Restless legs syndrome: Over 50 years of European contribution.

Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterised by an urge to move the limbs with a circadian pattern (occurring in the evening/at night), more prominent at rest, and relieved with movements. RLS is one of the most prevalent sleep disorders, occurring in 5%-10% of the European population. Thomas Willis first described RLS clinical cases already in the 17th century, and Karl-Axel Ekbom described the disease as a modern clinical entity in the 20th century. Despite variable severity, RLS can markedly affect sleep (partly through the presence of periodic leg movements) and quality of life, with a relevant socio-economic impact. Thus, its recognition and treatment are essential. However, screening methods present limitations and should be improved. Moreover, available RLS treatment options albeit providing sustained relief to many patients are limited in number. Additionally, the development of augmentation with dopamine agonists represents a major treatment problem. A better understanding of RLS pathomechanisms can bring to light novel treatment possibilities. With emerging new avenues of research in pharmacology, imaging, genetics, and animal models of RLS, this is an interesting and constantly growing field of research. This review will update the reader on the current state of RLS clinical practice and research, with a special focus on the contribution of European researchers

Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study

The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (≥300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time

The long-term treatment of restless legs syndrome/Willis–Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group

AbstractA Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis–Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6months or longer presented at meetings over the past 2years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, “What is the efficacy of this treatment in patients with RLS/WED?” and “What is the safety of this treatment in patients with RLS/WED?”The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5years: gabapentin enacarbil, pramipexole, and ropinirole (1year); levodopa (2years); and rotigotine (5years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED.The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or α2δ calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient’s severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions

10-year anniversary of the European Somnologist examination - A historic overview and critical appraisal

The European Somnologist certification programme was developed by the European Sleep Research Society to improve patient care in sleep medicine by providing an independent evaluation of theoretical and practical knowledge. The examination of eligible experts plays a key role in this procedure. A process was started more than 15 years ago to create the European sleep medicine curriculum, eligibility criteria for certification, and sleep centre accreditation criteria. The process was characterised by interdisciplinary collaboration, consensus, and achieving new solutions. During the past 10 years, experience has been gained by the examination and certification of more than 1000 sleep medicine experts from more than 50 countries. The process has continuously been improved. However, as the programme was designed and administered mainly by medical experts in the field, systematic influence from teaching and pedagogic experts was partially underrepresented. The current critical appraisal pinpoints several missing links in the process - mainly as a missing constructive alignment between learning objectives, learning and teaching activities, and the final assessment. A series of suggestions has been made to further improve the ESRS certification programme.Peer reviewe

Process simulation and economic feasibility assessment of the methanol production via tri-reforming using experimental kinetic equations

The purpose of this paper is to assess via techno-economic metrics the feasibility of a tri-reforming coupled methanol process. The simulation of the tri-reforming reactor considered empiric kinetic equations, developed by our group in previous studies. The flue gas coming from the furnace that provides the energy required by the reforming reactor was also used as feed, in order to reduce the CO2 emissions. A sensitivity analysis was carried out to determine the influence of the feed composition and temperature in the tri-reforming process results, studying H2O/CH4 and O2/CH4 ratios (0.5–1.5 and 0.35–0.40, respectively), and varying the temperature between 850 and 1050 °C. The methanol plant was also simulated, and an economical study was carried out to know if the proposed process would be economically feasible. The most relevant economic parameters (including the Net Present Value, the Internal Rate of Return, the Payback Period and the break-even) were calculated, showing a quite robust process from an economical point of view.El propósito de este documento es evaluar a través de métricas tecnoeconómicas la viabilidad de un proceso de metanol acoplado de triple reforma. La simulación del reactor de tri-reformado consideró ecuaciones cinéticas empíricas, desarrolladas por nuestro grupo en estudios previos. También se utilizó como alimentación el gas de combustión procedente del horno que proporciona la energía requerida por el reactor de reformado, con el fin de reducir las emisiones de CO 2 . Se realizó un análisis de sensibilidad para determinar la influencia de la composición y temperatura de la alimentación en los resultados del proceso de tri-reformado, estudiando H 2 O/CH 4 y O 2 /CH 4proporciones (0.5-1.5 y 0.35-0.40, respectivamente), y variando la temperatura entre 850 y 1050 °C. También se simuló la planta de metanol y se realizó un estudio económico para saber si el proceso propuesto sería económicamente factible. Se calcularon los parámetros económicos más relevantes (incluyendo el Valor Presente Neto, la Tasa Interna de Retorno, el Periodo de Recuperación y el punto de equilibrio), mostrando un proceso bastante robusto desde el punto de vista económico

Influence of air pollutants on circulating inflammatory cells and microRNA expression in acute myocardial infarction.

Air pollutants increase the risk and mortality of myocardial infarction (MI). The aim of this study was to assess the inflammatory changes in circulating immune cells and microRNAs in MIs related to short-term exposure to air pollutants. We studied 192 patients with acute coronary syndromes and 57 controls with stable angina. For each patient, air pollution exposure in the 24-h before admission, was collected. All patients underwent systematic circulating inflammatory cell analyses. According to PM2.5 exposure, 31 patients were selected for microRNA analyses. STEMI patients exposed to PM2.5 showed a reduction of CD4+ regulatory T cells. Furthermore, in STEMI patients the exposure to PM2.5 was associated with an increase of miR-146a-5p and miR-423-3p. In STEMI and NSTEMI patients PM2.5 exposure was associated with an increase of miR-let-7f-5p. STEMI related to PM2.5 short-term exposure is associated with changes involving regulatory T cells, miR-146a-5p and miR-423-3p.This work was supported by Ministerio de Ciencia e Innovación [SAF2017-82886-R, to F.S.M] Proyecto de Investigación en Salud [PI21/01583 to H.F.]. Grant from the Sociedad Española de Cardiologia to F.A. Ministerio de Ciencia, Innovación y Universidades, Carlos III Institute of Health-Fondo de Investigación Sanitaria [PI19/00545 to P.M.] From the Comunidad de Madrid [S2017/BMD-3671-INFLAMUNE-CM] to FSM and PM. Tis research has been co-fnanced by Fondo Europeo de Desarrollo Regional (FEDER).S

Study cases methodology in process dynamic and industrial plants control subject

Dynamic simulation has been incorporated into Chemical Engineering Master at the University of Castilla‐La Mancha as a teaching tool together with working cases. Concretely, this study presents the activities, evaluating criteria and a set of case of studies performed by master students in the process dynamic and industrial plants control course. It is described in detail, the Aspen HYSYS® simulations carried out to study the influence of main tuning parameters of proportional, integral, and derivative controllers (gain, integral time, and derivative time) and other relevant parameters such dead‐time, amplitude, or period of sine wave disturbances. The dynamic simulation helps the students to understand the previously mentioned concepts, analyzing their effect in the realistic behavior and control of simple processes. Finally, anonymous online surveys were conducted to evaluate the effectiveness of the proposed training activities and methodology. Students felt that Aspen HYSYS enhances the control theory understanding from a chemical engineering perceptive, eliminating the tediousness and time‐consuming aspect of process calculation. Thus, this learning methodology promotes a successful achievement of learning outcomesLa simulación dinámica se ha incorporado al Máster de Ingeniería Química en la Universidad de Castilla-La Mancha como herramienta docente junto con casos de trabajo. Concretamente, este estudio presenta las actividades, los criterios de evaluación y un conjunto de casos de estudio realizados por los alumnos del máster en la asignatura de dinámica de procesos y control de plantas industriales. Se describe en detalle, las simulaciones Aspen HYSYS® realizadas para estudiar la influencia de los principales parámetros de sintonía de los controladores proporcional, integral y derivativo (ganancia, tiempo integral y tiempo de derivación) y otros parámetros relevantes como el tiempo muerto, la amplitud o el periodo de las perturbaciones sinusoidales. La simulación dinámica ayuda a los estudiantes a comprender los conceptos mencionados anteriormente, analizando su efecto en el comportamiento realista y el control de procesos sencillos. Por último, se realizaron encuestas anónimas encuestas anónimas en línea para evaluar la eficacia de las actividades actividades de formación y metodología propuestas. Los estudiantes consideraron que Aspen HYSYS mejora la comprensión de la teoría de control desde la perspectiva de la ingeniería química eliminando el aspecto tedioso y lento del cálculo de procesos. Por lo tanto, esta metodología de aprendizaje favorece la consecución de resultados del aprendizaj

Sleep disturbance by pramipexole is modified by Meis1 in mice

Meis homeobox 1 (Meis1) is a transcription factor functioning in the development of the nervous system and the cardiovascular system. Both common and rare variants within the gene have been associated with restless legs syndrome (RLS), while its association with symptoms of insomnia has also been discovered recently. RLS is associated with sleep disturbances, and while Meis1 haploinsufficiency is one of the most promising strategies for an RLS animal model, sleep phenotyping of Meis1 knockout mice has never been conducted. We report a detailed sleep analysis of heterozygous Meis1 knockout mice and challenge it with pramipexole, a dopamine agonist used in the treatment of RLS. At baseline, the Meis1-haploinsufficient mice had a trend towards lower delta power in the electroencephalogram (EEG) during sleep compared to the wild-type littermates, possibly indicating reduced sleep quality, but not sleep fragmentation. Pramipexole had a sleep disrupting effect in both genotype groups. In addition, it exerted differential effects on the EEG power spectra of the two mouse lines, remarkably elevating the theta power of the mutant mice during recovery more than that of the wild-types. In conclusion, Meis1 haploinsufficiency seems to have only a modest effect on sleep, but the gene may interact with the sleep-disrupting effect of dopamine agonists

Lung ultrasound as a translational approach for non-invasive assessment of heart failure with reduced or preserved ejection fraction in mice

Aims: Heart failure (HF) has become an epidemic and constitutes a major medical, social, and economic problem worldwide. Despite advances in medical treatment, HF prognosis remains poor. The development of efficient therapies is hampered by the lack of appropriate animal models in which HF can be reliably determined, particularly in mice. The development of HF in mice is often assumed based on the presence of cardiac dysfunction, but HF itself is seldom proved. Lung ultrasound (LUS) has become a helpful tool for lung congestion assessment in patients at all stages of HF. We aimed to apply this non-invasive imaging tool to evaluate HF in mouse models of both systolic and diastolic dysfunction. Methods and results: We used LUS to study HF in a mouse model of systolic dysfunction, dilated cardiomyopathy, and in a mouse model of diastolic dysfunction, diabetic cardiomyopathy. LUS proved to be a reliable and reproducible tool to detect pulmonary congestion in mice. The combination of LUS and echocardiography allowed discriminating those mice that develop HF from those that do not, even in the presence of evident cardiac dysfunction. The study showed that LUS can be used to identify the onset of HF decompensation and to evaluate the efficacy of therapies for this syndrome. Conclusions: This novel approach in mouse models of cardiac disease enables for the first time to adequately diagnose HF non-invasively in mice with preserved or reduced ejection fraction, and will pave the way to a better understanding of HF and to the development of new therapeutic approaches.This study was supported by grants from the Spanish Ministerio de Economia y Competitividad (SAF2015-65722-R), Comunidad Autonoma de Madrid (2010-BMD2321, FIBROTEAM Consortium), European Union's FP7 (CardioNeT-ITN-289600, CardioNext-ITN-608027) and the Spanish Instituto de Salud Carlos III (CPII14/00027 to E.L-P, RD12/0042/0054 to B.I. and RD12/0042/066 to P.G.-P. and E.L-P). This work was also supported by the Plan Estatal de I+D+I 2013-2016 - European Regional Development Fund (FEDER) "A way of making Europe", Spain. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

Activation of amino acid metabolic program in cardiac HIF1-alpha-deficient mice.

HIF1-alpha expression defines metabolic compartments in the developing heart, promoting glycolytic program in the compact myocardium and mitochondrial enrichment in the trabeculae. Nonetheless, its role in cardiogenesis is debated. To assess the importance of HIF1-alpha during heart development and the influence of glycolysis in ventricular chamber formation, herein we generated conditional knockout models of Hif1a in Nkx2.5 cardiac progenitors and cardiomyocytes. Deletion of Hif1a impairs embryonic glycolysis without influencing cardiomyocyte proliferation and results in increased mitochondrial number and transient activation of amino acid catabolism together with HIF2α and ATF4 upregulation by E12.5. Hif1a mutants display normal fatty acid oxidation program and do not show cardiac dysfunction in the adulthood. Our results demonstrate that cardiac HIF1 signaling and glycolysis are dispensable for mouse heart development and reveal the metabolic flexibility of the embryonic myocardium to consume amino acids, raising the potential use of alternative metabolic substrates as therapeutic interventions during ischemic events.This project has been supported by Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Spain and by grants to S.M.-P. from the European Research Council, European Union, FP7-PEOPLE-2010-RG_276891; Fundación TV3 La Marató, Spain, 201507.30.31; Comunidad de Madrid (CAM); Spain and European Union (EU), B2017/BMD-3875; Instituto de Salud Carlos III, Spain, PI17/01817; Universidad Francisco de Vitoria (UFV), Spain and LeDucq Foundation, France, 17CVD04. I.M.-M. was supported by La Caixa-CNIC and Fundacion Alfonso Martín Escudero fellowships, Spain. T.A.-G. was supported by a predoctoral award granted by CAM/EU and UFV, Spain, PEJD-2018-PRE/SAL-9529 and SM-P by a Contrato de Investigadores Miguel Servet (CPII16/00050) and UFV, Spain.S