Red wine polyphenols modulate bone loss in the ovariectomized rat model of postmenopausal osteoporosis

Σκοπός αυτής της μελέτης ήταν να εξεταστεί η επίδραση του εκχυλίσματος πολυφαινολών του κόκκινου κρασιού (RWPs) στην οστική πυκνότητα (BMD) σε μοντέλο ωοθηκεκτομημένων επίμυων. Τριάντα πέντε Wistar επίμυες, ηλικίας 10 μηνών, χωρίστηκαν στις εξής ομάδες: ομάδα ελέγχου (CTRL), ωοθηκεκτομής (OVX) και την ομάδα ωοθηκεκτομής που έλαβε το εκχύλισμα RWPs (OVX+RWPs) σε συγκέντρωση 50 mg/kg σωματικού βάρους ανά ημέρα, ξεκινώντας αμέσως μετά από την ωοθηκεκτομή για 6 μήνες. Προσδιορίστηκε η οστική πυκνότητα πριν από οποιαδήποτε παρέμβαση, στους 3 και 6 μήνες. Οι επίμυες ευθανατώθηκαν και τα μηριαία οστά εξετάστηκαν με την δοκιμασία κάμψης τριών σημείων. Η σύγκριση των τιμών οστικής πυκνότητας ολόκληρης της κνήμης μεταξύ των ομάδων, ανέδειξε στατιστικά σημαντική μείωση στις ομάδες OVX και OVX+RWPs τόσο από την αρχική μέτρηση στους 3 και 6 μήνες, όσο και από τους 3 στους 6 μήνες, ενώ στην ομάδα CTRL δεν υπήρξε σημαντική αλλαγή. Η ποσοστιαία μεταβολή της οστικής πυκνότητας στην εγγύς μετάφυση της κνήμης από την αρχική μέτρηση στους 3 και 6 μήνες και από τους 3 στους 6 μήνες, αποκάλυψε στατιστικά σημαντικές διαφορές μεταξύ των ομάδων OVX και OVX + RWPs (P = 0.000). Η ωοθηκεκτομή προκάλεσε σημαντική μείωση των εμβιομηχανικών παραμέτρων όπως αναμενόταν, η δοκιμασία κάμψης τριών σημείων έδειξε ότι η μέγιστη φόρτιση πριν από τη θραύση, η απορρόφηση ενέργειας και η τάση θραύσης αυξήθηκε στατιστικά σημαντικά στην ομάδα OVX που υποβλήθηκε σε θεραπεία με RWPs σε σύγκριση με τους OVX επιμύες (P = 0.048, P = 0.002 και P = 0.003 αντίστοιχα). Η διατροφική πρόσληψη RWPs για 6 μήνες απέτρεψε την ταχεία οστική απώλεια και βελτίωσε την αντοχή των οστών σε ωοθηκεκτομημένους επίμυες.The aim of this study was to examine the effect of Red Wine Polyphenols (RWPs) extract on bone mineral density (BMD) in the ovariectomized (OVX) rat model. Thirty-five 10-month-old Wistar rats were separated into controls (CTRL), OVX and OVX plus RWPs in their drinking water (dose, 50 mg/kg body weight per day), starting immediately after OVX for 6 months. Βody and uterine weight, BMD of the tibia at baseline, 3 and 6 months post-OVX, and 3-pointing bending of the femur, were examined. Statistical comparison of the total tibia BMD within groups during the study period showed a significant reduction in the OVX and OVX+RWPs groups both from baseline to 3 and 6 months and from 3 to 6 months, whereas in the CTRL group, there was no significant change. For the proximal tibial metaphysis, comparison of BMD percentage changes from baseline to 3 months and 6 months and from 3 to 6 months revealed highly statistical differences between OVX and OVX+RWPs groups (P = 0.000). OVX induced a significant reduction of biomechanical parameters as expected; the 3-point bending test showed that the maximum force before fracture, energy absorption and fracture stress significantly increased in the OVX group treated with RWPs compared with the nontreated OVX rats (P = 0.048, P = 0.002 and P = 0.003, respectively). Dietary intake of RWPs for 6 months significantly prevented trabecular bone loss and improved bone strength in estrogen-deficient ovariectomized rats

Homozygous knockout of the piezo1 gene in the zebrafish is not associated with anemia

We have now examined the erythroid phenotype in this zebrafish strain carrying a ZFN genomic knockout of piezo1. Genotyping was performed as previously described. In contrast to the anemic phenotype observed in zebrafish subjected to morpholino knockdown of piezo, the genomic ZFN knockout of piezo1 did not segregate either with anemia in the 3-dpf embryo or with dysmorphic erythrocyte morphology in the adult fish

Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.

OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. METHODS: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. RESULTS: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). CONCLUSIONS: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.Funding for collection, genotyping, and analysis of stroke samples was provided by Wellcome Trust Case Control Consortium-2, a functional genomics grant from the Wellcome Trust (DNA-Lacunar), the Stroke Association (DNA-lacunar), the Intramural Research Program of National Institute of Ageing (Massachusetts General Hospital [MGH] and Ischemic Stroke Genetics Study [ISGS]), National Institute of Neurological Disorders and Stroke (Siblings With Ischemic Stroke Study, ISGS, and MGH), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (MGH), Deane Institute for Integrative Study of Atrial Fibrillation and Stroke (MGH), National Health and Medical Research Council (Australian Stroke Genetics Collaborative), and Italian Ministry of Health (Milan). Additional support for sample collection came from the Medical Research Council, National Institute of Health Research Biomedical Research Centre and Acute Vascular Imaging Centre (Oxford), Wellcome Trust and Binks Trust (Edinburgh), and Vascular Dementia Research Foundation (Munich). MT is supported by a project grant from the Stroke Association (TSA 2013/01). HSM is supported by an NIHR Senior Investigator award. HSM and SB are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. VT and RL are supported by grants from FWO Flanders. PR holds NIHR and Wellcome Trust Senior Investigator Awards. PAS is supported by an MRC Fellowship. CML’s research is supported by the National Institute for Health Research Biomedical Research Centre (BRC) based at Guy's and St Thomas' NHS Foundation Trust and King's College London, and the BRC for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000226

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

The Compact Linear Collider (CLIC) - 2018 Summary Report

The Compact Linear Collider (CLIC) is a TeV-scale high-luminosity linear $e^+e^-$ collider under development at CERN. Following the CLIC conceptual design published in 2012, this report provides an overview of the CLIC project, its current status, and future developments. It presents the CLIC physics potential and reports on design, technology, and implementation aspects of the accelerator and the detector. CLIC is foreseen to be built and operated in stages, at centre-of-mass energies of 380 GeV, 1.5 TeV and 3 TeV, respectively. CLIC uses a two-beam acceleration scheme, in which 12 GHz accelerating structures are powered via a high-current drive beam. For the first stage, an alternative with X-band klystron powering is also considered. CLIC accelerator optimisation, technical developments and system tests have resulted in an increased energy efficiency (power around 170 MW) for the 380 GeV stage, together with a reduced cost estimate at the level of 6 billion CHF. The detector concept has been refined using improved software tools. Significant progress has been made on detector technology developments for the tracking and calorimetry systems. A wide range of CLIC physics studies has been conducted, both through full detector simulations and parametric studies, together providing a broad overview of the CLIC physics potential. Each of the three energy stages adds cornerstones of the full CLIC physics programme, such as Higgs width and couplings, top-quark properties, Higgs self-coupling, direct searches, and many precision electroweak measurements. The interpretation of the combined results gives crucial and accurate insight into new physics, largely complementary to LHC and HL-LHC. The construction of the first CLIC energy stage could start by 2026. First beams would be available by 2035, marking the beginning of a broad CLIC physics programme spanning 25-30 years

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec