Oral Treatment with Iododiflunisal Delays Hippocampal Amyloid-β Formation in a Transgenic Mouse Model of Alzheimer's Disease: A Longitudinal in vivo Molecular Imaging Study

Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein, which reduces Aβ toxicity. The TTR/Aβ interaction can be enhanced by a series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer's disease. Objective: We monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF), which acts as small-molecule chaperone of the TTR/Aβ interaction, and tolcapone, which does not behave as a small-molecule chaperone, in an animal model of Alzheimer's disease using positron emission tomography (PET). Methods: Female mice (AβPPswe/PS1A246E/TTR+/-) were divided into 3 groups (n=7 per group): IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100mg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aβ in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18F]florbetaben. Immunohistochemical analysis was performed at age=14 months. Results: Standard uptake values relative to the cerebellum (SUVr) of [18F]florbetaben in CTX and HIP of non-treated animals progressively increased from age=5 to 11 months and stabilized afterwards. In contrast, [18F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages=5 and 11 months and significantly increased at 14 months. In the tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in the non-treated group. No significant treatment effect was observed in CTX. Results from immunohistochemistry matched the in vivo data at age=14 months. Conclusion: Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions

Effects of a short-term high-nitrate diet on exercise performance

It has been reported that nitrate supplementation can improve exercise performance. Most of the studies have used either beetroot juice or sodium nitrate as a supplement; there is lack of data on the potential ergogenic benefits of an increased dietary nitrate intake from a diet based on fruits and vegetables. Our aim was to assess whether a high-nitrate diet increases nitric oxide bioavailability and to evaluate the effects of this nutritional intervention on exercise performance. Seven healthy male subjects participated in a randomized cross-over study. They were tested before and after 6 days of a high (HND) or control (CD) nitrate diet (~8.2 mmol 19day(-1) or ~2.9 mmol 19day(-1), respectively). Plasma nitrate and nitrite concentrations were significantly higher in HND (127 \ub1 64 \ub5M and 350 \ub1 120 nM, respectively) compared to CD (23 \ub1 10 \ub5M and 240 \ub1 100 nM, respectively). In HND (vs. CD) were observed: (a) a significant reduction of oxygen consumption during moderate-intensity constant work-rate cycling exercise (1.178 \ub1 0.141 vs. 1.269 \ub1 0.136 L\ub7min(-1)); (b) a significantly higher total muscle work during fatiguing, intermittent sub-maximal isometric knee extension (357.3 \ub1 176.1 vs. 253.6 \ub1 149.0 Nm\ub7s\ub7kg(-1)); (c) an improved performance in Repeated Sprint Ability test. These findings suggest that a high-nitrate diet could be a feasible and effective strategy to improve exercise performance

Computerized cognitive training and brain derived neurotrophic factor during bed rest: Mechanisms to protect individual during acute stress

Acute stress, as bed rest, was shown to increase plasma level of the neurotrophin brain-derived neurotrophic factor (BDNF) in older, but not in young adults. This increase might represent a protective mechanism towards acute insults in aging subjects. Since computerized cognitive training (CCT) is known to protect brain, herein we evaluated the effect of CCT during bed rest on BDNF, muscle mass, neuromuscular function and metabolic parameters. The subjects that underwent CCT did not show an increase of BDNF after bed rest, and showed an anti-insular modification pattern in metabolism. Neuromuscular function parameters, already shown to beneficiate from CCT, negatively correlated with BDNF in research participants undergoing CCT, while positively correlated in the control group. In conclusion, BDNF increase can be interpreted as a standardized protective mechanism taking place whenever an insult occurs; it gives low, but consistent preservation of neuromuscular function. CCT, acting as an external protective mechanism, seems to modify this standardized response, avoiding BDNF increase or possibly modifying its time course. Our results suggest the possibility of differential neuroprotective mechanisms among ill and healthy individuals, and the importance of timing in determining the effects of protective mechanism

Status Quo and Future Development of Sustainability Reporting in Central and Eastern Europe

This is the final version of the article. Available from the publisher via the DOI in this record.Reporting on corporate social responsibility (CSR) has broadened widely within the last decade. A great deal of research on sustainability reporting (SR) has focused on American and Western Europe companies. Only fragmentary studies exist that compare reporting patterns of CEE countries. There is substantial room for investigating how and to what extend companies in CEE disclose sustainability information. This study examined the reporting behaviour of the 50 largest companies in nine CEE countries and two WE countries in order to investigate the practice and divergence of sustainability reporting in CEE countries

Effects of gravitational versus iso-inertial resistance training on leg muscle force and metabolic cost of walking in healthy older adults

BACKGROUND: The purpose was to compare the effects of 8-week resistance training programs (flywheel iso-inertial [FW] versus traditional gravity-dependent resistance training [GD]) performed twice a week at the same rate of perceived exertion (RPE), on muscle force and power capacities and physical performance in healthy older participants. METHODS: Twenty-four participants were randomly assigned to either FW (male/female ratio: 7/5, age: 67.1±3.8 years) or GD (male/female ratio: 6/6, age 68.3±3.0 years) group. Knee extension maximal isometric voluntary contractions (MVC), lower limb maximal explosive power (MEP), Six-Minute Walking Test (6MWT), Timed Up-and-Go Test (TUG), metabolic cost of walking (CW) and agonist-antagonist co-contraction time (CCT) during walking were evaluated before and after training. RESULTS: absolute MEP and MEP normalized for body mass increased only in FW than GD group (+10.8% vs. +0.31%, P=0.056, respectively; +14.8% vs. +13.9%, P<0.001, respectively). Both training modalities improved MVC to a similar extent (+11.1% in FW vs. +13.4% in GD, P<0.001). Analogously, 6MWT distance increased in FW and GD (+5.2 and +5.5%, P<0.041, respectively). No effects of time and training modality were observed on the other parameters. CONCLUSIONS: The results of this study suggest that when FW and GD are administered at the same RPE with FW performed at higher movement speed in the concentric phase, both the trainings generate similar improvements in muscle strength but only the former can promote greater muscle power enhancements than GDin healthy older adults

Effects of nitrate supplementation on repeated sprint performance in healthy subjects

Introduction: Several studies have shown that short term (3-6 days) of either pharmacological (NaNO3- and KNO3-) or dietary nitrate (NO3-) supplementation reduces the whole body oxygen cost during continuous moderate-intensity exercise, improving eendurance exercise tolerance. Furthermore, The nitrate supplementation appears to be particularly effective in enhancing performance in hypoxia (Kenjale et al. 2011; Vanhatalo et al. 2011; Masschelein et al. 2012) and it may specifically improve O2 delivery and force production in type II muscle fibres (Hernandez et al.2012, Ferguson et al. 2013). During high-intensity intermittent exercise, type II muscle fibres are heavily recruited. Thus, an impaired O2delivery/O2uptake may result in the development of muscle hypoxia, as well as low muscle pH and disturbances of ionic balance. The aim of this study was to examine in vivo the effects of nitrate supplementation (by spinach juice) on intermittent high-intensity performance. Methods: Seven healthy male subjects (age: 25 \ub1 2 years) participated in a randomized double-blind placebo-controlled cross-over study. They were tested after 6 days of supplementation of either 0.5 l per day of spinach juice (5.5 mol/day nitrate) (SPINACH) or placebo (PLACEBO). Subjects performed a Repeated Sprint Ability test (RSA), which consisted in five \u201call out\u201d 6 seconds sprints on a cycloergometer (894E, Monark, Sweden) separated by 24 seconds of inactive recovery. Results: After PLACEBO, plasma [NO3-] and [NO2-] were 11 \ub1 2 \ub5M and 0.3 \ub1 0.04 \ub5M, respectively. After SPINACH, plasma [NO3-] significantly increased to 127 \ub1 24 \ub5M, whereas [NO2-] was not significantly different from PLACEBO (0.3 \ub1 0.04 \ub5M). As for RSA, there was no difference in absolute peak power output of the first two sprints between SPINACH (701.9 \ub1 8.1 and 703.9 \ub1 8.0 W) and PLACEBO (684.4 \ub1 6.7 and 690.3 \ub1 7.1 W). In contrast, the peak power output of the 3rd, 4th and 5th sprint were significantly higher in SPINACH (695.9 \ub1 8.3, 682.5 \ub1 7.6 and 666.1 \ub1 7.1 W, respectively) than in PLACEBO (663.9 \ub1 6.5, 641.2 \ub1 7.2 and 622.1 \ub1 7.2 W, respectively). Conclusion: This study has shown that short term dietary nitrate supplementation can improve repeated sprint performance in healthy subjects. This finding suggestconfirmed that NO3- may be an effective ergogenic aid not only for endurance-typeaerobic activitiesperformance but also for team sport or racquet players

Longitudinal evaluation of a novel BChE PET tracer as an early in vivo biomarker in the brain of a mouse model for Alzheimer disease

Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging. Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples. Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aβ plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age. Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aβ accumulation, suggesting that BChE is a promising early biomarker for incipient AD

Sustainability Reporting in Central and Eastern European Companies: Results of an International and Empirical Study

This collection of expert articles highlights the standards and practices concerning sustainability reporting among companies in Central and Eastern Europe (CEE). Due to the growing interest in corporate social responsibility issues, sustainability reporting has become increasingly common among businesses that claim to adhere to certain social, environmental and economic standards. While it can be observed that sustainability reporting is widely practiced in Western and Northern European countries, only few studies have been conducted on this topic in the CEE region. Drawing on a major empirical study involving researchers from 10 different CEE countries, this book addresses the status quo of sustainability reporting, outlines future prospects and provides essential recommendations for practitioners