The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis

Tofisopam is a member of the 2,3-benzodiazepine compound family which is marketed for the treatment of anxiety in some European countries. In contrast to classical 1,4-benzodiazepines, the compound does not bind to the benzodiazepine binding site of the γ-aminobutyric acid receptor and its psychopharmacological profile differs from such compounds. In addition to anxiolytic properties, antipsychotic effects are reported. We now show that tofisopam, 50 mg/kg intraperitoneally (i.p.), administered in parallel to repeated doses of dizocilpine 0.2 mg/kg i.p. can ameliorate dizocilpine-induced prolongation of immobility, which is considered to be a model of negative symptoms of psychosis. We further show that tofisopam acts as an isoenzyme-selective inhibitor of phosphodiesterases (PDEs) with highest affinity to PDE-4A1 (0.42 μM) followed by PDE-10A1 (0.92 μM), PDE-3 (1.98 μM) and PDE-2A3 (2.11 μM). The data indicate that tofisopam is an interesting candidate for the adjuvant treatment of psychosis with focus on negative symptoms. Combined partial inhibition of PDE-4 and PDE-10 as well as PDE-2 may be the underlying mechanism to this activity. Due to the good safety profile of tofisopam as evident from long-term use of this agent in patients, it may be concluded that dual or triple inhibition of PDE isoenzymes with additive or synergistic effects may be an interesting approach to pharmacological activity, resulting in active compounds with beneficial safety profile. Dose-limiting side effects such as emesis induced by selective inhibition of PDE-4 may be prevented by such strategies

L-arginine Supplementation Improves Responses to Injury and Inflammation in Dextran Sulfate Sodium Colitis

Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis (UC), results in substantial morbidity and is difficult to treat. New strategies for adjunct therapies are needed. One candidate is the semi-essential amino acid, L-arginine (L-Arg), a complementary medicine purported to be an enhancer of immunity and vitality in the lay media. Using dextran sulfate sodium (DSS) as a murine colonic injury and repair model with similarities to human UC, we assessed the effect of L-Arg, as DSS induced increases in colonic expression of the y+ cationic amino acid transporter 2 (CAT2) and L-Arg uptake. L-Arg supplementation improved the clinical parameters of survival, body weight loss, and colon weight, and reduced colonic permeability and the number of myeloperoxidase-positive neutrophils in DSS colitis. Luminex-based multi-analyte profiling demonstrated that there was a marked reduction in proinflammatory cytokine and chemokine expression with L-Arg treatment. Genomic analysis by microarray demonstrated that DSS-treated mice supplemented with L-Arg clustered more closely with mice not exposed to DSS than to those receiving DSS alone, and revealed that multiple genes that were upregulated or downregulated with DSS alone exhibited normalization of expression with L-Arg supplementation. Additionally, L-Arg treatment of mice with DSS colitis resulted in increased ex vivo migration of colonic epithelial cells, suggestive of increased capacity for wound repair. Because CAT2 induction was sustained during L-Arg treatment and inducible nitric oxide (NO) synthase (iNOS) requires uptake of L-Arg for generation of NO, we tested the effect of L-Arg in iNOS−/− mice and found that its benefits in DSS colitis were eliminated. These preclinical studies indicate that L-Arg supplementation could be a potential therapy for IBD, and that one mechanism of action may be functional enhancement of iNOS activity

Novel Echocardiographic Biomarkers in the Management of Atrial Fibrillation

Purpose of Review: Atrial fibrillation (AF) is the most common arrhythmia in adults. The number of patients with AF is anticipated to increase annually, mainly due to the aging population alongside improved arrhythmia detection. AF is associated with a significantly elevated risk of hospitalization, stroke, thromboembolism, heart failure, and all-cause mortality. Echocardiography is one of the key components of routine assessment and management of AF. Therefore, the aim of this review is to briefly summarize current knowledge on “novel” echocardiographic parameters that may be of value in the management of AF patients. Recent Findings: Novel echocardiographic biomarkers and their clinical application related to the management of AF have been taken into consideration. Both standard parameters such as atrial size and volume but also novels like atrial strain and tissue Doppler techniques have been analyzed. Summary: A number of novel echocardiographic parameters have been proven to enable early detection of left atrial dysfunction along with increased diagnosis accuracy. This concerns particularly experienced echocardiographers. Hence, these techniques might improve the prediction of stroke and thromboembolic events among AF patients and need to be further developed and disseminated. Nonetheless, even the standard imaging parameters could be of significant value and should not be discontinued in everyday clinical practice. © 2019, The Author(s)

Data Descriptor : A European Multi Lake Survey dataset of environmental variables, phytoplankton pigments and cyanotoxins

Under ongoing climate change and increasing anthropogenic activity, which continuously challenge ecosystem resilience, an in-depth understanding of ecological processes is urgently needed. Lakes, as providers of numerous ecosystem services, face multiple stressors that threaten their functioning. Harmful cyanobacterial blooms are a persistent problem resulting from nutrient pollution and climate-change induced stressors, like poor transparency, increased water temperature and enhanced stratification. Consistency in data collection and analysis methods is necessary to achieve fully comparable datasets and for statistical validity, avoiding issues linked to disparate data sources. The European Multi Lake Survey (EMLS) in summer 2015 was an initiative among scientists from 27 countries to collect and analyse lake physical, chemical and biological variables in a fully standardized manner. This database includes in-situ lake variables along with nutrient, pigment and cyanotoxin data of 369 lakes in Europe, which were centrally analysed in dedicated laboratories. Publishing the EMLS methods and dataset might inspire similar initiatives to study across large geographic areas that will contribute to better understanding lake responses in a changing environment.Peer reviewe

Selective phosphodiesterase inhibitors: a promising target for cognition enhancement

# The Author(s) 2008. This article is published with open access at Springerlink.com Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer’s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. Objective The aim of this review was to provide an overvie

Stratification strength and light climate explain variation in chlorophyll a at the continental scale in a European multilake survey in a heatwave summer

To determine the drivers of phytoplankton biomass, we collected standardized morphometric, physical, and biological data in 230 lakes across the Mediterranean, Continental, and Boreal climatic zones of the European continent. Multilinear regression models tested on this snapshot of mostly eutrophic lakes (median total phosphorus [TP] = 0.06 and total nitrogen [TN] = 0.7 mg L−1), and its subsets (2 depth types and 3 climatic zones), show that light climate and stratification strength were the most significant explanatory variables for chlorophyll a (Chl a) variance. TN was a significant predictor for phytoplankton biomass for shallow and continental lakes, while TP never appeared as an explanatory variable, suggesting that under high TP, light, which partially controls stratification strength, becomes limiting for phytoplankton development. Mediterranean lakes were the warmest yet most weakly stratified and had significantly less Chl a than Boreal lakes, where the temperature anomaly from the long-term average, during a summer heatwave was the highest (+4°C) and showed a significant, exponential relationship with stratification strength. This European survey represents a summer snapshot of phytoplankton biomass and its drivers, and lends support that light and stratification metrics, which are both affected by climate change, are better predictors for phytoplankton biomass in nutrient-rich lakes than nutrient concentrations and surface temperature

Effect of α-Tomatine and Tomatidine on the Growth and Development of the Colorado Potato Beetle (Coleoptera: Chrysomelidae): Studies Using Synthetic Diets

Glycoalkaloids are found throughout the genera Solanum (potato) and Lycopersicon (tomato). Certain glycoalkaloids, i.e. , α-tomatine, solanocardenine, and leptine, have been implicated as resistance factors to the Colorado potato beetle, Leptinotarsa decemlineata Say. The allelochemical properties of these glycoalkaloids have primarily been demonstrated by studies in p/anta, correlating Colorado potato beetle resistance with high levels of foliar glycoalkaloids: solanocardenine in S. neocardenasii, α-tomatine in S. pinnatisectum, and leptine in S. chacoense. Although the evidence that these glycoalkaloids mediate resistance is compelling, controlled analyses of Colorado potato beetle response to purified glycoalkaloids, fed to insects in synthetic diets, are necessary to characterize the allelochemic nature of these compounds. In this study, Colorado potato beetle reared on a meridic, synthetic diet supplemented with increasing concentrations of α-tomatine exhibit retarded growth and delayed development. These effects were evident throughout the insects\u27 development, from egg to prepupal stage. Toma· tidine (the aglycone of α-tomatine) has no effect on Colorado potato beetle, suggesting that the tetrasaccharide moiety of the glycoalkaloid is essential for insecticidal activity, consistent with a membrane-lytic mechanism of action