Showing papers by "University of Modena and Reggio Emilia published in 2018"

Minimal information for studies of extracellular vesicles 2018 (MISEV2018) : a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer

Abstract: PurposeNivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported.Patients and MethodsPatients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR.ResultsOf 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reac...

EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice.

Abstract: To develop evidence-based recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV) including giant cell arteritis (GCA) and Takayasu arteritis (TAK). European League Against Rheumatism (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound, MRI, CT and [18F]-fluorodeoxyglucose positron emission tomography (PET) in LVV. Based on evidence and expert opinion, the task force consisting of 20 physicians, healthcare professionals and patients from 10 EULAR countries developed recommendations, with consensus obtained through voting. The final level of agreement was voted anonymously. A total of 12 recommendations have been formulated. The task force recommends an early imaging test in patients with suspected LVV, with ultrasound and MRI being the first choices in GCA and TAK, respectively. CT or PET may be used alternatively. In case the diagnosis is still in question after clinical examination and imaging, additional investigations including temporal artery biopsy and/or additional imaging are required. In patients with a suspected flare, imaging might help to better assess disease activity. The frequency and choice of imaging modalities for long-term monitoring of structural damage remains an individual decision; close monitoring for aortic aneurysms should be conducted in patients at risk for this complication. All imaging should be performed by a trained specialist using appropriate operational procedures and settings. These are the first EULAR recommendations providing up-to-date guidance for the role of imaging in the diagnosis and monitoring of patients with (suspected) LVV.

Predicting Human Eye Fixations via an LSTM-based Saliency Attentive Model.

Abstract: Data-driven saliency has recently gained a lot of attention thanks to the use of convolutional neural networks for predicting gaze fixations. In this paper, we go beyond standard approaches to saliency prediction, in which gaze maps are computed with a feed-forward network, and present a novel model which can predict accurate saliency maps by incorporating neural attentive mechanisms. The core of our solution is a convolutional long short-term memory that focuses on the most salient regions of the input image to iteratively refine the predicted saliency map. In addition, to tackle the center bias typical of human eye fixations, our model can learn a set of prior maps generated with Gaussian functions. We show, through an extensive evaluation, that the proposed architecture outperforms the current state-of-the-art on public saliency prediction datasets. We further study the contribution of each key component to demonstrate their robustness on different scenarios.

2018 update of the EULAR recommendations for the management of Behçet’s syndrome

Abstract: Several new treatment modalities with different mechanisms of action have been studied in patients with Behcet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.

Plant Growth Promoting and Biocontrol Activity of Streptomyces spp. as Endophytes.

Abstract: There has been many recent studies on the use of microbial antagonists to control diseases incited by soilborne and airborne plant pathogenic bacteria and fungi, in an attempt to replace existing methods of chemical control and avoid extensive use of fungicides, which often lead to resistance in plant pathogens. In agriculture, plant growth-promoting and biocontrol microorganisms have emerged as safe alternatives to chemical pesticides. Streptomyces spp. and their metabolites may have great potential as excellent agents for controlling various fungal and bacterial phytopathogens. Streptomycetes belong to the rhizosoil microbial communities and are efficient colonizers of plant tissues, from roots to the aerial parts. They are active producers of antibiotics and volatile organic compounds, both in soil and in planta, and this feature is helpful for identifying active antagonists of plant pathogens and can be used in several cropping systems as biocontrol agents. Additionally, their ability to promote plant growth has been demonstrated in a number of crops, thus inspiring the wide application of streptomycetes as biofertilizers to increase plant productivity. The present review highlights Streptomyces spp.-mediated functional traits, such as enhancement of plant growth and biocontrol of phytopathogens.

Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis

Abstract: Summary Background In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. Methods Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. Findings We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (p interactions >0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI −2·71 to −2·15], p vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p Interpretation Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance. Funding National Institute for Health Research.

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Abstract: Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors.

Abstract: CD8+ T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined By high-dimensional single cell analysis of millions of CD8+ T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood Besides exhausted and activated cells, we identified CXCR5+ TIM-3- CD8+ T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome Ex vivo, CXCR5+ TIM-3- CD8+ T cells displayed enhanced self-renewal and multipotency compared with more differentiated subsets and were largely polyfunctional Analysis of inhibitory and costimulatory receptors revealed PD-1, TIGIT, and CD27 as possible targets of immunotherapy We thus demonstrate a hierarchy of differentiation in the context of T cell exhaustion in human cancer similar to that of chronically infected mice, which is further shown to disappear with disease progression

Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer.

Abstract: In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB1 and CB2. CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ9-THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa, since it contains only few levels of Δ9-THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ9-THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ9-THC deprived hemp.

Cardiac resynchronization therapy: a comparison among left ventricular bipolar, quadripolar and active fixation leads.

Abstract: We evaluated the performance of 3 different left ventricular leads (LV) for resynchronization therapy: bipolar (BL), quadripolar (QL) and active fixation leads (AFL). We enrolled 290 consecutive CRTD candidates implanted with BL (n = 136) or QL (n = 97) or AFL (n = 57). Over a minimum 10 months follow-up, we assessed: (a) composite technical endpoint (TE) (phrenic nerve stimulation at 8 V@0.4 ms, safety margin between myocardial and phrenic threshold 15%). Baseline characteristics of the 3 groups were similar. At follow-up the incidence of TE was 36.3%, 14.3% and 19.9% in BL, AFL and QL, respectively (p < 0.01). Moreover, the incidence of RR was 56%, 64% and 68% in BL, AFL and QL respectively (p = 0.02). There were no significant differences in CE (p = 0.380). On a multivariable analysis, “non-BL leads” was the single predictor of an improved clinical outcome. QL and AFL are superior to conventional BL by enhancing pacing of the target site: AFL through prevention of lead dislodgement while QL through improved management of phrenic nerve stimulation.

Latent Space Autoregression for Novelty Detection

Abstract: Novelty detection is commonly referred to as the discrimination of observations that do not conform to a learned model of regularity. Despite its importance in different application settings, designing a novelty detector is utterly complex due to the unpredictable nature of novelties and its inaccessibility during the training procedure, factors which expose the unsupervised nature of the problem. In our proposal, we design a general framework where we equip a deep autoencoder with a parametric density estimator that learns the probability distribution underlying its latent representations through an autoregressive procedure. We show that a maximum likelihood objective, optimized in conjunction with the reconstruction of normal samples, effectively acts as a regularizer for the task at hand, by minimizing the differential entropy of the distribution spanned by latent vectors. In addition to providing a very general formulation, extensive experiments of our model on publicly available datasets deliver on-par or superior performances if compared to state-of-the-art methods in one-class and video anomaly detection settings. Differently from prior works, our proposal does not make any assumption about the nature of the novelties, making our work readily applicable to diverse contexts.

Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4.

Abstract: Cancer cells rely on dysregulated gene expression This establishes specific transcriptional addictions that may be therapeutically exploited Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology

Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations

Abstract: Recent evidence indicates synaptic dysfunction as an early mechanism affected in neuroinflammatory diseases, such as multiple sclerosis, which are characterized by chronic microglia activation. However, the mode(s) of action of reactive microglia in causing synaptic defects are not fully understood. In this study, we show that inflammatory microglia produce extracellular vesicles (EVs) which are enriched in a set of miRNAs that regulate the expression of key synaptic proteins. Among them, miR-146a-5p, a microglia-specific miRNA not present in hippocampal neurons, controls the expression of presynaptic synaptotagmin1 (Syt1) and postsynaptic neuroligin1 (Nlg1), an adhesion protein which play a crucial role in dendritic spine formation and synaptic stability. Using a Renilla-based sensor, we provide formal proof that inflammatory EVs transfer their miR-146a-5p cargo to neuron. By western blot and immunofluorescence analysis we show that vesicular miR-146a-5p suppresses Syt1 and Nlg1 expression in receiving neurons. Microglia-to-neuron miR-146a-5p transfer and Syt1 and Nlg1 downregulation do not occur when EV-neuron contact is inhibited by cloaking vesicular phosphatidylserine residues and when neurons are exposed to EVs either depleted of miR-146a-5p, produced by pro-regenerative microglia, or storing inactive miR-146a-5p, produced by cells transfected with an anti-miR-146a-5p. Morphological analysis reveals that prolonged exposure to inflammatory EVs leads to significant decrease in dendritic spine density in hippocampal neurons in vivo and in primary culture, which is rescued in vitro by transfection of a miR-insensitive Nlg1 form. Dendritic spine loss is accompanied by a decrease in the density and strength of excitatory synapses, as indicated by reduced mEPSC frequency and amplitude. These findings link inflammatory microglia and enhanced EV production to loss of excitatory synapses, uncovering a previously unrecognized role for microglia-enriched miRNAs, released in association to EVs, in silencing of key synaptic genes.

Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting

Abstract: Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.

On the effectiveness of machine and deep learning for cyber security

Abstract: Machine learning is adopted in a wide range of domains where it shows its superiority over traditional rule-based algorithms. These methods are being integrated in cyber detection systems with the goal of supporting or even replacing the first level of security analysts. Although the complete automation of detection and analysis is an enticing goal, the efficacy of machine learning in cyber security must be evaluated with the due diligence. We present an analysis, addressed to security specialists, of machine learning techniques applied to the detection of intrusion, malware, and spam. The goal is twofold: to assess the current maturity of these solutions and to identify their main limitations that prevent an immediate adoption of machine learning cyber detection schemes. Our conclusions are based on an extensive review of the literature as well as on experiments performed on real enterprise systems and network traffic.

Regional variation of Guillain-Barre syndrome

Abstract: Guillain-Barre syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barre syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barre Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barre syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barre syndrome was observed in patients from all countries participating in the International Guillain-Barre Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barre syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barre overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barre syndrome.

Selenium exposure and the risk of type 2 diabetes: a systematic review and meta-analysis

Abstract: In 2007, supplementation with the trace element selenium in a trial was unexpectedly found to be associated with an excess risk of type 2 diabetes. Given the concerns raised by these findings and the large number of recent studies on this topic, we reviewed the available literature with respect to this possible association. In this paper, we assessed the results of both experimental and nonexperimental epidemiologic studies linking selenium with type 2 diabetes incidence. Through a systematic literature search, we retrieved 50 potentially eligible nonexperimental studies and 5 randomized controlled trials published through June 11, 2018. To elucidate the possible dose–response relation, we selected for further analysis those studies that included multiple exposure levels and serum or plasma levels. We computed a pooled summary risk ratio (RR) of diabetes according to selenium exposure in these studies. We also computed a RR for diabetes incidence following supplementation with 200 µg/day of selenium compared with placebo in trials. In the nonexperimental studies, we found a direct relation between selenium exposure and risk of diabetes, with a clear and roughly linear trend in subjects with higher plasma or serum selenium levels, with RR at 140 µg/L of selenium exposure compared with a referent category of < 45 µg/L equal to 3.6 [95% confidence interval (CI) 1.4–9.4]. A dose–response meta-analysis focusing on studies with direct assessment of dietary selenium intake showed a similar trend. In experimental studies, selenium supplementation increased the risk of diabetes by 11% (RR 1.11, 95% CI 1.01–1.22) compared with the placebo-allocated participants, with a higher RR in women than in men. Overall, results from both nonexperimental and experimental studies indicate that selenium may increase the risk of type 2 diabetes across a wide range of exposure levels. The relative increase in risk is small but of possible public health importance because of the high incidence of diabetes and the ubiquity of selenium exposure.

Environmental Selenium and Human Health: an Update

Abstract: Selenium, a trace element, is ubiquitous in the environment. The main source of human exposure is diet. Despite its nutritional benefits, it is one of the most toxic naturally occurring elements. Selenium deficiency and overexposure have been associated with adverse health effects. Its level of toxicity may depend on its chemical form, as inorganic and organic species have distinct biological properties. Nonexperimental and experimental studies have generated insufficient evidence for a role of selenium deficiency in human disease, with the exception of Keshan disease, a cardiomyopathy. Conversely, recent randomized trials have indicated that selenium overexposure is positively associated with type 2 diabetes and high-grade prostate cancer. In addition, a natural experiment has suggested an association between overexposure to inorganic hexavalent selenium and two neurodegenerative diseases, amyotrophic lateral sclerosis and Parkinson’s disease. Risk assessments should be revised to incorporate the results of studies demonstrating toxic effects of selenium. Additional observational studies and secondary analyses of completed randomized trials are needed to address the uncertainties regarding the health risks of selenium exposure.

Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors.

Abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. Numerous studies have shown that the expression and/or function of nAChRs is compromised in many neurological and psychiatric diseases. Furthermore, recent studies have shown that neuronal nAChRs are found in a large number of nonneuronal cell types including endothelial cells, glia, immune cells, lung epithelia and cancer cells where they regulate cell differentiation, proliferation and inflammatory responses. The aim of this review is to describe the most recent findings concerning the structure and function of native nAChRs inside and outside the nervous system.

Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP).

Abstract: Colentina University Hospital, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania; University Hospital of Sabadell (University Autonoma of Barcelona), Plaça Cı́vica, Campus de la UAB, Barcelona, Spain; Oslo University Hospital Ullevål, Norway; Institute of Clinical Sciences, University of Oslo, Søsterhjemmet, Oslo, Norway; Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy; Universitaetsmedizin Mannheim, Medizinische Klinik, Mannheim, Germany; Department of Medical Sciences, University of Turin, Citta’ della Salute e della Scienza Hospital, Turin, Italy; Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Cardiology, Eskisehir Osmangazi University, Büyükdere Mahallesi, Odunpazarı/Eskişehir, Turkey; Molecular and Clinical Sciences Research Institute, St. George’s, University of London, London, UK; Copenhagen University Hospital (Holbæk Hospital), Holbæk, Institute for Clinical Medicine, Copenhagen University, Copenhagen, Denmark; Department of Health Science and Technology, Aalborg University, Aalborg, Denmark; Institute of Cardiovascular Sciences, University of Birmingham, Centre For Cardiovascular Sciences, City Hospital, Birmingham, UK; Aalborg Thrombosis Research Unit, Aalborg University, Aalborg, Denmark; Heart and Vascular Center, Semmelweis University, Budapest, Hungary; Saiseikai Akumamoto Hospital, Kumamoto, Japan; Department of Medicine, Duke Clinical Research Institute, Durham, USA; School of Medicine, Belgrade University; Cardiology Clinic, Clinical Centre of Serbia, Belgrade, Serbia; Aarhus University Hospital, Klinisk Farmakologisk Enhed, Aalborg, Denmark; Department of Pharmacology, School of Medicine, Universidad Complutense Madrid, Madrid, Spain; Department of Medicine Cardiology, Klinikum Ludwigsburg, Ludwigsburg, Germany; Department of Cardiology, University Hospital Basel, Basel, Switzerland; Medizinische Klinik IKardiologie, Angiologie, Pneumologie, Wiesbaden, Germany; Barts Heart Centre, Trustee Arrhythmia Alliance and Atrial Fibrillation Association, London, UK; Department of Cardiology, University Hospital Centre Sestre milosrdnice, Croatia; Cardiology Department, Olv Aalst, Belgium; Uniwersytet Medyczny w Łodzi, Kierownik Kliniki Kardiologii

Quality Traits of "Cannabidiol Oils": Cannabinoids Content, Terpene Fingerprint and Oxidation Stability of European Commercially Available Preparations

Abstract: Cannabidiol (CBD)-based oil preparations are becoming extremely popular, as CBD has been shown to have beneficial effects on human health. CBD-based oil preparations are not unambiguously regulated under the European legislation, as CBD is not considered as a controlled substance. This means that companies can produce and distribute CBD products derived from non-psychoactive hemp varieties, providing an easy access to this extremely advantageous cannabinoid. This leaves consumers with no legal quality guarantees. The objective of this project was to assess the quality of 14 CBD oils commercially available in European countries. An in-depth chemical profiling of cannabinoids, terpenes and oxidation products was conducted by means of GC-MS and HPLC-Q-Exactive-Orbitrap-MS in order to improve knowledge regarding the characteristics of CBD oils. Nine out of the 14 samples studied had concentrations that differed notably from the declared amount, while the remaining five preserved CBD within optimal limits. Our results highlighted a wide variability in cannabinoids profile that justifies the need for strict and standardized regulations. In addition, the terpenes fingerprint may serve as an indicator of the quality of hemp varieties, while the lipid oxidation products profile could contribute in evaluation of the stability of the oil used as milieu for CBD rich extracts.