Xenopus NM23-X4 regulates retinal gliogenesis through interaction with p27Xic1

Background. In Xenopus retinogenesis, p27Xic1, a Xenopus cyclin dependent kinase inhibitor, functions as a cell fate determinant in both gliogenesis and neurogenesis in a context dependent manner. This activity is essential for co-ordination of determination and cell cycle regulation. However, very little is known about the mechanism regulating the context dependent choice between gliogenesis versus neurogenesis. Results. We have identified NM23-X4, a NM23 family member, as a binding partner of p27Xic1. NM23-X4 is expressed at the periphery of the ciliary marginal zone of the Xenopus retina and the expression overlaps with p27Xic1 at the central side. Our in vivo functional analysis in Xenopus retina has shown that knockdown of NM23-X4 activates gliogenesis. Furthermore, co-overexpression of NM23-X4 with p27Xic1 results in the inhibition of p27Xic1-mediated gliogenesis, through direct interaction of NM23-X4 with the amino-terminal side of p27Xic1. This inhibitory effect on gliogenesis requires serine-150 and histidine-148, which correspond to the important residues for the kinase activities of NM23 family members. Conclusion. This study demonstrates that NM23-X4 functions as an inhibitor of p27Xic1-mediated gliogenesis in Xenopus retina and suggests that this activity contributes to the proper spatio-temporal regulation of gliogenesis

Spatial and temporal expressions of prune reveal a role in Muller gliogenesis during Xenopus retinal development

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Evaluation of contemporary treatment of high- and very high-risk patients for the prevention of cardiovascular events in Europe – Methodology and rationale for the multinational observational SANTORINI study

Publisher Copyright: © 2021 The AuthorsBackground and aims: Clinical practice before 2019 suggests a substantial proportion of high and very high CV risk patients taking lipid-lowering therapy (LLT) would not achieve the new LDL-C goals recommended in the 2019 ESC/EAS guidelines (<70 and < 55 mg/dL, respectively). To what extent practice has changed since the last ESC/EAS guideline update is uncertain, and quantification of remaining implementation gaps may inform health policy. Methods: The SANTORINI study is a multinational, multicentre, prospective, observational, non-interventional study documenting patient data at baseline (enrolment) and at 12-month follow-up. The study recruited 9606 patients ≥18 years of age with high and very high CV risk (as assigned by the investigators) requiring LLT, with no formal patient or comparator groups. The primary objective is to document, in the real-world setting, the effectiveness of current treatment modalities in managing plasma levels of LDL-C in high- and very high-risk patients requiring LLT. Key secondary effectiveness objectives include documenting the relationship between LLT and levels of other plasma lipids, high-sensitivity C-reactive protein (hsCRP) and overall predicted CV risk over one year. Health economics and patient-relevant parameters will also be assessed. Conclusions: The SANTORINI study, which commenced after the 2019 ESC/EAS guidelines were published, is ideally placed to provide important contemporary insights into the evolving management of LLT in Europe and highlight factors contributing to the low levels of LDL-C goal achievement among high and very high CV risk patients. It is hoped the findings will help enhance patient management and reduce the burden of ASCVD in Europe.Peer reviewe

Δημιουργία βλαστικών κυττάρων με ομόζυγη έλλειψη του γονιδίου ERF (ETS2 repressor factor)

Διατμηματικό, συνεργαζόμενα Τμήματα Βιολογίας και Ιατρικής του Πανεπιστημίου Κρήτης. The Erf (Ets-2 Repressor Factor) gene codes for a transcriptional repressor of the Ets2 (E26 Transformation Specific) family of transcriptional regulators and has been shown to be an effector of the mitogenic Ras/MAPK pathway. Homozygous deletion of the gene in mouse results in embryonic death at day 10p.c. due to placental defects. In particular, there is complete loss of the labyrinthe, expanded chorion and increase in the trophoblast giant cell layer. In order to further investigate the role of the gene, it is necessary to create embryonic stem cells homozygous for the Erf gene deletion. Heterozygous ES cells lacking one functional allele have been used in a second round of targeting to obtain homozygous clones. We have isolated an ES clone in which the second allele has been deleted by the replacement of the hygromycin cassette. Culture of these cells will allow the study of their developmental potential and in vitro differentiation towards the different cell fates. Furthermore, the phenotype of Erf knockout in the placenta of mouse syggests that the gene is involved in the maintenance and differentiation of trophoblast stem cells. For this reason, we have tried to isolate blastocysts and establish trophoblast stem cell lines. From the procedure, one wild type trophoblast stem cell line has been produced and established successfully.Το γονίδιο του Erf (Ets-2 Repressor Factor) κωδικοποιεί για ένα μεταγραφικό καταστολέα της Ets (E26 Transformation Specific) οικογένειας και έχει δειχθεί ότι αποτελεί μεσολαβητή του μιτογενετικού Ras/MAPK μονοπατιού. Η απενεργοποίηση του γονιδίου σε ομόζυγη κατάσταση στο ποντίκι έχει σαν αποτέλεσμα τον εμβρυϊκό θάνατο την ημέρα Ε10 λόγω ανωμαλιών στον πλακούντα. Συγκεκριμένα, παρατηρείται πλήρης απουσία του λαβυρίνθου, εκτεταμένο χόριο και αύξηση του στρώματος των τροφοβλαστικών γιγαντιαίων κυττάρων. Για την περαιτέρω διερεύνηση του ρόλου του γονιδίου είναι απαραίτητη η δημιουργία βλαστικών κυττάρων με ομόζυγη έλλειψη του Erf. Ετερόζυγα βλαστικά κύτταρα, στα οποία το ένα αλλήλιο έχει απενεργοποιηθεί μέσω ομόλογου ανασυνδυασμού, χρησιμοποιήθηκαν σε ένα δεύτερο γύρο στόχευσης για την παραγωγή ομόζυγων κλώνων. Απομονώθηκε ένας κλώνος ES κυττάρων, στον οποίο το δεύτερο λειτουργικό αλλήλιο έχει απαλοιφθεί μέσω αντικατάστασης από κασέτα υγρομυκίνης. Η καλλιέργεια αυτών των κυττάρων επιτρέπει τη μελέτη του αναπτυξιακού τους δυναμικού αλλά και την in vitro διαφοροποίησή τους προς μια από τις κυτταρικές τύχες. Περαιτέρω, ο φαινότυπος της έλλειψης του Erf στον πλακούντα του ποντικού υποδεικνύει ότι το γονίδιο πιθανόν εμπλέκεται στην ανάπτυξη και διαφοροποίηση των τροφοβλαστικών κυττάρων. Γι αυτό το σκοπό, προχωρήσαμε στην απομόνωση βλαστοκύστεων και την καθιέρωση τροφοβλαστικών κυτταρικών σειρών. Από τη διαδικασία προέκυψε και καθιερώθηκε τελικά μια τροφοβλαστική κυτταρική σειρά αγρίου τύπου

Patients’ perspective on the burden of migraine in Europe: a cross-sectional analysis of survey data in France, Germany, Italy, Spain, and the United Kingdom

Abstract Background Migraine is a distinct neurological disease that imposes a significant burden on patients, society, and the healthcare system. This study aimed to characterize the incremental burden of migraine in individuals who suffer from ≥4 monthly headache days (MHDs) by examining health-related quality of life (HRQoL), impairments to work productivity and daily activities, and healthcare resource utilization (HRU) in the EU5 (France, Germany, Italy, Spain, United Kingdom). Methods This retrospective cross-sectional study used data from the 2016 National Health and Wellness Survey (NHWS; N = 80,600). Short-Form 36-Item Health Survey, version 2 (SF-36v2) physical and mental component summary scores (PCS and MCS), Short-form-6D (SF-6D), and EuroQoL (EQ-5D), impairments to work productivity and daily activities (Work Productivity and Activity Impairment Questionnaire (WPAI), and HRU were compared between migraine respondents suffering from ≥4 MHDs (n = 218) and non-migraine controls (n = 218) by propensity score matching using sociodemographic characteristics. Chi-square, T-tests, and Mann-Whitney tests were performed to determine significant differences between the groups after propensity score matching. Results HRQoL was lower in migraine individuals suffering from ≥4 MHDs compared with non-migraine controls, with reduced SF-36v2 PCS (46.00 vs 50.51) and MCS (37.69 vs 44.82), SF-6D health state utility score (0.62 vs 0.71), and EQ-5D score (0.68 vs 0.81) (for all, p < 0.001). Respondents with migraine suffering from ≥4 MHDs also reported higher levels of absenteeism from work (14.43% vs 9.46%; p = 0.001), presenteeism (35.52% vs 20.97%), overall work impairment (38.70% vs 23.27%), and activity impairment (44.17% vs 27.75%) than non-migraine controls (for all, p < 0.001). Additionally, HRU was significantly higher for individuals with ≥4 MHDs compared to their matched controls. Consistently, migraine subgroups (4–7 MHDs, 8–14 MHDs and CM) had lower HRQoL, greater overall work and activity impairment, and higher HRU compared to non-migraine controls. Conclusions Migraine of ≥4 MHDs was associated with poorer HRQoL, greater work productivity loss, and higher HRU compared with non-migraine controls. The findings of the study suggest that an unmet need exists among individuals suffering from ≥4 MHDs in the EU5 suggesting the need for effective prophylactic treatments to lessen the humanistic and economic burden of migraine

Cost-Effectiveness of Apixaban vs. Other New Oral Anticoagulants for the Prevention of Stroke: An Analysis on Patients with Non-Valvular Atrial Fibrillation in the Greek Healthcare Setting

Background and Objectives Three new oral anticoagulants (NOACs) are currently approved for stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objective of this analysis was to assess the cost effectiveness of apixaban against other NOACs for the prevention of stroke in patients with NVAF in Greece. Methods A Markov model that evaluated clinical events, quality-adjusted life expectancy, and costs for patients treated with apixaban or other NOACs formed the basis of the analysis. Clinical events were modeled for a lifetime horizon, based on clinical efficacy data from an indirect comparison, using the ARISTOTLE, ROCKET-AF, and RE-LY clinical trials. Resource use associated with patient monitoring was elicited via a panel of experts (cardiologists and internists). Cost calculations reflect the local clinical setting and followed a third-party payer perspective (Euros, discounted at 3 %). Results Apixaban was projected to reduce the occurrence of clinical events and increase quality-adjusted life expectancy and incremental costs of treatment compared with other NOACs. Taking into account costs of medications, patient monitoring, and management of events, the incremental cost-effectiveness ratios for apixaban 5 mg twice daily vs. dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, and rivaroxaban 20 mg once daily were estimated at (sic)9907/quality-adjusted life-year (QALY), (sic)13,727/QALY, and (sic)6936/QALY gained, respectively. Extensive sensitivity analyses indicated that results were robust over a wide range of inputs. Conclusions Based on the results of this analysis, apixaban can be a cost-effective alternative to other NOACs for the prevention of stroke in patients with NVAF in Greece

Cost Effectiveness of Apixaban versus Warfarin or Aspirin for Stroke Prevention in Patients with Atrial Fibrillation: A Greek Perspective

Background Strokes attributed to atrial fibrillation (AF) represent a major cause of adult disability and a great burden to society and healthcare systems. Objectives Our objective was to assess the cost effectiveness of apixaban, a direct acting oral anticoagulant (DOAC), versus warfarin or aspirin for patients with AF in the Greek healthcare setting. Methods We used a previously published Markov model to simulate clinical events for patients with AF treated with apixaban, the vitamin K antagonist (VKA) warfarin, or aspirin. Clinical events (ischemic and hemorrhagic stroke, intracranial hemorrhage, other major bleed, clinically relevant non-major bleed, myocardial infarction, and cardiovascular [CV] hospitalizations) were modeled using efficacy data from the ARISTOTLE and AVERROES clinical trials. The cohort’s baseline characteristics also sourced from these trials. Among VKA-suitable patients, 64.7% were men with a mean age of 70 years and average CHADS(2) (cardiac failure, hypertension, age, diabetes, stroke(2)) score of 2.1, whereas 58.5% of VKA-unsuitable patients were men with a mean age of 70 years and a CHADS(2) score of 2.0. A panel of experts (cardiologists and internists) provided information on the resource use associated with the management of AF. Cost calculations reflect the local clinical setting and a third-party payer perspective (epsilon, discounted at 3%). Results Based on a simulation of 1000 VKA-suitable patients over a lifetime horizon, the use of apixaban versus warfarin resulted in 26 fewer strokes and systemic embolisms in total, 65 fewer bleeds, 41 fewer myocardial infarctions, and 29 fewer CV-related deaths, with an incremental cost-effectiveness ratio (ICER) of epsilon 14,478/quality-adjusted life-year (QALY). For VKA-unsuitable patients, apixaban versus aspirin resulted in 72 fewer strokes and systemic embolisms and 57 fewer CV-related deaths, with an ICER of (sic)7104/QALY. Sensitivity analyses indicated that results were robust. Conclusions Based on the present analysis, apixaban represents a cost-effective treatment option versus warfarin and aspirin for the prevention of stroke in patients with AF from a Greek healthcare payer perspective over a lifetime horizon

Transcriptional Repressor Erf Determines Extraembryonic Ectoderm Differentiation▿ †

Extraembryonic ectoderm differentiation and chorioallantoic attachment are fibroblast growth factor (FGF)- and transforming growth factor β-regulated processes that are the first steps in the development of the placenta labyrinth and the establishment of the fetal-maternal circulation in the developing embryo. Only a small number of genes have been demonstrated to be important in trophoblast stem cell differentiation. Erf is a ubiquitously expressed Erk-regulated, ets domain transcriptional repressor expressed throughout embryonic development and adulthood. However, in the developing placenta, after 7.5 days postcoitum (dpc) its expression is restricted to the extraembryonic ectoderm, and its expression is restricted after 9.5 dpc in a subpopulation of labyrinth cells. Homozygous deletion of Erf in mice leads to a block of chorionic cell differentiation before chorioallantoic attachment, resulting in a persisting chorion layer, a persisting ectoplacental cone cavity, failure of chorioallantoic attachment, and absence of labyrinth. These defects result in embryo death by 10.5 dpc. Trophoblast stem cell lines derived from Erfdl1/dl1 knockout blastocysts exhibit delayed differentiation and decreased expression of spongiotrophoblast markers, consistent with the persisting chorion layer, the expanded giant cell layer, and the diminished spongiotrophoblast layer observed in vivo. Our data suggest that attenuation of FGF/Erk signaling and consecutive Erf nuclear localization and function is required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment

Treatment and low-density lipoprotein cholesterol levels in patients with hypercholesterolaemia or mixed dyslipidaemia at high or very high cardiovascular risk: a population-based cross-sectional study in the Netherlands

Objective: To describe treatment patterns, low-density lipoprotein cholesterol (LDL-C) levels and healthcare resource utilization (HCRU) in the Netherlands in 2018 of patients with hypercholesterolaemia or mixed dyslipidaemia at high or very high cardiovascular (CV) risk.Methods: From the PHARMO Database Network adult patients with a diagnosis for hypercholesterolaemia or mixed dyslipidaemia or treated with lipid lowering therapy (LLT) between 2009 and 2018 were selected and the proportion at high or very high CV risk according to 2016 ESC/EAS guidelines was determined. The study population comprised patients at high or very high CV risk for whom LDL-C levels were recorded and who were treated with LLT or were characterized as statin intolerant in 2018. LLT treatment patterns, LDL-C levels and HCRU (GP consultations and hospitalizations) were assessed.Results: The study population included 54,346 patients with hypercholesterolaemia/mixed dyslipidaemia, of which 70% (37,978) were at very high CV risk and 30% (16,368) at high CV risk. The majority of patients (93%) were treated with statin monotherapy, consisting mostly (73%) of moderate intensity and 15% of high intensity statin. Only 3% were treated with a combination of statin and ezetimibe. Statin intolerance, based on a treatment algorithm, was estimated at 3%. Average LDL-C decreased with intensification of LLT with more intensive statins or combination therapy. Overall, 74% reached LDL-C <2.5 mmol/l and 34% <1.8 mmol/l with their current treatment, and 46% reached their LDL-C goal according to 2016 ESC/EAS guidelines. The highest rates of hospitalizations and GP consultations, including home visits, were recorded in patients with peripheral artery disease or polyvascular disease.Conclusion: The treatment of hypercholesterolaemia and mixed dyslipidaemia in patients at high or very high CV risk in the Netherlands was suboptimal in 2018. To further lower CV risk alternative treatment strategies using add-on therapies are needed