cantoni, Andreas Holbro, Adrian Schmidt, Thomas Lehmann, C. Matthias Wilk, Volker Arndt
Myelodysplastic syndromes (MDS) are emerging disorders of the elderly with an increasing burden on healthcare systems. He we report on the first population-based, epidemiological analysis of patients diagnosed with MDS in Switzerland between 2001 and 2012. The aim of this study was to characterize the extent and limitations of currently available population-based, epidemiological data and formulate recommendations for future health services research. The investigated outcomes comprised trends of annual case frequency, classification of morphological subtypes, incidence, mortality and survival. Annual case frequency increased by 20% (from 263 to 315 cases per year), whereas age-standardized incidence-/mortality-rates remained stable (2.5/1.1 per 100′000 person-years). This observation reflects population growth as well as higher diagnostic awareness and not an increase of age-specific risk. However, it will inevitably influence the future prevalence of MDS and the impact on healthcare systems. Reporting of classification in MDS subtypes was poor with modest improvement from 20% to 39% and increased awareness for mainly higher-risk diseases. Relative survival for all patients at 5-years (RS) ranged between 37 and 40%. Significant better RS was found for younger compared to older higher-risk MDS patients (48% vs. 17%), reflecting the effect of allogeneic hematopoietic stem-cell transplantation. However, no survival advantage was found in elderly patients after introduction of hypomethylating agents as standard for care in this patient group. Our data is in line with results from other MDS and cancer registries. It allows formulating recommendations for future collaborative health services research on MDS patients with national and international partners.



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Proton pump inhibitors on pancreatic cancer risk and survival

Publication date: February 2017
Source:Cancer Epidemiology, Volume 46
Author(s): Malcolm D. Kearns, Ben Boursi, Yu-Xiao Yang
BackgroundHypergastrinemia may promote the development and progression of pancreatic cancer. Proton pump inhibitor (PPI) therapy is known to cause hypergastrinemia. We sought to determine the association between PPI therapy and the risk of developing pancreatic cancer as well as survival following pancreatic cancer diagnosis.MethodsWe conducted a nested case-control study and a retrospective cohort study in The Health Improvement Network (THIN), a medical records database representative of the UK population. In the case-control study, each patient with incident pancreatic cancer was matched with up to four controls based on age, sex, practice site and both duration and calendar time of follow-up using incidence density sampling. The odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer risk associated with PPI use were estimated using multivariable conditional logistic regression. The retrospective cohort study compared the survival of pancreatic cancer patients according to their PPI exposure at the time of diagnosis. The effect of PPI use on pancreatic cancer survival was assessed using a multivariable Cox regression analysis.ResultsThe case-control study included 4113 cases and 16,072 matched controls. PPI use was more prevalent in cases than controls (53% vs. 26% active users). Adjusting for diabetes, smoking, alcohol use and BMI, PPI users including both former users and active users with longer cumulative PPI use had a higher risk of pancreatic cancer compared to non-users. When assessing survival following pancreatic cancer diagnosis, only short-term, active users had a modest decrease in survival.ConclusionsLong-term PPI therapy may be associated with pancreatic cancer risk. While PPI users recently started on treatment had a slightly worse survival, this result likely is from reverse causation.



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Hyperfractionated accelerated reirradiation for rectal cancer: An analysis of outcomes and toxicity

Publication date: Available online 3 January 2017
Source:Radiotherapy and Oncology
Author(s): Randa Tao, Chiaojung Jillian Tsai, Garrett Jensen, Cathy Eng, Scott Kopetz, Michael J. Overman, John M. Skibber, Miguel Rodriguez-Bigas, George J. Chang, Yi-Qian Nancy You, Brian K. Bednarski, Bruce D. Minsky, Marc E. Delclos, Eugene Koay, Sunil Krishnan, Christopher H. Crane, Prajnan Das
Background and purposeTo evaluate outcomes and toxicity in patients treated with hyperfractionated pelvic reirradiation for recurrent rectal cancer.Materials and methods102 patients with recurrent rectal adenocarcinoma were treated with pelvic reirradiation with a hyperfractionated accelerated approach, consisting of 1.5Gy twice daily fractions to a total dose of 30–45Gy (median 39Gy), with the most common total dose 39Gy (n=90, 88%). The median dose of prior pelvic radiation therapy (RT) was 50.4Gy (range: 25–63Gy).ResultsThe median follow-up was 40months for living patients (range, 3–150months). The 3-year freedom from local progression (FFLP) rate was 40% and the 3-year overall survival (OS) rate was 39%. Treatment with surgery was significantly associated with improved FFLP and OS, with 3-year FFLP rate of 49% vs. 30% (P=0.013), and 3-year OS rate of 62% vs. 20% (P<0.0001), compared to those without surgery. The actuarial 3-year rate of grade 3–4 late toxicity was 34%; patients who underwent surgery had a significantly higher rate of grade 3–4 late toxicity compared to those without surgery (54% vs. 16%, P=0.001).ConclusionsThis large, retrospective, single-institution study shows that hyperfractionated accelerated reirradiation was well tolerated. The rate of FFLP was promising, given that the study comprised heavily pre-treated patients with recurrences. Rates of FFLP and OS were particularly impressive in patients who underwent both reirradiation and surgery.



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Functional genomics: Screening for lncRNA function

Nature Reviews Genetics. doi:10.1038/nrg.2016.168

Author: Linda Koch

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Ground rules of the pluripotency gene regulatory network

Nature Reviews Genetics. doi:10.1038/nrg.2016.156

Authors: Mo Li & Juan Carlos Izpisua Belmonte

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IFC(EDITORIAL BOARD)

Publication date: January 2017
Source:DNA Repair, Volume 49





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Changes in lower limb muscle activity after walking on a split-belt treadmill in individuals post-stroke

Publication date: Available online 3 January 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Martina Betschart, Séléna Lauzière, Carole Miéville, Bradford J. McFadyen, Sylvie Nadeau
Background: There is growing evidence that stroke survivors can adapt and improve step length symmetry in the context of split-belt treadmill (SBT) walking. However, less knowledge exists about the strategies involved for such adaptations. This study analyzed lower limb muscle activity in individuals post-stroke related to SBT-induced changes in step length. Methods: Step length and surface EMG activity of six lower limb muscles were evaluated in individuals post-stroke (n=16) during (adaptation) and after (after-effects) walking at unequal belt speeds. Results: During adaptation, significant increases in EMG activity were mainly found in proximal muscles (p⩽0.023), whereas after-effects were observed particularly in the distal muscles. The plantarflexor EMG increased after walking on the slow belt (p⩽0.023) and the dorsiflexors predominantly after walking on the fast belt (p⩽0.017) for both, nonparetic and paretic-fast conditions. Correlation analysis revealed that after-effects in step length were mainly associated with changes in distal paretic muscle activity (0.522⩽ r ⩽0.663) but not with functional deficits. Based on our results, SBT walking could be relevant for training individuals post-stroke who present shorter paretic step length combined with dorsiflexor weakness, or individuals with shorter nonparetic step length and plantarflexor weakness.



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Evidence for ERP biomarkers of eating disorder symptoms in women

Publication date: Available online 3 January 2017
Source:Biological Psychology
Author(s): Katie Groves, Steffan Kennett, Helge Gillmeister
Growing evidence suggests that the brain processes bodies distinctively from other stimuli, but little research has addressed whether visual body perception is modulated by the observer's thoughts and feelings about their own body. The present study thus investigated the relationship between body image and electrophysiological signatures of body perception, with the aim of identifying potential biomarkers of body image disturbances. Occipito-parietal (P1 and N1) and fronto-central (VPP) processing of body and non-body stimuli were assessed in 29 weight-restored eating disordered (ED) women and compared to 27 healthy controls. Rapid early visual processing was seen in the ED group, as the entire P1-N1 complex unfolded significantly earlier compared to controls. ED women also showed a gender-selective response to other women's bodies over N1 and VPP components. Such gender-selectivity was not evident in controls. Moreover, ERP effects correlated with scores on the Eating Disorder Inventory-II (EDI-2), indicating a close link between the observers' ED symptomatology, including body image, and the visual analysis of human bodies during very early stages of cortical processing. The temporal dynamics of visual body perception may therefore serve as potential neural markers for the identification of ED symptomatology in 'at risk' populations.



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Cosmetics, Vol. 4, Pages 2: In Vitro Methodologies to Evaluate the Effects of Hair Care Products on Hair Fiber

Consumers use different hair care products to change the physical appearance of their hair, such as shampoos, conditioners, hair dye and hair straighteners. They expect cosmetics products to be available in the market to meet their needs in a broad and effective manner. Evaluating efficacy of hair care products in vitro involves the use of highly accurate equipment. This review aims to discuss in vitro methodologies used to evaluate the effects of hair care products on hair fiber, which can be assessed by various methods, such as Scanning Electron Microscopy, Transmission Electron Microscopy, Atomic Force Microscopy, Optical Coherence Tomography, Infrared Spectroscopy, Raman Spectroscopy, Protein Loss, Electrophoresis, color and brightness, thermal analysis and measuring mechanical resistance to combing and elasticity. The methodology used to test hair fibers must be selected according to the property being evaluated, such as sensory characteristics, determination of brightness, resistance to rupture, elasticity and integrity of hair strain and cortex, among others. If equipment is appropriate and accurate, reproducibility and ease of employment of the analytical methodology will be possible. Normally, the data set must be discussed in order to obtain conclusive answers to the test.

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Cosmetics, Vol. 4, Pages 1: Cosmetics Europe Guidelines on the Management of Undesirable Effects and Reporting of Serious Undesirable Effects from Cosmetics in the European Union

The European Union (EU) Cosmetics Regulation (EC) No. 1223/2009 requires companies to collect and assess reports of adverse health effects from the cosmetic products (undesirable effects) they market. Furthermore, undesirable effects that are considered as serious need to be reported to the national competent authorities. Cosmetics Europe, representing the European cosmetics industry, has developed these guidelines to promote a consistent practical approach for the management of undesirable effects and the notification of serious undesirable effects. Following these guidelines allows companies concerned to demonstrate due diligence and compliance with the legal requirements.

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Ordering fibers in green nanocomposites is a stretch

Publication date: Available online 2 January 2017
Source:Nano Today





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Functional genomics: Screening for lncRNA function

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Ground rules of the pluripotency gene regulatory network

In this article, the authors review the mechanisms by which the pluripotency gene regulatory network governs the acquisition, maintenance and dissolution of the pluripotent state, including the interaction of these networks with chromatin-mediated and RNA-mediated regulatory mechanisms. They discuss recent evidence for alternative pluripotency states and the factors that affect transitions between these states.

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