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Tweetable abstract #eHealth and #ArtificialIntelligence (AI) bring new possibilities for #HeartFailure (HF) care. We elaborate on potential benefits of #AI in #HF and highlight important bottlenecks for its implementation. #Editorial #Cardiology.

The foundation of how students usually learn is laid early in their academic lives. However, many or even most students do not primarily rely on those learning strategies that are most favorable from a scientific point of view. To change students’ learning behavior when they start their university education, we developed a computer-based adaptive learning environment to train favorable learning strategies and change students’ habits using them. This learning environment pursues three main goals: acquiring declarative and conditional knowledge about learning strategies, consolidating that knowledge, and applying these learning strategies in practice. In this report, we describe four experimental studies conducted to optimize this learning environment ( n = 336). With those studies, we improved the learning environment with respect to how motivating it is, investigated an efficient way to consolidate knowledge, and explored how to facilitate the formation of effective implementation intentions for applying learning strategies and changing learning habits. Our strategy-training module is implemented in the curriculum for freshman students at the Department of Psychology, University of Freiburg (Germany). Around 120 students take part in our program every year. An open version of this training intervention is freely available to everyone.

A set of 12 first-in-class, biobased pyrazine-containing polyesters was synthesized based on dimethylpyrazine dipropionic acid. These new diacid monomers were obtained from underutilized nitrogen-rich biomass. The polyester materials were synthesized via a two-step melt transesterification-polycondensation procedure with molecular weights between 12 300 and 47 500 g/mol and dispersities between 1.9 and 2.3. Six of the obtained polymers were amorphous and six were semi-crystalline. The thermal properties of the materials were studied; thermal degradation was found to take place at the monomer degradation temperature. The effect of methyl groups on the glass transition temperature was investigated, and the materials were found to behave mostly as aliphatic polyesters in this regard. The melting points of the methyl-substituted polyesters were found to be high and within the range of those of current high-performance polyesters. These materials are thus a welcome addition to current biobased polyesters.

Anthracyclines, including doxorubicin, idarubicin, and epirubicin, are common antitumor drugs as well as well-known cardiotoxic agents. This study analyzed the proteomics alteration in cardiac tissues caused by these 3 anthracyclines analogs. The in vitro human cardiac microtissues were exposed to drugs in 2 weeks; the proteomic data were measured at 7 time points. The heart biopsy data were collected from heart failure patients, in which some patients underwent anthracycline treatment. The anthracyclines-affected proteins were separately identified in the in vitro and in vivo dataset using the WGCNA method. These proteins engage in different cellular pathways including translation, metabolism, mitochondrial function, muscle contraction, and signaling pathways. From proteins detected in 2 datasets, a protein-protein network was established with 4 hub proteins, and 7 weighted proteins from both cardiac microtissue and human biopsies data. These 11 proteins, which involve in mitochondrial functions and the NF-κB signaling pathway, could provide insights into the anthracycline toxic mechanism. Some of them, such as HSPA5, BAG3, and SH3BGRL, are cardiac therapy targets or cardiotoxicity biomarkers. Other proteins, such as ATP5F1B and EEF1D, showed similar responses in both the in vitro and in vivo data. This suggests that the in vitro outcomes could link to clinical phenomena in proteomic analysis.

BACKGROUND: The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure.METHODS: A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class >= II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA >= III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index.RESULTS: Sixty-one percent of patients had a Clinical Congestion Index >= 3 at baseline, which decreased to 18% at month 18. During the median [interquartile range] follow-up of 27.2 [14.3-39.8] months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and >= 3 at inclusion, respectively, died (P CONCLUSIONS: The extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure. (C) 2019 Elsevier Inc. All rights reserved.

International audience; Introduction: Combining exercise training with hypoxic exposure has been recently proposed as a new therapeutic strategy to improve health status of obese individuals. Whether hypoxic exercise training (HET) provides greater benefits regarding body composition and cardiometabolic parameters than normoxic exercise training (NET) remains, however, unclear. We hypothesized that HET would induce greater improvement in exercise capacity and health status than NET in overweight and obese individuals.Methods: Twenty-three subjects were randomized into 8-wk HET (11 men and 1 woman; age, 52 ± 12 yr; body mass index, 31.2 ± 2.4 kg·m) or NET (eight men and three women; age, 56 ± 11 yr; body mass index, 31.8 ± 3.2 kg·m) programs (three sessions per week; constant-load cycling at 75% of maximal heart rate; target arterial oxygen saturation for HET 80%, FiO2 ~0.13, i.e., ~3700 m a.s.l.). Before and after the training programs, the following evaluations were performed: incremental maximal and submaximal cycling tests, measurements of pulse-wave velocity, endothelial function, fasting glucose, insulin and lipid profile, blood NO metabolites and oxidative stress, and determination of body composition by magnetic resonance imaging.Results: Peak oxygen consumption and maximal power output increased significantly after HET only (peak oxygen consumption HET + 10% ± 11% vs NET + 1% ± 10% and maximal power output HET + 11% ± 7% vs NET + 3% ± 10%, P < 0.05). Submaximal exercise responses improved similarly after HET and NET. Except diastolic blood pressure which decreased significantly after both HET and NET, no change in vascular function, metabolic status and body composition was observed after training. Hypoxic exercise training only increased nitrite and reduced superoxide dismutase concentrations.Conclusions: Combining exercise training and hypoxic exposure may provide some additional benefits to standard NET for obese individual health status.

Background Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer’s disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown. Methods This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation. Results Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau. Conclusions Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions. Electronic supplementary material The online version of this article (10.1186/s13024-019-0326-4) contains supplementary material, which is available to authorized users.

Considering genetic variability in population studies focusing on the health risk assessment of exposure to environmental carcinogens may provide improved insights in individual environmental cancer risks. Therefore, the current study aims to determine the impact of genetic polymorphisms on the relationship between exposure and gene expression, by identifying exposure-dependently coregulated genes and genetic pathways. Statistical analysis based on mixed models, was performed to relate gene expression data from 134 subjects to exposure measurements of multiple carcinogens, 28 polymorphisms, age, sex and biomarkers of cancer risk. We evaluated the combined exposure to cadmium, lead, polychlorinated biphenyls, p, p'-dichlorodiphenyldichloroethylene, hexachlorobenzene and 1-OH-pyrene, and the outcome was biologically interpreted by using ConsensusPathDB, thereby focusing on carcinogenesis-related pathways. We found generic and carcinogenesis-related pathways deregulated in both sexes, but males showed a stronger transcriptome response than females. We highlighted NOTCH1, CBR1, ITGB3, ITGA4, ADI1, HES1, NCOA2 and SMARCA2 in view of their direct link with cancer development. Two of these, NOTCH1 and ITGB3, are also known to respond to PCBs and cadmium chloride exposure in rodents and to lead in humans. Subjects carrying a high number of risk alleles appear more responsive to combined carcinogen exposure with respect to the induced expression of some of these cancer-related genes, which may be indicative of increased cancer risk as a consequence of environmental factors.

Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.

Motivation: Comparing time courses of gene expression with time courses of phenotypic data may provide new insights in cellular mechanisms. In this study, we compared the performance of five pattern recognition methods with respect to their ability to relate genes and phenotypic data: one classical method (k-means) and four methods especially developed for time series [Short Time-series Expression Miner (STEM), Linear Mixed Model mixtures, Dynamic Time Warping for -Omics and linear modeling with R/Bioconductor limma package]. The methods were evaluated using data available from toxicological studies that had the aim to relate gene expression with phenotypic endpoints (i.e. to develop biomarkers for adverse outcomes). Additionally, technical aspects (influence of noise, number of time points and number of replicates) were evaluated on simulated data. Results: None of the methods outperforms the others in terms of biology. Linear modeling with limma is mostly influenced by noise. STEM is mostly influenced by the number of biological replicates in the dataset, whereas k-means and linear modeling with limma are mostly influenced by the number of time points. In most cases, the results of the methods complement each other. We therefore provide recommendations to integrate the five methods. Availability: The Matlab code for the simulations performed in this research is available in the Supplementary Data (Word file). The microarray data analysed in this paper are available at ArrayExpress (E-TOXM-22 and E-TOXM-23) and Gene Expression Omnibus (GSE39291). The phenotypic data are available in the Supplementary Data (Excel file). Links to the pattern recognition tools compared in this paper are provided in the main text. Contact: d.hendrickx@maastrichtuniversity.nl Supplementary information: Supplementary data are available at Bioinformatics online.

Chemical carcinogenesis can be induced by genotoxic (GTX) or non-genotoxic (NGTX) carcinogens. GTX carcinogens have a well-described mode of action. However, the complex mechanisms by which NGTX carcinogens act are less clear and may result in conflicting results between species [e.g. Wy-14,643 (Wy)]. We hypothesise that common microRNA response pathways exist for each class of carcinogenic agents. Therefore, this study compares and integrates mRNA and microRNA expression profiles following short term acute exposure (24 and 48h) to three GTX [aflatoxin B1 (AFB1), benzo[a]pyrene (BaP) and cisplatin (CisPl)] or three NGTX (2,3,7,8-tetrachloordibenzodioxine (TCDD), cyclosporine A (CsA) and Wy) carcinogens in primary mouse hepatocytes. Discriminative gene sets, microRNAs (not for 24h) and processes were identified following 24 and 48h of exposure. From the three discriminative microRNAs found following 48h of exposure, mmu-miR-503-5p revealed to have an interaction with mRNA target gene cyclin D2 (Ccnd2 - 12444) which was involved in the discriminative process of p53 signalling and metabolism. Following exposure to NGTX carcinogens Mmu-miR-503-5p may have an oncogenic function by stimulating Ccnd2 possibly leading to a tumourigenic cell cycle progression. By contrast, after GTX carcinogen exposure it may have a tumour-suppressive function (repressing Ccnd2) leading to cell cycle arrest and to increased DNA repair activities. In addition, compound-specific microRNA-mRNA interactions [mmu-miR-301b-3p-Papss2 (for AFB1), as well as mmu-miR-29b-3p-Col4a2 and mmu-miR-24-3p-Flna (for BaP)] were found to contribute to a better understanding of microRNAs in cell cycle arrest and the impairment of the DNA damage repair, an important hallmark of GTX-induced carcinogenesis. Overall, our results indicate that microRNAs represent yet another relevant intracellular regulatory level in chemical carcinogenesis.

Acetaminophen (APAP) overdosage results in hepatotoxicity, but the underlying molecular mechanisms are still not completely understood. In the current study, we focused on mitochondrial-specific oxidative liver injury induced by APAP exposure. Owning to genetic polymorphisms in the CYP2E1 gene or varying inducibility by xenobiotics, the CYP2E1 mRNA level and protein activity vary extensively among individuals. As CYP2E1 is a known ROS generating enzyme, we chose HepG2 to minimize CYP2E1-induced ROS formation, which will help us better understand the APAP induced mitochondrial-specific hepatotoxicity in a subpopulation with low CYP2E1 activity. HepG2 cells were exposed to a low and toxic dose (0.5 and 10mM) of APAP and analyzed at four time points for genome-wide gene expression. Mitochondria were isolated and electron spin resonance spectroscopy was performed to measure the formation of mitochondrial ROS. The yield of ATP was measured to confirm the impact of the toxic dose of APAP on cellular energy production. Our results indicate that 10mM APAP significantly influences the expression of mitochondrial protein-encoding genes in association with an increase in mitochondrial ROS formation. Additionally, 10mM APAP affects the expression of genes encoding the subunits of electron transport chain (ETC) complexes, which may alter normal mitochondrial functions by disrupting the assembly, stability, and structural integrity of ETC complexes, leading to a measurable depletion of ATP, and cell death. The expression of mitochondrium-specific antioxidant enzyme, SOD2, is reduced which may limit the ROS scavenging ability and cause imbalance of the mitochondrial ROS homeostasis. Overall, transcriptome analysis reveals the molecular processes involved in the observed APAP-induced increase of mitochondrial ROS formation and the associated APAP-induced oxidative stress.

Background: Diagnostic biomarkers for heart failure (HF) such as the natriuretic peptides (NPs) are widely used but have limitations. Innovative biomarkers could provide improved diagnostic performance. Methods: We launched a prospective case-control proteomic study and investigated for polypeptides specific to HF through a capillary electrophoresis-mass spectrometry (CE-MS) proteomic analysis. The putative biomarker was identified by Orbitrap liquid chromatography-MS, validated by western blot, then by ELISA using plasmas from multicentric international cohorts. A rat model of HF was tested for biomarker expression levels. Results: We identified insulin like growth factor binding protein 2 (IGFBP2) as a new diagnostic biomarker for HF with a high sensitivity and specificity (AUC = 0.93; 95% CI, 0.89-0.96; p

The application of transcriptome analyses in molecular epidemiology studies has become a promising tool in order to evaluate the impact of environmental exposures. These analyses have a great value in establishing the exposome, the totality of human exposures, both by identifying the chemical nature of the exposures and the induced molecular responses. Transcriptomic signatures can be regarded as biomarker of exposure as well as markers of effect which reflect the interaction between individual genetic background and exposure levels. However, the biological interpretation of modulated gene expression profiles is a challenging task and translating affected molecular pathways into risk assessment, for instance in terms of cancer promoting or disease preventing responses, is a far from standardised process. Here, we describe the in-depth analyses of the gene expression responses in a human dietary intervention in which the interaction between genotype and exposure to a blueberry-apple juice containing a complex mixture of phytochemicals is investigated. We also describe how data on differences in genetic background combined with different effect markers can provide a better understanding of gene-environment interactions. Pathway analyses of differentially expressed genes in combination with gene were used to identify complex but strong changes in several biological processes like immune response, cell adhesion, lipid metabolism and apoptosis. These observed changes may lead to upgraded growth control, induced immunity, reduced platelet aggregation and activation, diminished production of reactive oxidative species by platelets, blood glucose homeostasis, regulation of blood lipid levels and increased apoptosis. Our findings demonstrate that applying transcriptomics to well-controlled human dietary intervention studies can provide insight into mechanistic pathways involved in disease prevention by dietary factors.

Individuals who have experienced a stroke need to (re) learn motor skills. Analogy learning has been shown to facilitate motor learning in sports and may also be an attractive alternative to traditional approaches in therapy. The aim of this study was to assess the feasibility and utility of analogies to improve the walking performance in long-term stroke survivors. Three men aged 76, 87 and 70 years who were 6, 1 and 3 years poststroke, respectively, presented with different walking deficits. An analogy, targeted at improving the walking performance was designed with the help of each participant. During a 3-week intervention period, the analogy was practiced once weekly under supervision and daily at home. To assess feasibility, a structured interview was conducted at the end of the intervention period. To assess utility, walking performance was assessed using the 10-Metre Walking Test. All three participants were supportive of the feasibility and benefits of analogy learning. Two of the participants had a meaningful improvement on the 10-Metre Walking Test (0.1 and 0.3 m/s). The third participant did not improve most likely because of medication issues during the week of the retest. Developing analogies in therapy is a creative and challenging process, as analogies must not only guide the correct movement pattern, but also be meaningful to the individual. However, as participants were supportive of the use of analogies, and positive trends were seen in walking speed it seems worthwhile to pursue the use of analogies in future research. (C) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

One of the main challenges of toxicology is the accurate prediction of compound carcinogenicity. The default test model for assessing chemical carcinogenicity, the 2 year rodent cancer bioassay, is currently criticized because of its limited specificity. With increased societal attention and new legislation against animal testing, toxicologists urgently need an alternative to the current rodent bioassays for chemical cancer risk assessment. Toxicogenomics approaches propose to use global high-throughput technologies (transcriptomics, proteomics and metabolomics) to study the toxic effect of compounds on a biological system. Here, we demonstrate the improvement of transcriptomics assay consisting of primary human hepatocytes to predict the putative liver carcinogenicity of several compounds by applying the connectivity map methodology. Our analyses underline that connectivity mapping is useful for predicting compound carcinogenicity by connecting in vivo expression profiles from human cancer tissue samples with in vitro toxicogenomics data sets. Furthermore, the importance of time and dose effect on carcinogenicity prediction is demonstrated, showing best prediction for low dose and 24 h exposure of potential carcinogens.

Purpose. The goal of the present study was to analyze long-term results of fractionated stereotactic radiotherapy (SRT) in patients with a meningioma. Methods and materials. A total of 72 patients treated between 1996 and 2008 in MAASTRO clinic (n = 45) and University Hospital Zurich (n = 27) were included. SRT was given as primary treatment (n = 46), postoperatively (n = 19) or at recurrence (n = 7); 49 tumours (68%) were located in the skull base. Median total dose was 54 Gy. Results. Median follow-up was 4.13 years (range 0.66-11 years). The 3- and 5-year overall survival were 92 and 79% for grade 0 and I meningioma. Progression-free survival for grade 0 and I was 95% at 3 and 5 years, and 40% for grade II and III at 3 years. In 98.4% of patients, clinical symptoms were stable or improved. The majority of symptoms improved within 24 months after SRT. Local control is significantly better if patients are irradiated immediately after diagnosis compared to a watchful waiting policy (p = 0.017). Grade IV toxicity was low (4.2%, n = 3) Conclusion. SRT is an effective treatment with high local and clinical control. Early SRT resulted in better outcome than late treatment at progression.

Microarray-based transcriptomic analysis has been demonstrated to hold the opportunity to study the effects of human exposure to, e.g., chemical carcinogens at the whole genome level, thus yielding broad-ranging molecular information on possible carcinogenic effects. Since genes do not operate individually but rather through concerted interactions, analyzing and visualizing networks of genes should provide important mechanistic information, especially upon connecting them to functional parameters, such as those derived from measurements of biomarkers for exposure and carcinogenic risk. Conventional methods such as hierarchical clustering and correlation analyses are frequently used to address these complex interactions but are limited as they do not provide directional causal dependence relationships. Therefore, our aim was to apply Bayesian network inference with the purpose of phenotypic anchoring of modified gene expressions. We investigated a use case on transcriptomic responses to cigarette smoking in humans, in association with plasma cotinine levels as biomarkers of exposure and aromatic DNA-adducts in blood cells as biomarkers of carcinogenic risk. Many of the genes that appear in the Bayesian networks surrounding plasma cotinine, and to a lesser extent around aromatic DNA-adducts, hold biologically relevant functions in inducing severe adverse effects of smoking. In conclusion, this study shows that Bayesian network inference enables unbiased phenotypic anchoring of transcriptomics responses. Furthermore, in all inferred Bayesian networks several dependencies are found which point to known but also to new relationships between the expression of specific genes, cigarette smoke exposure, DNA damaging-effects, and smoking-related diseases, in particular associated with apoptosis, DNA repair, and tumor suppression, as well as with autoimmunity.

Dietary nitrate (NO3(-)) supplementation has been proposed as an emerging treatment strategy for type 2 diabetes. We hypothesized that ingestion of a single bolus of dietary NO3(-) ingestion improves oral glucose tolerance in patients with type 2 diabetes. Seventeen men with type 2 diabetes (glycated hemoglobin, 7.3% ± 0.2%) participated in a randomized crossover experiment. The subjects ingested a glucose beverage 2.5 hours after consumption of either sodium NO3(-) (0.15 mmol NaNO3(-) · kg(-1)) or a placebo solution. Venous blood samples were collected before ingestion of the glucose beverage and every 30 minutes thereafter during a 2-hour period to assess postprandial plasma glucose and insulin concentrations. The results show that plasma NO3(-) and nitrite levels were increased after NaNO3(-) as opposed to placebo ingestion (treatment-effect, P = .001). Despite the elevated plasma NO3(-) and nitrite levels, ingestion of NaNO3(-) did not attenuate the postprandial rise in plasma glucose and insulin concentrations (time × treatment interaction, P = .41 for glucose, P = .93 for insulin). Despite the lack of effect on oral glucose tolerance, basal plasma glucose concentrations measured 2.5 hours after NaNO3(-) ingestion were lower when compared with the placebo treatment (7.5 ± 0.4 vs 8.3 ± 0.4 mmol/L, respectively; P = .04). We conclude that ingestion of a single dose of dietary NO3(-) does not improve subsequent oral glucose tolerance in patients with type 2 diabetes.

IN BRIEF The introduction of continuous glucose monitoring (CGM) several years ago enabled researchers to investigate the impact of exercise strategies on 24-hour glycemic control. Such unique information on the glucoregulatory properties of exercise will ultimately lead to more effective exercise programs to prevent and treat type 2 diabetes. This article reviews the role of exercise and physical activity in the treatment of type 2 diabetes, complemented by recent data obtained by CGM. Although exercise is an important treatment strategy to improve long-term glycemic control in people with type 2 diabetes, the impact of exercise on 24-hour glycemic control has remained largely unexplored. The introduction of continuous glucose monitoring (CGM) several years ago enabled researchers to investigate the impact of exercise strategies on 24-hour glycemic control. Such unique information on the glucoregulatory properties of exercise will ultimately lead to more effective exercise intervention programs to prevent and treat type 2 diabetes. This article reviews the role of exercise and physical activity in the treatment of type 2 diabetes, complemented by recent data obtained by CGM. Based on current evidence, practical implications for the prescription of exercise in the treatment of type 2 diabetes are discussed.

Background: Serotonin (5-HT) has long been implied in the pathophysiology of Parkinson's disease (PD). In addition, the 5-HT2A receptor is associated with the regulation of motor function and mood. Objective: To assess regional 5-HT2A receptor expression in unmedicated patients with de novo PD. Methods: Eight de novo, drug naive patients with PD and eight healthy control subjects underwent a single photon emission computed tomography (SPECT) scan with the highly selective 5-HT2A radioligand I-123-5-I-R91150. Results: In de novo PD patients 5-HT2A receptor binding was significantly reduced in the anterior striatum and the premotor cortex in PD patients compared to controls. In addition, occipital binding was elevated in PD patients. No changes in 5-HT2A receptor binding were found in the prefrontal and parietal cortex. Conclusion: In de novo PD patients, 5-HT2A receptor expression is changed in key areas of the basal ganglia-thalamocortical motor circuit and occipital cortex. This suggests altered 5-HT neurotransmission to contribute to development of PD motor and non-motor symptoms.

In evaluating the mechanisms of acetaminophen hepatotoxicity in experimental systems, it is critical to keep in mind the relevance of the model system for humans. Important aspects of the human toxicity include formation of a reactive metabolite by the cytochrome P450 system and protein adduct formation, which is thought to trigger mitochondrial dysfunction and oxidant stress ultimately causing necrotic cell death. If models that miss critical parts of this well-established mechanism are used, the relevance of the new information for the human toxicity has to be questioned. Therefore, we feel it is necessary to express our concern regarding the recent publication by Jiang et al. (2015).

International audience; Neuromuscular function can change under different conditions such as ageing, training/detraining, long-term spaceflight, environmental conditions (e.g. hypoxia, hyperthermia), disease, therapy/retraining programs and also with the appearance of fatigue. Neuromuscular fatigue can be defined as any decrease in maximal voluntary strength or power. There is no standardized method to induce fatigue and various protocols involving different contraction patterns (such as sustained or intermittent submaximal isometric or dynamic contractions on isokinetic or custom chairs) have been used. Probably due to lack of motivation/cooperation, results of fatigue resistance protocols are more variable in patients than in healthy subjects. Magnetic and electrical stimulation techniques allow non-invasive assessment of central and peripheral origins of fatigue. They also allow investigation of different types of muscle fatigue when combining various types of stimulation with force/surface EMG measurements. Since maximal electrical stimuli may be uncomfortable or even sometimes painful, several alternative methods have been recently proposed: submaximal muscle stimulation, low/high-frequency paired pulses instead of tetanic stimuli and the use of magnetic stimulation at the peripheral level.