The Obemat2.0 Study: A Clinical Trial of a Motivational Intervention for Childhood Obesity Treatment.

The primary aim of the Obemat2.0 trial was to evaluate the efficacy of a multicomponent motivational program for the treatment of childhood obesity, coordinated between primary care and hospital specialized services, compared to the usual intervention performed in primary care. This was a cluster randomized clinical trial conducted in Spain, with two intervention arms: motivational intervention group vs. usual care group (as control), including 167 participants in each. The motivational intervention consisted of motivational interviewing, educational materials, use of an eHealth physical activity monitor and three group-based sessions. The primary outcome was body mass index (BMI) z score increments before and after the 12 (+3) months of intervention. Secondary outcomes (pre-post intervention) were: adherence to treatment, waist circumference (cm), fat mass index (z score), fat free mass index (z score), total body water (kg), bone mineral density (z score), blood lipids profile, glucose metabolism, and psychosocial problems. Other assessments (pre and post-intervention) were: sociodemographic information, physical activity, sedentary activity, neuropsychological testing, perception of body image, quality of the diet, food frequency consumption and foods available at home. The results of this clinical trial could open a window of opportunity to support professionals at the primary care to treat childhood obesity. The clinicaltrials.gov identifier was NCT02889406

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Ab42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognitionenhancing anti-AD lead

Utilitat de la tonometria arterial perifèrica per a l’avaluació del risc cardiovascular

• Contributions and new knowledge: This work demonstrates that the peripheral artery tonometry is a useful technique for the cardiovascular risk evaluation and is associated to endothelial dysfunction markers, arterial stiffness and morphologic lesions of the arterial wall. Therapeutic life-style changes may cause improvement on digital reactive hyperaemia index. These findings may contribute to a more accurate cardiovascular risk stratification of patients. • Methods and main relevant conclusions: The studies described are based in 816 patients without cardiovascular disease and at moderate cardiovascular risk recruited from the Vascular Medicine and metabolism clinic of the Hospital Universitari Sant Joan in Reus. Clinical visits, blood analyses, therapeutic life-style changes, carotid ultrasonography methods and endothelial function and arterial stiffness evaluation are described in each study. Main results showed that small artery reactivity is directly associated with HDL cholesterol levels and indirectly with tobacco habit, abdominal circumference and triglyceride levels. Central arterial stiffness calculated by the augmentation index was the main determinant of the carotid intimae-media thickness together with the LDL cholesterol levels and the systolic arterial pressure. A one-year prospective study on the therapeutic life-style changes impact on arterial reactivity in 150 volunteers showed that those patients with better adherence presented endothelial function improvement and lower carotid intimae-media thickness progression. Furthermore, the augmentation index measured in 125 patients with familial hypercholesterolemia was positively associated with carotid intimae-media thickness and Apo B100 levels. Endothelial function biomarkers were analysed in orde• Contribucions i coneixements nous que aporta la tesi: Els treballs en què es basa la tesi doctoral demostren que la tonometria arterial perifèrica és una eina útil per detectar el risc cardiovascular, que s'associa a marcadors de disfunció endotel•lial, a lesió morfològica i rigidesa arterials i, que amb actituds terapèutiques com els canvis d'estil de vida es pot assolir millores en la reactivitat hiperèmica digital. Aquestes troballes poden ajudar a estratificar millor el risc cardiovascular dels pacients. • Metodologia emprada i conclusions més rellevants: Els estudis que es presenten es basen en 816 pacients d'ambdós sexes i d'edat adulta, sense evidència de malaltia cardiovascular, reclutats de la consulta externa de la Unitat de Medicina Vascular i Metabolisme de l'Hospital Universitari Sant Joan de Reus, amb risc cardiovascular estimat segons les taules de Framingham com risc moderat. Tal i com es descriu en cadascun dels treballs, a aquestes persones se'ls va efectuar una visita mèdica, el consell sobre canvis terapèutics d'estil de vida, diverses anàlisi sanguínies i l’estudi d’arteriosclerosi subclínica consistent en ecografia carotídia i l’avaluació de la reactivitat i rigidesa arterial per tonometria perifèrica digital. Els resultats més rellevants demostren que la reactivitat arterial d'artèries de petita mida es relacionà de forma positiva amb els nivells de colesterol HDL i de forma negativa amb el tabaquisme, el perímetre abdominal i la trigliceridèmia. La rigidesa arterial central, mesurada segons l'índex d'augment, fou un dels principals determinants del gruix íntima-mitja carotidi, juntament amb el colesterol LDL i la pressió arterial sistòlica. En un treball prospectiu a 1 any, en 150 voluntaris d'aquests 816, es va examinar l'efecte dels

HDL Triglycerides: A New Marker of Metabolic and Cardiovascular Risk

While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL–triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by 1H-NMR, in patients with metabolic diseases and their association with classical biomarkers. In this cross-sectional study, we included 502 patients with type 2 diabetes or metabolic syndrome attending the lipid unit of our University Hospital. The presence of arteriosclerotic plaques was assessed by ultrasonography. A complete lipoprotein profile was performed by 1H-NMR (Liposcale test). HDL-TG was strongly positively correlated with total triglycerides, glycerol, and fatty liver index, while a strong negative correlation was observed with HDL-cholesterol (HDL-C) and HDL-particle number (HDL-P). HDL-TG was associated with all triglyceride-rich lipoprotein parameters and had an opposite association with HDL-C and HDL-P. It was also significantly correlated with circulating cholesterol ester transfer protein (CETP). HDL-TG concentrations were higher as metabolic syndrome components increased. HDL-TG was also higher with worsening glucose metabolism. Patients with carotid plaques also showed higher HDL-TG. In contrast to HDL-C, HDL-TG is directly associated with metabolism and arteriosclerotic vascular alterations. HDL-TG should be considered a biomarker of metabolic and cardiovascular risk and could be a marker of HDL dysfunction

The Circulating GRP78/BiP Is a Marker of Metabolic Diseases and Atherosclerosis: Bringing Endoplasmic Reticulum Stress into the Clinical Scenario

Background: Glucose-regulated protein 78/Binding immunoglobulin protein (GRP78/BiP) is a protein associated with endoplasmic reticulum stress and is upregulated by metabolic alterations at the tissue-level, such as hypoxia or glucose deprivation, and it is hyper-expressed in fat tissue of obese individuals. Objective: To investigate the role of the GRP78/BiP level as a metabolic and vascular disease biomarker in patients with type 2 diabetes (DM), obesity and metabolic syndrome (MS). Methods: Four hundred and five patients were recruited, of whom 52.5% were obese, 72.8% had DM, and 78.6% had MS. The intimae media thickness (cIMT) was assessed by ultrasonography. The plasma GRP78/BiP concentration was determined, and its association with metabolic and vascular parameters was assessed. Circulating GRP78/BiP was also prospectively measured in 30 DM patients before and after fenofibrate/niacin treatment and 30 healthy controls. Results: In the cross-sectional study, the GRP78/BiP level was significantly higher in the patients with obesity, DM, and MS. Age-, gender- and BMI-adjusted GRP78/BiP was directly associated with LDL-cholesterol, non-HDL-cholesterol, triglycerides, apoB, and cIMT. GRP78/BiP was positively associated to carotid plaque presence in the adjusted model, irrespective of obesity, DM and MS. In the prospective study, nicotinic acid treatment produced a significant reduction in the GRP78/BiP levels that was not observed with fenofibrate. Conclusions: GRP78/BiP plasma concentrations are increased in patients with both metabolic derangements and subclinical atherosclerosis. GRP78/BiP could be a useful marker of metabolic and cardiovascular risk