Dementia and risk of visual impairment in Chinese older adults

We had previously identified visual impairment increasing risk of incident dementia. While a bi-directional vision-cognition association has subsequently been proposed, no study has specifically examined the longitudinal association between dementia and incidence of clinically defined visual impairment. In this territory-wide community cohort study of 10,806 visually unimpaired older adults, we examined their visual acuity annually for 6 years and tested if dementia at baseline was independently associated with higher risk of incident visual impairment (LogMAR ≥ 0.50 in the better eye despite best correction, which is equivalent to moderate visual impairment according to the World Health Organization definition). By the end of Year 6, a total of 3151 (29.2%) participants developed visual impairment. However, we did not find baseline dementia associating with higher risk of incident visual impairment, after controlling for baseline visual acuity, cataract, glaucoma, diabetes, hypertension, hypercholesterolemia, heart diseases, stroke, Parkinson's disease, depression, hearing and physical impairments, physical, intellectual and social activities, diet, smoking, age, sex, educational level, and socioeconomic status. Among different covariables, baseline visual acuity appears to be more important than dementia in contributing to the development of visual impairment. Our present findings highlight the need for re-evaluating whether dementia is indeed a risk factor for visual impairment

Environmental Suitability of Vibrio Infections in a Warming Climate: An Early Warning System

Background: Some Vibrio spp. are pathogenic and ubiquitous in marine waters with low to moderate salinity and thrive with elevated sea surface temperature (SST). Objectives: Our objective was to monitor and project the suitability of marine conditions for Vibrio infections under climate change scenarios. Methods: The European Centre for Disease Prevention and Control (ECDC) developed a platform (the ECDC Vibrio Map Viewer) to monitor the environmental suitability of coastal waters for Vibrio spp. using remotely sensed SST and salinity. A case-crossover study of Swedish cases was conducted to ascertain the relationship between SST and Vibrio infection through a conditional logistic regression. Climate change projections for Vibrio infections were developed for Representative Concentration Pathway (RCP) 4.5 and RCP 8.5. Results: The ECDC Vibrio Map Viewer detected environmentally suitable areas for Vibrio spp. in the Baltic Sea in July 2014 that were accompanied by a spike in cases and one death in Sweden. The estimated exposure–response relationship for Vibrio infections at a threshold of 16°C revealed a relative risk (RR)=1.14 (95% CI: 1.02, 1.27; p=0.024) for a lag of 2 wk; the estimated risk increased successively beyond this SST threshold. Climate change projections for SST under the RCP 4.5 and RCP 8.5 scenarios indicate a marked upward trend during the summer months and an increase in the relative risk of these infections in the coming decades. Conclusions: This platform can serve as an early warning system as the risk of further Vibrio infections increases in the 21st century due to climate change. https://doi.org/10.1289/EHP219

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

Loss of heterozygosity at the ATBF1-A locus located in the 16q22 minimal region in breast cancer

Abstract Background Loss of heterozygosity (LOH) on the long arm of chromosome 16 is one of the most frequent genetic events in solid tumors. Recently, the AT-motif binding factor 1 (ATBF1)-A gene, which has been assigned to chromosome 16q22.3-23.1, was identified as a plausible candidate for tumor suppression in solid tumors due to its functional inhibition of cell proliferation and high mutation rate in prostate cancer. We previously reported that a reduction in ATBF1-A mRNA levels correlated with a worse prognosis in breast cancer. However, the mechanisms regulating the reduction of ATBF1-A mRNA levels (such as mutation, methylation in the promoter region, or deletion spanning the coding region) have not been fully examined. In addition, few studies have analyzed LOH status at the ATBF1-A locus, located in the 16q22 minimal region. Methods Profiles of ATBF1-A mRNA levels that we previously reported for 127 cases were used. In this study, breast cancer specimens as well as autologous blood samples were screened for LOH using 6 polymorphic microsatellite markers spanning chromosome band 16q22. For mutational analysis, we selected 12 cases and analyzed selected spots in the ATBF1-A coding region at which mutations have been frequently reported in prostate cancer. Results Forty-three cases that yielded clear profiles of LOH status at both D16S3106 and D16S3018 microsatellites, nearest to the location of the ATBF1-A gene, were regarded as informative and were classified into two groups: LOH (22 cases) and retention of heterozygosity (21 cases). Comparative assessment of the ATBF1-A mRNA levels according to LOH status at the ATBF1-A locus demonstrated no relationship between them. In the 12 cases screened for mutational analysis, there were no somatic mutations with amino acid substitution or frameshift; however, two germ line alterations with possible polymorphisms were observed. Conclusion These findings imply that ATBF1-A mRNA levels are regulated at the transcriptional stage, but not by genetic mechanisms, deletions (LOH), or mutations.</p

A summer heat wave decreases the immunocompetence of the mesograzer, Idotea baltica

Extreme events associated with global change will impose increasing stress on coastal organisms. How strong biological interactions such as the host–parasite arms-race are modulated by environmental change is largely unknown. The immune system of invertebrates, in particular phagocytosis and phenoloxidase activity response are key defence mechanisms against parasites, yet they may be sensitive to environmental perturbations. We here simulated an extreme event that mimicked the European heat wave in 2003 to investigate the effect of environmental change on the immunocompetence of the mesograzer Idotea baltica. Unlike earlier studies, our experiment aimed at simulation of the natural situation as closely as possible by using long acclimation, a slow increase in temperature and a natural community setting including the animals’ providence with natural food sources (Zostera marina and Fucus vesiculosus). Our results demonstrate that a simulated heat wave results in decreased immunocompetence of the mesograzer Idotea baltica, in particular a drop of phagocytosis by 50%. This suggests that global change has the potential to significantly affect host–parasite interactions

Altered Composition of Liver Proteasome Assemblies Contributes to Enhanced Proteasome Activity in the Exceptionally Long-Lived Naked Mole-Rat

The longest-lived rodent, the naked mole-rat (Bathyergidae; Heterocephalus glaber), maintains robust health for at least 75% of its 32 year lifespan, suggesting that the decline in genomic integrity or protein homeostasis routinely observed during aging, is either attenuated or delayed in this extraordinarily long-lived species. The ubiquitin proteasome system (UPS) plays an integral role in protein homeostasis by degrading oxidatively-damaged and misfolded proteins. In this study, we examined proteasome activity in naked mole-rats and mice in whole liver lysates as well as three subcellular fractions to probe the mechanisms behind the apparently enhanced effectiveness of UPS. We found that when compared with mouse samples, naked mole-rats had significantly higher chymotrypsin-like (ChT-L) activity and a two-fold increase in trypsin-like (T-L) in both whole lysates as well as cytosolic fractions. Native gel electrophoresis of the whole tissue lysates showed that the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous. Western blot analyses revealed that both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults. It thus appears that proteasomes in this species are primed for the efficient removal of stress-damaged proteins. Further characterization of the naked mole-rat proteasome and its regulation could lead to important insights on how the cells in these animals handle increased stress and protein damage to maintain a longer health in their tissues and ultimately a longer life

Epigenetic Activation of a Subset of mRNAs by eIF4E Explains Its Effects on Cell Proliferation

BACKGROUND: Translation deregulation is an important mechanism that causes aberrant cell growth, proliferation and survival. eIF4E, the mRNA 5′ cap-binding protein, plays a major role in translational control. To understand how eIF4E affects cell proliferation and survival, we studied mRNA targets that are translationally responsive to eIF4E. METHODOLOGY/PRINCIPAL FINDINGS: Microarray analysis of polysomal mRNA from an eIF4E-inducible NIH 3T3 cell line was performed. Inducible expression of eIF4E resulted in increased translation of defined sets of mRNAs. Many of the mRNAs are novel targets, including those that encode large- and small-subunit ribosomal proteins and cell growth-related factors. In addition, there was augmented translation of mRNAs encoding anti-apoptotic proteins, which conferred resistance to endoplasmic reticulum-mediated apoptosis. CONCLUSIONS/SIGNIFICANCE: Our results shed new light on the mechanisms by which eIF4E prevents apoptosis and transforms cells. Downregulation of eIF4E and its downstream targets is a potential therapeutic option for the development of novel anti-cancer drugs

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figuresMajor update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figuresThe preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess

Advances in structure elucidation of small molecules using mass spectrometry

The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules